SIMPAR 2013

Transcription

SIMPAR 2013

SIMPAR 2013
STUDY IN MULTIDISCIPLINARY PAIN RESEARCH
5th MEETING
Pavia, March 22-23, 2013
ACUTE AND CHRONIC PAIN
Where we are and where we have to go.
From bench to bedside
Presidents
A. Braschi, G. Fanelli
Scientific Committee
M. R. Clark, J. De Andrés, P. Ingelmo, M. Allegri
Scientific Organization
D. Bugada, M. De Gregori, C. E. Minella
Supported by an educational grant
of Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
MINERVA ANESTESIOLOGICA
Vol. 79
March 2013
Suppl. 1 to No. 3
CONTENTS
ABSTRACTS
6
How animal model could teach us opioid activity and
its genetic variability response
Baron R.
1
Tapentadol: two mechanisms of action. A new pharmacologic class on the horizon?
Mogil J.
8
1
Endogenous opioid system driven placebo
Oxycodone and naloxone: a new combination for a
better chronic pain control in elderly people
Gracely R. H.
Minella C. E., Di Matteo M., Allegri M.
2
10
Livigni S.
Maixner W.
4
10
Stein C.
Rollason V., Roulet L., Samer C., Daali Y., Besson M.,
Piguet V., Escher M., Dayer P., Desmeules J. A.
4
12
Klepstad P.
Cruccu G., Truini A.
Genetic architecture of mu-opioid gene locus and
responses to opioids
Peripherally acting opioids and clinical implications
for pain control
Pharmacokinetics of opioids. Influenced by genetic
variability?
Mechanisms of post-opioid exposure hyperalgesia and
tolerance
Rotation of opioids: from theory to practice
Neuropathic pain: a challenging entity with complex
mechanisms
6
13
Fillingim R. B.
Pergolizzi J.
Male and female: differences in opioid response and
pain perception
Vol. 79 - Suppl. 1 to No. 3
Chronic pain: identifying underlying mechanisms
that benefit from multimodal approaches
VII
CONTENTS
14
26
Clark M. R.
Ramirez M. F., Cata J. P.
Centrally acting drugs and dependence circuits: a
clinical point of view
15
NSAIDs and acetaminophen: which role in chronic
pain management?
Schmidt W. K.
The effects of regional anesthesia-analgesia on the
immune system
28
Regional anesthesia and analgesia and mortality. Is
this the real important outcome?
De Andrés J., Reinac M. A.
17
Best practices in safe NSAID use in the elderly: a preview to the FDA safe use initiative – ACPP project
Taylor R.
30
Role of regional anesthesia in fast-track surgery.
Beyond analgesia?
Carli F.
18
Breakthrough pain: how to effectively treat. New old
drugs with different pharmacokinetic approaches
Gharibo C.
32
Ultrasound guidance in regional anesthesia: what is
the evidence?
Mariano E. R.
19
Localized neuropathic pain and transdermal therapeutical approach
Baron R.
35
Role of multimodal anesthetic and analgesic regimens
in cancer surgery
Gottumukkala V.
20
Practical overview of interventional pain management
techniques: “What the everyday interventionist needs
to know”
36
Hurschman A. B.
Asenjo J. F.
20
38
Benzon H. T.
Cata J. P., Gebhardt R.
23
40
Linderoth B.
Lavand’homme P.
Radiofrequency in interventional pain management:
what is the evidence?
Pharmacological enhancement of spinal stimulation
for pain. A new strategy
Paravertebral blocks
The tranverse abdominis plabe block. Beyond pain
outcomes
Is there an alternative to epidural blocks? Intra wound
infusion
24
41
Huntoon M. A.
Cervero F.
Regional anesthesia: why must I choose it?
VIII
Pain: friend or foe? A neurobiological perspective
March 2013
CONTENTS
42
Medical publishing in pain: future directions
Huntoon M. A.
57
Possibility of particulated steroids injection for selective root blocks in the cervical and lumbar regions:
anatomical study
Reina M. A., De Andrés J. A., Hernández J. M., López A.,
Fernández Domínguez M., Prats-Galino A.
44
Ultrasound for chronic pain intervention: a new era?
Peng P.
POSTERS
63
45
Altered central pain processing: current status of
translational research
Curatolo M.
Survival on controlled-release (CR) morphine versus
cr oxycodone in opioid-naïve patients with nonmalignant pain: data from Danish national health
registers
Christensen R., Bliddal H., Tarp S., Vestergaard P.
47
An injectable nano-delivery platform for the sustained
release of lidocaine
Khaled S. M., Yazdi I. K., Van Eps J., Taghipour N.,
Martinez J., Fernandez-Moure J., Haddix S., Weiner B.,
Tasciotti E.
63
The role of tramadol in labor analgesia
Di Gennaro T. L., Passavanti M. B., Pace M. C., Coletta F.,
D’arienzo S., Stumbo R., Pota V., Sansone P., Aurilio C.
64
49
Postoperative latent pain sensitisation: can we prevent
acute pain to become chronic?
Puig M. M.
Efficacy of pain therapy and quality of life in opioidnaïve patients treated with oxycodone/naloxone or
other strong opioids
Hesselbarth S.
65
50
How can we prolong at-home postoperative regional
analgesia?
Mariano E. R.
Low dose of lidocaine (ld) enhances in vitro natural
killer (nk) cell function
Ramirez M. F., Bergesio L., Truty M. J., Cata J. P.
67
53
Mechanisms of chronification of acute into chronic
pain
Neuropsychological effects of opioid drugs in chronic
pain patients: state of art
Schumacher M. A.
Caserio V., Rossi F., Allegri N., Minella C. E., Govoni S.,
Liccione D.
54
68
RaffaR. B.
Schiappa E., Compagnone C., Tagliaferri F., Berti M.,
Fanelli G.
54
69
Benzon H. T.
Sacco M., Fanelli G., Micheli F.
Drug-drug combinations in the management of
chronic pain
Steroid injections in chronic spinal pain: indications,
effectiveness, and safety
Analgesia nociception index: a new system of monitoring of pain of patient under general anesthesia
Treatment of disk herniation by intradiscal oxygenozone (O2-O3) injection technique
IX
CONTENTS
70
75
De Carolis G., Tollapi L., Bondi F., Paroli M., Ciaramella
A., Poli P.
Golubovska I., Miscuks A., Arons M., Rubins U.
Intra-articular pulsed radiofrequency treatment in
chronic knee osteoarthritis pain with ultrasoundguided tecnique
70
Pain relief and quality of life after spinal cord stimulation for fbss: a comparison between paddle and
cylindrical lead
De Carolis G., Paroli M., Tollapi L., Bondi F., Ciaramella
A., Poli P.
71
Ultrasound guided tap block as part of fast-track multimodal rehabilitation after cesarean section
Torrano V., Bolis C., Santangelo E., Russo G.
Non-contact optical photoplethysmography imaging
technique make safe decisions before neurotomy or
neurolysis
75
Ultrasound guided costovertebral canal block: a novel
approach for ipsilateral analgesia of the trunk
Yutaka S.
76
Relevance of Cytochrome p450 determination (genotype and phenotype) for analgesic efficacy or resistance in a multidisciplinary pain center
Rollason V., Lorenzini K. I., Samer C., Daali Y., Besson
M., Piguet V., Escher M., Dayer P., Desmeules J. A.
71
Lumbar intra-articular facet joint injections in the
treatment of facet mediated low back pain
Badran S., Madkor M., Alkader A. A., Khatab A., Mewida T.
72
Ultrasound-guided alcohol injection in the treatment
of Morton’s neuroma
Russo G., Bolis C., Santangelo E., Torrano V.
72
Comparison of analgesic effect of paracetamol and
morphine infusion after elective laparotomy surgeries
Yazdkhasti P., Safari S., Motavaf M.
77
Impacts of high concentration of ropivacaine in second stage of labour during epidural analgesia
Poma S., Broglia F., Ciceri M., Domenegati E., Fuardo
M., Noli S., Pellicori S., Repossi F., Sportiello D., Zizzi
S., lardi M., Bugada D., Pistone B., Delmonte M. P.,
Iotti G.
77
Ayx1: a single-dose intrathecal dna-decoy for the
prevention of acute and chronic postsurgical pain
Mamet J. M., Manning D., Scott H., Schmidt W.,
Klukinov M., Yeomans D.
73
Percutaneous disc decompression for lumbar pain,
what is new?
Salah Al-Ali
78
Magnesium sulphate as a novel treatment in resistant
tic douloureux
74
Epidural steroid use in Northern Ireland. Are we missing the point?
Soleimanpour H., Ghafouri R. R., Aghamohammadi D.,
Safari S., Marjani K., Soleimanpour M. , Motavaf M.
Maguire R.
74
78
Radiofrequency pain treatment in hip and knee osteoarthritis patients unsuitable for surgery
Baldi C., Tagariello V.
X
The effect of low level laser therapy on knee osteoarthritis: prospective, descriptive study
Soleimanpour H., Gahramani K., Taheri R., Safari S., Ej
Golzari S., Esfanjani R. M., Motavaf M.
March 2013
ABSTRACTS
How animal model could teach us opioid
activity and its genetic variability response
Jeffrey Mogil
Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada
Genetic approaches to pain have two major
aims: 1) to attempt to explain inherited variability
in biological systems, and 2) to aid in drug development using an unbiased and systematic approach.
Pain is associated with much variability, including
in the propensity to develop painful pathologies
and in the response to analgesic manipulations. We
have performed extensive studies of the sensitivity
of inbred mice to basal nociception, hypersensitivity after injury, and to multiple analgesic classes,
including opioid, non‑opioid, and non‑steroidal
anti‑inflammatory drugs. Recent and ongoing
gene mapping efforts are identifying the chromosomal locations of genes underlying the variability in these traits. These efforts may lead to novel
clinical treatments for pain and/or facilitate the
patient-centered, individualized treatment of pain
using current pharmaceuticals. However, the large
number of genes likely playing similar roles suggests that this day is not near.
Endogenous opioid system driven placebo
Richard H Gracely
Center for Neurosensory Disorders, School of Dentistry, University of North Carolina, Chapel Hill, NC 27599, USA
An inert substance, a placebo, may mimic the
effects of an active substance. This placebo effect
has been known for centuries and has been demonstrated in many branches of medicine. Placebo
effects are particularly potent in studies of agents
that attenuate pain. Double-blind placebo-controlled trials are required for the demonstrations of
analgesic efficacy and these trials usually reveal a
substantial proportion of subjects who achieve the
analgesic effects of the active drug after receiving
only placebo. These subjects have been regarded in
a negative light as unreliable or overly suggestible,
while a more positive view posits the presence of an
innate capability to activate endogenous analgesic
systems. The understanding of such systems was
advanced considerably by the exciting discovery of
endogenous opioid systems that produce analgesic
and other effects similar to those produced by exogenous opioids such as morphine. In a landmark
study in 1978, Levine and Fields administered a
placebo analgesic to patients in the post-operative
period after oral surgical extraction of third molar
teeth. Ratings of postsurgical pain were reduced after placebo, demonstrating a placebo effect. These
investigators then delivered an infusion of 10 mg
naloxone, a narcotic antagonist used in smaller
(0.4 mg) doses to reverse exogenous opioid analgesia. The postoperative pain increased, apparently reversing the placebo effect. These investigators
conservatively concluded that these results were
consistent with an endogenous opioid placebo effect that was reversed by the narcotic antagonist. In
a following study, our own laboratory expanded on
the original design to demonstrate the role of endogenous opioids in placebo postoperative dental
analgesia. In addition to the original three groups
of no treatment and the open administration of
naloxone or placebo, we found it necessary to include a fourth group since the open administration
of naloxone could serve as both an antagonist and
a placebo. This fourth group received naloxone without placebo. This was accomplished by administering the naloxone in a hidden infusion without
the subjects’ knowledge that a substance had been
infused. All four groups received a double blind
hidden infusion followed by no further treatment
or an open infusion of placebo that was observed
by the subjects. Of these four groups, two did not
receive naloxone in the hidden infusion, followed
by either placebo or no treatment. The results comparing these two groups showed a placebo effect,
in this case with a functioning endogenous opioid
system. The other two groups first received naloxone by the hidden infusion and then placebo or no
treatment. The results also showed a placebo effect,
1
ABSTRACT
in this case with the endogenous opioid system
blocked. Thus the placebo effect occurred whether
the opioid system was blocked or not, indicating
that the placebo analgesia was not mediated by release of endogenous opioids. Interestingly, naloxone had an effect. It increased pain in the placebo
group, and also increased pain in the no treatment
group. This result is consistent with reversal of endogenous analgesia in all subjects receiving naloxone, including those in the no treatment group.
The endogenous opioids mediating this analgesia
were likely released during surgery and in the postoperative period due to the stress, pain and tissue
damage associated with surgery. These effects were
independent of a placebo effect that occurred with
either a functioning or blocked endogenous opioid
system. We concluded that opioid placebo analgesia is possible but was not demonstrated in this
experiment. Since these preliminary experiments,
studies of placebo analgesia have blossomed with a
consistent set of findings. These studies have both
identified factors that increase the probability of a
placebo response and identified mechanisms that
mediate this response. Accumulating evidence indicates that situations that create expectancies of
analgesia and situations that provide a learned,
conditioned effect of analgesia both promote placebo analgesia. The effects of conditioning are increased by increasing the number of conditioning
trials. The resultant placebo effect may be mediated
by activation of either endogenous opioid systems
or non-opioid systems. Opioid systems are implicated if placebo analgesia is attenuated by administration of an opioid antagonist or of a cholecystokinin-2 receptor agonist such as pentagastrin,
while non-opioid effects are implicated if analgesia
is unaffected by these manipulations. Such studies
have shown that conditions of strong expectation
activate opioid systems while weak expectations
activate non-opioid systems. Conditioning to an
opioid results in opioid analgesia while conditioning to a non-opioid drug results in a placebo effect that is not mediated by endogenous opioids.
Opioid placebo analgesia can be spatially specific,
affecting only a restricted region such as a single
extremity. Recent evidence suggests that nonopioid analgesia may be mediated by activation of
cannabinoid receptors. Methods that use hidden
infusions administer antagonists independent of a
placebo response
and, in addition, demonstrate the placebo component to active treatments by comparing the effects observed after hidden or open administration.
2
These effects continue to be evaluated by verbal report and by physiological measures, including the
use of modern neuroimaging methods, that have
further refined the understanding of the mechanisms that mediate placebo analgesia and the conditions that activate these mechanisms.
Genetic architecture of mu-opioid gene
locus and responses to opioids
Luda Diatchenko
Centre for Neurosensory Disorders, University of North Carolina at Chapel Hill, Chapel Hill, USA.
Opioid analgesics are the most widely used
drugs to treat moderate to severe pain. Unfortunately, these agents produce significant individual
side effects consisting of miosis, pruritus, sedation,
nausea and vomiting, cognitive impairment, constipation, hypotension and life-threatening respiratory depression.1-4 Furthermore, there is considerable inter-individual variability in the clinical
response to opioid analgesics. For example, the
minimal effective analgesic concentration (MEAC)
for opioids, such as morphine, pethidine, alfentanil
and sufentanil, vary among patients by factors of
5 to 10.5, 6 As such, there is a substantial need to
develop new biological markers that will provide
valid and reliable predictions of individual responses to opioid therapy.
OPRM1 is the primary target of both endogenous and exogenous opioid analgesics, which
mediates basal nociception as well as μ-opioid receptor agonists responses.7-10 The suggested genetic polymorphisms in the human OPRM1 gene,
which codes for OPRM1, is the primary candidate
for sources of clinically relevant variability in opiate sensitivity and baseline nociception.11-13 The
OPRM1 receptor is a member of G-protein-coupled receptors (GPCRs) family. It has an extracellular N-terminus and intracellular C-terminus, with
seven membrane-spanning domains that comprise
the binding pocket for exogenous drugs. OPRM1
induces analgesia via pertussis toxin (PTX)-sensitive inhibitory G protein (G i/o), which inhibits
cAMP formation and Ca2+ conductance and activates K+ conductance, leading to hyper-polarization of cells thereby, exerting an inhibitory effect.14,
15 Nevertheless, opposite, cellular stimulatory effects of opiates have also been demonstrated in a
manner that depends on the concentration of the
drug and the duration of incubation.16, 17 Both ex-
March 2013

ABSTRACT
tremely low and extremely high doses of morphine, as well as chronic administration of opioids can
elicit a hyperalgesia in animal models of pain.18, 19
Furthermore, a dual effect of opioids on cAMP formation has been reported in cell culture.20-23 While
the molecular mechanism mediating the excitatory
effects of opiates is unclear, a switch in the G protein coupling profile of the OPRM1 from Gi to
both Gs 24-26 and Gq,27 as well as adenylyl cyclase
(AC) activation by Gβγ21,28 has been suggested.
The stimulatory effects of opiates is believed to
provide a cellular mechanism underling opioid
receptor-mediated hyperanalgesia, tolerance and
dependence.29
The major form of OPRM1, also called MOR1, is coded by exons 1, 2, 3 and 4, whereas exon
1 codes for first transmembrane domain and exon
2 and 3 code for the second through seven transmembrane domains.30 There is growing evidence
from rodent studies that demonstrate an important
role of alternatively-spliced forms of OPRM1 in
mediating opiate analgesia.30 The synergistic activities of these splice variants has been proposed to
explain the complex pharmacology of μ-opioids.30
Yet, it is unclear whether the findings from rodent
studies are applicable to human opioid responses
because there is a striking discrepancy between
the genomic organization of mouse OPRM1 and
the genomic organization of human OPRM1. In
accordance with the NCBI database, the mouse OPRM1 gene consists of 20 exons and codes
for 41 alternative-spliced forms, while the human
OPRM1 gene consists of only 9 exons and codes
for only 19 alternative-spliced forms (see Unigene databases).30-33 For the majority of exons of the
mouse OPRM1 gene there are no human homologues. There are two common splicing patterns
of OPRM1 that involve the C-terminus and Nterminus. C-terminus variants contain exons 1, 2
and 3 and code for all seven transmembrane domains, but differ structurally and functionally at
the intracellular domain, a region important in
transduction of the signal following receptor activation. The mouse also has a number of variants
that differ in their N-terminus, some of which
encode for truncated receptors. Reported mouse
N-terminus variants are initiated from exon 11.
Exon 11 is located approximately 30 kb upstream
of exon 1 and is under the control of a different upstream promoter, suggesting alternative regulation
of transcription. Three of these variants are predicted to code for truncated receptors with only six
transmembrane domains (6TM). The functional
significance of truncated receptors is not clear, but
in other receptor systems, they have been reported
to modulate the activity of the full version of receptor 34-36 or to change the biological activity of
the protein, sometimes in the opposite direction.37
Several polymorphisms within OPRM1 gene locus have been found in the promoter, coding and
intron regions of the gene that are associated with
several pharmacological and physiological effects
mediated by OPRM1 stimulation.38 However,
among SNPs with relatively high reported allelic
frequency, which can mediate a significant degree
of the variable clinical effects observed in a population, only the A118G OPRM1 SNP (Asp40Asn) has been repeatedly shown to have functional
consequences. This missense SNP changes the Nterminal region amino acid Asn to Asp, which decreases the number of sites for N-linked glycosylation of the OPRM1 receptor from five to four, and
thus, the G allele is reported to increase the affinity
of OPRM1 receptor for β-endorphin by threefold.39 On the other hand, it has been shown that
the transfection of an allelic variants of OPRM1
cDNA constructs into Chinese hamster ovary cells expresses more than a 10-fold lower OPRM1
protein levels for OPRM1-G118.40 Several studies have demonstrated associations between the
A118G polymorphisms and various OPRM1-dependent phenotypes, including responses to opiates. However, only a small percentage of the variability of related phenotypes has been explained and
conflicting and/or inconsistent results have been
reported.41-44 Collectively, these findings suggest
the existence of the other functional SNPs within
OPRM1 gene locus and possibly within other yet
undiscovered functional elements of the gene.
In addition to the A118G polymorphism, another functional SNP (rs563649), which is located
within an alternatively-spliced OPRM1 isoform
(MOR-1K), has been identified. The MOR-1K alternatively-spliced variant codes for 6TM OPRM1
isoforms that display excitatory rather than the
inhibitory cellular effects, which are characteristic
of the canonical 7TM isoforms. Thus, stimulation
of the 6TM isoforms may underlie the molecular
mechanisms mediating opioid-dependent hyperalgesia, tolerance and dependence. However, the
functional contribution of 6TM MOR into clinical responses to opioids is still emerging.
In summary, elucidation of genetic architecture of human OPRM1 gene locus will significantly
contribute to our understanding of the genetics of
opioid responses and human pain perception. It
3
ABSTRACT
will facilitate the future development of valid and
reliable genetic tests that can be used to predict the
safety and efficacy of opioids on an individual basis
and will open the door to novel strategies for opioid drug development.
lation of tight junction proteins in the perineurium to facilitate peripheral opioid analgesia. Anesthesiology 2012;
116(6):1323-34.
Pharmacokinetics of opioids. Influenced
by genetic variability?
Peripherally acting opioids and clinical
implications for pain control
Christoph Stein
Klinik für Anaesthesiologie und operative Intensivmedizin,
Freie Universität Berlin, Charité Campus Benjamin Franklin,
Hindenburgdamm 30, D-12200 Berlin, Germany
This presentation will discuss novel approaches
and molecules for the treatment of pain without
central side effects such as addiction, tolerance, respiratory depression or sedation. Opioid receptors
are present and upregulated on peripheral sensory neurons, and opioid peptides are expressed in
immune cells within injured tissue. Environmental
stress and releasing agents can lead to secretion of
these peptides and to local analgesia by inhibiting
the excitability of peripheral sensory neurons. We
have examined perineurial permeability, G-protein
coupling and signaling of opioid receptors in sensory neurons, opioid peptide processing, release
and extracellular degradation by immune cells,
and adhesion molecules, chemokines and growth
factors governing the migration of opioid containing cells to inflamed tissue. As a result of the
interaction between immune cell-derived opioid
peptides and opioid receptors on peripheral sensory neurons, tolerance does not develop to the analgesic effects of locally applied exogenous opioids in
inflammatory pain. Clinical data will be discussed
demonstrating that peripherally active or locally
administered opioids can potently inhibit acute
and chronic inflammatory pain associated with
surgery or arthritis.
References
1. Stein C, Schäfer M, Machelska H: Attacking pain at its
source: new perspectives on opioids. Nature Med 2003;
9(8):1003-8.
2. Zöllner C, Mousa SA, Fischer O, Rittner HL, Shaqura
M, Brack A, Shakibaei M, Binder W, Urban F, Stein C,
Schäfer M: Chronic morphine use does not induce peripheral tolerance in a rat model of inflammatory pain. J
Clin Invest 2008;118(3):1065-73.
3. Stein C, Machelska H: Modulation of peripheral sensory
neurons by the immune system: implications for pain
therapy. Pharmacol Rev 2011;63:860-81.
4. Rittner HL, Amasheh S, Moshourab R, Hackel D, Yamdeu RS, Mousa SA, Fromm M, Stein C, Brack A. Modu-
4
Pål Klepstad
Department of Anesthesiology and Acute Medicine,
St. Olavs University Hospital, Trondheim, Norway.
Opioids are metabolized primarily in the liver
to either inactive or active substances. Therefore,
reductions in metabolism may both give enhanced efficacy in the case of inactive metabolites or
increased efficacy in the case of active metabolites. CYP enzymes metabolize most opioids, with
the most notable exceptions being morphine and
hydromorphone, which are glucuronidated. For
some opioids it is discussed whether metabolism
is influenced by genetic variability in genes coding
enzymes. In this review the influence of genetic variability will be briefly described for some selected
and clinically widespread used opioids.
Codeine is often administered in order to give
relief from minor or moderate pain, and is recommended as a step II analgesic in the WHO cancer
pain ladder.1 Codeine is metabolized by CYP2D6
to morphine and a major part of codeine efficacy is
believed executed after its degradation to morphine. Due to genetic variability individuals may be
slow, extensive or ultrarapid metabolizers of codeine. Slow metabolizers of codeine have less effects
from codeine while fast metabolizers may have
increased efficacy and toxicity.2, 3 This variability
is also connected to race; Caucasian having about
10% of individuals as slow metabolizers while
Africans have a higher number of patients who are
extensive or rapid metabolizers.4 The genetic variability related to codeine is clinically recognized
as relevant, but can easily be bypassed by simply
replacing codeine with low dose of a WHO step
III opioid such as morphine.5 The latter perhaps a
pharmacological better alternative, but often not
used due to legislations and patients barriers.
Oxycodone is primarily metabolized by
CYP3A4 to the inactive metabolite noroxycodone. However, the pharmacology of oxycodone
is complex with 6-keto reduction to the inactive
metabolites α- and β-oxycodol, by CYP2D6 to
the active metabolite oxymorphone, and finally
indirectly a conversion by CYP2D6 from noroxycodone to the active metabolite noroxymorpho-
March 2013

ABSTRACT
ne.6, 7 The gene coding the CYP3A4 enzyme has
several polymorphisms, but there is no evidence
for a clinical relevant influence on oxycodone efficacy. Reduction in CYP2D6 activity is shown
to lower the serum concentrations of oxymorphone and noroxymorphone in cancer pain patients.
However, this did not result in changes in the
symptom reported by the patients.8
The most important metabolic pathway for fentanyl is metabolism by CYP3A4 to the inactive
metabolite norfentanyl.9 The influence from genetic variability in the CYP3A4 gene on fentanyl
pharmacokinetics and on clinical efficacy is not
well studied and there are no conclusive data.
Methadone has a complex pharmacology and
is metabolized by several CYP enzymes including CYP3A4, CYP2C8 and CYP2D6.10 There
is some evidence for that poor metabolizers have
an improved success rate in methadone maintenance programs compared to CYP2D6 ultrarapid
metabolizers,11 but there is no convincing clinical
evidence suggesting that genetic variability related to methadone metabolism is important for
methadone induced pain relief.
Morphine is primarily conjugated to the active
metabolite morphine-6-glucoronide (M6G) and
the inactive metabolite morphine-3-glucuronide.
Other metabolites are also formed but these are
not quantitatively important. During chronic
administration of morphine M6G is present in
higher concentrations than morphine and as
M6G is the more potent agonist at the mu-opioid receptor, it is not surprising that M6G contributes to the analgesic effects from morphine.12
UGT2B7, UGT1A1 and UGT1A8 are enzymes
that degrade morphine of which UGT2B7 has
the quantitatively largest impact.13 UGT2B7
have several known and frequent polymorphisms, which in one study was shown to alter the
morphine/metabolite ratios,14 a finding not reproduced in other populations.15 In a recent
study two common haplotypes in the UGT1A1
gene predicted a reduced M6G/morphine ratio.16
However, no clinical implications for genetic variability related to metabolism of morphine have
been established.
In conclusion, variable metabolism of opioids
may both increase and decrease opioid efficacy dependent on if the metabolite is clinically active or
not. There are several well-established polymorphisms in the genes that code enzymes which metabolite clinically used opioids. This renders these
genes as candidate genes to explain some of the
observed interindividual variability in opioid responses. Variability in the CYP2D6 gene is shown
to be clinically relevant as slow and ultrarapid
metabolizers show a decreased or an increased,
respectively, codeine efficacy. For other opioids
some results suggest that genetic variability influence the production of metabolites, but there are
so far no convincing evidence that this changes
the clinical results from opioid treatment. Consequently, with the exception of codeine there
is no evidence that genetic variability related to
metabolism is a factor to consider during clinical
decision making.
References
1. World Health Organisation. Cancer pain relief. Geneva:
WHO; 1996.
2. Poulsen L, Riishede L, Brosen K, Clemensen S, Sindrup
SH. Codeine in post-operative pain. Study of the influence of sparteine phenotype and serum concentration of
morphine and morphine-6-glucuronide. Eur J Clin Pharmacol 1998;54:451-4.
3. Ferreirós N, Dresen S, Hermanns-Clausen M, Auwaerter
V, Thierauf A, Müller C et al. Fatal and severe codeine intoxication in 3-year-old twins--interpretation of drug and
metabolite concentrations. Int J Legal Med 2009;123:38794.
4. Aklillu E, Persson I, Bertilsson L, Johansson I, Rodrigues F, Ingelman-Sundberg M. Frequent distribution
of ultrarapid metabolizers of debrisoquine in an ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. J Pharmacol Exp Ther
1996;278:441-6.
5. Caraceni A, Hanks G, Kaasa S, Bennett MI, Brunelli C,
Cherny N, et al. Use of opioid analgesics in the treatment
of cancer pain: evidence-based recommendations from the
EAPC. The lancet oncology 2012;13:e58-e68.
6. Lalovic B, Kharasch ED, Hoffer C, Risler L, Liu-Chen
L-Y, Shen DD. Pharamacokinetics and phramacodynamics of oral oxycodone in healthy human subjects: Role
of circulating active metabolites. Clin Pharmacol Ther
2006;79:461-79.
7. Lalovic B, Phillps B, Risler LL, Howald W, Shen DD.
Quantitative contribution of CYP2D6 and CYP3A4 to
oxycodone metabolsim in human liver and intestinal microsomes. Drug Metab Dispos 2004;32:447-54.
8. Andreassen TN, Eftedal I, Klepstad P, Davies A, Bjordal
K, Lundström S, et al. Do CYP2D6 genotypes reflect oxycodone requirements for cancer patients treated for cancer
pain? A cross-sectional multicentre study. Eur J Clin Pharmacol 2011;68:55-64.
9. Labroo RB, Paine MF, Thummel KE, Kharasch ED.
Fentanyl metabolism by human hepatic and intestinal
cytochrome P450 3A4: Implications for interindividual
variability in disposition, efficacy, and drug effects. Drug
Metab Dispos 1997;25:1072-80.
10. Wang JS, DeVane CL. Involvement of CYP3A4, CYP2C8,
and CYP2D6 in the metabolism of (R)- and (S)-methadone in vitro. Drug Metab Dispos 2003;31:742-7.
11. Eap CB, Broly F, Mino A et al. Cytochrome P450 2D6
genotype and methadone steady-state concentrations. J
Clin Psychopharmacol 2001;21:229-34.
12. Klepstad P, Kaasa S, Borchgrevink PC. Start of oral morphine to cancer patients: effective serum morphine concentrations and contribution from morphine-6-glucuro-
5
ABSTRACT
nide to the analgesia produced by morphine. Eur J Clin
Pharmacol 2000;55:713-9.
13. Balliet RM, Chen G, Gallagher CJ, Dellinger RW, Sun D,
Lazarus P. Characterization of UGTs active against SAHA
and association between SAHA glucuronidation activity
phenotype with UGT genotype. Cancer Res 2009;69:
2981-9.
14. Sawyer MB, Innoceti F, Das S, Cheng C, Ramirez J, Pantle-Fisher FH et al. A pharmacogenetic study of uridine
disphosphate-glucuronosyltransferase 2B7 in patients receiving morphine. Clin Pharmacol Ther. 2003;73:566-74.
15. Holthe M, Rakvåg TN, Klepstad P, Idle JR, Kaasa S,
Krokan HE et al. Sequence variation in the UDP-glucurosyltransferase 2B7 (UGT2B7) gene: identification
of 10 novel single nucleotide polymorphisms (SNPs) and
analysis of their relevance to morphine glucuronidation in
cancer patients. Pharmacogenomics J 2003;3:17-26.
16. Fladvad T, Klepstad P, Langaas M, Dale O, Kaasa S, Caraceni A et al. Variability in UDP-glucuronosyltransferase
genes and morphine metabolism. Observations from a
cross-sectional multicenter study in advanced cancer patients with pain. Pharmacogenetic Genomics 2012; In
press.
Male and female: differences in opioid response and pain perception
Roger B. Fillingim, Ph.D.
University of Florida, College of Dentistry, and North Florida/
South Georgia Veterans Health System, Gainesville, Florida
32610-3628, USA
Research on sex and gender differences in
pain and its treatment has proliferated over the
past two decades. Epidemiologic studies demonstrate that women are at increased risk for several
chronic pain disorders. Also, in the general population women report more frequent pain than
do men, and findings from the clinical setting
suggest that women may experience more severe
pain than men. These sex differences in clinical
pain have led investigators to compared laboratory pain responses across sexes to explore the
possibility that women and men may differ in
their pain sensitivity. Laboratory studies demonstrate sex differences in pain perception, with females consistently demonstrating greater sensitivity to experimentally evoked pain, though the
magnitude of sex differences varies across studies. In addition, an increasing number of clinical and experimental studies have investigated
sex differences in responses to opioid analgesics.
Findings from these studies indicate that women
and men may respond differently to opioids,
both in terms of analgesic and non-analgesic effects of these drugs. However, this literature is
far from consistent, with findings varying sub-
6
stantially based on study methodology. These
findings refer to quantitative sex differences (i.e.
does the magnitude of pain or analgesia differ
across sexes?), which have been the primary emphasis of prior research on sex, gender and pain.
However, it is of equal if not greater importance
to consider qualitative sex differences. That is,
do the factors mediating pain and analgesic responses differ in women versus men? Increasing
evidence indicates the presence of such qualitative sex differences. For example, several findings
in both non-human and human subjects suggest
that genetic associations with pain and analgesia
may be sex-dependent. Moreover, psychological
factors have been differentially associated with
pain responses across sex. Such findings are of
particular interest, because they suggest the possibility of fundamentally different pain modulatory systems in females and males, which may
require sex-specific tailoring of treatment. These
areas of research will be reviewed, and the clinical implications of sex differences in pain and
analgesic responses will be discussed.
Tapentadol: two mechanisms of action. A
new pharmacologic class on the horizon?
Ralf Baron
Division of Neurological Pain Research and Therapy, Department of Neurology, Christian-Albrechts-Universität Kiel, Kiel,
Germany
Tapentadol has been developed to combine
µ-opioid receptor agonism (MOR) and noradrenaline reuptake inhibition (NRI) in a single
molecule with the rationale to produce an ‘opioid-sparing’ effect; i.e. to produce fewer opioidrelated side effects than classical µ-opioid receptor
agonists at a distinct level of analgesia. Based on
these mechanisms of action, it was hypothesized
that tapentadol is effective in nociceptive as well
as neuropathic pain states. From preclinical testing tapentadol is known to have a high analgesic
potency in acute nociceptive and chronic neuropathic pain.
In line with the MOR-NRI concept clinical
trials have confirmed tapentadol’s analgesic effectiveness in patients with neuropathic as well as
nociceptive pain states, i.e. osteoarthritis, diabetic
painful neuropathy and lumbar back pain. In the
following experience with tapentadol in back pain
and neuropathic pain will be summarized.
March 2013

ABSTRACT
Neuropathic pain
Tapentadol has shown efficacy in patients with
painful diabetic polyneuropathy known as one
standard model to test efficacy in neuropathic
pain: This was proven in two phase III, placebocontrolled randomized-withdrawal study with a
12 week tapentadol PR treatment at doses of 100250 mg bid, in which tapentadol PR also provided
significant improvements in pain versus placebo.
Following the 3 weeks open-label treatment with
tapentadol PR (100-250 mg bid), patients who
continued to receive tapentadol PR maintained
their improvement in health status over the 12
weeks of the study significantly better than patients
who were switched to placebo.
Lumbar back pain
Clinical trials have also confirmed tapentadol’s analgesic effectiveness in patients with
chronic low back pain with fewer adverse events
than with doses of oxycodone producing comparable analgesia: In a phase III trial involving
981 patients with low back pain, tapentadol PR
100 to 250 mg bid provided effective pain relief
similar to oxycodone CR 20-50 mg, but showed
better gastrointestinal tolerability compared to
oxycodone (nausea 20.1 vs. 34.5 %; vomiting
9.1 vs. 19.2 %; constipation 13.8 vs. 26.8 %;
p<0.05) and lesser treatment discontinuations
due to AEs.
Treatment with tapentadol PR was associated
with significant improvements in overall health
and physical health status : Analyses of the SF36 results showed that patients in the tapentadol
PR group had significantly greater improvements
in 4 of the 8 health dimensions compared with
patients in the placebo group: physical functioning, role-physical, bodily pain, and vitality (P
<0.05 for all comparisons), whereas oxycodone
CR was significantly different from placebo in
only 2 of these domains (role-physical and bodily pain; P <0.001 for both comparisons).
Nociceptive and neuropathic back pain
Different pathophysiological mechanisms are
thought to operate in chronic back pain. Nociceptive and neuropathic pain components can be
distinguished. Neuropathic pain may be caused by
lesions of nociceptive sprouts within the degenerated disc (local-neuropathic), mechanical compression of the nerve root (mechanical-neuropathic
root pain) or by action of inflammatory mediators
(inflammatory-neuropathic root pain) originat-
ing from the degenerative disc even without any
mechanical compression. Since different paingenerating mechanisms possibly underlie chronic
back pain the term mixed pain syndrome was established.
It is a diagnostic challenge to identify which
components are prominent and to estimate the
impact of the different pain types. This knowledge
is essential for tailoring treatment to the individual
patient. The PainDetect Questionnaire is a reliable
screening tool to detect the neuropathic pain component in patients with chronic back pain with a
high sensitivity and specificity. In a cohort of 8000
patients with chronic back pain a prevalence of
37% of a predominant neuropathic component
was found. Furthermore, an immense impact of
(co)existing neuropathic pain on the occurrence
and severity of different co-morbid symptoms such
as depression, panic/anxiety- and sleep disorders,
functionality or even on pain intensity was demonstrated. Patients with a neuropathic pain component suffer more and more severe than those
without, seriously affecting their quality of life.
The data provide further evidence for the impact
of neuropathic pain on healthcare resource utilisation.
The treatment of chronic low back pain is a
challenge because of the high impact on patients’
quality of life, the range of different causes, the frequent presence of neuropathic components, lack of
consensus on best practice, and opioid-related side
effects. One strategy to cope with the limitations
of current treatment options is to take a multimechanistic approach using two or more analgesic
agents with different mechanisms of action to produce additive or synergistic effects. As mentioned
above tapentadol has been developed to combine
µ-opioid receptor agonism and noradrenaline reuptake inhibition in a single molecule and because
of this it should be assumed that tapentadol is effective in both, nociceptive and neuropathic back
pain components.
In an open-label, phase 3b study the effectiveness and tolerability of tapentadol prolonged
release for severe, chronic low back pain with or
without a neuropathic component was evaluated
that was inadequately managed in patients taking
World Health Organization (WHO) Step I or II
analgesics or who were not regularly treated with
analgesics. Patients received tapentadol prolonged
release (50-250 mg bid) during a 5-week titration
and 7-week maintenance period. The painDETECT questionnaire was used to define subsets of
7
ABSTRACT
patients based on the probability of a neuropathic
component to their low back pain as “negative,”
“unclear,” or “positive”.
In the painDETECT negative (n = 49) and
unclear/positive (n = 126) subsets, respectively,
mean (SD) changes in pain intensity from baseline to Week 6 were −2.4 (2.18) and −3.0 (2.07;
both P <0.0001). Among patients who had not
received prior WHO Step II treatment, lower
doses of tapentadol prolonged release were generally required with increasing likelihood of a
neuropathic pain component. Based on the painDETECT questionnaire and the Neuropathic
Pain Symptom Inventory, tapentadol prolonged
release treatment was also associated with significant improvements in neuropathic pain symptoms and with decreases in the number of pain
attacks and the duration of spontaneous pain in
the last 24 hours in patients with low back pain
with a neuropathic pain component (painDETECT positive or unclear). The most common
treatment-emergent adverse events (incidence
≥10%, n = 176) were nausea, dizziness, headache, dry mouth, fatigue, constipation, diarrhea,
nasopharyngitis, and somnolence.
References
1. Afilalo M, Etropolski MS, Kuperwasser B et al. Efficacy
and safety of tapentadol extended release compared with
oxycodone controlled release for the management of
moderate to severe chronic pain related to osteoarthritis
of the knee: a randomized, double-blind, placebo- and
active-controlled phase III study. Clin Drug Investig
2010;30:489-505.
2. Baron R, Binder A, Wasner G. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol. 2010;9(8):807-19.
3. Buynak R, Shapiro DY, Okamoto A et al. Efficacy and
safety of tapentadol extended release for the management of chronic low back pain: results of a prospective, randomized, double-blind, placebo- and activecontrolled Phase III study. Expert Opin Pharmacother
2010;11:1787-804.
4. Freynhagen R, Baron R, Gockel U, Tolle TR. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med
Res Opin 2006;22:1911-20.
5. Schmidt CO, Schweikert B, Wenig CM et al. Modelling
the prevalence and cost of back pain with neuropathic
components in the general population. Eur J Pain 2009;
6. Schroder W, Tzschentke TM, Terlinden R et al. Synergistic Interaction between the Two Mechanisms of Action of Tapentadol in Analgesia. J Pharmacol Exp Ther
2011;337:312-20.
7. Schwartz S, Etropolski M, Shapiro DY et al. Safety
and efficacy of tapentadol ER in patients with painful
diabetic peripheral neuropathy: results of a randomizedwithdrawal, placebo-controlled trial. Curr Med Res Opin
2011;27:151-62.
8. Steigerwald I, Müller M, Davies A, Samper D, Sabatowski
R, Baron R, Rozenberg S, Szczepanska-Szerej A, Gatti A,
8
Kress HG. Effectiveness and safety of tapentadol prolonged
release for severe, chronic low back pain with or without
a neuropathic pain component: results of an open-label,
phase 3b study. Curr Med Res Opin. 2012 Jun;28(6):91136.
Oxycodone and naloxone: a new combination for a better chronic pain control in elderly people
CE Minella1, M Di Matteo1, M Allegri1,2
1Pain Therapy Service, Fondazione IRCCS Policlinico San
Matteo Pavia, Italy,
2Department of Medical, Surgical, Diagnostic and Paediatric
Sciences University of Pavia, Italy
Chronic pain recognizes several pathophysiological mechanisms with complex interactions with
different patient’s features. “Pain disease” should
be recognized as a challenging major health and
research problem remaining one of the most costly
and investigated clinical entity in our society (Pizzo
and Clark, 2012).
Osteoarthritis is a common joint disorder among
the older adult population representing one of the
most common cause of chronic pain syndromes (it
affects as many as one in every four adults over 65
years of age). Severe chronic pain is associated with
this disease contributing substantially to patient’s
disability and impacting negatively on motor function, sleep, mood, and quality of life.
Guidelines for the management of symptoms
associated with osteoarthritis recommend, as
first-line therapy options, physical therapy, patient education, weight loss and exercise programs; pharmacologic therapy is recommended
for patients who do not experience sufficient
pain relief from non-pharmacologic measures
alone. Usually, analgesics, as paracetamol, and
nonsteroidal anti-inflammatory drugs (NSAIDs)
are used. However, paracetamol could result inadequate to control a severe, long-lasting pain
and, on the other side, NSAIDs should be used
carefully, due their gastrointestinal and cardiovascular adverse events. Furthermore Doherty
et al., comparing ibuprofen, paracetamol and
combination of paracetamol/ibuprofen in the
management of chronic knee pain, found that
paracetamol in combination with NSAID shows
only modest short-term benefits (without any
long-term effect) and, when administered alone
(3 g/day), may cause similar degrees of blood
loss as ibuprofen 1200 mg/day. Finally, the com-
March 2013

ABSTRACT
bination of the two medications appeared to be
additive in terms of blood loss (Doherty et al.,
2011).
The appropriate prescribing of analgesics in the
older people with osteoarthritis is difficult: polypharmacy, co-morbid conditions and poor compliance occur very frequently. In general, elderly are
more likely to intake several drugs: a survey conducted in 2004 found that 40% of elderly take
nine or more concurrent agents.
Coping with these premises, pharmacologic
treatment of osteoarthritis pain should be planned
carefully, looking at clinical conditions and comorbidities and knowing properly the pharmacologic
treatment.
Several trials have showed opioids efficacy and
tolerability in the treatment of moderate-severe
chronic osteoarthritis pain (Taylor et al., 2012).
The WHO analgesic ladder approach is not as it
does not consider patient’s own characteristics and
pain features.
Nevertheless, opioid therapy may be associated
with some side effects, such as nausea/vomiting,
dizziness, itching, immunologic and hormonal
changes and opioid induced bowel dysfunction
(OBD). The frequency and severity of central side
effects constantly decreases over time. In contrast,
OBD, mediated by interaction with peripheral μ
receptors, could persist for the whole duration of
opioid treatment. The symptoms of OBD include
constipation, decreased gastric emptying, abdominal cramping, spasm, bloating, delayed gastrointestinal (GI) transit and formation of hard dry stools
(Panchal et al., 2007). OBD often results in insufficient pain therapy in many patients.
Laxatives are commonly used to treat OBD;
however, as they have a non-specific mechanism of
action, therapy often requires combinations of different agents. Aggressive laxative therapy may itself
result in side effects, contributing to poor treatment compliance and reducing quality of life for
patients already coping with a chronic, debilitating
illness.
Use of peripherally acting opioid antagonists
has been identified as a promising approach; these
agents specifically target GI receptors without
limiting the central analgesic activity of opioids.
Naloxone is a peripherally acting opioid antagonist with low systemic bioavailability (<3%) following oral administration. Consequently, orally
administered naloxone acts almost exclusively on
GI opioid receptors. Hence, targeting peripheral
receptors whilst sparing central analgesic func-
tion, through combining naloxone with oxycodone, has emerged as promising approach to treat
OBD.
To overcome this disabling side-effect, in recent
years combined formulations (opioids+naloxone)
have been developed.
Oxycodone has been proven as one of the
most effective opioid in several pain syndromes,
such as cancer-related, neuropathic and osteoarthritis-related pain. Moreover oxycodone is considered a useful alternative to morphine in the
treatment of visceral pain syndromes. Taylor and
colleagues reviewed the available literature about
the effectiveness of oxycodone in the treatment
of osteoarthritis pain in placebo-controlled and
comparative trials; the authors found the evidence that oxycodone is safe and effective and
significantly reduces moderate to severe chronic
pain in osteoarthritis patients.
The combined prolonged release oxycodonenaloxone has been demonstrated to provide same
effective analgesia of oxycodone but to improve
bowel guaranteeing long-term efficacy and tolerability in the management of moderate to severe
chronic non-malignant and malignant pain (Lowenstein et al., 2008; Sandner-Kiesling et al.,
2010). Finally, Hermanns and colleagues have
published encouraging results on the effectiveness
and safety of oxycodone/naloxone in the management of neuropathic pain
In conclusion, this association guarantees the
optimal effectiveness of opioids in the treatment
but significantly improving e and reducing those
side effects that limit the long term use.
References
1. Pizzo PA, Clark NM. Alleviating suffering 101--pain relief
in the United States. N Engl J Med 2012;366(3):197-9.
2. Doherty M, Hawkey C, Goulder M, et al. A randomised
controlled trial of ibuprofen, paracetamol or a combination tablet of ibuprofen/paracetamol in community-derived people with knee pain. Ann Rheum Dis
2011;70(9):1534-41.
3. Taylor R Jr, Raffa RB, Pergolizzi JV Jr. Controlled release
formulation of oxycodone in patients with moderate to
severe chronic osteoarthritis: a critical review of the literature. J Pain Res 2012;5:77-87.
4. Panchal SJ, Müller-Schwefe P, Wurzelmann JI. Opioidinduced bowel dysfunction: prevalence, pathophysiology
and burden. Int J Clin Pract 2007;61(7):1181-7.
5. Simpson K, Leyendecker P, Hopp M et al. Fixed-ratio
combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in
moderate-to-severe noncancer pain. Curr Med Res Opin
2008;24(12):3503-12.
6. Sandner-Kiesling A, Leyendecker P, Hopp M et al. Longterm efficacy and safety of combined prolonged-release
oxycodone and naloxone in the management of non-cancer
chronic pain. Int J Clin Pract 2010;64(6):763-74.
9
ABSTRACT
Mechanisms of post-opioid exposure
hyperalgesia and tolerance
William Maixner
Department of Endodontics, Center for Neurosensory Disorders,
University of North Carolina at Chapel Hill,
North Carolina 27599-7455, USA
While opioids are effective in ameliorating
pain, it is recognized that there is substantial variation amongst individuals with respect to the
pharmacodynamic properties of opioids, including the desired analgesic response. One important event that contributes to variations in the
analgesic responses to opioids is the previous
exposure to opioids. Both acute and chronic
exposure to opioids produce pharmacological
tolerance and a phenomenon commonly referred to as “opioid induced hyperalgesia” (OIH).
Within recent years, several neural mechanisms
have been advanced to explain OIH and the
pharmacological tolerance to opioids. OIH and
pharmacological tolerance have been associated
with cellular signaling through toll-like receptor
4, β2-adrenergic receptors, β-arrestin, as well as
through recently identified slice variants of the
human µ-opioid receptor. These, and several
other candidate pathways, have been proposed
to play a pivotal role in the attenuation of opioid analgesia and appear to mediate OIH. Dr.
Maixner will present and discuss several of the
underling cellular mechanisms that have been
proposed to mediate OIH and tolerance.
Rotation of opioids: from theory to practice
V Rollason, Lucien Roulet, C Samer, Y Daali, M Besson,
V Piguet, M Escher, P Dayer, J A Desmeules
Division of Clinical Pharmacology and Toxicology and
Multidisciplinary Pain Center,
University Hospitals of Geneva,
Switzerland
Introduction
Opioids are widely used to treat cancerous
and non-cancerous pain. Their efficacy is not
questioned but they can cause unbearable side
effects that limit their use. It is in this context
that a rotation of opioids can be a useful strategy. To date no randomised controlled trial has
evaluated the pertinence of opioid rotations or
10
the comparative efficacy of different methods
of rotation, mainly due to methodological pitfalls related to the population to be studied and
the pharmacokinetic differences of the different
opioids. Therefore opioid rotation in clinical
practice is based on case-reports, retrospective
studies and, at the best, prospective non-randomised studies.
Rationale
When treating severe pain, the maximal doses
of opioid is determined by the balance between
efficacy and occurrence of adverse drug reactions
(ADR). The first step is to deal with the ADR by
correcting the contributory causes, adapting the
comedications, treating the side effects, using
adjuvant medications or changing the administration route of the opioid. When these different
steps are insufficient, an opioid rotation can be
a good alternative, bearing in mind that the goal
is to reduce side-effects whilst keeping the analgesic efficacy. Six different opioids have been described in the literature for rotations: morphine,
hydromorphone, oxycodone, buprenorphine,
fentanyl and methadone.
Several hypotheses have been suggested to explain the improvement of the benefit/risk balance
when changing the opioid treatment.
The first assumption is based on the different
affinities for the opioid receptors. There are three
different opioid receptors, namely μ (mu), δ (delta)
and κ (kappa). Each opioid and its potential active
metabolite bind to these receptors with their own
affinity and sensitivity. For example, the binding
profile to the μ receptor varies by a factor of 200 to
300 between the main opioids. A rotation allows
to play with these characteristics and reach a better
analgesia with less ADRs.
Secondly, the pharmacokinetic profiles of
the opioids differ in such a way that the treatment can be adapted to the comedications and
comorbidities of the patient. Regarding the absorption and distribution processes, some opioids, such as morphine, are P-glycoprotein (Pgp)
substrates. Pgp is a transmembrane transport
protein that modulates transport across many
tissue barriers, primarily gastrointestinal and
cerebral. Therefore, inhibition or induction
of Pgp by other medications or environmental
factors may theoretically modulate the analgesic effect by changing the concentrations of the
opioid in the blood and the brain. As for the
hepatic metabolism, some opioids depend on
March 2013

ABSTRACT
phase I enzymes (cytochrome P450) and others
on phase II enzymes (glucuronidation). Again,
induction and inhibition of these metabolic
pathways due to the patient’s comedications
and comorbidities can affect the efficacy and
ADR profile of a specific opioid whereas another opioid would be the drug of choice.
Finally, several genetic polymorphisms may
contribute to modulate the response to opioids. A genetic polymorphism is considered
when differences in gene expression is observed
with a frequency greater than 1% of the population. Interindividual variability in response
to opioids in terms of efficacy and safety is
in part due of this phenomenon. The major
genetic polymorphism to take into account
when opioid treatment is considered it that of
cytochromes P450. A deficiency in these enzyme systems (poor metabolisers) can lead to
the accumulation of the parent drug with the
occurrence of ADRs or, for an opioid that has
to be bioactivated through these cytochromes,
such as oxycodone, a decreased effectiveness.
Conversely, in patients that are ultra-rapid
metabolisers, the parent drug will be inefficacious whereas, for the opioids that have to be
bioactivated, ADRs could occur. At the present
time, the findings from studies describing the
clincal effect of genetic polymorphisms of Pgp,
μ receptor and UDP-glucuronosyltransferase
(UGT2B7, enzyme responsible for the conjugation of morphine) on efficacy and/or ADRs
are conflicting. To date, pharmacogenetics in
pain medicine has been used retrospectively
to identify and explain the causes of abnormal responses (either inefficacy or toxicity) in
indiv idual patients. Although it may appear
premat ure to recommend the application of a
single genetic test before the start of the treatment, pharmacogenetics might already help to
ident ify the right analgesic for the right patient
more than the right effective and safe dose,
such as avoiding prodrug opioids in PMs for
CYP2D6 as well as in UMs concomitantly taking a CYP3A inhibitor. Testing could support
opioid rotations in specific circumstances and
has the potential to increase the efficacy while
reducing the toxicity of therapeutic agents, simultaneously avoiding prescription of expensive, useless medications in individual patients.
This may also ultimately help to design more
useful pain medications with better efficacy
and lower toxicity profiles.
Opioid rotation in practice
An opioid rotation should be considered only
after other potentially treatable causes for the
inefficacy or the ADRs have been considered:
Knowledge of the pharmacodynamics and pharmacokinetics of the different opioids, as well as
the patient comorbidities and comedications,
allows the choice of the most appropriate opioid because the rotation should be individualised and cannot be based on predefined criteria.
Three key elements regarding the pharmacology
of opioids are taken into account: the administration route, the possible drug-drug interactions and the dose.
Considering the administration route, the oral
route should always be preferred. When oral intake is impossible or there is doubt about the absorption, subcutaneous administration is preferred
unless an implantable chamber or a central venous
access is available. Transdermal administration is a
good option when the analgesic treatment is stabilized.
For drug-drug interactions, opioid substrates of
cytochrome P450 isoenzymes are likely to see their
effectiveness and tolerance affected by drug inducers or inhibitors of these enzymes.
When searching for the correct dose, many
tables are available for equivalent analgesic potency between opioids. These data are however
based on a low level of evidence and it is risky
to strictly apply the suggested conversion rates,
that must be taken as general indicators. In
clinical practice, security should be a priority
and therefore the lowest conversion coefficients
should be applied.
Finally, to better adapt the dose of the new treatment to the patient, it is important to re-evaluate
its safety and efficacy in steady-state conditions,
after four half-lives, and then regularly.
Conclusion
The indication for an opioid rotation is
based on the fact that the pharmacodynamic
and pharmacokinetic profiles of opioids differ.
This rotation should be chosen after a careful
evaluation that includes the search and correction of metabolic factors, the adjustment of the
(co-) medications and the overall context and
co-morbidities of the patient. The particular
conditions of each patient (comorbidities, comedications) and the characteristics of the different molecules available dictate the selection
of the opioid of choice.
11
ABSTRACT
Neuropathic pain: a challenging entity
with complex mechanisms
G. Cruccu, A. Truini
EFNS Panel on Neuropathic Pain and
Department of Neurology and Psychiatry, Sapienza University,
Rome, Italy
It is largely acknowledged that multiple and
complex pathophysiological mechanisms may be
at play in neuropathic pains, although these have
been mainly demonstrated in animal studies and
much less in patients (Costigan er al. 2009). The
most recent pathophysiological advances regard
specification of sub-types of membrane receptors
or neurotransmitter mechanisms in animal models. Although such information is by all means
important because it may be useful for the development of future drugs, it may be less relevant in
clinical practice. Clinical history, sensory testing,
and laboratory investigations, however, are often
helpful to determine the nature of the nerve damage, i.e. demyelination and peripheral axonal loss,
or cell death and central denervation.
1. Neural mechanisms of sensitization in tissue damage or inflammation (with no nerve damage)
Tissue injury or inflammation increase nociceptor activity through inflammatory mediators
released by the damaged tissue or carried by the
blood stream (histamine, serotonin, bradykinin,
prostaglandins, etc); the nociceptors themselves
release transmitters, such as substance P, CGRP,
that increase the local inflammation (neurogenic
inflammation) (Fields et al., 1998).
These events induce local vasodilation and lower
the nociceptor threshold, thus inducing thermal
and mechanical hyperalgesia (area of primary hyperalgesia). This primary area tends to expand,
through the antidromic invasions of collaterals of
nociceptors (axon reflex). The term “peripheral sensitization” should be attributed to the nociceptors
activated by the initial injury directly or through
the axon reflex. An area of hyperalgesia also develops in the undamaged tissue adjacent to the site of
injury (area of secondary hyperalgesia). The area of
secondary hyperalgesia arises because the ongoing
spontaneous activity from the primary nociceptors
sensitizes second-order nociceptive neurons (central sensitization) [2](Treede et al., 1992). In sensitised second-order nociceptive neurons receptive
fields enlarge and responses to afferent impulses
increase. In this pathological condition, Aβ lowthreshold mechanoreceptors (LTM), normally re-
12
sponsible for touch sensations, can activate secondorder nociceptive neurons, thus causing pain (i.e.
allodynia). The role of non-nociceptive Aβ-fibres
in mediating allodynia was shown by selective intraneural microstimulation of LTMs, related to
Aβ-fibres, which elicited a sensation of touch in
normal skin but became painful when the receptive
fields were part of an area of secondary “hyperalgesia” after adjacent injection of capsaicin. In turn,
this LTM-mediated secondary “hyperalgesia” was
completely abolished by A-fibre conduction block
(Koltzenburg et al., 1992).
However the mechanisms underlying secondary hyperalgesia and allodynia are far from being
completely ascertained. An alternative and opposite view suggests that allodynia could reflect the
lowered mechanical threshold in sensitised primary
nociceptors. This view is supported by several neurophysiological studies showing that in patients
with painful neuropathies allodynia is related to
abnormal C nociceptor firing triggered by light
mechanical touch (Truini et al., 2012).
2. Mechanisms of neuropathic pain in patients without sensory and axonal loss
Many of the above events also take place in neuropathic pain. Neurogenic inflammation, as measured by basal and capsaicin-induced CGRP release
from the skin, is increased in rats with experimental
diabetic neuropathy compared with controls, indicating an increased sensitivity of C-fibres to capsaicin and related stimuli (Zimmermann, 2001).
There is now good evidence that uninjured fibres
within an injured nerve take part in the signalling
of pain, exhibiting spontaneous activity and sensitization.
The high-frequency bursts generated ectopically
are thought to correspond to the paroxysmal attacks of shooting, stabbing, or electric-shock-like
pains. In addition to the sensitized peripheral
terminals, the cell bodies and the region near the
dorsal ganglion may easily generate spontaneous
bursts. Several studies demonstrated that the ectopic impulses generated in inflamed, compressed,
or demyelinating nerve fibres are associated with
an up-regulation of mRNA for specific voltagegated sodium channels in nociceptive primary afferents. The abnormal expression of these sodium
channels leads to hyperexcitability of primary afferents (both lowered threshold and higher firing
rate) (Wood et al., 2004).
Central sensitization is more likely to develop in
conditions that induce ectopic activity along nerve
March 2013

ABSTRACT
fibres because of the high frequency of impulses of
the paroxysmal bursts, a frequency that cannot be
reached by receptors or post-synaptic neurons: it is
the very-short interval between afferent impulses
that produces the excessive membrane depolarization that makes calcium pouring into the postsynaptic neuron.
3. Mechanisms of neuropathic pain that imply sensory
and axonal loss
Some of the above mechanisms (e.g. ectopic activity) may also take place in peripheral or central
neurological diseases that typically induce axonal
degeneration. Animal models of peripheral nerve
damage showed that the regenerating sprouts of
damaged axons develop spontaneous activity and
an increased sensitivity to chemical, thermal and
mechanical stimuli. Consistently with findings in
animals, microelectrode recordings from transected nerves in human amputees with phantom limb
pain revealed spontaneous afferent activity. In
these patients tapping the neuroma increases pain
and enhances the afferent discharges. Injection of
lidocaine into the neuroma blocks the tap-induced
nerve activity ant its related pain (though it does
not relieve spontaneous ongoing pain) (Fields et
al.,1998).
Other mechanisms, however, may take place
only in patients with axonal degeneration and
sensory loss. For example, mild afferent signal loss
might induce major changes in dorsal horn neuron
excitability. When large Aβ-fibre input decreases,
the interneurons that inhibit nociceptive neurons
become hypoactive (loss of afferent inhibition)
(Koike et al., 2008). In neurological diseases characterized by degeneration of the axons projecting
onto the dorsal horn neurons (e.g. neuronopathies,
sensory root avulsion), the fall of presynaptic terminal buttons leaves the post-synaptic receptors
exposed to neurotransmitters and postsynaptic
neurons begin to fire spontaneously (deafferentation supersensitivity) (Zimmermann, 2001). Hypoactivity of the descending antinociceptive systems (loss of descending inhibition) has been often
proposed but never demonstrated (Porreca et al.,
2001).
References
1. Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a
maladaptive response of the nervous system to damage.
Annu Rev Neurosci. 2009;32:1-32.
2. Fields HL, Rowbotham M, Baron R. Postherpetic neuralgia: irritable nociceptors and deafferentation. Neurobiol
Dis. 1998;5:209-27.
3. Koike H, Iijima M, Mori K, et al. Neuropathic pain cor-
4.
5.
6.
7.
8.
9.
relates with myelinated fibre loss and cytokine profile
in POEMS syndrome. J Neurol Neurosurg Psychiatry
2008;79:1171-9.
Koltzenburg M, Lundberg LE, Torebjörk HE. Dynamic
and static components of mechanical hyperalgesia in human hairy skin. Pain 1992;51:207-219.
Porreca F, Burgess SE, Gardell LR, et al. Inhibition of neuropathic pain by selective ablation of brainstem medullary cells expressing the mu-opioid receptor. J Neurosci.
2001;21:5281-8.
Treede RD, Meyer RA, Raja SN, et al. Peripheral and central mechanisms of cutaneous hyperalgesia. Prog Neurobiol. 1992;38:397-421.
Truini A, Biasiotta A, Di Stefano G, et al. Peripheral nociceptor sensitization mediates allodynia in patients with
distal symmetric polyneuropathy. J Neurol. Oct 2012.
Wood JN, Boorman JP, Okuse K, et al. Voltage-gated sodium channels and pain pathways. J Neurobiol
2004;61:55–71.
Zimmermann M. Pathobiology of neuropathic pain. Eur J
Pharmacol. 2001;429:23–37.
Chronic pain: identifying underlying
mechanisms that benefit from multimodal approaches
Joseph Pergolizzi
Department of Medicine, School of Medicine
Johns Hopkins University, Baltimore, MD, USA
Pain processing occurs in the central nervous
system (spinal cord and brain) and periphery.1
Although pain is a normal process, pathologic
mechanisms may contribute to its transduction
and perception.1 Neuroplastic changes in the pain
processing can lead to changes in pain perception.1
Acute pain may be healthy and adaptive, allowing
a protective reflexive response resolving with the
healing of an injury.2 Other types of pain may be
maladaptive; in fact, persistent pain ceases to have
a protective function and becomes known for its
disruptive effects.1, 2 Chronic pain syndromes occur when pain is not associated with identifiable
injury or when pain extends beyond healing of the
injury. Normal pain processing involves transmission of pain via ascending pathways, with modulation (either inhibitory or facilitatory) occurring
via descending pathways.2 Numerous disease states
involve persistent pain. Maladaptive pain states,
including inflammatory/joint pain, neuropathic
pain, and non-inflammatory/non-neuropathic
pain often result from peripheral and central sensitization. Nociceptive, neuropathic and inflammatory pain are responses to different, possibly
overlapping, stimuli and mechanisms, and have
different characteristics. As chronic moderate to
severe pain is often multifactorial and is associated
13
ABSTRACT
with plasticity of the nervous system, treatment
decisions should take into account the underlying
mechanisms.
The rationale for mechanism-orientated treatment is that pain can be caused by multiple mechanisms, and is processed and modulated by multiple
excitatory and inhibitory systems.
The μ-opioid receptor system, which exerts an
inhibitory effect on the spinal and supraspinal
level, is mainly responsible for modulating acute
nociceptive pain. In chronic pain, the relative contribution of the monoaminergic system increases
via the descending pain pathway; generally, noradrenaline reduces pain, while serotonin has both
inhibitory and facilitatory effects. Pain relief may
be achieved either by blocking excitatory transmission or activating inhibitory systems. Thus the
analgesic efficacy of drugs may differ according to
the underlying mechanism(s). For example, opioids act both presynaptically and postsynaptically in
the spinal cord as well as supraspinally, while tricyclic antidepressants reduce the reuptake of noradrenaline or serotonin via the descending pain pathway. Chronic pain often involves more than one
causative mechanism, so combining with different
mechanisms of action increases the probability of
attenuating the pain signal. Two pain modulation
systems (opioidergic and monoaminergic) are relevant in chronic pain; simultaneous activation of
both may produce analgesic synergy.
References
1. Scholz J, Woolf CJ. Can we conquer pain? Nat Neurosci.
2002;(5 suppl):1062-7.
2. Woolf CJ. Pain: moving from symptom control toward
mechanism-specific pharmacologic management. Ann Intern Med. 2004;140:441-51.
3. Pergolizzi J. Chronic pain - moving from symptom control to mechanism-based treatment. Current Medical Research & Opinion 2011;27(10):2079-80.
Centrally acting drugs and dependence
circuits: a clinical point of view
Michael R. Clark
Department of Psychiatry and Behavioral Sciences,
The Johns Hopkins University School of Medicine, Baltimore
MD 21287-5371, USA.
Brain systems that process reward can be separated into hedonic/liking and motivational/
wanting aspects. The former is mediated by the
orbitofrontal cortex and opioids while the latter is
predominantly a function of the ventral striatum
14
and dopamine. These systems may also manage similar aspects of the experience of pain and pain
relief. The core reward circuitry has been described
as an in-series circuit linking the ventral tegmental
area, nucleus accumbens and ventral pallidum via
the medial forebrain bundle. These circuits manage
complex aspects of the experience of reward such
as attention, expectation, motivation, risk-taking,
and learning.
Analgesics relieve pain. Independent of any direct euphoric effects of medications, the relief of
pain is a reward with positive effects for the suffering organism. Local anesthetics activate ventral
tegmental dopaminergic cells. This release of dopamine in the nucleus accumbens is associated with
conditioned place preference behaviors in animal
models of postsurgical pain. In humans with chronic low back pain, the administration of morphine was associated with dosage-correlated volumetric decreases in the right amygdala and increases
in right hypothalamus, left inferior frontal gyrus,
right ventral posterior cingulate, and right caudal
pons. These changes persisted for months after the
discontinuation of opioids.
Adjuvant analgesics such as anticonvulsants and
antidepressants can produce pain relief through
a variety of pharmacological actions, especially
within a hyperexcitable or sensitized nociceptive
system. These pathophysiological mechanisms of
chronic pain range from modified dynamics of voltage-gated sodium channels to modulating calcium
ion influx for neurotransmitter release to changes
in modulatory effects of monoamines like dopamine, serotonin, and norepinephrine. Interactions
occur with parallel systems that affect anxiety and
depression beyond the usual suffering or unpleasantness of pain.
Habits are the choices that all of us deliberately
make at some point and then stop thinking about
but continue doing every day. The characteristics of habits include that they are easily intitiated,
manifest automatic execution, produce results that
are highly reinforcing and whose outcome is not
questioned. The result is that the behavior is likely
to be repeated. Habits save us effort, keep us from
being overwhelmed by minute details of daily life,
and allow us to ignore the insignificant. Habits exist as loops that begin with a cue that triggers an
automatic action, a series of actions called a routine, and the reward, which is reinforcing such that
this loop is formed and worth remembering for the
future. As the cue and the reward become intertwined, anticipation and craving emerge signalling
March 2013

ABSTRACT
that the habit has been successfully created. At this
point, the craving is accompanied by a suspension
of decision-making. The behavioral routine unfolds automatically. Bad habits divert our efforts
from productive activities, distract us from significant details, and interfere with our ability to meet
the demands of daily life.
Allostasis is defined as the process of achieving
stability through physiological or behavioral change such as drug addiction. Initially the drug elicits
its primary and unconditioned reinforcing actions
that are opposed and neutralized within the same
neurobiological system. Later, between-system interactions develop. Repeated compromised activity
in the dopaminergic system coupled with activation of the corticotropin releasing factor system
during withdrawal have been hypothesized to create an allostatic load that results in the transition to
drug addiction.
Addiction is characterized by a compulsion to
seek and take a drug, loss of control in limiting its
intake, and the emergence of a negative emotional
state when access to the drug in prevented, even
when taking the drug is resulting in adverse consequences for the individual. Addiction is a disorder
that progresses from impulsivity and positive reinforcement of drug taking to one of compulsivity
associated more with negative reinforcement. Decreases in the salience of reward have been linked
to deficient dopaminergic and GABA-ergic function in the ventral striatum along with increases
in activity of brain stress systems in the amygdala.
Discrete circuits are hypothesized to mediate the
three stages of the addiction cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation/craving. Each step results in
a more widespread recruitment of circuits until
a distributed network emerges. There is evidence
to suggest that addiction is a result of the failure
of the executive system that process reward, pain,
stress, emotion, habits, and decision-making.
The building of habits, particularly new habits
that replace less effective ones is an important skill.
Building new habits really relies on simple, obvious
cues that represent universal triggers that are impossible to ignore. In addition, the rewards for a
new habit are most likely to reinforce the routine
if they are sought after and clearly defined. As habits become stronger, a sense of anticipation emerges. Now the pleasure of the reward begins to be
experienced even before the routine is performed
and the reward realized. In fact, if the anticipated
reward is not provided, both frustration and desire
build with focus and effort increased not only to
achieve the reward itself but also to avoid the disappointment of not receiving it.
Creating a new habit often is desired as a way of
replacing or ending a bad habit. If the power of the
bad habit is harnessed, the new habit is more likely
to take hold. In other words, a new habit is easier
to acquire if there is something familiar about the
cue and the reward. It is the craving of the reward
of the old habit that will increase the temptation
to stop the new habit. Therefore, to change a habit, the old cue and reward are retained but a new
routine is inserted. The process of change can be
broken down into specific components: creating
an awareness of cues, characterizing the reward,
designing a competing response, and delivering the
same reward. While these steps are concrete, the
more elemental ingredient is a belief that the new
habit will address the underlying cause of the old
habit. This concept is developed by understanding
why new habits fail, especially at critical moments.
Belief itself becomes the fuel for believing first in
change and then more specifically that life’s problems are solvable.
NSAIDs and acetaminophen: which role
in chronic pain management?
William K. Schmidt, PhD
CG Pharmaceuticals, Emeryville, CA, USA
The first use of plants containing salicylates and
other anti-inflammatory and antipyretic substances may be known only to antiquity, but the use of
willow bark and salicylate-rich plants was recorded
more than 3,500 years ago in the Ebers papyrus
from the Pharonic period in Egypt. Not much
had changed by the time that the New World was
discovered by Columbus (1492) or the Lewis &
Clark expedition (1803-1806) began the westward
expansion in the United States. Willow bark tea
used by Meriwether Lewis was known for its ability
to reduce pain, fever, and inflammation. Aspirin,
as an active ingredient, was introduced into pain
medicine in 1899, but it was preceded by acetanilide (1896) and phenacetin (1887) as the first totally
synthetic antipyretic analgesic drugs. While aspirin
is still one of the most widely used drugs today, in
particular for its anti-platelet cardioprotective properties, its use for children and for many postoperative procedures was replaced by acetaminophen
(paracetamol) beginning in the 1950s since the lat-
15
ABSTRACT
ter does not inhibit platelets, enhance postoperative bleeding, or produce gastric ulcers. While over
30 synthetic anti-inflammatory, antipyretic analgesics have been introduced worldwide, with the
greatest number of new drugs being introduced in
the 1970s to 1990s, 10 have been withdrawn due
to severe life-threatening adverse effects including
methemoglobinemia (acetanilide), renal toxicity
(phenacetin, suprofen), blood dyscrasias (phenylbutazone, oxphenbutazone), anaphylaxis (zomepirac), hepatotoxicity (benoxaprofen, bromfenac),
and more recently, cardiovascular toxicity that can
lead to an elevated risk of myocardial infarctions
and strokes (rofecoxib, valdecoxib). In the United
States, all NSAIDs including drugs sold over-thecounter in pharmacies and convenience stores now
carry a black-box warning indicating that the lowest doses should be taken for the shortest period
of time to reduce the risk of severe cardiovascular
toxicity.
The advent of the COX-2 selective drugs in the
late 1990s initially seemed to provide us with a way
to achieve the desired anti-inflammatory, analgesic,
and antipyretic activity of NSAID drugs without
the risk of GI ulcers and bleeding, but as we all
know starting with the worldwide withdrawal of
rofecoxib in 2004, selective inhibition prostacyclin
and prostaglandin pathways without the corresponding inhibition of thromboxane can lead to
vasoconstriction, increased platelet adhesion, platelet aggregation, hypertension, and severe cardiovascular complications.
The withdrawal of rofecoxib and valdecoxib,
coupled with the refusal of the U.S. FDA to grant
approval to etoricoxib and lumiracoxib in 2007,
has largely stopped innovation in the development
of traditional NSAIDs and shifted most analgesic
drug discovery to other pathways that may be involved in pain and inflammation. The most recent
FDA approvals for NSAIDs and acetaminophen
related compounds have been formulations such
as Duexis (ibuprofen + famotidine; 2011), Ofirmev (acetaminophen i.v.; 2010), Sprix (ketorolac
tromethamine nasal; 2010), Vimovo (naproxen
+ esomeprazole; 2010), Zipsor (diclofenac potassium; 2009), Pennsaid (diclofenac topical solution;
2009), and Caldolor (ibuprofen injection). The
i.v. and nasal formulations are approved only for
short-term use, often in a hospital setting.
However, this may not be the last story in the
development of novel NSAID-related drugs for the
treatment of chronic pain. For the past 6 years, I’ve
had the opportunity to lead a clinical development
16
program for the development of CG100649, a novel and highly potent inhibitor of COX-1, COX-2,
and human carbonic anhydrase I and II. Early Phase I studies showed that CG100649 bound reversibly with very high affinity to carbonic anhydrase
enzymes in red blood cells and other tissues, using
them as intracellular drug transporters. The vast
majority of orally administered compound is quickly locked away within red blood cells and other
tissues with very high molar concentrations of carbonic anhydrase, and protected from interactions
with the gastrointestinal (GI) and cardiovascular
systems.
The typical PK profile in six consecutive clinical
studies conducted to date has been that whole blood concentrations of CG100649 are 75-80x higher
than plasma concentrations. Only purpose-made
carbonic anhydrase inhibitors, such as methazolamide (12.5x whole blood to plasma ratio) come
close to this type of stealth drug transport technology. In tissues where carbonic anhydrase levels are
low or absent such as inflamed joints, CG100649
is free to dissociate from carbonic anhydrase, bind
to COX-1 and COX-2, and inhibit production of
prostaglandin E2, thromboxane, and related prostaglandins. Plasma levels of CG100649 tend to
remain very low (mean of approximately 15-42
ng/mL after therapeutic-range doses of 1.2 to 2
mg/day) with comparatively little within-day or
day-to-day variation due to replacement of plasma
levels of drug from the much larger red blood cell
reserves. In practice, this allows subjects to maintain therapeutic drug levels even if they miss 1-2
days of oral dosing.
Data from a 21-day osteoarthritis Phase 2a efficacy trial showed that CG100649 significantly
reduced the total WOMAC OA score (p=0.01)
and WOMAC pain, stiffness, and physical function subscores (p<0.05) following an initial loading dose of 8 mg, followed by constant dosing
at 1.2 mg/day (Schmidt et al., 2009). More recent
data from a Phase 2b study confirmed that fixed
dosing at 2 mg/day reduced the mean WOMAC
pain score by 50% at the end of 28 days of daily
dosing (Study CG100649-2-02; ClinicalTrials.gov
identifier NCT01341405). There were no treatment-emergent adverse GI effects or cardiovascular
effects that were higher in drug treatment groups
than in the placebo group in either of these studies.
A recent biomarker study (CG100649-1-04;
ClinicalTrials.gov identifier NCT01154790)
showed that CG100649 is a balanced COX-1
and COX-2 inhibitor at therapeutic and supra-
March 2013

ABSTRACT
therapeutic doses in healthy volunteers. The data
showed that ex vivo LPS-stimulated PGE2 was
maximally inhibited (89-96%; p<0.001) by all 3
dose levels of CG100649 at Day 7. Serum TxB2
was reduced by 68-91% in all three active-drug cohorts (p<0.001). Urinary TxB-M was decreased by
33-67% in the two higher dose groups receiving 4
or 8 mg/day (p=0.012 and p=0.009, respectively).
Urinary prostaglandin E metabolite (PGE-M) decreased 65-69% in all 3 dose cohorts (p≤0.001 on
Day 7). Inhibition of PGE2 and TxB2 in this study
compares favorably with traditional NSAIDs (ibuprofen, naproxen) and is uniquely different than
COX-2 selective drugs such as celecoxib. PK analyses confirmed the unique preferential high-affinity
binding of CG100649 to red blood cell carbonic
anhydrase in all subjects; CG100649 concentrations were 50-70x higher in whole blood than in
plasma in all 3 dose cohorts, in both males and
females.
CG100649 will enter Phase 3 clinical studies
with extended dosing for up to 6 months in early
2013. We believe that the data may continue to
show a favorable GI and cardiovascular profile in
subjects with osteoarthritis pain through the reduction of exposure in sensitive tissues to the deleterious effects of NSAIDs while maintaining full
therapeutic effects in inflamed and painful arthritic
joints. History has shown that we have learned to
avoid many of the life-threatening adverse effects
of early NSAIDs that were first developed over 125
years ago. The challenge remains to develop effective and safe anti-inflammatory drugs that have
reduced adverse gastrointestinal and cardiovascular
effects that were first promised (but not delivered)
with COX-2 selective compounds over a decade
ago.
References
1. Schmidt WK et al. Osteoarthritis Cartilage 2009;17(supplement 1):S173.
Best practices in safe NSAID use in the
elderly: a preview to the FDA safe use initiative – ACPP project
Robert Taylor Jr., PhD
Nema Research Inc., Naples, FL 34108, USA
Background: Millions of people rely on both
prescription and over-the-counter (OTC) medications to enhance their quality of life. Ho-
wever, many people end up suffering from injury due to inappropriate use of medications.
These injuries are preventable and their risk
can be grouped into broad categories: medication errors, unintended exposures, and
intentional drug misuse/abuse. Medication
errors, unintended exposures and intentional drug misuse are a product of inadequate
education and information for physicians and
patients regarding the risks and optimal use of
a drug. This lack of appropriate knowledge for
both physician and patient may result in improper prescribing and patient use which can
lead to preventable drug harm. Non-steroidal
anti-inflammatory drugs (NSAIDs) is a class
of medications that functions best when both
the physician and patient are aware of proper
prescribing and use practices, however, when
NSAIDs are not prescribed and/or used correctly serious injury can be the result. NSAIDs
are effective as pain relievers and are available in both prescription and over-the-counter
formulations. Their mechanism of action and
toxicology are well understood. They are used
quite frequently, especially in older adults (>
65 years old). Nevertheless, despite warnings
and language about NSAIDs risks in the drug
labels, the incidence of injury associated with
them is high. Hundreds of thousands of people
are hospitalized each year because of NSAID
related complications with approximately >
16,500 deaths related to GI bleeding in the
United States. Gastrointestinal (GI) complications including bleeding, peptic ulcers and
bleeding of pre-existing ulcers may occur in up
to 3% of all chronic NSAID users. NSAIDrelated renal function impairment may precipitate acute or chronic renal damage, and/or
worsen cardiovascular conditions (e.g., hypertension and heart failure). Additional injuries
that are associated with NSAIDs include atherosclerotic events such as myocardial infarction
and stroke. With chronic NSAID use, patient
cardiovascular risk can increase up to threefold. Other less common side effects include
allergic reactions, drug-induced liver injury
and CNS-effects (e.g., dizziness). As a result
of natural physiological and other changes associated with aging, NSAID-related risks are
more prevalent in older adults. Older adults
are at a higher risk of multiple morbidities
including GI complications, renal and hepatic impairment, and cardiovascular events. As
17
ABSTRACT
a result of these multiple morbidities, many
older adults consume multiple medications.
The addition of NSAIDs to their multi-drug
regimen increases the risk of injuries as a result of drug-drug interactions which might
differentially affect their various morbidities.
NSAID-related injuries have been coined as
the ‘silent epidemy’. Many physicians and
patients are unaware of the growing number
of injuries associated with improper NSAID
use. Many health care providers and patients
are unfamiliar with the risks associated with
NSAIDs; and are either unaware or do not
adhere to the prescribing and use guidelines.
There are more than one set of guidelines, and
physicians have admitted to being overwhelmed and confused by various guidelines and
their lack of consistency. In addition patients
may have the misconception that OTC drugs
are by default safer than prescribed drugs. Failure to recognize such risks or follow the most
current prescribing recommendations increases
the risk of serious injury. In an effort to minimize the harm associated with inappropriate
use of NSAIDs, the Food and Drug Administration’s Safe Use Initiative, the Association of
Chronic Pain Patients (ACPP) and international key opinion leaders have come together to
compile and disseminate a state of the art and
clinically relevant information guide regarding
NSAIDs, and the most up-to-date information
on their safe and appropriate use with a focus
on older adults. Many areas related to NSAIDs
including mechanism of action, pharmacodynamics, pharmacokinetics, efficacy and safety
in acute/chronic pain management and drugdrug interactions will be included. An emphasis will be made on practices from guidelines as
well as physician experiences that have demonstrated significant effects on reducing the risk
of injuries associated with inappropriate use of
NSAIDs. The BEACON (The Best Practices of
Safe NSAID Use) project was the outcome of
the above mentioned collaboration. The BEACON project will provide a complete compilation of the most current and established
guidelines/best practices for safe NSAID use.
The ultimate goal of the project is to give both
physicians and patients the tools necessary to
increase awareness as well as promote the safe
and appropriate use of these analgesics. Despite the risks associated with this class of medications, NSAIDs have become a mainstay and
18
valuable option for pain management in the
older adult population, and promoting/ensuring appropriate and safe use of these medications is a must.
Breakthrough pain: how to effectively treat. New old drugs with different pharmacokinetic approaches
Christopher Gharibo, MD
Department of Anesthesiology, NYU Langone-Hospital for
Joint Diseases, NYU School of Medicine, New York, NY
A majority of patients with acute and chronic pain experience breakthrough pain above
their baseline, despite a fixed regimen. The
characteristics of current short-acting oral medications are not optimal because they often
peak too late and last beyond the duration of
pain. Oral absorption limits the onset time,
whereas the development of newer routes can
shorten onset times. A number of medications,
both opioid and nonopioid, are being developed for intranasal delivery with promising
results. In addition to the intranasal administration route being efficacious, it also provides better patient satisfaction by allowing the
patient to titrate their own pain medication.
There are legitimate concerns for abuse and
addiction with these medications, which will
need to be minimized with proper dispensing modifica- tions. A number of nonopioid
agents are also entering the market that will
allow for multimechanistic analgesic plans.
Although ketamine is not a common component of current pain treatment plans, the development of an intranasal formulation may
potentially produce wider acceptance. Many
traditional medications, including ibuprofen
and acetaminophen, have been developed for
parenteral administration. Intravenous ibuprofen or diclofenac can be administered for a
longer duration and have a lower bleeding risk
then ketorolac. Intravenous acetaminophen
can provide balanced analgesia when nonsteroidal anti-inflammatory drugs are contraindicated, as is common in the postoperative
period. The role of individual agents in each
specialty is not currently clear, but the future
treatment of pain, both acute and chronic, is
brighter with the addition of these formulations.
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ABSTRACT
Localized neuropathic pain and transdermal therapeutical approach
Ralf Baron
Division of Neurological Pain Research and Therapy, Department of Neurology, Christian-Albrechts-Universität Kiel, Kiel,
Germany
Chronic neuropathic pain is common in clinical
practice, is a major economical health problem and
greatly impairs the quality of life of patients. Estimates of point prevalence for neuropathic pain in
the general population are as high as 5%, a quarter
of them suffering from severe intensity.
Rational for topical treament
Animal work demonstrated that nerve injury is
matched by an increased expression of messenger
RNA for voltage gated sodium channels in primary afferent neurons (e.g., Nav1.3, Nav1.8, Nav1.9)
leading to an increased electrical excitability and
spontaneous activity. There is increasing evidence
that also uninjured fibers running in a partially
lesioned nerve may express sodium channels and
thus take part in pain signaling. Furthermore, a
nerve injury induces a modulation of the transient
receptor potential V1 (TRPV1). The TRPV1 is
located on subtypes of peripheral nociceptive endings and is physiologically activated by noxious
heat at about 41°C. After nerve lesion TRPV1 is
down-regulated on injured nerve fibers, but upregulated on uninjured C-fibers. Such a novel expression of TRPV1 and additional sensitization to
heat by intracellular signal transduction may lead
to spontaneous nerve activity induced by normal
body temperature, if threshold of TRPV1 were reduced below 38°C.
The modern concepts of pain generation in
neuropathies focus on these pathological processes
of sensitization, i.e. hyperexcitability of primary
afferent neurons, with the consequence of secondary central sensitization. Clinically many patients
suffer from spontaneous pain that is perceived in
the affected skin and cutaneous hypersensibility, i.e. mechanical and thermal allodynia. These
symptoms are summarized under the umbrella
term localized neuropathic pain. Localized neuropathic pain is suggested to be defined as “a type
of peripheral neuropathic pain that is characterized
by consistent and circumscribed area(s) of maximum pain associated with abnormal sensitivity of
the skin and/or spontaneous symptoms characteristic of neuropathic pain, for example, burning
pain”. Since patients with localized neuropathic
symptoms likely have hyperexcitable afferents in
their affected skin this patient group is ideal for the
use of topical medication:
Topical lidocaine
Topical lidocaine directly targets the sodium
channels of sensitized afferents in the affected skin.
Despite this direct and effective peripheral action
there is no systemic absorption of the lidocaine
which is reflected by a superior tolerability of the
treatment. Beside the pharmacological effect on afferent neurons lidocaine patches have a protective
component that deprives the skin from mechanical
and thermal stimuli. There is evidence from randomized controlled studies in patients with neuropathic pain demonstrating efficacy of topical
lidocaine patches. A meta-analysis of three studies
including patients with PHN and brush induced
allodynia showed greater pain relief from 5% lidocaine plaster on the painful area compared to a
vehicle although the therapeutic gain was modest
(Khaliq et al 2007). Two other studies confirmed
this efficacy: one used an enrichment enrolment
design with a primary outcome measure time-toexit (Galer et al 1999) and the other (Wasner et al
2005) was extracted from a study of multi-aetiology neuropathic pain (Meier et al 2003). A subsequent trial using an enriched-enrolment design
failed to show a difference between lidocaine and
placebo on the primary outcome measure (timeto-exit) but most secondary outcome measures
favoured lidocaine. However the groups were not
balanced at baseline and many patients withdrew
prematurely from the study (Binder et al 2009). In
an enriched-design non-inferiority open label trial
lidocaine plaster had a more favourable side effect
profile and seemed of similar efficacy as pregabalin
(Baron et al 2009).
Because of the topical mode of action lidocaine
patches have a favorable side effect profile and are
well tolerated even in the long-term administration
(up to 2 years). Furthermore, since there are no
pharmacokinetic interactions an add-on therapy
to all available systemic drugs is possible and has
additional efficacy.
Topical capsaicin
Patients who are characterized by an up-regulation of TRPV1 receptors might be ideal for the
use of topically applied capsaicin: Topical capsaicin directly targets TRPV1 receptors of sensitized
afferents in the affected skin, thus desensitizing
the hyperactive neurons and reducing pain. Sin-
19
ABSTRACT
ce there are no pharmacokinetic interactions an
add-on therapy to all available systemic drugs is
possible.
A high concentration capsaicin formulation
is now available. In clinical trials of postherpetic
neuralgia and painful HIV-neuropathy one application of this 8% capsaicin patch induced pain
reduction for about 12 weeks.
Based on these trial results the currently available treatment recommendations include lidocaine
and capsaicin patches for the treatment of localized
neuropathic pain syndromes as monotherapy or in
combination with systemic treatment.
References
1. Khaliq W, Alam S, Puri N. Topical lidocaine for the treatment of postherpetic neuralgia. Cochrane Database Syst
Rev. 2007 Apr 18;(2):CD004846
2. Galer BS, Rowbotham MC, Perander J, Friedman E. Topical lidocaine patch relieves postherpetic neuralgia more
effectively than a vehicle topical patch: results of an enriched enrollment study. Pain 1999 April;80(3):533-8
3. Wasner G, Kleinert A, Binder A, Schattschneider J,
Baron R. Postherpetic neuralgia: topical lidocaine is effective in nociceptor-deprived skin. J. Neurol. 2005
Jun;252(6):677-86
4. Meier T, Wasner G, Faust M, Kuntzer T, Ochsner F,
Hueppe M, Bogousslavsky J, Baron R. Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind,
placebo-controlled study. Pain 2003 Nov;106(1-2):151-8
5. Binder A, Bruxelle J, Rogers P, Hans G, Bösl I, Baron R.
Topical 5% lidocaine (lignocaine) medicated plaster treatment for post-herpetic neuralgia: results of a double-blind,
placebo-controlled, multinational efficacy and safety trial.
Clin Drug Investig. 2009;29(6):393-408
6. Baron R, Mayoral V, Leijon G, Binder A, Steigerwald I,
Serpell M. 5% lidocaine medicated plaster versus pregabalin in post-herpetic neuralgia and diabetic polyneuropathy:
an open-label, non-inferiority two-stage RCT study. Curr
Med Res Opin. 2009 Jul;25(7):1663-76
Practical overview of interventional pain
management techniques: “What the everyday interventionist needs to know.”
Alan B Hurschman
Plaza Medical Center Fort Worth Texas and Health South.
Rehabilitation Hospital Fort Worth, Texas, USA.
We are standing on the shoulders of great
researchers, professors, doctors and scientist in
the field of medicine. I personally have not participated in any research projects. The information that I provide is regrettably only from my
personal experience as a clinician. What I have
observed, monitored. and written in progress
and procedure notes are what I base my medical
20
opinion on. Unfortunately double blind studies
are difficult to carry out in our field of interventional pain medicine due to the concern for
the patient as well as the risk. It would be hard
to find a patient in pain that would agree to be
part of the control group and receive normal saline at the spine or peripheral nerves since every
patient with chronic pain demands relief of the
suffering yesterday. I applaud the research of Dr.
Lax Manchikanti who has set up guidelines for
“evidence based medicine.” This is a buzz word
in the American medical community especially
in the insurance company and political arenas.
At the same time American politics as in European politics are demanding cost saving measures from the medical community without sacrificing “quality care”, another buzz word. What
I propose is a cost saving procedural measure
that may be controversial. I have gone through
medical literature in the physical medicine and
rehabilitation and anesthesiology sub-specialties of pain medicine. I have found a paucity
of research on performing most spinal interventional procedures with just local anesthesia. In
view of that fact, I have not done any research
on local anesthesia spinal procedures I can provide some guidelines on performing procedures
under local anesthesia. My abstract will provide
case studies. Hopefully, this will stimulate researchers to explore the concept of performing
interventions without using conscious sedation
or general anesthesia routinely.
Radiofrequency in interventional pain
management: what is the evidence?
Honorio T. Benzon, MD
Northwestern University Feinberg School of Medicine, Chicago
Illinois. USA
Radiofrequency (RF) treatments include thermal, water-cooled, or pulsed RF. The role of thermal RF has been established while evidence for the
efficacy of pulsed RF is still lacking. Thermal RF
involves heating the tip of the needle to 80 degrees
centigrade for 90 seconds while in pulsed RF, a
temperature of 42 degrees centigrade is applied for
120 seconds. The lesions caused by water-cooled
RF are bigger than the thermal RF. Prognostic/
diagnostic blocks should be done before radiofrequency is performed.
March 2013

ABSTRACT
Thermal radiofrequency
Head and face pain
Studies on thermal RF for trigeminal neuralgia
are mostly retrospective in nature. The effectiveness of the procedure however is accepted based
on extensive experience. Kanpolat et al reviewed
their 25-year experience on 1600 patients and noted acute pain relief in 98% of patients, complete
pain relief at 5 years in 58% of patients, and pain
relief in 100% of patients who had multiple procedures at their 20-year follow-up.1 Complications
included diminished corneal reflex, masseter weakness and paralysis, dysesthesia, anesthesia dolorosa,
keratitis, and transient/permanent paralysis of cranial nerves III and VI, CSF leak, carotid-cavernous
fistula in one, and aseptic meningitis.
Spine pain
A randomized double-blind sham-controlled
study showed the efficacy of thermal RF in patients
with cervical facet joint pain after whiplash injury.
The median time before the pain returned to 50%
of baseline was 263 days in the RF group compared
to 8 days in the control group.2 The effectiveness
of thermal RF in facet-mediated was confirmed in
several reviews.3-6 For the treatment of cervicogenic
headache, a prospective study showed thermal RF
to reduce the headache severity, number of headache days per week, and analgesic intake per week.7
A randomized study showed thermal RF to have
better short-term (3 months) efficacy than a sham
procedure but long-term relief was not noted.8 A
pilot study showed the procedure to be no more effective than an occipital nerve block.9 For cervical
radicular pain, a prospective study showed that RF
of the dorsal root ganglion (DRG) with the needle
tip heated to 67 degrees C resulted in relief in 75%
of patients at 3 months and in 50% of patients at
6 months.10 No sign of motor denervation or deafferentation was noted. However, there was tendency for the pain to recur 3-9 months after treatment.
In a double-blind randomized study, RF-DRG at
67 degrees C resulted in significantly better results
than a sham procedure.11 Another double-blind
study noted equal efficacy between RF-DRG at 67
degrees and at 40 degrees C.12 Reviews however
showed limited efficacy of RF-DRG in cervical
radicular pain.3, 5
Studies on thermal RF of the thoracic medial
branches for facet-mediated pain were prospective
series, without a control group.13, 14 Both studies
showed some benefit. One of the studies showed
no difference in results in the cervical-, thoracic-,
and lumbar- facet mediated pain (14). For thoracic
radicular pain, retrospective studies showed thermal RF-DRG at 67 degrees C, to result in shortterm relief. One study showed complete relief in
67% of the patients and greater than 50% relief in
another 24% at 2months with excellent long-term
(13-46 months follow up) results in 49% of the patients.15 The other study showed significantly better short-term and long-term pain relief in patients
with clearly localized pain confined to one or two
segmental levels.16
Several randomized, controlled studies showed
the efficacy of thermal RF in lumbar facet-mediated pain.17-19 The relief lasted 6 to 12 months. Other studies showed lack of superiority of thermal
RF but there were problems in the methodologies
used: high percentage of screened patients as fitting
the criteria of facet pain and questionable positive
diagnostic response, i.e. > 24 hour relief after lidocaine.20 The other study showed no superiority of
RF in terms of pain scores and medication usage
but did show a greater percentage of patients with
> 50% reduction in complaints.21 Two randomized
studies comparing thermal and pulsed RF showed
better results with thermal RF.22, 23 Studies on RFDRG are mostly retrospective. A prospective study
on RF-DRG at 70-80 degrees for 120 seconds in
26 patients with low back and neck pain showed
beneficial results in 10.24 A retrospective study
showed an initial success rate of 60% with a mean
duration of pain reduction of 3.7 years.25 However,
a randomized double-blind study showed the effects of RF-DRG (67 degrees for 90 seconds) and
sham treatment were similar.26
Water-cooled radiofrequency
A placebo-controlled study on water-cooled
RF of the L4-5 primary dorsal rami and S1-3
lateral branches for sacroiliac joint pain showed
better results of the water-cooled RF.27 The small
number of patients calls for a larger trial.
Pulsed radiofrequency
Head, face, and spine pain
The evidence for pulsed RF of the trigeminal
ganglion is weak, a randomized study showed it
not to be effective (28). The evidence of pulsed RF
of the sphenopalatine ganglion for chronic head
and face pain is also weak, based mostly on case reports or case series.29 A randomized controlled trial
showed PRF-DRG was more effective than placebo in patients with cervical radicular pain.30 The
difference was statistically significant at 3 months,
21
ABSTRACT
but not at 6 months, and analgesic requirements
were less.
Complications
Complications from pulsed RF are minor. Complications from thermal RF include post-procedure
burning pain that lasts 1-3 weeks, hematoma and
bruising, infection, spinal cord trauma, and pneumothorax.
Conclusions
Pulsed RF-DRG should be used in cervical
radicular pain since it appears to be as effective
and is safe. The evidence of efficacy for thoracic
RF-DRG is low. Thermal RF for lumbar facetmediated pain results in acceptable pain relief for
6-12 months. The role of lumbar RF-DRG has
not been established. Initial results show watercooled RF to be effective in relieving sacroiliac
joint pain.
References
1. Kanpolat Y, Savas A, Bekar A, Berk C. Percutaneous controlled radiofrequency trigeminal rhizotomy for the treatment of idiopathic trigeminal neuralgia: 25-year experience with 1,600 patients. Neurosurgery 2001;48:524-32.
2. Lord SM, Barnsley L, Wallis BJ, McDonald GJ, Bogduk
N. Percutaneous radio-frequency neurotomy for chronic cervical zygapophyseal-joint pain. N Engl J Med
1996;335: 1721-6.
3. Geurts JW, van Wijk RM, Stolker RJ, Groen GJ. Efficacy
of radiofrequency procedures for the treatment of spinal
pain: a systematic review of randomized clinical trials. Reg
Anesth Pain Med 2001;26:394-400.
4. Manchikanti L, Singh V, Vilims BD et al. Medial branch
neurotomy in management of chronic spinal pain: systematic review of the evidence. Pain Physician 2002;5:405-18.
5. Niemisto L, Kalso E, Malmivaara A, et al. Radiofrequency
denervation for neck and back pain: a systematic review
within the framework of the cochrane collaboration back
review group. Spine 2003;28:1877-88.
6. Boswell MV, Trescot AM, Datta S et al. American Society of Interventional Pain P: Interventional techniques:
evidence-based practice guidelines in the management of
chronic spinal pain. Pain Physician 2007;10:7-111.
7. van Suijlekom JA, van Kleef M, Barendse G, et al. Radiofrequency cervical zygapophyeal joint neurotomy for
cervicogenic headache. A prospective study in 15 patients.
Functional neurology 1998;13:297-303.
8. Stovner LJ, Kolstad F, Helde G. Radiofrequency denervation of facet joints C2-C6 in cervicogenic headache: a
randomized, double-blind, sham-controlled study. Cephalalgia 2004;24:821-30.
9. Haspeslagh SR, Van Suijlekom HA, et al. Randomised
controlled trial of cervical radiofrequency lesions as a treatment for cervicogenic headache [ISRCTN07444684].
BMC Anesthesiol 2006;16:1.
10. van Kleef M, Spaans F, Dingemans W et al. Effects and
side effects of a percutaneous thermal lesion of the dorsal root ganglion in patients with cervical pain syndrome.
Pain 1993;52:49-53.
11. van Kleef M, Liem L, Lousberg R et al. Radiofrequency
lesion adjacent to the dorsal root ganglion for cervicobra-
22
chial pain: a prospective double blind randomized study.
Neurosurgery 1996;38:1127-31.
12. Slappendel R, Crul BJ, Braak GJ et al. The efficacy of radiofrequency lesioning of the cervical spinal dorsal root
ganglion in a double blinded randomized study: no difference between 40 degrees C and 67 degrees C treatments.
Pain 1997;73:159-63.
13. Stolker RJ, Vervest AC, Groen GJ. Percutaneous facet
denervation in chronic thoracic spinal pain. Acta Neurochir (Wien) 1993;122:82-90.
14. Tzaan WC, Tasker RR. Percutaeous radiofrequency facet
rhizotomy--experience with 118 procdedures and reappraisal of its value. Can J Neurol Sci 2000;27:125-30.
15. Stolker RJ, Vervest AC, Groen GJ. The treatment of
chronic thoracic segmental pain by radiofrequency percutaneous partial rhizotomy. J Neurosurg 1994;80:986-92.
16. van Kleef M, Spaans F. The effects of producing a radiofrequency lesion adjacent to the dorsal root ganglion in
patients with thoracic segmental pain by radiofrequency
percutanious partial rhizotomy. Clin J Pain 1995;11:32532.
17. Gallagher J, Vadi PLP, Wesley JR. Radiofrequency facet
joint denervation in the treatment of low back pain-a prospective controlled double-blind study in assess to efficacy.
Pain Clinic 1994;7:193-8.
18. van Kleef M, Barendse GA, Kessels A et al. Randomized
trial of radiofrequency lumbar facet denervation for
chronic low back pain. Spine 1999;24:1937-42.
19. Nath S, Nath CA, Pettersson K. Percutaneous lumbar zygapophysial (Facet) joint neurotomy using radiofrequency
current, in the management of chronic low back pain: a
randomized double-blind trial. Spine 2008;33:1291-7;
discussion 1298.
20. Leclaire R, Fortin L, Lambert R et al. Radiofrequency
facet joint denervation in the treatment of low back pain:
a placebo-controlled clinical trial to assess efficacy. Spine
2001; 26:1411-6; discussion 1417.
21. van Wijk RM, Geurts JW et al. Radiofrequency denervation of lumbar facet joints in the treatment of chronic
low back pain: a randomized, double-blind, sham lesioncontrolled trial. Clin J Pain 2005;21:335-44.
22. Tekin I, Mirzai H, Ok G, Erbuyun K, Vatansever. A comparison of conventional and pulsed radiofrequency denervation in the treatment of chronic facet joint pain. Clin J
Pain 2007;23:524-9.
23. Kroll HR, Kim D, Danic MJ et al. A randomized, doubleblind, prospective study comparing the efficacy of continuous versus pulsed radiofrequency in the treatment of
lumbar facet syndrome. J Clin Anesth 2008;20:534-7.
24. Nash TP. Percutaneous radiofrequency lesioning of dorsal
root ganglia for intractable pain. Pain 1986;24:67-73.
25. van Wijk RM, Geurts JW, Wynne HJ. Long-lasting analgesic effect of radiofrequency treatment of the lumbosacral
dorsal root ganglion. J Neurosurg 2001;94:227-31.
26. Geurts JW, van Wijk RM, Wynne HJ, Hammink E,
Buskens E, Lousberg R, Knape JT, Groen GJ. Radiofrequency lesioning of dorsal root ganglia for chronic lumbosacral radicular pain: a randomised, double-blind, controlled trial. Lancet 2003;361:21-6.
27. Cohen SP, Hurley RW, Buckenmaier CC, et al. Randomized placebo-controlled study evaluating lateral branch
radiofrequency denervation for sacroiliac joint pain. Anesthesiology 2008;109:279-88.
28. Erdine S, Ozyalcin NS, Cimen A, Celik M, Talu GK,
Disci R. Comparison of pulsed radiofrequency with conventional radiofrequency in the treatment of idiopathic
trigeminal neuralgia. Eur J Pain 2007;11:309-13.
29. Bayer E, Racz GB, Miles D, Heavner J. Sphenopalatine
ganglion pulsed radiofrequency treatment in 30 patients
March 2013

ABSTRACT
suffering from chronic face and head pain. Pain Practice
2005;5:223-7.
30. Van Zundert J, Patijn J, Kessels A, et al. Pulsed radiofrequency adjacent to the cervical dorsal root ganglion in
chronic cervical radicular pain: a double blind sham controlled randomized clinical trial. Pain 2007;127:173-82.
Pharmacological enhancement of spinal
stimulation for pain. A new strategy
Bengt Linderoth
Dept. Clin. Neuroscience, Karolinska Institutet and Dept.
Neurosurgery, Karolinska University Hospital, Stockholm,
Sweden
Background
A troublesome observation with SCS therapy
in patients with neuropathic pain is that between
30-50% experience an insufficient effect initially
or after some year of stimulation. Up to recently
there has been no rational remedy for this problem. Only during the two last decades have experimental studies of SCS in animals provided
some knowledge about the pivotal neurochemical
mechanisms forming a basis for clinical trials with
“drug-enhanced SCS” when SCS per se has proven
insufficient.
Experimental basis
In a series of experiments with nerve lesioned
rats it was demonstrated that SCS reduces the release of excitatory amino acids (e.g. glutamate) in
the dorsal horn and at the same time augments
the GABA release, but only in rats that in preceding behavioural experiments had been found to
respond to SCS. These findings were supplemented by behavioral experiments where it was shown
that i.t. administration of GABA or the GABAB
agonist, baclofen, markedly enhanced the effect
of SCS. In subsequent studies it was found that
rats that were non-responders to SCS, could be
converted to responders with intrathecal administration of low, by themselves ineffective, doses
of baclofen.
Later studies also demonstrated that gabapentin, pregabalin and clonidine may have similar
potentiating effects in non-responding rats. In
particular, the results obtained with clonidine are
of interest since it is known that the antinociceptive effect of this substance is related to activation
of the spinal cholinergic system. A further study
showed that the release of acetylcholine (Ach) in
the dorsal horn was augmented in rats responding
to SCS during stimulation while the Ach levels
in the non-responders were unchanged. Further
studies using Ach receptor antagonists administered intrathecally indicated the pivotal importance of the muscarinic M4 and M2 receptors for
the SCS effect.
When combining SCS with a subeffective dose
of oxotremorine (a muscarinic agonist) the suppressive effect of SCS on the pain related symptoms was dramatically enhanced in rats failing to
obtain a satisfactory effect with SCS alone.
Since some antidepressants are also used for
treatment of neuropathic pain we studied interactions between three antidepressants and SCS. Subeffective doses were given intrathecally together
with SCS in non-responding animals. Three drugs
were tested: a tricyclic antidepressant (amitriptyline), a selective serotonin reuptake inhibitor,
(fluoxetine) and a selective serotonin/noradrenalin reuptake inhibitor, (milnacipran). This study
showed that both amitriptyline and milnacipran
produced a significant enhancement of the SCS
effect.
In a recent study ketamine (a NMDA receptor antagonist) was used with a similar strategy to
convert rats not responding to SCS therapy after
a partial sciatic nerve lesion to SCS responders
using individually determined subeffective doses
of the i.t. drug. The aim here was to depress the
glutamine-induced central sensitization partly with
the drug and additionally with SCS. The combined
treatment of non-responders to SCS resulted in a
significant reduction of the withdrawal thresholds
thereby converting them into responders.
Clinical studies: On the basis of such animal
studies as those reviewed above clinical trials were
initiated where it was demonstrated that the SCS
effect can be effectively enhanced/restored by the
simultaneously administration of intrathecal baclofen, and later also clonidine, in low doses.
In the first study baclofen was first injected as
i. t. boluses in doses ranging from 25-100 micrograms. It appears that maximally 20-25% of
the bolus tested patients responded so well that
a pump implantation was warranted. In animals
it proved possible to actually convert a complete
non-responder into an SCS responding rat but for
humans it seemed to be a requirement that a small,
modest effect existed before the drug trial.
Follow-up studies were performed during 2005
and 2006 where all patients treated with either
SCS enhanced by baclofen, or by i.t. baclofen only
were reviewed.
23
ABSTRACT
Of the implanted 11 patients two were lost
due to technical failures, but the remaining nine
were examined with an average follow-up period
of 73 months. At the follow-up these still enjoyed the same pain-relief as initially (decrease
from VAS 76 pre-implant via an average of VAS
33 at an earlier follow-up (2003-2004) , to the
late FU; average 40). During the study period
there was an average dose increase of 30 %. This
study demonstrates that a deficient SCS effect in
neuropathic pain, in selected patients, may be
considerably improved by intrathecal baclofen
administration and that this enhanced effect
persists for a long time.
Other SCS + drug trials.
In a more recent study patients with neuropathic pain syndromes demonstrating insufficiant
pain relief with SCS alone in spite of good paresthesia coverage were enrolled in randomized i.t.
trials with blinded bolus injections of clonidine,
baclofen and saline. Ten cases were enrolled and
seven out of these demonstrated a significant enhancement of the SCS effect with the addition of
the drug.
Four of the patients were successfully implanted
with a pump for combined therapy with SCS; two
with clonidine and two with baclofen therapy.
In cases of mixed pain components (neuropathic/ nociceptive pain) e.g. in FBSS (failed back
surgery syndrome), of course the SCS effect could
be supported by common analgesics e.g. opioids.
Treatment with combined SCS and spinal opioid infusion is performed in some centers and an
analysis of a number of cases has been published.
Conclusions
The use of SCS therapy will probably increase
in the future and thereby also the number of cases
with insufficient benefits from the stimulation per
se.
The above examples of strategies to enhance the
effects of SCS should be considered as only examples since possibly many new mechanisms will be
detected in the near future leading us to new agonistic – or even antagonistic pharmaceuticals to
examine. Thus, what we see here is only the beginning of drug-enhanced spinal stimulation.
References
1. Virtually all basic and clinical studies referred to above can
be found in the two articles below.
2. Linderoth B, Foreman RD. Pain Medicine 2006;7(Suppl.
1):14-26.
3. Lind G, Linderoth B. Pain Management. 2011;1(5):441449, Future Medicine. 2011.
24
Regional anesthesia: why must I choose it?
Marc A. Huntoon, M.D.
Professor of Anesthesiology, Vanderbilt University, Nashville
TN, USA.
Introduction
One of the enduring goals of many who perform regional anesthesia techniques has been to
show an added value to the service. Proponents of
regional anesthesia believe that the techniques are
able to improve postoperative pain control, reduce
supplementary analgesic use, improve side effects
such as respiratory depression, cardiac ischemia,
pulmonary embolic events, wound infections, reduce surgical stress, and potentially lead to reduced
lengths of stay in the hospital, enhanced functional
recovery times, and ultimately, produce significant
health care cost savings. In the more recent past,
there have been multiple articles that suggest that
there may effects of regional anesthesia and local
anesthetics on cancer survival. Well- designed trials of many of these concepts are still lacking, and
several meta-analyses and reviews have been inconsistent in this regard.
Perioperative Outcomes: Length of Stay, Rehabilitation, and Chronic Persistent Pain
At the Mayo Clinic, implementation of an analgesic pathway that emphasized peripheral nerve
blocks ( lumbar plexus continuous catheter infusions for total hip arthroplasty patients and femoral
nerve catheter infusions coupled with single injection sciatic nerve blocks for total knee arthroplasty
patients were most commonly utilized. Many patients also received subarachnoid anesthesia or light
general anesthetics for the primary anesthesia technique. All patients received acetaminophen supplementation, oral opioids, and NSAIDs (ketorolac 15 mg every 6 hours times 4 doses maximum).
One hundred patients were studied and compared
to 100 matched controls receiving traditional anesthetics. The primary outcome variable studied was
length of hospital stay, with secondary outcomes
including time to ambulation, discharge eligibility,
and joint range of motion. Numerical ratings of
pain, opioid requirements, and perioperative complications were also recorded. The authors demonstrated a shorter length of stay in patients treated
with the CPNB analgesic pathway( 3.8 versus 5
days; p<.001) and also had sooner discharge eligibility and greater joint range of motion.1 Earlier,
Capdevila and colleagues 2 studied 56 patients sep-
March 2013

ABSTRACT
arated into 3 groups to examine whether rehabilitation treatment goals were impacted by regional
techniques. They showed that implementation of
either epidural continuous infusions or continuous
femoral nerve blocks were associated with shorter
stays in rehabilitation after total knee arthroplasty,
and patients tolerated continuous passive motion
(CPM) with better analgesia than those patients
that received IV-PCA. The authors concluded that
the CPNB and epidural groups both decreased the
rehabilitation convalescence time by allowing better early CPM, but that there were more complications in the epidural group. Many researchers have
sought to show that implementation of regional
anesthetic techniques resulted in other long-term
tangible benefits. An interesting series of studies by
Ilfeld and colleagues looked at the comparison of
short term (24 hour) versus 4 day CPNBs to see if
there were any long term benefits manifested by
increasing the time of infusion.3 The investigators
concluded that simply extending the infusion to
4 days did not result in any additional improvement or worsening of pain, stiffness or functional
disability.
Perkins and Kehlet outlined the problem of
chronic persistent pain after many types of surgery
more than one decade ago.4 The realization that
surgery can lead to chronic pain has galvanized
anesthesiologists to find responsible solutions
during the perioperative period that can change
these outcomes. Multiple pian syndromes such as
post-thoracotomy pain, post -mastectomy pain,
post -herniorraphy pain, and post-amputation
phantom /stump pain continue to occur in large
numbers. There are few studies that demonstrate
long term improvement or “preemptive analgesic”
effects from a regional technique in isolation. One
study of patients who were prospectively treated
with thoracic epidural initiated either preoperatively, postoperatively or receiving only IV-PCA
was performed.5 The authors later surveyed the patients at 6 months, and those patients who had received preoperative initiation of their bupivacaine
and morphine epidurals had decreased long-term
pain compared to those who had received only IVPCA. Most studies have applied a multimodal approach, however. For example, Buvanendran and
colleagues applied a large dose of pregabalin (300
mg) prior to surgery and continued the drug during a 15 day period after surgery with a terminal
phase tapering dose. All patients in their study had
regional anesthesia (combined spinal-epidural infusions). They were able to demonstrate a reduc-
tion in the incidence of chronic persistent pain at
6 months (0% versus 5.2% inn the placebo group;
p=0.014) they also noted less analgesic use, and
sooner range of motion targets for knee flexion.6
Analgesia
One large trial that evaluated the effectiveness
and safety of a large number of patients in Germany (18,925) over a period from 1998-2006 included 14,223 patients that received patient-controlled
epidural analgesia (PCEA), 3001 brachial plexus or
femoral/sciatic continuous peripheral nerve blocks
(CPNBs), and 1591 intravenous patient –controlled analgesia infusions (IV-PCAs). The authors
analyzed this prospectively- collected data, and
were able to demonstrate that PCEA and CPNB
provided superior pain relief compared to IV-PCA
with an overall low rate of complications.7 A meta-analysis of 19 trials enrolling over 600 patients
found that the analgesia from CPNBs was superior
to that from opioids across all times (p<0.001).8
Though the data for the perioperative period producing good analgesia is clear, there are potential
drawbacks to these CPNB techniques. One of the
potential shortcomings of performing continuous
blocks of peripheral nerves is the potential for muscular weakness that might manifest as a fall. Ilfeld
and colleagues showed that this is a real phenomenon that must be considered when utilizing this
type of treatment.9
Cancer Recurrence
One of the first studies to examine the effects
of local anesthetics and regional anesthesia on cancer recurrence was performed by Exadaktylos and
colleagues.10 The authors retrospectively examined
the records of 129 patients who had received either
paravertebral anesthesia/analgesia combined with
general anesthesia, versus patients who received
analgesia via morphine intravenously. The group
treated with paravertebral blocks had better (less)
recurrence and metastasis free survival 94% versus 77% at 36 months (p=0.012) despite similar
tumor and surgical factors. A more recently published retrospective trial examined the effects of
intraoperative use of epidural infusions compared
to patient who either received only post-operative
epidural infusions, or intravenous opioids. The
group that received intraoperative epidural infusions had a mean time to ovarian cancer recurrence
of 73 months, versus 33 or 38 months in the postoperative epidural and no-epidural groups. The
authors concluded that the recurrence was delayed
25
ABSTRACT
due to preservation of immune function.11 An even
larger population based study utilized a database of
42,151 patients who either did or did not receive
epidurals at the time of surgery for non-metastatic
colon cancer. They found cancer recurrence rates
were significantly less in the epidural group after at
least 4 year follow-up.12
Conclusions
Regional anesthesia use for multiple surgeries
can be associated with improved analgesia, faster
attainment of rehabilitation goals, and shorter
lengths of hospital stay. Primary regional anesthesia by itself may not provide for decreased incidence of chronic pain, but may be improved by a
multimodal analgesic strategy. Prevention of cancer recurrences is a fascinating new area of inquiry
that holds great promise.
References
1. Hebl JR, Dilger JA, Byer DE, Kopp SL, Stevens SR, Pagnano MW, Hanssen AD, Horlocker TT. A Pre-emptive
multimodal pathway featuring peripheral nerve blockade
improves perioperative outcomes after major orthopedic
surgery. Reg Anesth Pain Med 2008;33:510-7.
2. Capdevila X, Barthelet Y, Biboulet P, Rickwaert Y,
Rubinovitch J, d’Athis F. Effects of perioperative analgesic technique on the surgical outcome and duration of
rehabilitation after major knee surgery. Anesthesiology
1999;91:8-15.
3. Ilfeld BM, Shuster JJ, Theriaque DW, Mariano ER, Girard PJ, Loland VJ, Meyer RS, Donovan JF, Pugh GA, Le
LT, Sessler DI, Ball ST. Long -term pain, stiffness, and
functional disability after total knee arthroplasty, with
and without an extended ambulatory continuous femoral
nerve block: A prospective 1-year follow- up of a multicenter, randomized, triple-masked placebo-controlled
trial. Reg Anesth Pain Med 2011;36:116-20.
4. Perkins FM, Kehlet H. Chronic pain as an outcome of
surgery: A review of predictive factors. Anesthesiology
2000;93:1123-33.
5. Senturk M, Ozcan PE, Talu GK et al. The effects of three
different analgesia techniques on long-term post-thoracotomy pain. Anesth Analg. 2002;94:11-5.
6. Buvanendran A, Kroin JS, Della Valle CJ, Kari M, Moric M, Tuman KJ. Perioperative oral pregabalin reduces
chronic pain after total knee arthroplasty: a prospective
randomized controlled trial. Anesth Analg 2010;110:199207.
7. Pöpping DM, Zahn PK, Van Aken HK,Dasch R, Boche
R, Pogatski-Zahn EM. Effectiveness and safety of postoperative pain management: a survey of 18925 consecutive
patients between 1998 and 2006 (2nd revision): a database analysis of prospectively raised data. British J Anaesthesia 2008;6:832-40.
8. Richman JM, Liu SS, Courpas G, Wong R, Rowlingson
AJ, McGready J, Cohen SR, Wu CL. Does continuous
peripheral nerve block provide superior pain control to
opioids? A meta-analysis. Anesth Analg 2006;102:248-57.
9. Ilfeld BM, Duke KB, Donahue MC. The association between lower extremity continuous peripheral nerve blocks
and patient falls after knee and hip arthroplasty. Anesth
Analg 2010; 111:1552-4.
26
10. Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis?Anesthesiology
2006;105:660-4.
11. de Oliveira Jr GS, Ahmad S, Schink JC, Singh DK, Fitzgerald PC, McCarthy RJ. Intraoperative neuraxial anesthesia but not postoperative neuraxial analgesia is associated with increased relapse-free survival in ovarian cancer
patients after primary cytoreductive surgery. Reg Anesth
Pain Med 2011;36:271-7.
12. Cummings KC, Xu F, Cummings LC, Cooper GS. A
comparison of epidural analgesia and traditional pain
management effects on survival and cancer recurrences
after colectomy. A population-based study. Anesthesiology
2012;116:797-806.
The effects of regional anesthesia-analgesia on the immune system
María F. Ramirez MD* and Juan P. Cata MD*
*Department of Anesthesiology and Perioperative Medicine
The University of Texas -‐ MD Anderson Cancer Center.
Houston, Texas. USA
The immune system involves a complex network
of cells and soluble mediators. Among the
former, we Kind macrophages, antigen presenting cells (APCs) and lymphocytes.
Interleukins (IL), prostaglandins (PGs), chemokines (CX) and growth factors are the soluble
mediators that not only modulate the function
of those cells but also have speciKic actions on foreign pathogens such as virus and cancer cells. The
immune system can be positively or negatively modulated through a variety of non-‐pharmacological
and pharmacological interventions. Surgery itself
is able to trigger immune suppression. The activation of the sympathetic system that is associated to
surgery is perhaps one of the driving mechanisms
behind the surgery-‐induced immune suppression.
(Cata, Gottumukkala et al. 2012) This phenomenon is characterized by a decrease in the function
of an important subset of lymphocytes, the natural
killer (NK) cells that play a key role in the innate immune response. SpeciKically, NK cells cause
virus or cancer cell death through direct cytotoxic
contact.
Most surgical procedures, even minimally invasive, are performed under either general anesthesia,
regional anesthesia or their combination. Anesthetics and analgesics used for general anesthesia have
strong action on the immune. For instance, opioids and volatile anesthetics are known to depress
the function NK cells, T cells and APCs.(Beagles,
Wellstein et al. 2004; Sacerdote 2006) Ketamine
March 2013

ABSTRACT
another widely used anesthetic also depress the
function of NK cells, in contrast propofol appears
to preserve the function of NK cells and other lymphocytes.(Melamed, Bar-‐Yosef et al. 2003) Thus,
regional anesthesia represents an interesting alternative to modulate the immune system because it
might ameliorate the stress response associated to
surgery and reduce or eliminate the need of immune suppressive anesthetics and analgesics.(Cata,
Gottumukkala et al. 2012) The beneKicial effects of
regional anesthesia on NK killer cells were demonstrated in a randomized controlled trial in which
patients were randomized to have videothoracoscopy under either general anesthesia or awake-‐epidural anesthesia. The authors of this clinical trial
found that patients who were assigned to awake-‐
epidural anesthesia did not show a postoperative
decrease in the count of NK cells.(Vanni, Tacconi
et al. 2010) Unfortunately, our group demonstrated that patients who underwent thoracotomy or
abdominal surgery under general anesthesia followed by postoperative epidural analgesia still showed a depress function of their NK cells (submitted for publication), thus suggesting that, in fact,
a complete avoidance of general anesthetics and a
dense anesthetic block may be needed to preserve
some of the elements of the innate immune response. To complicate more this mater, a randomized
controlled study in women undergoing laparoscopic abdominal surgery did not demonstrated any
beneKicial effect of “preemtive” epidural anesthesia
compared to postoperative epidural analgesia on
the postoperative count of lymphocytes. (Hong
and Lim 2008) In a different population of patients, Volk et al demonstrated that postoperative
intravenous analgesia was associated with a higher
percentage of NK cells than postoperative epidural
analgesia.(Volk, Schenk et al. 2004) Thus, it appears that the potential immune protective effects of
regional anesthesia at least on the innate immunity
may depend on factors such as type of surgery, use
of intra-‐ versus postoperative regional anesthesia,
and patient population (cancer versus non-‐cancer
center).
A key piece in any regional anesthesia technique
are local anesthetics. The effects of these agents on
the immune cells are not well understood. It has
been shown that local anesthetics, at concentrations
found for wound inKiltration, depress the function
of natural killer cells(Takagi, Kitagawa et al. 1983;
Krog, Hokland et al. 2002) however, it is unknown
if this phenomenon is still observed a lower concentration. Preliminary data from our laboratory
suggest that lidocaine a doses 10 to 100 times (nanomolar) lower than those found in plasma during
regional anesthesia increase the sensitivity of cancer
cells to the cytotoxic effects of NK cells from cancer
patients without affecting the viability of the latter.
The balance between cytokines that have
immune stimulating (Th1) versus immune depressive (Th2) properties is also changed in the
perioperative period. It is well known there is a
predominant shift towards a Th2 state during the
perioperative period.(Decker, Schondorf et al.
1996; Ishikawa, Nishioka et al. 2009) Whether
regional anesthesia is able to preserve or restore
the Th1/Th2 balance is largely unknown. Volk et
al found that the postoperative balance between
the Th1 and Th2 cytokines, IL-‐8 and IL-‐10 respectively, were unchanged by the use of epidural or intravenous analgesia.(Volk, Schenk et al.
2004) Similarly, the use of spinal anesthesia was
not associated with a change in the Th1/Th2 balance in patients undergoing urological surgery.
(Zura, Kozmar et al. 2012) Interestingly, Alhers
et al found that only the use on intraoperative
thoracic epidural anesthesia compared to postoperative thoracic analgesia was associated with a
predominant Th1 state.(Ahlers, Nachtigall et al.
2008) Again suggesting that the use of intraoperative regional anesthesia in order to ameliorate
surgery-‐induced stress, anesthetics and opioids is
more important than the initiation of regional
analgesia in the postoperative period.
Whether the effects of regional anesthesia/
analgesia on the immune system are linked to
better postoperative clinical outcomes such as
cancer recurrence has been the topic of recent
publications. Early studies indicated that the
use of regional analgesia was associated to lower
cancer recurrence for breast and prostate cancer.
(Exadaktylos, Buggy et al. 2006; Biki, Mascha
et al. 2008; Capmas, Billard et al. 2012) More
recent studies have refuted those early Kindings;
three of these studies were conducted in patients
with gastrointestinal malignancies and demonstrated no association between the use of epidural analgesia and better oncological outcomes.
(Myles, Peyton et al. 2011; Cummings, Xu et al.
2012; Day, Smith et al. 2012) Our group has
investigated if the use of postoperative epidural
analgesia was associated with a longer recurrence free survival and mortality in patients with
non-‐small cell lung cancer and in line with the
studies in gastrointestinal patients, we could not
Kind an association between regional analgesia
27
ABSTRACT
and better oncological outcomes. Unfortunately,
all those clinical studies were retrospective hence
their results and conclusions have be considered
cautiously.
References
1. Ahlers, O, I. Nachtigall et al. Intraoperative thoracic epidural anaesthesia attenuates stress-‐induced immunosuppression in patients undergoing major abdominal surgery.
Br J Anaesth 2008;101(6):781-‐7.
2. Beagles, K., A. Wellstein et al. Systemic morphine administration suppresses genes involved in antigen presentation.” Molecular pharmacology 2004;65(2):437-42.
3. Biki, B., E. Mascha et al. Anesthetic technique for radical
prostatectomy surgery affects cancer recurrence: a retrospective analysis. Anesthesiology 2008;109(2):180-7.
4. Capmas, P., V. Billard et al. Impact of epidural analgesia on survival in patients undergoing complete cytoreductive surgery for ovarian cancer. Anticancer Res
2012;32(4):1537-42.
5. Cata JP, Gottumukkala V et al. How regional anesthesia
might reduce postoperative cancer recurrence. Eur J Pain
2012;Suppl 5(S2):345-55.
6. Cummings KC. Xu F et al. A comparison of epidural analgesia and traditional pain management effects on survival
and cancer recurrence after colectomy: a population-‐based
study. Anesthesiology 2012;116(4):797-806.
7. Day AR. Smith, et al. Retrospective analysis of the effect
of postoperative analgesia on survival in patients after
laparoscopic resection of colorectal cancer. Br J Anaesth
2012;109(2):185-‐190.
8. Decker, D, Schondorf M et al. Surgical stress induces a
shift in the type-‐1/type-‐2 T-‐helper cell balance, suggesting
down-‐regulation of cell-‐mediated and up-‐regulation of antibody-‐mediated immunity commensurate to the trauma.
Surgery 1996;119(3):316-25.
9. Exadaktylos AK, Buggy DJ et al. Can anesthetic technique
for primary breast cancer surgery affect recurrence or metastasis?” Anesthesiology 2006;105(4):660-4.
10. Hong JY, Lim KT. Effect of preemptive epidural analgesia
on cytokine response and postoperative pain in laparoscopic radical hysterectomy for cervical cancer. Reg Anesth
Pain Med 2008;33(1):44-51.
11. Ishikawa MM, Nishioka et al. Perioperative immune responses in cancer patients undergoing digestive surgeries.”
World journal of surgical oncology 2009;7:7.
12. Krog J, Hokland M et al. Lipid solubility-‐ and concentration-‐dependent attenuation of in vitro natural killer cell
cytotoxicity by local anesthetics. Acta Anaesthesiol Scand
2002;46(7):875-81.
13. Melamed R, Bar-‐Yosef S et al. Suppression of natural
killer cell activity and promotion of tumor metastasis by
ketamine, thiopental, and halothane, but not by propofol:
mediating mechanisms and prophylactic measures. Anesth
Analg 2003;97(5):1331-9.
14. Myles PS, Peyton P et al. Perioperative epidural analgesia
for major abdominal surgery for cancer and recurrence-‐free
survival: randomised trial. BMJ 2011;342:d1491.
15. Sacerdote, P. Opioids and the immune system. Palliative
medicine 2006;20(Suppl 1):s9-‐15.
16. Takagi S, Kitagawa S et al. Effect of local anaesthetics
on human natural killer cell activity. Clin Exp Immunol
1983;53(2):477-81.
17. Vanni, G, Tacconi F. et al. Impact of awake videothoracoscopic surgery on postoperative lymphocyte responses.”
The Annals of thoracic surgery 2010;90(3):973-8.
18. Volk,T, Schenk M et al. Postoperative epidural an-
28
esthesia preserves lymphocyte, but not monocyte, immune function after major spine surgery. Anesth Analg
2004;98(4):1086-92, table of contents.
19. Zura M, Kozmar A et al. Effect of spinal and general
anesthesia on serum concentration of pro-‐inKlammatory and anti-‐inKlammatory cytokines. Immunobiology
2012;217(6): 622-7.
Regional anesthesia and analgesia and
mortality. Is this the real important outcome?
José De Andrés a,,b Miguel A. Reinac,d .
aValencia University Medical School. b Anesthesia Department
bDirector Multidisciplinary Pain Management Center Department of Anesthesiology and Critical Care
Valencia University General Hospital. Valencia (Spain).
cDepartment of Anaesthesiology, Madrid-Montepríncipe
University Hospital, Madrid, Spain
dDepartment of Clinical Medical Sciences and Applied Molecular Medicine Institute
CEU San Pablo University School of Medicine, Madrid, Spain
The debate on the outcome benefits of regional
anaesthesia and analgesia over general anaesthesia
and systemic analgesia has led to a large number of
published papers, in particular systematic reviews
and meta-analyses.
If not before, at least in 1954, we found the first
reference published in an indexed journal, analyzing the different anesthetic techniques used, and
the variables that could result in a different outcome and possible associated morbidity (Beecher
and Todd 1954). Already in this article addresses
the “anesthesia as a part of the overall surgical care
of the patient”. In 1987, we published an article
and editorial in which we defined within the perioperative process, the variables of mortality, specifically related to anesthetic practice (Vila and De
Andres 1987). From these remote references, there
are a considerable number of publications on the
topic, some very recently, but hovewer, the complex issues around the effect of regional anaesthesia
on outcome is not completely resolved, possibly
because the data are often not procedure specific.
Meta-analyses have shown consistently improved
analgesia with epidural techniques, but the results
are by far less consistent with regard to other outcomes, in particular morbidity and mortality (Tziavrangos and Schug 2006). Although it is true
that according to the evidence collected, neuraxial
blockade reduces postoperative mortality and other serious complications. The size of some of these
benefits remains uncertain, and further research is
required to determine whether these effects are due
March 2013

ABSTRACT
solely to benefits of neuraxial blockade or partly to
avoidance of general anaesthesia (Rodgers A, et al.
2000).
Perioperative regional anesthesia and analgesia
have been shown to attenuate perioperative pathophysiology, possibly being the key factor, of patient’
improvement outcomes. Obvious benefits, such as
the quality of postoperative analgesia and the decrease in hospital stay or in hospital costs, are easy
to demonstrate, but proof that regional anesthesia
improves the outcome from surgery is still lacking
(Capdevila and Choquet 2008). It is difficult to
measure differences in outcome between regional
anaesthesia and general anaesthesia for perioperative mortality. Also, data interpretation is difficult
because, even the best randomized studies do not
have large enough patient numbers to demonstrate
a clear difference in outcome. Furthermore, patient
outcome examined varies from mortality to paramount of morbidity conditions (most commonly
pulmonary (Ballantyne et al 1998), cardiovascular
(Beattie et al 2001), and gastrointestinal (Jorgensen
et al 2000)), each of which in turn have different
associated variables that determine clear differences
in their profile, and therefore, in its possibility of
global analysis.
There is general agreement that continuous thoracic epidural analgesia in major abdominal and
thoracic surgery can reduce postoperative cardiovascular and pulmonary complications (Liu and
Wu 2007; Pöpping et al. 2008) , improve paralytic ileus (Marret et al. 2007) , improve pain relief and attenuate catabolism (Ahlers, et al 2008;
Lattermann, et al. 2007). Nevertheless, the benefit
evidence appears to be limited to high-risk patients
and those undergoing high-risk procedures.
Two Cochrane analyses showed benefits of epidural analgesia for major abdominal surgery (Werawatganon and Charuluxanun 2005), abdominal
aortic surgery (Nishimori et al. 2006), and various
procedures in elderly patients, showed that epidural analgesia provides superior analgesia compared
with opioid-based analgesia. The use of epidural
analgesia resulted in reduced need for postoperative
mechanical ventilation, reduced rate of postoperative myocardial infarction, and reduced gastric and
renal complications. However, these benefits did
not result in a reduction in mortality. In another
Cochrane review (Parker et al, 2004), found a reduced risk for postoperative deep venous thrombosis (30% compared with 47%) and acute postoperative confusión (9.4% compared with 19.2%)
in patients treated with neuraxial (mainly spinal)
anaesthesia compared with general anaesthesia.
There was no evidence for reduced perioperative
mortality or other outcome parameters (myocardial infarction, pulmonary embolism, etc.).
Specifically in patients undergoing hip fracture
repair regional anesthesia showed reduced 1-month
mortality plus a reduction in the rate of deep vein
thrombosis (Urwin et al, 2000) , but 3 months
mortality, is the same as for general anaesthesia.
The largest and most significant meta-analysis
(Rodgers et al, 2000) evaluated 144 published papers, involved over 9500 patients, and confirmed
several benefits of regional anaesthesia (alone or in
combination with general anaesthesia) compared
with general anaesthesia alone. There was a reduction in the risk of mortality from all causes after
major surgery of 30% in the regional anaesthesia group compared with the general anaesthesia
group.
After all the data reviewed, the important question is whether the benefits associated with regional anaesthesia lead directly to measurable clinical
improvements such as fewer complications, lower
mortality and better outcome from surgery. We
consider, the present data do not allow us to answer
these questions satisfactorily. Under our consideration is, because the answer depends on many interdependent factors: patients, surgery, outcomes,
other factors that control the outcomes, how the
regional anaesthesia is being used, and what it is
being compared.
In healthy patients adverse outcome is extremely
rare, so there is unlikely to be a difference in outcome between regional anaesthesia and general
anaesthesia. On the other hand, in patients with
lung desease, and those undergoing thoracic and
upper abdominal procedures, postoperative epidural analgesia is likely to be beneficial (Ballantyne
et al 1998). In patients with heart disease regional
anesthesia may be beneficial, by reducing pain and
stress, improving pulmonary function and oxygenation, and improving mobility and decreasing
hospital stay (Yeager et al., 1998).
Since regional anesthesia alone is only suitable
for extremity, head and neck and body surface
surgery, the comparison with general anesthesia
can only by made for this limited range of procedures. Combining regional anesthesia with general
anesthesia broadens the scope, and increases the
difficulty in the right answer.It is obvious there is
not a standard general anaesthetsia procedure. This
makes it an independent variable and different
comparator. No outcome study or meta-analysis
29
ABSTRACT
considers the individual skills and the directly associated success rates. In the author’s opinion, failed
blocks are probably the most important factors for
negative outcome (Kettner et al. 2011).
Some authors consider the main factor for not
having consistent data, the lack of consistent graded regional anesthetic morbidity and mortality system according to the intensity of therapy required
for the treatment of the defined complication (Stojadinovic et al., 2009; Buckenmaieret al, 2009).
According these authors structured format for the
reporting of regional anesthesia complications allows for identifying important issues in risk management in regional anesthesia, thereby providing
opportunities for further investigation and clinical
practice refinement.
Whether specific regional anaesthetic techniques or local anaesthetics influence the course of
illness is currently an important topic, and we consider will be an special research topic in the future.
What we can say regional anaesthesia in the right
patients and the right situations, it can improve
surgical outcome.
References
1. Ahlers O, Nachtigall I, Lenze J et al. Intraoperative tho-
racic epidural anaesthesia attenuates stress-induced immunosuppression in patients undergoing major abdominal
surgery. Br J Anaesth 2008;101:781-7.
2. Ballantyne JC, Carr DB, de Ferranti S et al. The comparative effects of postoperative analgesic therapies on pulmonary outcome: cumulative meta-analysis of randomised
controlled trials. Anesth Analg 1998;86:598-612.
3. Beattie WS, Badner NH, Choi P. Epidural analgesia reduces postoperative myocardial infarction: a meta-analysis. Anesth Analg 2001;93:853-8.
4. Beecher H, Todd DP. Study of the deaths associated waith
anesthesia and surgery. Based on a study of 599,548 anesthesias in ten institutions 1948-1952, inclusive. Annals
of Surgery 1954;140:2-34.
5. Buckenmaier CC 3rd, Croll SM, Shields CH, Shockey SM,
Bleckner LL, Malone G, Plunkett A, McKnight GM, Kwon
KH, Joltes R, Stojadinovic A. Advanced regional anesthesia
morbidity and mortality grading system: regional anesthesia
outcomes reporting (ROAR). Pain Med 2009;10(6):111522.
6. Capdevila X, Choquet O. Does regional anaesthesia improve outcome? Facts and dreams Techniques in Regional
Anesthesia and Pain Management 2008;12:161-2.
7. Jorgensen S, Wettersler J, Moiniche S, Dahl JB. Epidural
local anaesthetics versus opioid-based analgesic regimens
on postoperative gastrointestinal paralysis, PONV and
pain after abdominal surgery. Cochrane Database of Systematic Reviews 2000;4:CD 001893.
8. Kettner SC, Willschke H, Marhofer P. Does regional anaesthesia really improve outcome? Br J Anaesth. 2011;107
Suppl 1:i90-i955.
9. Lattermann R, Wykes L, Eberhart L et al. A randomized
controlled trial of the anticatabolic effect of epidural analgesia and hypocaloric glucose. Reg Anesth Pain Med
2007; 32:227-32.
10. Liu SS, Wu CL. Effect of postoperative analgesia on major
30
postoperative complications: a systematic update of the
evidence. Anesth Analg 2007;104:689-702.
11. Marret E, Remy C, Bonnet F et al. Meta-analysis of epidural analgesia versus parenteral opioid analgesia after
colorectal surgery. Br J Surg 2007;94:665-73.
12. Nishimori M, Ballantyne JC, Low JH. Epidural pain
relief versus systemic opioid-based pain relief for abdominal aortic surgery. Cochrane Database Syst Rev
2006;3:CD005059.
13. Parker MJ, Handoll HH, Griffiths R. Anaesthesia for hip
fracture surgery in adults. Cochrane Database Syst Rev
2004;CD000521.
14. Pöpping DM, Elia N, Marret E et al. Protective effects of
epidural analgesia on pulmonary complications after abdominal and thoracic surgery: a meta-analysis. Arch Surg
2008;143:990-9.
15. Rodgers A, Walker N, Schug S, McKee A, Kehlet H, van
Zundert A, Sage D, Futter M, Saville G, Clark T, MacMahon S. Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomised trials. BMJ. 2000;321:1493.
16. Stojadinovic A, Shockey SM, Croll SM, Buckenmaier CC
3rd. Quality of reporting of regional anesthesia outcomes
in the literature. Pain Med. 2009;10(6):1123-31.
17. Tziavrangos E, Schug SA. Regional anaesthesia and perioperative outcome. Curr Opin Anaesthesiol. 2006;19:521-5.
18. Urwin S C, Parker M J, Griffiths R. General versus regional anaesthesia for hip fracture surgery: a meta-analysis of
randomised trials. Br J Anaesth 2000;84:450-5.
19. Vila M., De Andres JA. Editorial: Epidemiology in Anesthesiology. One subject, pending in Spain. Rev Esp Anestesiol Reanim1987;34:171-2 (english Abstract).
20. Vila M., De Andres JA. Morbidity and mortality in the
clinical practice of anesthesiology-Critical Care. An updated review and recommendations for our country. Rev
Esp Anestesiol Reanim 1987;34:196-205(english Abstract).
21. Werawatganon T, Charuluxanun S. Patient controlled
intravenous opioid analgesia versus continuous epidural
analgesia for pain after intra-abdominal surgery. Cochrane
Database Syst Rev 2005; CD004088.
22. Yeager MP, Glass DD, Neff RK., Brinck-Johnsen T. Epidural anaesthesia and analgesia in high-risk surgical patients. Anesthesiology 1987;66:729-36.
Role of regional anesthesia in fast-track
surgery. Beyond analgesia?
Franco Carli, MD
Department of Anesthesia, McGill University Health Centre,
Montreal, QC, Canada
Regional anesthesia, whether conduction
blockade or peripheral nerve block or infiltration of local anesthetics, has been shown to be
associated with several recognized physiologic
advantages These beneficial effects could, in
principle, provide optimal conditions for a successful implementation of fast-track surgery.
However, on a critical analysis, the literature
is not always clear whether the influence of
regional anesthesia techniques can always be
March 2013

ABSTRACT
positive or negative, and whether these physiologic benefits can be translated in facilitating
the implementation of fast-track methods, thus
accelerating surgical rehabilitation. On the basis of what has been reported with regard to
the physiologic effects of regional anesthesia
on various organ functions, the clinical impact
of regional anesthesia techniques on some of
the components of fast-track surgery has been
identified. From the published literature, there
is a strong indication that in most circumstances both central neural blockade and peripheral
neural blockade have positive effect and therefore can contribute to an improved outcome.
It might still be difficult to determine how a
sole intervention such as regional anesthesia might have an impact on outcome; thus,
it is necessary to consider regional anesthesia
more as a therapeutic modality aimed at limiting organ dysfunction in the context of surgical stress. However, we wish to emphasize that
other components associated with traditional
anesthesia and surgical practice have to be revised to facilitate the positive effects of regional
anesthesia and the components of enhanced
rehabilitation. For example, the revised practice of preoperative fasting, bowel cleansing,
and the earlier removal urinary catheters and
drains has been shown to have a positive impact
on patient outcome. The concept of integrating regional anesthesia within a multimodal,
evidence-based program requires collaboration
from the anesthesiologist, with particular attention to each surgical procedure. This can be
achieved if there is a process by which members of the medical and nursing team address
all aspects of care starting from the preoperative preparation and continuing after surgery.
During the last decade, efforts have been made
to provide scientific evidence for the fast-track
concept, with the intent to improve patient
outcome and contain health-related costs. Fasttrack surgery represents an extension of the
clinical pathway, integrating new modalities
in surgery, anesthesia, and nutrition, enforcing early mobilization and oral feeding, with
an emphasis on reduction of the surgical stress
response. This strategy is designed not only to
improve efficiency by reducing hospital stay
and variability, like any standardized protocol,
but also to decrease the physiologic impact of
major surgery and thereby reduce organ dysfunction and recovery time. Guidelines and
multimodal programs have been published, and
regional anesthesia and multimodal analgesia
techniques specific for some surgical procedures
have been included. Nevertheless, there are several publications on fast-track where anesthesia
and analgesia are briefly mentioned, indicating
the absence of an anesthesiologist as part of
the perioperative team. This demonstrates that
there is more work tobe done to determine how
the anesthetic and surgical interventions can
integrate appropriately. Several elements seem
relativelyconsistent between fast-track centers,
at least in colorectalsurgery (eg, thoracic epidural, philosophy to feed and ambulateearly),
whereas several others are more variable (eg,
use of bowel preparation, feeding protocol,
preoperative carbohydrate, specific anesthesia
protocol). With time, large multi-institutional
studies are undertaken, and the results become
reproducible andgeneralizable. From the review
of the present literature, it is clear that there is a
need to expand the knowledge on how to optimize the existing regional anesthesia techniques
and develop new ones within the context of
fast-track procedures. This is particularly true
with the continuous advances in surgical technology and the minimally invasive surgery. To
achieve such a goal, it is necessary to set up a
multidisciplinary systematic approach, and examples such as ERAS and PROSPECT are worthy attempts in this direction. Although there
have been several publications in the surgical
literature on the positive impact of fast-track
programs on outcome, studies to assess the specific role of regional anesthesia techniques in
the context of fast-track surgery and assess the
impact on outcome have been few.
Some explanations can be proposed: the
lack of awareness of advances in fast-track
surgery among the anesthesia community, the
lack of interest in accessing surgical literature, issues of liability in initiating something
new, the realization that the process of implementation is too long with many barriers,
the belief that fast-track is a surgical and not
anesthetic issue, andfinally resistance to new
ideas. Even introduction of innovations based
on published evidence is a long process that
requires education and unbiased information.
To address these issues, collaboration with
surgical teams needs to be strengthened, views
on various aspects of perioperative care exchanged, and scientific articles on the impact
31
ABSTRACT
of anesthesia on fast-track surgery published.
Another challenge facing the anesthesiologist
is how to assess the impact of anesthetic techniques on outcome in the patient can return
home to step into a rehabilitation program. As
yet, little research has been undertaken to better describe the process of recovery, and currently there is no accepted outcome measure
to define the length of clinical recovery. Other
clinical outcomes often used are readmission
rate and complication rate. Although both are
useful indicators of recovery progress, there is
a need to define whether the complication is
directly related to the surgical technique per se
or trauma-induced organ dysfunction. Assessment of the effectiveness of regional anesthesia techniques can be based on the assumption
that these interventions have an immediate
direct impact on pain, mobilization, and oral
feeding as a result of their physiologic effect
and hopefully on the process of rehabilitation. In summary, the future may be bright
for regional anesthesia, provided that the positive effect on perioperative pathophysiology is
used when combined with the fast-track methodology. context of fast track. Hospital stay is
the most common outcome measure used to
assess the success of fast-track program, but
this measure is confounded by nonphysiologic
parameters that are more related to administrative and organizational issues. In fact, even
within fast-track programs, a minority of patients are discharged on the day of functional
recovery. Nevertheless, if length of hospital
stay reflects how well patients reach the criteria for discharge, then it can be a valuable
indicator assuming that patient can return
home to step into a rehabilitation program. As
yet, little research has been undertaken to better describe the process of recovery, and currently there is no accepted outcome measure
to define the length of clinical recovery. Other
clinical outcomes often used are readmission
rate and complication rate. Although both are
useful indicators of recovery progress, there is
a need to define whether the complication is
directly related to the surgical technique per se
or trauma-induced organ dysfunction. Assessment of the effectiveness of regional anesthesia techniques can be based on the assumption
that these interventions have an immediate
direct impact on pain, mobilization, and oral
feeding as a result of their physiologic effect
32
and hopefully on the process of rehabilitation. In summary, the future may be bright
for regional anesthesia, provided that the positive effect on perioperative pathophysiology is
used when combined with the fast-track methodology.
Ultrasound guidance in regional anesthesia: what is the evidence?
Edward R. Mariano, MD, MAS (Clinical Research)
Department of Anesthesia VA Palo Alto Health Care System,
Palo Alto, CA, USA; Stanford University School of Medicine,
Stanford, CA, USA
The use of ultrasound guidance in the practice of regional anesthesia arguably began in the
late 1980s,1 although ultrasound Doppler technology was used to direct needle insertion for
peripheral nerve blockade in the 1970s.2 This
past decade has seen a rapid increase in practical
applications and clinical research in the field of
ultrasound-guided regional anesthesia (UGRA),
and the American Society of Regional Anesthesia and Pain Medicine (ASRA) and European
Society of Regional Anesthesia have even published joint committee guidelines for training in
this discipline.3
Given the rapid evolution of UGRA, evidence to support this practice was initially limited; however, many studies have emerged recently in an attempt to determine the role of
ultrasound guidance. In 2010, ASRA published
a series of important articles which distill the
body of evidence related to UGRA up to that
time point.4-12 Publications evaluated for contribution to the evidence included randomized
clinical trials (RCTs), meta-analyses and systematic reviews, and case series of 10 or more
patients;9 RCTs were assessed for quality using
the Jadad scoring system.13 Additional studies
have been completed and published since 2010
and will be included in the update to be presented at the 2013 ASRA Spring annual meeting and subsequently published.
Ultrasound Guidance for Extremity Peripheral Nerve
Blocks
The 2010 ASRA systematic review of ultrasound in terms of block characteristics includes
24 RCTs which compare ultrasound guidance
to an alternative nerve localization technique for
March 2013

ABSTRACT
either upper or lower extremity peripheral nerve
blockade.5 For both upper and lower extremity
blocks, the majority of studies report faster block
onset when ultrasound is employed,5, 6, 11 although 5 of 15 studies in the upper extremity and 2
of 5 studies in the lower extremity fail to find
a difference in onset time.5 There is evidence to
support a decrease in procedural time when ultrasound is used for upper and lower extremity
blocks;6, 11 however, set-up time and pre-scanning
with ultrasound are not consistently measured or
reported. In terms of block quality, lower extremity studies are more likely to report an advantage with ultrasound than upper extremity studies; only 4 of 16 upper extremity studies show
improvement with ultrasound, and these studies
use nerve stimulation or transarterial injection as
the comparator.5 When a fixed time point was
used for assessing block success, ultrasound use is
more likely to show an advantage in success rate
although the definitions of successful block vary
widely.6, 11 Only one study in the upper extremity
shows a difference in block duration in favor of
ultrasound while all other RCTs do not demonstrate a difference.5 For femoral and subgluteal
sciatic nerve blocks, ultrasound use decreases the
minimum effective anesthesia volume to achieve
a successful block in 50% of patients.11 There is
no evidence to support an improvement in patient safety when using ultrasound versus other
techniques.8
Ultrasound for Continuous Peripheral Nerve Blocks
Although many large case series describing
ultrasound-guided techniques for continuous peripheral nerve block (CPNB) performance have
been published, there are relatively-fewer RCTs
comparing ultrasound to other nerve localization
techniques for CPNB. When an exclusively ultrasound-guided technique is compared to a stimulating catheter technique, procedural duration is
shorter with ultrasound at four distinct insertion
sites 14-17 with less procedure-related pain for lower extremity catheters 14, 16 and fewer inadvertent
vascular punctures for femoral and infraclavicular
catheters.14, 15 Most studies report similar analgesia and other acute pain outcomes from catheters
placed with ultrasound when compared to other
methods,18-20 with the exception of one study involving popliteal-sciatic catheters which suggests
that stimulating catheters may provide an analgesic
advantage although successful placement occurs
less often.21
Ultrasound for Truncal and Neuraxial Blocks
To date, RCTs comparing ultrasound guidance to traditional techniques for paravertebral blockade or transversus abdominis plane
(TAP) blocks have yet to be reported. For both
of these procedures, the 2010 ASRA systematic
review recommends the use of ultrasound although this recommendation is based on case
series data only.4 In one study comparing ultrasound-guided TAP to conventional ilioinguinal/
iliohypogastric nerve blocks for inguinal hernia
repair, subjects who received ultrasound-guided
TAP blocks reported lower pain scores for the
first 24 hours.22 Ultrasound-guidance and the
landmark-based technique for ilioinguinal/iliohypogastric nerve blocks have been compared in
children with the ultrasound-guided technique
resulting in decreased need for systemic analgesic supplementation.23 For neuraxial blocks,
there is evidence to support ultrasound scanning
prior to employing conventional neuraxial block
techniques rather than relying solely on surface
landmarks,10 especially in patients with challenging anatomy.24 However, there are relativelyfewer RCTs related to ultrasound for neuraxial
blockade compared to peripheral nerve blockade. Studies involving neuraxial blocks in adults
primarily employ pre-scanning to identify midline, select the most appropriate interspace, or
estimate depth to the target. Pre-scanning with
ultrasound may decrease the number of needle
redirections and number of interspaces attempted in adults and reduce instances of bony contact when used for real-time epidural placement
in children.10
Ultrasound for Regional Anesthesia in Special Populations
Ultrasound-guided techniques for peripheral
25 and neuraxial 26 blocks in children have been
described previously. The 2010 ASRA evidencebased review on ultrasound for pediatric regional
anesthesia included 6 RCTs involving peripheral
nerve blocks and one randomized trial in neuraxial
blockade in addition to case series of >10 patients.12
In this population, ultrasound may improve the
speed of block onset and duration of analgesia for
peripheral nerve blocks, increase the success rates
for truncal blocks compared to blind techniques,
and reduce the volume of local anesthetic required for successful blocks.12 In obese patients, ultrasound may play a role in identifying target peripheral and neuraxial structures as well as real-time
33
ABSTRACT
procedural performance.27 For epidural placement
in obese parturients, ultrasound-estimated depth
to the epidural space correlates well with actual
depths measured by needle insertion.28 When performing CPNB in obese patients, procedural time
is not prolonged compared to non-obese patients
when using ultrasound.29
In summary, there is sufficient evidence to support the use of ultrasound guidance for peripheral
nerve blockade based on short-term outcomes. Additional prospective studies are needed to further
define the role of ultrasound in neuraxial blockade, long-term patient outcomes, and advantages in
special populations.
References
1. Ting PL, Sivagnanaratnam V. Ultrasonographic study of
the spread of local anaesthetic during axillary brachial
plexus block. Br J Anaesth 1989;63:326-9.
2. la Grange P, Foster PA, Pretorius LK. Application of the
Doppler ultrasound bloodflow detector in supraclavicular
brachial plexus block. Br J Anaesth 1978;50:965-7.
3. Sites BD, Chan VW, Neal JM, Weller R, Grau T, Koscielniak-Nielsen ZJ, Ivani G. The American Society of Regional Anesthesia and Pain Medicine and the European
Society Of Regional Anaesthesia and Pain Therapy Joint
Committee recommendations for education and training
in ultrasound-guided regional anesthesia. Reg Anesth Pain
Med 2009;34: 40-6.
4. Abrahams MS, Horn JL, Noles LM, Aziz MF. Evidencebased medicine: ultrasound guidance for truncal blocks.
Reg Anesth Pain Med 2010;35:S36-42.
5. Liu SS, Ngeow J, John RS. Evidence basis for ultrasoundguided block characteristics: onset, quality, and duration.
Reg Anesth Pain Med 2010;35:S26-35.
6. McCartney CJ, Lin L, Shastri U. Evidence basis for the
use of ultrasound for upper-extremity blocks. Reg Anesth
Pain Med 2010;35:S10-5.
7. Narouze SN. Ultrasound-guided interventional procedures in pain management: Evidence-based medicine. Reg
Anesth Pain Med 2010;35:S55-8.
8. Neal JM. Ultrasound-guided regional anesthesia and patient safety: An evidence-based analysis. Reg Anesth Pain
Med 2010;35:S59-67.
9. Neal JM, Brull R, Chan VW, Grant SA, Horn JL, Liu
SS, McCartney CJ, Narouze SN, Perlas A, Salinas FV,
Sites BD, Tsui BC. The ASRA evidence-based medicine
assessment of ultrasound-guided regional anesthesia and
pain medicine: Executive summary. Reg Anesth Pain Med
2010;35:S1-9.
10. Perlas A. Evidence for the use of ultrasound in neuraxial
blocks. Reg Anesth Pain Med 2010;35:S43-6.
11. Salinas FV. Ultrasound and review of evidence for lower
extremity peripheral nerve blocks. Reg Anesth Pain Med
2010;35:S16-25.
12. Tsui BC, Pillay JJ. Evidence-based medicine: Assessment of ultrasound imaging for regional anesthesia in
infants, children, and adolescents. Reg Anesth Pain Med
2010;35:S47-54.
13. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds
DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of
reports of randomized clinical trials: is blinding necessary?
Control Clin Trials 1996;17:1-12.
14. Mariano ER, Cheng GS, Choy LP, Loland VJ, Bellars
RH, Sandhu NS, Bishop ML, Lee DK, Maldonado RC,
34
Ilfeld BM. Electrical stimulation versus ultrasound guidance for popliteal-sciatic perineural catheter insertion:
a randomized controlled trial. Reg Anesth Pain Med
2009;34:480-5.
15. Mariano ER, Loland VJ, Bellars RH, Sandhu NS, Bishop
ML, Abrams RA, Meunier MJ, Maldonado RC, Ferguson EJ, Ilfeld BM. Ultrasound guidance versus electrical
stimulation for infraclavicular brachial plexus perineural
catheter insertion. J Ultrasound Med 2009;28:1211-8.
16. Mariano ER, Loland VJ, Sandhu NS, Bellars RH, Bishop
ML, Afra R, Ball ST, Meyer RS, Maldonado RC, Ilfeld
BM. Ultrasound guidance versus electrical stimulation for
femoral perineural catheter insertion. J Ultrasound Med
2009; 28:1453-60.
17. Mariano ER, Loland VJ, Sandhu NS, Bellars RH, Bishop ML, Meunier MJ, Afra R, Ferguson EJ, Ilfeld BM.
A trainee-based randomized comparison of stimulating
interscalene perineural catheters with a new technique
using ultrasound guidance alone. J Ultrasound Med
2010;29:329-36.
18. Ilfeld BM. Continuous peripheral nerve blocks: a review
of the published evidence. Anesth Analg 2011;113:90425.
19. Fredrickson MJ, Danesh-Clough TK: Ambulatory continuous femoral analgesia for major knee surgery: a randomised study of ultrasound-guided femoral catheter
placement. Anaesth Intensive Care 2009;37:758-66.
20. Choi S, Brull R. Is ultrasound guidance advantageous for
interventional pain management? A review of acute pain
outcomes. Anesth Analg 2011;113:596-604.
21. Mariano ER, Loland VJ, Sandhu NS, Bishop ML, Lee
DK, Schwartz AK, Girard PJ, Ferguson EJ, Ilfeld BM.
Comparative efficacy of ultrasound-guided and stimulating popliteal-sciatic perineural catheters for postoperative
analgesia. Can J Anaesth 2010;57:919-26.
22. Aveline C, Le Hetet H, Le Roux A, Vautier P, Cognet
F, Vinet E, Tison C, Bonnet F. Comparison between
ultrasound-guided transversus abdominis plane and
conventional ilioinguinal/iliohypogastric nerve blocks
for day-case open inguinal hernia repair. Br J Anaesth
2011;106:380-6.
23. Willschke H, Marhofer P, Bosenberg A, Johnston S, Wanzel O, Cox SG, Sitzwohl C, Kapral S. Ultrasonography for
ilioinguinal/iliohypogastric nerve blocks in children. Br J
Anaesth 2005;95:226-30.
24. Chin KJ, Perlas A, Chan V, Brown-Shreves D, Koshkin A,
Vaishnav V. Ultrasound imaging facilitates spinal anesthesia in adults with difficult surface anatomic landmarks.
Anesthesiology 2011;115:94-101.
25. Tsui B, Suresh S. Ultrasound imaging for regional anesthesia in infants, children, and adolescents: a review of current
literature and its application in the practice of extremity and
trunk blocks. Anesthesiology 2010;112:473-92.
26. Tsui BC, Suresh S. Ultrasound imaging for regional anesthesia in infants, children, and adolescents: a review of
current literature and its application in the practice of neuraxial blocks. Anesthesiology 2010;112:719-28.
27. Brodsky JB, Mariano ER. Regional anaesthesia in the obese
patient: lost landmarks and evolving ultrasound guidance.
Best Pract Res Clin Anaesthesiol 2011;25:61-72.
28. Balki M, Lee Y, Halpern S, Carvalho JC. Ultrasound imaging of the lumbar spine in the transverse plane: the correlation between estimated and actual depth to the epidural
space in obese parturients. Anesth Analg 2009;108:187681.
29. Mariano ER, Brodsky JB. Comparison of procedural
times for ultrasound-guided perineural catheter insertion in obese and nonobese patients. J Ultrasound Med
2011;30:1357-61.
March 2013

ABSTRACT
Role of multimodal anesthetic and analgesic regimens in cancer surgery
Vijaya Gottumukkala M.B;B.S, M.D (Anes), F.R.C.A
Cancer Anesthesia Fellowship Program Department of Anesthesiology & Perioperative Medicine. The University of Texas
M.D.Anderson Cancer CenterUnit-409, 1515 Holcombe
BlvdHouston,
Texas 77030-4009
Cancer is a major public health problem that affects citizens across all societies in the world. The
incidence of cancer is increasing at a rapid pace
due to environmental factors, life style choices,
and longer life expectancies. It is the plague of the
modern era. Cancer currently accounts for nearly
1 out of every 4 deaths in the United States. In
addition, people 65 years or older have a cancer
incidence rate 10 times greater than the rate for
younger people, and the mortality rate for older
cancer patients is 16 times greater than younger patients. Cancer is no longer a terminal disease. With
advances in diagnosis and therapeutic modalities,
cancer is now considered a chronic medical condition. As of January 2012, there are close to 14
million cancer survivors in the US alone. 64 % of
cancer survivors in the United States live for more
than 5 years, 15 % live for over 20 years and 45 %
of all cancer survivors are over 70 years of age. So,
it is likely that patients with Cancer will continue
to need the services of our specialty well beyond
their primary oncologic care. Cancer care currently
costs 60 billion dollars every year in the US aloneA number that is certain to increase with the impending demographic shift. Our understanding of
the mechanisms of perioperative tumor spread and
control is rapidly evolving and offers an opportunity to positively influence patient outcomes.
The perioperative period is characterized by a
state of intense emotional and surgical stress, pain,
inflammation, immune suppression, and an environment for pro-angiogenesis. While many of these
responses to surgical injury (incision) are important
for healing and recovery of function, uncontrolled
- they can have significant negative consequences
on long term outcomes. Despite significant advances in understanding the mechanisms of acute
surgical (incisional) pain, patient surveys continue
to show poor satisfaction rates with pain control
in the postoperative period. Goal of perioperative
management strategies in the Cancer patient are
not only to attenuate the surgical stress response
and provide effective analgesia, but also to focus on
patient centered outcomes and positively influence
recurrence free and overall survival.
While opioid medications have been the mainstay of analgesic regimens and may still be necessary to control acute post-surgical pain, they have
significant side effects. The opioid related side
effects are not inconsequential. A British study
looking at the incidence of inpatient adverse drug
reactions found that 16 percent were attributable
to opioids, making opioids one of the most frequently implicated drugs in adverse reactions. Of
the opioid-related adverse drug events reported to
The Joint Commission’s Sentinel Event database
(2004-2011), 47 percent were wrong dose medication errors, 29 percent were related to improper
monitoring of the patient, and 11 percent were
related to other factors, including excessive dosing, medication interactions and adverse drug reactions. These reports underscore the need for the
judicious and safe prescribing and administration
of opioids, the need for appropriate monitoring of
patients and most importantly to consider nonopioid multimodal strategies when appropriate.
In addition, it is well known that opioids have
depressant actions on the immune system (NK cell
function), and are thought to directly promote
tumor growth by suppressing tumor apoptosis,
increasing endothelial cell proliferation, migration, and protease release, increasing endothelial
permeability, and inducing angiogenesis. These
putative effects on tumor spread are however not
clinically proved through randomized control trials. Regional anesthesia/analgesia techniques using
local anesthetic agents offer an alternative to opioid based analgesic regimens. However, it should
also be realized that regional analgesic techniques
may be contraindicated (immune-suppressed,
coagulopathic) or inapplicable in some patients
(patient refusal or type of surgery) with Cancer.
Anesthesiologists and perioperative clinicians have
to therefore resort to multimodal techniques for
perioperative care of the cancer patient- where the
goal is to minimize the stress response, positively
modulate the inflammatory response, preserve immunological function and provide an environment
that minimizes tumor growth (angiogenesis) and
spread. Anesthetic drugs also appear to have direct
actions on neoplastic cells, possibly by upstream
effector-mediated activation of the Hypoxia Inducing Factor (HIF system).
Currently there are no randomized controlled
studies which offer clear benefits of one anesthetic
technique over the other in terms of recurrence
free survival or overall survival after cancer surgery.
Nonetheless, given the increasing numbers of pa-
35
ABSTRACT
tients undergoing cancer surgery worldwide, such
a strategy is warranted.
NANO (No Inhalational Agent No Systemic
Opioids) is one such multimodal approach for the
perioperative care of cancer patient when regional block is an acceptable technique for providing
perioperative analgesia. This technique involves an
effective regional block, avoiding volatile anesthetic agents and parenteral opioids, use of intravenous
agents (lidocaine, dexmedetomidine, propofol and
sub-anesthetic doses of ketamine) with known anti-inflammatory actions for intraoperative anesthesia, and preoperative COX-2 inhibitors- gabapentinoids - oral tramadol - IV acetaminophen as part
of the multimodal regimen. We also incorporate
active blood management protocols, intraoperative
temperature and glycemic control, and maintaining optimal hemodynamic and metabolic milieu
by goal directed fluid therapy. Feasibility studies in
our institution have shown this to be a very effective technique for even major procedures extending up to 15 hours. Our experience with over 130
patients has been very encouraging. Our hope is to
develop a multi-institutional collaborative to study
NANO on both short and long term outcomes in
patients with cancer.
References
1. American Cancer Society. Cancer Treatment and Survivorship Facts & Figures 2012-3.
2. J Natl Cancer Inst 2011;103:117-28.
3. The Global Economic Cost of Cancer: American Cancer
Society; 2010.
4. National Cancer Institute. SEER Cancer Statistics Review
1975-2008.
5. Davies EC et al. Adverse Drug Reactions in Hospital InPatients: A Prospective Analysis of 3695 Patient-Episodes,
PLOS ONE, February 2009;4(2):e4439.
6. Singleton & Moss. Future Oncol 2010;6(8):1237-42.
7. Apfelbaum JL, et al. Anesth Analg 2003;97:534-40.
8. Perkins FM, Kehlet H. Anesthesiology 2000;93:1123-33.
9. TJC Sentinel Event Alert, Issue 49 Page 2.
Paravertebral blocks
Juan Francisco Asenjo MD
Department of Anesthesia and Alan Edwards McGill Pain
Center, McGill University Health Center, Montreal Qc, Canada
The wedged space lateral to the Spine is the
Paravertebral region. It goes from the Cervical
Spine down to the Lumbar region. The Anterior
Paravertebral Space (APS) is the area lateral to de
spine anterior to the Transverse Processes (TP) of
36
the Vertebral Bodies and the Posterior Paravertebral Space is made of the structures lateral to the
spine posterior to the Transverse Processes. At the
Cervical and Lumbar levels, the APS contain muscles, but not so in the Thoracic segment where the
pleura and lung are found. The lateral extension of
the Paravertebral Space is ill defined and depends
of the level of the spine. In general it contains the
muscles that stabilize and move the spine, the
nerve roots, sympathetic chain, segmental arteries
and veins, fat, etc .1
The deposit of local anesthetics or other analgesic molecules in this area is called Paravertebral
Block and can be made by single shot injections or
continues techniques with catheters.
Although the original description of the approach to the Paravertebral Space was made almost
100 years ago, the technique did not gained clinical popularity until the 1990’s after a paper by Eason and Wyatt in 1979 2 revamped the block at
thoracic level and later in the 2000’s Boezaart used
the cervical access with the nerve stimulator.3
When deposited in the PVB space, local anesthethics become in close contact with the sympathetic communicants ramii as well as with the
nerve roots making them a good target for conduction blockade. Depending of the level of the spine
as well as the volume of local anesthetic utilized,
the block occasionally may become bilateral by
virtue of crossing in front of the spine to the contralateral paravertebral side or via the access of the
medication into the epidural space and then to the
contralateral roots.
Indications: PVB in the cervical region are generally used as a substitute for Interscalene plexus
blocks, covering better the superior and median
trunks. At the Thoracic level PVB are used to control pain of rib fractures, post thoracotomy pain,
after VATS, in the control of herpetic neuralgia
and in breast and cardiac surgery. Lumbar uses relate to hip/knee operations, bone marrow harvesting procedures as well as fractures between the hip
and knee. These approaches have also been used to
inject neurolytic agents to control cancer pain.
Contraindications: The traditional contraindications for regional blocks apply to PVB as well.
Cervical Paravertebral blockade: Andre Boezaart
promoted the posterior approach (or cervical paravertebral approach) to the brachial plexus. Later,
with the use of ultrasound, it became evident that
the paravertebral block was simple and safe to do
in lieu of the classic Interscalene block. With the
patient comfortably on lateral position, the ultra-
March 2013

ABSTRACT
sound transducer is placed on the side of the neck
in short axis to identify the interscalene groove,
the upper and middle trunks as well as the Middle
Scalenous muscle. The skin and muscles should be
generously frozen starting at an entry point about
1 – 2 cm posterior to the most posterior edge of the
transducer for an intended in-plane access. Then
the needle is advanced under direct view through
the skin, fascias and muscles to the interscalene
groove. Hydro dissection with 3-5 mls of local anesthetic is used to confirm appropriate spread of
the local anesthetic around the trunks/roots and a
catheter can be inserted under direct view. Once
the tip of the catheter is seen in the correct location, 15-30 ml of the solution (or 0.4-0.5 ml/kg in
children) are injected again with US view to check
that appropriate spread is achieved from the catheter to prevent secondary failure.
Thoracic Paravertebral blockade: The classic
thoracic paravertebral approach with nerve stimulator or by landmarks is performed with the patient sitting or prone. A point 2.5 cm lateral to
the Spinous Process is marked on the skin at the
levels intended to be blocked. Local anesthesia
is injected in the skin and deeper planes. The
needle is advanced perpendicular to the skin to
contact the Transverse Process or the Pars. 1 – 2
ml more of local anesthesia should be administered at that point. Then, the needle is “walked
over” or underneath the Transverse Process;
typically to 0.8 – 1.5 cm deeper than the first
bone contact. If nerve stimulation is used (usually higher current than for peripheral nerve is
requiered, start at 2-3 mAmps), the patient and
the operator will perceive a segmentary intercostal contraction. If Loss-of-Resistance is used,
(better with DW5% to allow for stimulation) a
“loss” will be felt on reaching target right after
crossing the Costo-transverse ligament. Three to
4 ml of local anesthethic are injected per level.
The rate of success is better when using nerve
stimulation.4 A catheter could be advanced to
achieve a continuous technique requiring about
3ml of anesthetic per level to block. Beside the
clinical effect in terms of good pain relief, when
the technique is used for thoracic surgery a bolus
of methylene blue can be injected in the intraoperative period to confirm by direct view the blue
color spreading along the paravertebral region. A
single level injection vs. multilevel seems to have
the same success rate with better patient satisfaction in VAT surgery.5 US-guidance is an excellent option to deliver local anesthetics into the
Paravertebral Space; with the patient in prone
decubitus, the paravertebral area is scanned in
short-axis with a curve probe in normal/large
patients and a straight probe in skinny individuals. Once the Spinous process, lamina and transverse process are identified, the probe is carefully moved laterally and progressively rotated
to become aligned with the intercostal spaces.
At that point, the optimal view should show the
transverse process and the intercostal space with
the brightness of the pleura clearly showing as
it “sinks” medially under the TP demarking the
lateral border of the APS. After proper preparation and local anesthesia, the needle is advanced
in-plane from lateral-to-medial to reach the area
immediately under the TP, where the echografic
shadow of the TP will hide the needle tip. At
that point the catheter can be advanced and or
the local anesthetic deposited. In the UK, PVB
is the most common technique to block pain after VATS.6
Lumbar Paravertebral Blockade: At this level
PVB are performed with the use of neurostimulation, clinical landmarks, fluoroscopy and US. Two
techniques are advocated using echo; One closer
to the spine in long axis view, and the second in
sort axis and with a postero-lateral approach. Using
the nerve stimulator, the entry point in a perpendicular approach is located at the level of the 4th
lumbar spinous process and 4 cm lateral, advancing the needle until getting a Quadriceps response
or contacting bone.
Once in target, 20-30 ml of local anesthetic are
injected to obtain excellent analgesia in the distribution of the lumbar plexo and a catheter can be
advanced for continuous techniques.
Complications of the PVB: They include epidural analgesia, intrathecal catheter placement, nerve
trauma, hematoma, pneumothorax, infection.
References
1. Hamilton WJ. Textbook of Human Anatomy.
2. Eason MJ, Wyatt R. Paravertebral thoracic block-a reappraisal. Anaesthesia 1979;34:638-42.
3. Boezaart A.P. Atlas of Peripheral Nerve Blocks and Anatomy for Orthopedic Anesthesia.
4. Aja MZ, Ziade MF, Rajab M, El Tayara K, Lonnqvist PA.
Varying anatomical injection points within the thoracic
paravertebral space: effect on spread of solution and nerve
blockade. Anaesthesia. 2004;59:459-63.
5. Kaya FN, Turker G, Mogol E, Bayraktar, S. Thoracic Paravertebral Block for Video-Assisted Thoracoscopic Surgery:
Single Injection Versus Multiple Injections. J Cardioth
Vasc Anesth 2012;1:90-4.
6, Kotemane NC, Gopinath N, Vaja R. Analgesic techniques
following thoracic surgery: A survey of United Kingdom
practice. Eur J Anaesthesiol 2010;27:897-9.
37
ABSTRACT
The tranverse abdominis plabe block. Beyond pain outcomes
J.P. Cata MD1 and Rodolfo Gebhardt MD2
of Anesthesiology and Perioperative Medicine
2Department of Pain Medicine. The University of Texas MD Anderson Cancer Center. Houston, Texas. USA.
1Department
The transversus abdominis plane (TAP) block is
a novel regional anesthesia technique that has become more commonly used in the last decade. It
consists of the deposit of local anesthetics and/or
analgesic adjuvants between the fascial plane along
the internal oblique and the transversus abdominis
muscles. Spinal nerves from T7 to T12, the ilioinguinal nerve and iliohypogastric nerves, and the lateral cutaneous branches of the dorsal rami of L1-3
provide nerve supply to the antero-lateral abdominal wall. These nerves run between those muscles,
hence the anesthetic blockade at this level can be
used to provide intraoperative and postoperative
analgesia for a wide variety of abdominal surgeries that produce abdominal wall pain.1, 2 There are
several techniques to perform a TAP block, however, we can classify them into 3 main groups: the
originally described “blind” technique; an “open”
technique, usually performed by surgeons, and the
“ultrasound” guided technique.3 Ultrasonographyguided TAP blocks are easy to perform and allow
the clinician to quickly identify relevant structures
and visualize the injectate spread. TAP blocks can
be performed as a single injection, or catheters can
be placed in order to continuously infuse local anesthetic solutions.
TAP blocks have been performed in a wide
variety of patients including pediatrics, pregnant
women, elders and critically ill patients.4, 5 Most
reports have shown that the block is safe when performed in experienced hands; however liver lacerations have been described even when ultrasound
was used to guide the needle placement.6, 7 One
clinical concern mainly after bilateral TAP blocks
is systemic toxicity of local anesthetics. Two recent
studies indicate that bilateral TAP blocks may be
associated with high to near toxic systemic concentrations of local anesthetics in about a third of the
patients.8, 9 Two means to reduce local anesthetic
toxicity is to decrease the volume or the concentration of the injected solution. Remarkably, a randomized-controlled trial demonstrated that the use of
0.25% of ropivacaine was associated with similar
postoperative outcomes to those obtained after the
administration of a solution of 0.5% of the same
local anesthetic. Thus, suggesting that the risk of
38
systemic toxicity could be decreased if lower concentrations of local anesthetics are administered.10
The clinical efficacy of this technique compared
to placebo has been proved in two recent metaanalysis; however, some studies have shown no beneficial effects.4, 11-15 For instance, the TAP block
failed to be superior to placebo when it was added
to a multimodal approach of postoperative pain
management after abdominal surgery. It is important to consider that some of these controversial
findings may be related to variables such as type
of abdominal incision (vertical versus transverse),
length of the incision (i.e. small laparoscopic versus
open laparotomy), obesity, type of technique and
the co-administration of long acting opioids neuraxially.12, 14, 16 In women undergoing C-section, the
addition of a TAP block to a multimodal analgesic
approach that does not include intrathecal morphine has shown to reduce opioid consumption
and pain intensity. These beneficial effects associated to the block are lost when morphine is added
spinally.4
Some studies may have failed to prove a significant improvement in pain control or analgesic
consumption because of the type of technique
used to perform the blockade. This is an important
consideration because recent studies demonstrate
that kinetics of the local anesthetics administered
to perform the block are complex due to at least 2
reasons. First, there is no communication between
the upper and lower TAP compartments and second, due to the fact that the spread of the anesthetic is not uniform within each compartment.17,
18 This emphasizes the need of performing single
injections to access each compartment to obtain
a complete abdominal wall block. This may also
explain why the use of a catheter is not always associated with significant pain relief.
The literature is limited in terms of studies that
have compared TAP blocks against other analgesia techniques. A very small retrospective study
demonstrates that for abdominal surgery the use
of continuous analgesia through a TAP block is
associated with a higher consumption of fentanyl
compared to epidural analgesia, however, patient
satisfaction was not different.19 Two more recent
studies demonstrate that the use of a TAP block
was associated with worse pain scores and higher
opioid consumption compared to intrathecal morphine when used to provide postoperative analgesia for C-section.20, 21 Similar results were reported
by McMorrow et al who did not find a beneficial
effect of adding a TAP block to intrathecal mor-
March 2013

ABSTRACT
phine in patients who underwent C-section. Interestingly, pruritus and postoperative nausea and
vomiting were more common in those patients
who received spinal morphine but patient satisfaction scores were comparable in all groups.21, 22 The
TAP block has also been compared to local anesthetic infiltration of the trocar insertion wound for
laparoscopic surgery. Interestingly, no differences
were found between both techniques in terms of
analgesic consumption and pain scores.23 In children, TAP block was inferior to ilioinguinal block
to provide adequate analgesia after abdominal surgery.24
Most of the clinical studies have investigated the
clinical effects of the TAP block with regards to postoperative pain levels and analgesic consumption.
Unfortunately, no clinical studies have investigated
the effects of the TAP block on the cardiovascular,
immunological or gastrointestinal systems. One
study demonstrated that the TAP block preserved
the respiratory function thus it can be used in patients with poor respiratory reserve who undergo
abdominal surgery.25
It can be inferred from the clinical studies on
postoperative pain that the TAP block may improve some gastrointestinal outcomes or partially
ameliorate the stress response only when compared
to intravenous opioid analgesic techniques but not
when compared to other regional anesthesia techniques such as neuraxial analgesia. It is important to
note that this last technique appears to be associated
with more nausea and vomiting than the TAP block.
The TAP block may also be preferred in patients in
which systemic hypotension is to be avoided. More
randomized controlled trials specifically comparing
the TAP block against other regional anesthesia techniques are needed to validate its clinical indication.
References
1. Mukhtar K, Singh S Ultrasound-guided transversus abdominis plane block. Br J Anaesth 2009;103:900; author
reply 900-1.
2. Mukhtar K, Singh S. Transversus abdominis plane block
for laparoscopic surgery. Br J Anaesth 2009;102:143-4.
3. Brady RR, Ventham NT, Roberts DM, Graham C, Daniel
T. Open transversus abdominis plane block and analgesic
requirements in patients following right hemicolectomy.
Ann R Coll Surg Engl 2012;94:327-30.
4. Abdallah FW, Halpern SH, Margarido CB. Transversus
abdominis plane block for postoperative analgesia after
Caesarean delivery performed under spinal anaesthesia? A systematic review and meta-analysis. Br J Anaesth
2012;109: 679-87.
5. Mai CL, Young MJ, Quraishi SA. Clinical implications of
the transversus abdominis plane block in pediatric anesthesia. Paediatr Anaesth 2012;22:831-40.
6. Farooq M, Carey M. A case of liver trauma with a blunt regional anesthesia needle while performing transversus ab-
dominis plane block. Reg Anesth Pain Med 2008;33:2745.
7. Lancaster P, Chadwick M. Liver trauma secondary to ultrasound-guided transversus abdominis plane block. Br J
Anaesth 2010;104:509-10.
8. Torup H, Mitchell AU, Breindahl T, Hansen EG, Rosenberg J, Moller AM. Potentially toxic concentrations in
blood of total ropivacaine after bilateral transversus abdominis plane blocks; a pharmacokinetic study. Eur J Anaesthesiol 2012; 29:235-8.
9. Kato N, Fujiwara Y, Harato M, Kurokawa S, Shibata Y,
Harada J et al. Serum concentration of lidocaine after
transversus abdominis plane block. J Anesth 2009;23:298300.
10. De Oliveira GS, Jr., Fitzgerald PC, Marcus RJ, Ahmad
S, McCarthy RJ. A dose-ranging study of the effect of
transversus abdominis block on postoperative quality of
recovery and analgesia after outpatient laparoscopy. Anesth Analg 2011;113:1218-25.
11. Freir NM, Murphy C, Mugawar M, Linnane A, Cunningham AJ. Transversus abdominis plane block for analgesia
in renal transplantation: a randomized controlled trial.
Anesth Analg 2012;115:953-7.
12. Kane SM, Garcia-Tomas V, Alejandro-Rodriguez M,
Astley B, Pollard RR. Randomized trial of transversus abdominis plane block at total laparoscopic hysterectomy:
effect of regional analgesia on quality of recovery. Am J
Obstet Gynecol 2012;207:419 e 411-5.
13. Johns N, O’Neill S, Ventham NT, Barron F, Brady RR,
Daniel T Clinical effectiveness of transversus abdominis
plane (TAP) block in abdominal surgery: a systematic review and meta-analysis. Colorectal Dis 2012;14:e635-42.
14. Mishriky BM, George RB, Habib AS. Transversus abdominis plane block for analgesia after Cesarean delivery:
a systematic review and meta-analysis. Can J Anaesth
2012; 59:766-78.
15. Charlton S, Cyna AM, Middleton P, Griffiths JD. Perioperative transversus abdominis plane (TAP) blocks for analgesia after abdominal surgery. Cochrane Database Syst
Rev 2010: CD007705.
16. Griffiths JD, Middle JV, Barron FA, Grant SJ, Popham
PA, Royse CF. Transversus abdominis plane block does
not provide additional benefit to multimodal analgesia in
gynecological cancer surgery. Anesth Analg 2010;111:797801.
17. Borglum J, Jensen K, Christensen AF, Hoegberg LC,
Johansen SS, Lonnqvist PA et al. Distribution patterns,
dermatomal anesthesia, and ropivacaine serum concentrations after bilateral dual transversus abdominis plane
block. Reg Anesth Pain Med 2012;37:294-301.
18. Latzke D, Marhofer P, Kettner SC, Koppatz K, Turnheim
K, Lackner E et al. Pharmacokinetics of the local anesthetic ropivacaine after transversus abdominis plane block
in healthy volunteers. European journal of clinical pharmacology 2012;68:419-25.
19. Kadam VR, Moran JL. Epidural infusions versus transversus abdominis plane (TAP) block infusions: retrospective
study. J Anesth 2011;25:786-7.
20. Loane H, Preston R, Douglas MJ, Massey S, Papsdorf M,
Tyler J. A randomized controlled trial comparing intrathecal morphine with transversus abdominis plane block
for post-cesarean delivery analgesia. Int J Obstet Anesth
2012; 21:112-8.
21. Kanazi GE, Aouad MT, Abdallah FW, Khatib MI, Adham
AM, Harfoush DW et al. The analgesic efficacy of subarachnoid morphine in comparison with ultrasound-guided
transversus abdominis plane block after cesarean delivery: a
randomized controlled trial. Anesth Analg 2010;111:47581.
39
ABSTRACT
22. McMorrow RC, Ni Mhuircheartaigh RJ, Ahmed KA,
Aslani A, Ng SC, Conrick-Martin I et al. Comparison of
transversus abdominis plane block vs spinal morphine for
pain relief after Caesarean section. Br J Anaesth 2011;106:
706-12.
23. Ortiz J, Suliburk JW, Wu K, Bailard NS, Mason C, Minard
CG et al. Bilateral transversus abdominis plane block does
not decrease postoperative pain after laparoscopic cholecystectomy when compared with local anesthetic infiltration of
trocar insertion sites. Reg Anesth Pain Med 2012;37:18892.
24. Fredrickson MJ, Paine C, Hamill J Improved analgesia
with the ilioinguinal block compared to the transversus
abdominis plane block after pediatric inguinal surgery: a
prospective randomized trial. Paediatr Anaesth 2010;20:
1022-7.
25. Petersen M, Elers J, Borglum J, Belhage B, Mortensen J,
Maschmann C. Is pulmonary function affected by bilateral dual transversus abdominis plane block? A randomized,
placebo-controlled, double-blind, crossover pilot study in
healthy male volunteers. Reg Anesth Pain Med 2011;36:
568-71.
Is there an alternative to epidural blocks?
Intra wound infusion
P. Lavand’homme MD, PhD
Professor, Department of Anesthesiology, Université Catholique
de Louvain, St Luc Hospital UCL Medical School, Brussels,
Belgium
Despite the availability of various analgesic
drugs and techniques, to alleviate acute postoperative pain and specifically movement-associated
pain still remains a challenge in some 30% of the
patients.1 Poorly relieved acute pain influences the
quality of postoperative recovery, it not only impairs rehabilitation and may prolong hospital stay but
also reduces patient’s satisfaction and in fine may
lead to poor outcome like persistent pain.2 Going
“back to the periphery” i.e. intrawound analgesia
is a natural evolution of the modern perioperative
pain management which goes along with improved
perioperative efficiency and fast-track surgery.3 Beside its simplicity and safety aspects, there is also a
strong scientific rationale for intra-wound analgesia, supported by the pathophysiology of incisional
pain. In postoperative pain, peripheral sensitization processes play a major role and nociceptive
inputs originating from the wound are involved in
both the initiation and the maintenance of pain.4
Further studies have also highlighted the importance of deep tissue nociceptors in the processes
of sensitization after incision. The aforementioned
findings argue for a continuous wound infiltration
of analgesics deeply into the surgical wound to ensure the success of the technique.
40
Loco-regional analgesic techniques have always
been part of multimodal “opioid-sparing” (also called balanced) analgesia, the corner stone of current
perioperative pain management. In this regard,
all regional techniques including continuous intrawound infusions provide statistically superior
analgesia compared with systemic opioids.5 The
use of regional analgesia also allows an opioidsparing effect which helps to improve the quality
of recovery by reducing well-known opioid-related
side effects like nausea, sedation, urinary retension.
Although epidural analgesia has been considered for many years as the gold standard for pain
relief after major procedures, its popularity is now
waning for different reasons.6 Today, around 30%
of the patients are ineligible for a thoracic epidural analgesia (refusal, anticoagulation treatment).
Whether severe neurological complications are
fortunately very rare, the rate of epidural failure
may be as high as 28-32%. The development of
minimally invasive surgery and the inclusion of the
patients in fast-track programmes also promote the
use of alternative, less invasive and safer analgesic
techniques.
Moreover the aforementioned reasons, the immediate benefits observed with epidural blocks are
short-lasting as the technique only provides superior analgesia to intravenous opioids during the
first postoperative day.5 A better pain relief with
epidural analgesia is generally observed for movement-evoked pain and only when a local anesthetic
but not an opioid alone is administered.5 Beyonds,
there is actually a lack of evidence in favor of epidural analgesia as objective data supporting an improved quality of rehabilitation, a greater patient’s
satisfaction or long-term benefits like a reduction
of the risk for persistent pain 7 have rarely been
assessed. Finally, the economic conjuncture pushes
the caregivers also to face the cost-effectiveness of
their therapeutic choices. In a recent publication,8
costs of continuous wound infiltration compared
favorably (drug treatments, man power) with intravenous opioids and particularly with epidural
analgesia after open abdominal surgery. Consequently, it is necessary to question the place of such
an invasive technique in the context of modern postoperative analgesia.
Several clinical studies have demonstrated the
effectiveness of continuous wound infusions in
term of postoperative analgesia and opioid-sparing
effect. So, deep wound infiltrations (e.g. preperitoneal infusion after open colectomy,9 inter-parietal
muscles after open nephrectomy,10 sub-fascial in-
March 2013

ABSTRACT
fusion after cesarean section 11) are able to afford
a comfortable postoperative recovery with high
patient’s satisfaction in many surgical procedures
where epidural analgesia has been used for many
years. However, it is worth noting that studies providing a direct comparison between epidural technique and deep continuous wound infiltration are
scarce. A single study has compared lumbar epidural analgesia with incisional analgesia after cesarean
delivery, showing the superiority of epidural ropivacaine administration only for the first 6 hours.11
An other study (not double-blinded) in the same
setting has reported the superiority of ropivacaine
wound infiltration over epidural morphine in term
of analgesia, side effects and shorter hospital stay.12
It is evident that ethical concerns do exist regarding
the use of a placebo epidural technique, particularly at thoracic level. In the context of thoracic
surgery, continuous wound infiltration has often
been compared with paravertebral block. The paravertebral block knows a regain of interest thanks
to the development of ultrasound techniques and
seems to represent a current valuable alternative to
the thoracic epidural analgesia. Whether for breast
surgery,13 continuous wound infiltration is as effective, in more invasive procedures i.e. in the cases of
thoracotomy, the continuous paravertebral block
clearly demonstrates greater efficacy.14
In summary, the last years have bring more
studies involving continuous wound infiltrations
for various surgical procedures, helping to better
define its place among the loco-regional analgesic
techniques. In majority, these studies have only
assessed short-term outcomes, mainly immediate
postoperative analgesia as it is the case for other loco-regional techniques including epidural blocks.
Nevertheless, as modern analgesia also evoluates
toward the individualization of treatments, further
studies are mandatory to find out for whom less invasive intra-wound infiltration would provide the
best outcome and thereby, who should still benefit
of an invasive technique like epidural analgesia.
References
1. Fletcher D, Fermanian C, Mardaye A, Aegerter P. A patient-based national survey on postoperative pain management in France reveals significant achievements and persistent challenges. Pain 2008;137:441-51.
2. White PF, Kehlet H. Improving postoperative pain management: what are the unresolved issues? Anesthesiology
2010;112:220-5.
3. Kehlet H, Liu SS. Continuous local anesthetic wound
infusion to improve postoperative outcome: back to the
periphery? Anesthesiology 2007;107:369-71.
4. Brennan TJ. Pathophysiology of postoperative pain. Pain
2011;152:S33-40.
5. Liu SS, Wu CL. The effect of analgesic technique on postoperative patient-reported outcomes including analgesia: a
systematic review. Anesth Analg 2007;105:789-808.
6. Rawal N. Epidural technique for postoperative pain: gold
standard no more? Reg Anesth Pain Med 2012;37:310-7.
7. Andreae MH, Andreae DA: Local anaesthetics and regional anaesthesia for preventing chronic pain after surgery.
Cochrane Database Syst Rev 2012;10:CD007105.
8. Tilleul P, Aissou M, Bocquet F, Thiriat N, le Grelle O,
Burke MJ, Hutton J, Beaussier M. Cost-effectiveness analysis comparing epidural, patient-controlled intravenous
morphine, and continuous wound infiltration for postoperative pain management after open abdominal surgery. Br
J Anaesth 2012;108:998-1005.
9. Beaussier M, El’Ayoubi H, Schiffer E, Rollin M, Parc Y,
Mazoit JX, Azizi L, Gervaz P, Rohr S, Biermann C et al.
Continuous preperitoneal infusion of ropivacaine provides
effective analgesia and accelerates recovery after colorectal
surgery: a randomized, double-blind, placebo-controlled
study. Anesthesiology 2007;107:461-8.
10. Forastiere E, Sofra M, Giannarelli D, Fabrizi L, Simone
G. Effectiveness of continuous wound infusion of 0.5%
ropivacaine by On-Q pain relief system for postoperative
pain management after open nephrectomy. Br J Anaesth
2008; 101:841-7.
11. Ranta PO, Ala-Kokko TI, Kukkonen JE, Ohtonen PP,
Raudaskoski TH, Reponen PK, Rawal N. Incisional and
epidural analgesia after caesarean delivery: a prospective,
placebo-controlled, randomised clinical study. Int J Obstet Anesth 2006;15:189-94.
12. O’Neill P, Duarte F, Ribeiro I, Centeno MJ, Moreira J.
Ropivacaine continuous wound infusion versus epidural
morphine for postoperative analgesia after cesarean delivery: a randomized controlled trial. Anesth Analg 2012;
114:179-85.
13. Sidiropoulou T, Buonomo O, Fabbi E, Silvi MB, Kostopanagiotou G, Sabato AF, Dauri M. A prospective comparison of continuous wound infiltration with ropivacaine
versus single-injection paravertebral block after modified
radical mastectomy. Anesth Analg 2008;106:997-1001,
table of contents.
14. Fortier S, Hanna HA, Bernard A, Girard C. Comparison
between systemic analgesia, continuous wound catheter
analgesia and continuous thoracic paravertebral block:
a randomised, controlled trial of postthoracotomy pain
management. Eur J Anaesthesiol 2012;29:524-30.
Pain: friend or foe? A neurobiological perspective
Fernando Cervero
Anaesthesia Research Unit (Faculty of Medicine), Faculty of
Dentistry and The Alan Edwards Centre for Research on Pain,
McGill University Montreal, Quebec, Canada
Pain is a protective sensation, a useful component of our sensory repertoire, an alarm signal that
warns us of impending damage and a friend that
helps us to go through life reasonably unscathed.
But pain can also be a curse, an unnecessary evil, a
burden to our families and a foe that reduces our
existence to a depressing survival and challenges
the dignity of our lives.
41
ABSTRACT
The line that separates pain as a friend from pain
as a foe is a very tenuous one. It is related to the
time course and intensity of the pain, to chronification, to the underlying cause of the pain and to
the social and economic factors that impinge on
our own ability to endure and fight the pain. Mechanistically, the systems that mediate good pain
and bad pain are often the same, with bad pain
being the result of such mechanisms being triggered inappropriately, by irrelevant stimuli or with a
time course and intensity disproportionate to the
originating cause. In some cases, bad pain is just
pain without an apparent cause.
We know a great deal about the neurobiological mechanisms that mediate good pain. Noxious
stimuli activate specific nociceptors in the periphery which in turn stimulate discrete systems in the
spinal cord and brain leading to the perception of
pain as well as the triggering of motor and autonomic reflexes that remove us from the damage and
help us to heal. If the stimuli are intense or prolonged, the system is sensitized and remains in an
enhanced state of excitability that cause hyperalgesia. Hyperalgesic states contribute to the protective function of pain by reducing the mobility and
function of an injured body part until healing is
completed. The injury-induced inflammation that
accompanies the hyperalgesic state contributes to
the recovery process and to the restoration of function.
We are also beginning to know more about the
mechanisms of bad pain. Often they are linked to
dysfunction or disease of the nervous system, either
of the peripheral nerves or of the CNS itself. What
we see are abnormal expressions of existing normal
mechanisms, triggered inappropriately or with an
exaggerated intensity or a prolonged time course.
When the normal relationship between injury and
pain is broken then the bad pain begins. This lack of
correlation between injury and pain makes neuropathic pain particularly difficult to treat and greatly
distresses the patients who cannot understand the
reason for their excruciating pain.
An example of the reversal of a normal pain
control system into a pain enhancement process is
the mechanism of touch-evoked pain, a symptom
commonly observed in hyperalgesic states induced
by either chronic inflammation or neuropathy.
Normally, activity in large, myelinated A-fibers
inhibits nociceptive primary afferent inputs to the
spinal dorsal horn. The physiological substrate for
this mechanism is primary afferent depolarization
(PAD) a GABA mediated inhibitory process. Ho-
42
wever, in inflamed and neuropathic conditions
PAD might be enhanced such that it now leads to
excessive depolarization of A∂- and C-fibers above their thresholds for action potential generation.
This activation produce a novel A input to the
nociceptive channel which it has been hypothesized to be a potential mechanism for touch-evoked
pain in inflammatory and neuropathic conditions.
In addition, a large proportion of the GABA
mediated inhibition is via a postsynaptic action on
spinal cord neurons. Thus, another important site
where reversal of GABA function can have a dramatic impact is on the postsynaptic action of GABA
on dorsal horn neurons. Indeed, disinhibition of
local dorsal horn circuits can unmask polysynaptic
inputs (normally repressed by local inhibitory neurons) from low threshold afferents to nociceptive
pathways. Furthermore, the conversion of GABA/
glycine mediated transmission into net excitation
may, itself, provide a direct excitatory link from
low threshold input to nociceptive neurons.
These are examples from recent neurobiological
research, of the way in which nociceptive mechanisms in the brain and spinal cord that normally control and reduce pain can be altered to such an extent that the relationship between injury and pain
is lost and the same system changes so that innocuous stimuli now cause pain. Thus, the protective
feature of pain is lost and the resulting sensation
becomes a useless curse that burdens the patient
and is irrelevant to the healing process.
Our challenge is to understand these mechanisms to the point where we can reverse them therapeutically and restore the friendly and protective
qualities of normal pain sensation.
Medical publishing in pain: future directions
Marc A. Huntoon, M.D.
Professor of Anesthesiology Vanderbilt University Nashville
TN, USA.
Introduction. In many ways, we have more
information being published about pain and its
treatment than ever before. In the basic sciences,
the proliferation of animal models has produced genetic “knockouts” where specific genotypes can be bred and the effects of phenotypical changes can be examined in well-designed
experiments. Unfortunately, despite the large
number of positive studies featuring candidate
March 2013

ABSTRACT
therapies that work very well in animals, the true
breakthroughs occurring in the field are nominal. Spontaneous pain is understudied as compared to evoked or inflammatory states, and the
complex interaction of comorbid problems is
not appreciated.1 The practicing pain clinician
is often left bereft of any reasonable therapies
for chronic pain produced by surgery, cancer
therapies, or as sequelae of chronic disease. As a
practicing pain clinician and educator, it is now
a part of every day that one has to tell a student
or resident that we have completed the care algorithm and tell the patient that “we have nothing
left to offer you”, or fight with an insurer/payor
about whether to provide an expensive therapy
for the patient as a “last resort”. During these
times, some pain journals have opted for “guideline warfare” with the use of print for large
treatises about a drug, procedure, or surgery that
they are at least partially biased towards based
on their specialty of origin, academic standing,
or other factors.2 Pharmaceutical and device industry representatives also have biases, and often
contractually control the data from the research
they have underwritten. Study data may or may
not be published in entirety, depending on how
favorable or unfavorable said results are to their
product. Opioid use in the United States and
increasingly other areas of the world has exploded in popularity for treatment of chronic pain
despite essentially no evidence showing efficacy.
Increasingly though, there may be no other affordable options. It is against this backdrop that
the Editors-In-Chiefs (EICs) and their Editorial
Boards must wield their power and (hopefully)
integrity to publish quality science. In no particular order, the following trends and topics in
the field of pain medicine are where I think we
will be focusing over the next decade or so.
Neural Imaging and Mapping of Cortical Responses
to Treatment
Pain is in the brain. We have some evidence that
one can control the activation of certain areas of
the brain involved in pain perception, e.g. the prefrontal cortex, through biofeedback.3 The number
of studies supporting the use of cognitive behavioral functional restoration programs is increasing
quickly. These programs work on the pieces of the
pain puzzle that purely nociceptive therapies do
not. They meet patients at their point of need in
the middle of their dysfunctional lives, depressions
and drug-infatuations and teach them how to live
with their chronic diseases.4 Potentially, through
the development of cortical maps using fMRI, we
can see the specific effects produced by such varied
therapies as sensorimotor retraining, centrally- acting pharmacotherapies, and stimulation produced
analgesia.5
Bedside Diagnosis
Imaging as an extension of the physical exam
is already occurring to some extent with the use
of ultrasound. As the software becomes more and
more sophisticated, the ability to produce bedside
diagnoses may rival the information that can be
obtained from fixed scanners such as MRI or CT
scanners. In some cases, bedside US may be better
than other imaging modalities because of artifacts
produced by the appliance.6
New Devices at the Neural Interface
There are a number of novel devices for the treatment of pain that are on the near horizon. These
include stimulators that can be placed very near the
dorsal root ganglion.7 Studies suggest that the technique is technically facile, that it may compare very
favorably if not better than spinal cord stimulation,
and might be a therapeutic breakthrough for difficult to target areas such as the foot and groin. Future large scale non-inferiority trials compared to
conventional spinal cord stimulation devices and
potentially randomized controlled trials are possible. High frequency stimulation of the spinal cord,
and new devices to treat peripheral nerves at the
nerve-device interface are also being developed.8
The possibility of combination therapies utilizing
pharmacologic priming to enhance response to stimulation is becoming a reality.9
Transparency, Fraud, Plagiarism, Conflicts-of Interest
and other Ethical Issues
A recent survey of 183 medical editors-in-chiefs
was performed, showing that their level of familiarity and competence in dealing with publication
ethics topics was poor.10 Major cases of fraud and
fabrication of data by “accomplished researchers”
has rocked the scientific community and major
EICs.11, 12
Conclusion
Much progress has been made in pain research
and treatment despite multiple distractions. The
future should help us bring relief to our patients.
That is, if we can keep or heads in the game and act
responsibly.
43
ABSTRACT
References
1. Mogil JS. Animal models of pain: progress and challenges.
Nature Reviews Neuroscience 2009;10:283-94.
2. Chou R, Atlas SJ, Loeser JD, Rosenquist RW, Stanos SP.
Guideline warfare over interventional therapies for low
back pain: Can we raise the level of discourse? J Pain
2011;12:833-9.
3. deCharms RC, Maeda F, Glover GH, Ludlow D, Pauly
JM , Soneji D, Gabrieli JDE, Mackey SC. Control over
brain activation and pain learned by using real-time functional MRI. Proc Nat Acad Sciences 2005;102:18626-31.
4. Gillanders, D.T., Ferreira, N.B., Bose, S. and Esrich, T.
The relationship between acceptance, catastrophizing and
illness representations in chronic pain. European Journal
of Pain. 2012;doi: 10.1002/j.1532-2149.2012.00248.x
5. Jensen KB, Berna C, Loggia ML, Wasan AD, Edwards RR,
Gollub RL.The use of functional neuroimaging to evaluate
psychological and other non-pharmacological treatments
for clinical pain. Neuroscience Letters 2012;520:156-64.
6. Long SS, Surrey D, Nazarian LN. Common sonographic
findings in the painful hip after total hip arthroplasty. J
Ultrasound in Medicine 2012;31:301-12.
7. Deer TR, Grigsby E, Weiner RL, Wilcosky B, Kramer JM.
A prospective study of dorsal root ganglion stimulation for
the relief of chronic pain. Neuromodulation 2012; e-pub
ahead of print. DOI: 10.1111/ner.12013.
8. http://www.neurosmedical.com/ Accessed December 16,
2012.
9. Schectman G, Lind G, Winter J, Meyerson BA, Linderoth
B. Intrathecal Clonidine and Baclofen Enhance the PainRelieving Effect of Spinal Cord Stimulation: A Comparative Placebo-Controlled, Randomized Trial. Neurosurgery
2010;67:173-81.
10. Wong VSS, Callaham ML. Medical journal editors
lacked familiarity with scientific publication issues despite
training and regular exposure. J Clinical Epidemiology
2012;65:247-52.
11. Shafer S. Shadow of doubt. Anesth Analg 2011;112:498500.
12. Eisenach JC. Data fabrication and article retraction. How
not to get lost in the woods. Anesthesiology 2009;110:9556.
Ultrasound for chronic pain intervention:
a new era?
Philip Peng
Anesthesia Chronic Pain Program, Toronto Western Hospital,
University of Toronto, Canada
In general, interventional pain procedures can
be performed with or without image guidance.
The use of imaging equipment enhances safety
and accuracy of the procedure as well as patient’s
comfort. Traditionally, imaging equipment refers
to fluoroscopy and computed tomography (CT).
Because of the cost, risk of radiation and requirement of infrastructure, the image-guided techniques are not widely adopted in most of the pain
procedures except those injections in axial structures. Ultrasound imaging allows visualization of
44
the target structures and real-time guidance for injection. This also offers multiple advantages over
fluoroscopy or CT because of its affordability, portability, absence of radiation, and independence of
infrastructure of facilities. Their emerging popularity is evidenced by an upsurging of publications
and workshops in this field.1
Ultrasound for pain intervention can be divided
according to the targets: (1) peripheral; (2) axial;
and (3) musculoskeletal structures.2
The cervical sympathetic trunk (CST) block,
commonly described as stellate ganglion block, is
conventionally performed with landmark-based
or fluoroscopy-guided technique. The targets are
either the anterior tubercle or transverse process
at C6-7 level. However, the CST is defined by
the fascial plane (prevertebral fascia) and ultrasound, not fluoroscopy, can visualize. The needle
is inserted between the trachea and carotid artery.
Recent literature suggested a high prevalence of
presence of esophagus and vessels in this region.3,
4 Ultrasound imaging allows the visualization
and avoidance of this important structures and
enables a ‘lateral’ approach to the CST.4 Large
randomized controlled trial is required to confirm the safety, accuracy and outcome over the
conventional technique.
The standard practice for lumbar medial
branch block is by fluoroscopy-guidance as the
target is bone structure. Ultrasound-guided technique has been validated and compared with
fluoroscopy-guided injection. The accuracy was
approximately 90-95% 5 but success rate fell to
an unacceptable 62% 6 in patients with BMI
greater than 30 kgm-2. Thus, ultrasound technique should be restricted as an alterative to fluoroscopy technique in patient with low BMI. In
contrast, ultrasound-guided technique showed
promising result in cervical medial branch block
especially for the third occipital nerve.7 Contrast
to the lumbar region, obesity is less contributory
to the cervical region.
The use of ultrasound-guided injection for musculoskeletal structures is a well-accepted practice
and the interest is still growing. Literature is robust in supporting the superiority of accuracy with
ultrasound-guided technique, irrespective of the
experience and confidence factor of the practitioner.8-10 Accurate injection results in better outcome.10, 11 The target is defined by soft tissue (e.g.
subacromial bursa, peritendinous injection) and
ultrasound is definitely superior to fluoroscopy in
those targets. It is not that difficult to comprehend
March 2013

ABSTRACT
the superior accuracy with ultrasound-guided technique when one considers how narrow the target is
in glenohumeral joint from a posterior approach
perspective and the slender fascial plane of the subdeltoid subacromial bursa.10
In conclusion, ultrasound for pain medicine
(USPM) for peripheral structures is definitely promising but more outcomes studies are required.
The quality of the target visualization limits the clinical application of USPM for axial structures but
newer techniques such as fusion scan (combining
CT or Magnetic Resonance Image pictures with
ultrasonographic image), target-directing system
or “GPS” system, and real-time 3-dimension scan
can potentially enhance the accuracy and reliability of the USPM technique. The use of USPM
is musculoskeletal structures is well supported by
evidence. It is a matter of time to make this as a popular technique among practitioners. Is ultrasound
for chronic pain intervention a new era? It is just
the beginning.
References
1. Peng P, Narouze S. Ultrasound-guided interventional
procedures in pain Medicine: A review of anatomy, sonoanaotmy and procedures. Part I: Non-axial structures. Reg
2. Peng PWH. In: Peng PWH (ed). Ultrasound for Pain
Medicine Intervention: A Practical Guide. Volume 1. Peripheral Structures. Peng’s Education Series. iBook, Apple
Inc. California, US. (released in Feb 2013).
3. Siegenthaler A, Mlekusch S, Schliessbach J, Curatolo
M, Eichenberger U. Ultrasound Imaging to Estimate
Risk of Esophageal and Vascular Puncture After Conventional Stellate Ganglion Block. Reg Anesth Pain Med
2012;37:224-7.
4. Bhatia A, Flamer D, Peng P. Evaluation of sonoanatomy
relevant to the performance and safety in stellate ganglion
block in 100 subjects Can J Anesth 2012;59:1040-7.
5. Narouze S, Peng PWH. Ultrasound-guided interventional
procedures in pain medicine: A review of anatomy, sonoanaotmy and procedures. Part II: axial structures. Reg Anesth Pain Med 2010;35 386-96.
6. Rauch S, Kasuya Y, Turan A, Neamtu A, Vinayakan A,
Sessler D. Ultrasound-guided lumbar medial branch block
in obese patients: a fluoroscopically confirmed clinical feasibility study. Reg Anesth Pain Med 2009;34;340-2.
7. Siegenthaler A, Mlekusch S, Trelle S, Schliessbach J, Curatolo M, Eichenberger U. Accuracy of ultrasound guided
nerve blocks of the cervical zygapophysial joints. Anesthesiology 2012;117:347-52.
8. Daley El, Bajaj S, Bisson LJ, Cole BJ. Improving injection
accuracy of the elbow, knee, and shoulder. Does injection
site and imaging make a difference? A systematic review.
Am J Sports Med 2011;39:656-62.
9. Berkoff DJ, Miller LE, Block JE. Clinical utility of ultrasound guidance for intra-articular knee injections: a review. Clin Interv Aging 2012:789-95.
10. Peng PWH, Cheng P. Ultrasound-guided interventional
procedures in pain Medicine: A review of anatomy, sonoanaotmy and procedures. Part III: Shoulder. Reg Anesth
Pain Med 2011;36:592-605.
11. Sibbitt WL Jr, Kettwich LG, Band PA, Chavez-Chiang
NR, DeLea SL, Haseler LJ, Bankhurst AD. Does ultrasound guidance improve the outcomes of arthrocentesis
and corticosteroid injection of the knee? Scand J Rheumatol 2012; 41:66-72.
Altered central pain processing: current
status of translational research
Michele Curatolo
University of Bern, Switzerland.
Introduction
It is well known that pain signals from damaged tissues undergo central modulation, leading
to enhancement or attenuation of pain (Woolf,
2011). Following extensive animal research, several clinical studies have detected changes in the
central processing of the sensory input in patients
with pain syndromes. In particular, central hypersensitivity has been an almost consistent finding,
possible causes being an amplification of central
nociceptive processes and / or an imbalance in the
endogenous inhibitory mechanisms (Curatolo,
2011).
While this research has greatly improved our
understanding of the pathophysiology of pain,
attempts to translate the current knowledge into
benefits for patients are almost at its birth. In this
respect, questions that concern the domains of
diagnosis, prognosis and treatment need to be addressed.
Can we diagnose altered central pain processing?
Past research has consistently demonstrated that
groups of patients differ from groups of healthy
controls in terms of sensitivity of the central nervous system to nociceptive and non-nociceptive
stimuli (Curatolo et al., 2006). The fact that hypersensitivity is observed after stimulation of tissues that are not injured is strongly suggestive of
a widespread alteration of central pain processes.
However, this observation should not lead to the
conclusion that all pain patients have such a widespread central alteration. Indeed, the interindividual variability is typically high and data of patients
overlap with data of healthy controls. This means
that the magnitude of widespread hypersensitivity
is greatly variable, and probably not all patients
display this phenomenon.
These considerations clearly show the importance of being able to assess these pathophysiologi-
45
ABSTRACT
cal changes individually, which, in clinical terms,
implies diagnosing a pathological condition.
Different measures of central excitability in
humans are available, known as quantitative sensory tests (QST). QST involve the application of
stimuli and the recordings of responses. Examples
of responses are pain intensity, pain thresholds and
electrophysiological measures, such as evoked potentials or reflex responses. Altered reactions after
stimulation of non injured tissues are suggestive
for altered processes within the central nervous
system. Endogenous inhibitory control can be assessed by conditioned pain modulation (CPM),
whereby pain to a test stimulus is attenuated by a
concomitant painful conditioning stimulus (Pud et
al., 2009).
For any test to be diagnostic, different criteria
have to be fulfilled, the most important ones being
reliability, availability of reference values and validity. Several reliability studies on QST have been performed. Most of them have shown good reliability
(Chesterton et al., 2007; Biurrun Manresa et al.,
2011; May et al., 2012). However, the majority of
studies have been performed in healthy volunteers,
and the measurements have been repeated only few
days apart. More data in pain patients are needed
and the long-term reliability has still to be assessed.
Furthermore, reliability studies on more recent
models, such as methods for CPM, are lacking.
Normative values are becoming available for a
variety of assessments, particularly in the fields of
neuropathic and musculoskeletal pain (Rolke et al.,
2006; Neziri et al., 2010; Neziri et al., 2011).
Construct validity is typically estimated by evaluating the performance of a diagnostic test against
a reference standard. In the case of central pain
processes, no widely accepted reference standard
is available, as such an assessment should explore
directly the excitability of central neural structures.
In the absence of data on construct validity, the
clinical use of QST is based on face validity. An
example of face validity is the assumption that electromyographic recordings of the lower limb after
electrical stimulation (nociceptive reflex) assess
spinal excitability; this is supported by the consideration that a voluntary muscle contraction can be
ruled out if the latency between stimulus and contraction is below a certain cutoff.
Does altered central pain processing predict poor outcome?
In the field of prognosis, a relevant hypothesis
is that patients who display central hyperexcitabi-
46
lity or impaired endogenous modulation would
be more prone to poor outcome. This hypothesis
has been confirmed in studies on whiplash injury, which have shown persistence of pain and disability in the group of patients who had displayed sensory hypersensitivity soon after the trauma
(Sterling et al., 2003; Sterling, 2010). Accordingly,
impaired CPM before surgery was a predictor of
chronic post-thoracotomy pain (Yarnitsky et al.,
2008). These findings were not confirmed by a recent pilot study that analyzed patients during the
chronic phase of low back or neck pain: no significant associations between assessments of altered
central pain processes and clinical outcomes at 1215 months follow-up were found (Mlekusch et al.,
in press).
More studies are needed to establish the prognostic value of different assessments of altered
pain processing. The selection of the tests can be
supported by a recent study that ranked the pain
models according to their ability to discriminate
between patients and pain-free subjects (Neziri et
al., 2012).
Positive findings of prognostic studies would allow the identification of patients at risk who may
undergo preventive strategies or would be enrolled
in intervention studies.
Does altered central pain processing predict the efficacy of treatments?
If alterations in central pain processing are relevant for the determination of symptoms, their
treatment is expected to lead to clinical benefits.
An essential translational question is how to tailor treatments to the individual pathophysiology.
Ideally, a specific alteration would be treated by an
intervention that would act on that alteration, thereby leading to clinical improvement.
Research in this field is still sparse. In a preliminary analysis of a randomized controlled
study on patients with neck pain after whiplash
injury, the presence of both widespread mechanical and cold hyperalgesia was associated with
poor efficacy of a rehabilitation programme (Jull
et al., 2007). In a recent study, alteration of
CPM was a predictor of efficacy of the antidepressant duloxetine in diabetic polyneuropathy
(Yarnitsky et al., 2012).
These preliminary data offer the perspective of
stratifying patients according to possible mechanisms underlying their pain syndrome, and improve
our instruments to select treatments that are most
likely to be effective. Definitely, the available data
March 2013

ABSTRACT
are insufficient in this respect. Large trials that
analyze not only statistical associations, but also
quantify the predictive value of the tests are essential to establish the clinical applicability of this
concept.
ative pain: pre-operative DNIC testing identifies patients
at risk. Pain 2008;138:22-8.
17. Yarnitsky D, Granot M, Nahman-Averbuch H, Khamaisi
M, Granovsky Y. Conditioned pain modulation predicts
duloxetine efficacy in painful diabetic neuropathy. Pain
2012;153:1193-8.
References
1. Biurrun Manresa JA, Neziri AY, Curatolo M, ArendtNielsen L, Andersen OK. Test-retest reliability of the nociceptive withdrawal reflex and electrical pain thresholds
in chronic pain patients. Eur J Appl Physiol 2011;111:8392.
2. Chesterton LS, Sim J, Wright CC, Foster NE. Interrater
reliability of algometry in measuring pressure pain thresholds in healthy humans, using multiple raters. Clin J Pain
2007;23:760-6.
3. Curatolo M. Diagnosis of altered central pain processing.
Spine 2011;36:S200-4.
4. Curatolo M, Arendt-Nielsen L, Petersen-Felix S. Central
hypersensitivity in chronic pain: mechanisms and clinical
implications. Phys Med Rehabil Clin N Am 2006;17:287302.
5. Jull G, Sterling M, Kenardy J, Beller E. Does the presence
of sensory hypersensitivity influence outcomes of physical
rehabilitation for chronic whiplash? A preliminary RCT.
Pain 2007;129:28-34.
6. Mlekusch S, Schliessbach J, Camara RJA, Arendt-Nielsen
L, Jüni P, Curatolo M. Do Central Hypersensitivity and
Altered Pain Modulation Predict the Course of Chronic
Low Back and Neck Pain? Clin J Pain (in press).
7. May A, Rodriguez-Raecke R, Schulte A, Ihle K, Breimhorst M, Birklein F, Jurgens TP. Within-session sensitization and between-session habituation: A robust physiological response to repetitive painful heat stimulation. Eur J
Pain 2012;16:409-10.
8. Neziri AY, Andersen OK, Petersen-Felix S, Radanov B,
Dickenson AH, Scaramozzino P, Arendt-Nielsen L, Curatolo M. The nociceptive withdrawal reflex: Normative
values of thresholds and reflex receptive fields. Eur J Pain
2010;14:134-41.
9. Neziri AY, Curatolo M, Limacher A, Nuesch E, Radanov
B, Andersen OK, Arendt-Nielsen L, Juni P. Ranking of
parameters of pain hypersensitivity according to their
discriminative ability in chronic low back pain. Pain
2012;153:2083-91.
10. Neziri AY, Scaramozzino P, Andersen OK, Dickenson AH,
Arendt Nielsen L, Curatolo M. Reference Values of Mechanical and Thermal Pain Tests in a Pain-Free Population. Eur J Pain 2011;15:376-83.
11. Pud D, Granovsky Y, Yarnitsky D. The methodology of
experimentally induced diffuse noxious inhibitory control
(DNIC)-like effect in humans. Pain 2009;144:16-9.
12. Rolke R, Baron R, Maier C, Tolle TR, Treede RD, Beyer A,
Binder A et al. Quantitative sensory testing in the German
Research Network on Neuropathic Pain (DFNS): Standardized protocol and reference values. Pain 2006;123:23143.
13. Sterling M. Differential development of sensory hypersensitivity and a measure of spinal cord hyperexcitability following whiplash injury. Pain 2010;150:501-6.
14. Sterling M, Jull G, Vicenzino B, Kenardy J. Sensory hypersensitivity occurs soon after whiplash injury and is associated with poor recovery. Pain 2003;104:509-17.
15. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011;152:S2-15.
16. Yarnitsky D, Crispel Y, Eisenberg E, Granovsky Y, BenNun A, Sprecher E et al. Prediction of chronic post-oper-
An injectable nano-delivery platform for
the sustained release of lidocaine
Sm Khaled1, Iman K. Yazdi1,2, Jeff Van Eps1,3, Nima Taghipour1, Jonathan Martinez1, Joseph Fernandez-Moure1,3,
Seth Haddix1, Bradley Weiner4 and Ennio Tasciotti1
1Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, TX, USA
2Department of Biomedical Engineering, University of Houston, Houston, TX, USA
3Department of Surgery, The Methodist Hospital, Houston,
TX, USA
4Department of Orthopedic Surgery, The Methodist Hospital,
Houston, TX, USA
Background and aims
Non-opioid drug therapies are lacking in their
availability and efficacy to treat chronic radicular or acute incisional (post-operative) pain, and
the subsequent reliance on opioid drugs for analgesia has several consequences, including but
not limited to: addiction, GI dysmotility and socioeconomic loss. Providing adequate non-opioid
anesthesia in these clinical scenarios hinges upon
prolonged nerve blockade via long-term bioavailability of anesthetics. Aside from infusions via an
indwelling catheter, most currently available approaches for prolonged anesthetic action provide
no longer than 1-2 days of blockade. To overcome
this limitation of locally acting drugs in pain
management, it is essential to develop methods
of prolonging their efficacy. Recent advances in
nanotechnology place nano-inspired biomaterials
at the forefront of potential pathways to address
the existing shortcomings of pain management.
The aim of this study is to evaluate the ability of a
nanoscale delivery system to provide greatly prolonged, sustained release of lidocaine compared
to the current standard of care.
Methods
Poly(lactic-co-glycolic acid) (PLGA) microspheres, a widely studied delivery carrier for pain
medication, has been modified in this study with
nanostructured silica enclosure (Si) in order to
prolong the release of anesthetic. Si loaded with
lidocaine hydrochloride was embedded in PLGA
47
ABSTRACT
100
Percent Mass Release
80
60
40
20
0
0
1
2
3
Time (day)
4
5
Figure 1.—(a) Si; (b) PLGA-Si; (c) Fluorescent micrograph of PLGA-Si in pluronic gel and (d) SEM micrograph of PLGA-Si
in Pluronic gel (arrow heads showing the existence of PLGA-Si microspheres in gel matrix) and (e) Release profile of lidocaine
hydrochloride from different nanocomposite formulations over five days.
microspheres having two different formulations
(50/50 and 85/15) using solid-oil-water emulsion
technique. PLGA microspheres containing 5 wt%
of Si (PLGA-Si 5%) were mixed in an aqueous solution of 20% Pluronic F-127 at 4 ºC. For release
study, the polymer solution containing the loaded
PLGA-Si were injected in 48-well plates and left
at 37 ºC for one minute for complete gelation of
Pluronic. The pharmacokinetics of the composite
was performed using phosphate buffet saline (PBS)
as a release media under mild agitation at 37 ºC.
Samples of the release were collected at 6, 12 and
24 h, 2, 4, and 7 day time points. The amount
of lidocaine in PBS samples was quantified using
HPLC technique. As controls, lidocaine-loaded
pristine PLGA and Si were used separately as well
as embedded in the gel in this study.
Results
The silica nanoparticles were characterized
by SEM as shown in Figure 1a. Fluorescently
labeled silica nanoparticles integrated in the
PLGA microspheres and the composite microspheres embedded in pluronic gel were evaluated
using fluorescent microscopy as shown in Figure
1b and c. The gel matrix containing the composite microspheres was also analyzed by SEM
48
(Figure 1d). The release profile of lidocaine hydrochloride from control PLGA microspheres
and Si embedded in the gel showed faster release
compared to PLGA-Si composite microspheres
integrated in the gel (Figure 1 e). Control
PLGA(85/15 and 50/50 comonomer ratio)-gel
and Si-gel demonstrated 25-40 and 100% release of lidocaine respectively within two days
while the PLGA50/50-Si and PLGA 85/15-Si
embedded in the gel released 10-20% of total
drug content within the same time frame. Moreover, higher comonomer ratio (lactic to glycolic)
of PLGA used in the preparation of composite
microspheres delayed the release amount by approximately 10% over five days.
Conclusions
We have tangibly demonstrated the capability
to provide sustained release of the local anesthetic
lidocaine via a novel nano-delivery platform. This
biodegradable PLGA-Si system provides a promising new alternative for the delivery of local anesthetic in vitro, and demonstrates the potential to
produce prolonged nerve blockade for the management of acute and chronic pain in vivo. This in vivo
testing is currently being undertaken in our lab and
has great potential implications for translational
March 2013

ABSTRACT
application in the clinical realm of anesthesia and
surgery. Success in this realm could significantly
decrease the large burden of opioid analgesics currently existing in the medical community, and society at large.
Postoperative latent pain sensitisation: can
we prevent acute pain to become chronic?
Margarita M Puig, MD, PhD
Professor of Anaesthesiology and Pain Management,
Department of Anaesthesiology, Hospital del Mar,
Universitat Autònoma de Barcelona, Spain
Preventing the transition from acute to chronic pain is one of the main goals in pain medicine, but efforts have been mostly unsuccessful.
In surgical patients, acute postoperative pain is
followed by persistent pain in 10%–50% of patients after usual procedures.1 There is evidence
supporting the association of female sex, older
age, previous exposure to opioids, high (pre and
post-operative) pain intensity, and pre-injury
anxiety or depression, with persistent pain outcomes, although some risk factors have been
demonstrated only in certain types of surgeries.2,
3 The recognition that acute post-operative pain
may became chronic in predisposed individuals,
is under active investigation both in preclinical
models 4 and humans.
Acute and chronic pains have different mechanisms and the transition from acute to chronic involves, among other issues, peripheral and central
pain sensitisation (changes in neuronal plasticity),
enhanced descending facilitation from the rostral
ventromedial medulla (RVM) to the spinal cord,
and early glial cell activation with increased circulating pro-inflammatory cytokines.5
In a mouse model of post-surgical pain we
have shown that remifentanil based anaesthesia
enhances and extends postoperative pain sensitization.4, 6-8 We have also reported that animals previously injured or exposed to opioids
present long-lasting pain vulnerability shown by
increased susceptibility to develop hyperalgesia
in response to new stimuli or opioid administration.6 This phenomenon is known as latent
pain sensitization,9 and may reflect the transition from acute to chronic pain. In our model,
latent pain sensitisation can be evidenced by the
naloxone test in which the abrupt blockade of
opioid receptors precipitates hyperalgesia. The
effect is stereospecific, centrally originated, and
involves the dynorphin / kappa opioid receptor
system. The blockade of nor-binaltorphimineinduced hyperalgesia by MK-801, also suggests
that NMDA receptors are implicated. Thus surgery induces latent, long-lasting changes in the
processing of nociceptive information that can
be exposed by non-nociceptive detrimental stimuli such as the administration of opioid antagonists.10
Among the multiple possible mechanism implicated in pain hypersensitivity, spinal cord (SC)
and dorsal root ganglia (DRG) glial cell activation has been consistently reported after inflammation, nerve injury 11 and/or opioid exposure.12
However, up to date, glial contribution to postoperative latent pain sensitization is unknown. In
the mice model of post operative pain, we are
investigating adaptative transformations in glial
cells (SC and DRG) after surgery performed under remifentanil anaesthesia. Preliminary results
show long-lasting, latent, morphological changes in glial cells that involve opioid and toll-like
receptors, that might play an important role in
the development of latent pain sensitization in
mice. These results could contribute to establish
future cellular and anatomical targets to prevent
the development of latent pain sensitization after surgery, and the transformation of acute into
chronic pains.
References
1. Kehlet H, Jensen TS, Woolf CJ. Persistent Postsurgical
Pain: Risk Factors and Prevention. Lancet 2006;367:161825.
2. Shipton EA. The transition from acute to chronic post surgical pain. Anesth Intensive Care 2011;39;824-36.
3. Lavand’homme P. The progression from acute to chronic
pain. Curr Opin Anaesthesiol 2011;24:545-50.
4. Romero A, Rojas S, Cabañero D, Gispert JD, Herance
JR, Campillo A et al. A 18F-fluorodeoxyglucose MicroPET
imaging study to assess changes in brain glucose metabolism in a rat model of surgery-induced latent pain sensitization. Anesthesiplogy 2011;115;1072-83.
5. Wang CK, Myunghae JH, Ian C. Factors Contributing to
Pain Chronicity. Curr Pain Headache Rep 2009;13:7-11.
6. Cabañero, D, Campillo A, Célérier E, Romero, A, Puig
MM. Pronociceptive effects of remifentanil in a mouse
model of postsurgical pain: effect of a second surgery. Anesthesiology 2009;111;1334-45.
7. Cabañero, D, Célérier, E, Garcia-Nogales P, Mata M,
Roques BP, Maldonado R et al The pro-nociceptive effects
of remifentanil or surgical injury in mice are associated
with a decrease in delta-opioid receptor mRNA levels: Prevention of the nociceptive response by on-site delivery of
enkephalins. Pain 2009;141:88-96.
8. Campillo, A, Gonzalez-Cuello, A, Cabañero, D, GarciaNogales P, Romero A, Milanes MV et al. Increased spinal
dynorphin levels and phospho-extracellular signal-regulated kinases 1 and 2 and c-Fos immunoreactivity after
49
ABSTRACT
surgery under remifentanil anesthesia in mice. Mol Pharmacol 2010;77:185-94.
9. Rivat C, Laboureyras E, Laulin, JP, Le Roy C, Richebe
P, Simonnet G. Non-nociceptive environmental stress induces hyperalgesia, not analgesia, in pain and opioid-experienced rats. Neuropsychopharmacology 2007;32:221728.
10. Campillo A, Cabañero D, Romero A, García-Nogales P,
Puig MM. Delayed postoperative latent pain sensitization
revealed by the systemic administration of opioid antagonists in mice. Eur J Pharmacol 2011;657(1):89-96.
11. Peters CM, Eisenach JC, Contribution of the chemokine (C-C motif ) ligand 2 (CCL2) to mechanical hypersensitivity after surgical incision in rats. Anesthesiology
2010;112: 1250-8.
12. Horvath RJ, Landry RP, Romero-Sandoval EA, DeLeo JA.
Morphine tolerance attenuates the resolution of postoperative pain and enhances spinal microglial p38 and extracellular receptor kinase phosphorylation. Neuroscience
2010;25:843-54.
13. Berta T, Liu T, Liu YC, Xu ZZ, Ji RR. Acute morphine
activates satellite glial cells and up-regulates IL-1beta in
dorsal root ganglia in mice via matrix metalloprotease-9.
Mol. Pain 22, 2012;8:18.
How can we prolong at-home postoperative regional analgesia?
Edward R. Mariano, MD, MAS (Clinical Research)
Department of Anesthesia, VA Palo Alto Health Care System,
Palo Alto, CA, USA; and Stanford University School of Medicine, Stanford, CA, USA
Regional anesthesia offers patients many potential advantages in the immediate postoperative period such as decreased pain, nausea and
vomiting, and time spent in the postanesthesia
care unit (PACU).1, 2 However, these beneficial
effects are time-limited and do not last beyond
the duration of the block.2 While the clinical
effects of peripheral nerve blocks typically last
long enough for patients to meet discharge eligibility from PACU and avoid hospitalization for
pain control,3 these results can be easily negated if patients’ pain or opioid-related side effects
warrant a return trip to the hospital and readmission following block resolution.4 Thus, investigators have sought to extend block duration
to provide longer-term, site-specific analgesia for
patients on an ambulatory basis.
Continuous Peripheral Nerve Blocks
Continuous peripheral nerve block (CPNB)
techniques (also known as perineural catheters)
permit delivery of local anesthetic solutions to the
site of a peripheral nerve on an ongoing basis.5
Portable infusion devices can deliver local anesthetic for days after surgery with actual duration
50
depending on the reservoir volume and infusion
settings.6, 7 In a recent meta-analysis comparing CPNB to single-injection peripheral nerve
blocks, CPNB results in lower patient-reported
worst pain scores and pain scores at rest on postoperative day (POD) 0, 1, and 2; by POD 3, pain
outcomes appear similar.8 Patients who received
CPNB also experienced less nausea, consumed
less opioids, slept better, and rated their satisfaction with pain management higher during their
infusions.8
Managing CPNB patients at home takes a
hands-on approach, and not all patients are good
candidates for outpatient perineural infusion.7
Patients must have a reliable means of followup, and they should have a caretaker at home
for at least the first night after surgery.7 A health
care provider must be available at all times to
manage common issues associated with CPNB
and call patients once daily to assess for analgesic efficacy and side effects.9 Patients, especially
those undergoing lower extremity surgery, and
their caretakers should receive clear instructions
regarding the care of their infusion device and
catheter as well as their anesthetized extremities. Typical local anesthetic infusion doses in
femoral or lumbar plexus catheters produce clinically-significant quadriceps weakness.10, 11 An
association between femoral perineural catheter
infusions and patient falls has been identified,
which raises an important safety risk especially
for outpatients.12, 13
Although the optimal duration for CPNB is
unknown, 2 to 7 days has been reported for orthopedic inpatients14 with durations as long as
34 days at a United States military hospital.15 At
the completion of the local anesthetic infusion,
perineural catheters must be removed. According to a survey of ambulatory CPNB patients,
98% are comfortable removing their own CPNB
catheters at home, but 4% would have preferred
that a provider perform the removal.9
Despite more than a decade of published data
supporting CPNB for extending the duration
of postoperative pain control, adoption of these techniques is not universal. Many of the issues are arguably system-based, and the lack of
a separate regional anesthesia induction room
(“block” room) 16 or time pressure 17 may be
responsible. However, lack of training in these
techniques may also be a factor 18 or negative experiences with failed placement attempts using
traditional techniques.19
March 2013

ABSTRACT
Adjuvants to Local Anesthetic Solutions for SingleInjection Peripheral Nerve Blocks
Long-acting local anesthetics (e.g., bupivacaine, levobupivacaine, and ropivacaine) generally provide analgesia of similar duration
20-22 for 24 hours or less. 20,23 Several different
drugs have been investigated for their potential to extend single-injection peripheral nerve
block duration when added to local anesthetic
solutions. Epinephrine when added to local
anesthetic solutions provides vasoconstriction
to decrease uptake but has little or no clinical
effect on the duration of longer-acting local
anesthetics.24 Opioids in general likely do not
provide additional benefits in terms of duration, 25 with the possible exception of buprenorphine, 26 and exposes patients to potential
opioid-related side effects. To date, there are
insufficient data to support the addition of
tramadol or neostigmine to local anesthetic solutions. 25 Of the available adjuvants, clonidine
has been demonstrated in clinical studies and
systematic reviews to extend the duration of
analgesia for intermediate-acting local anesthetics (e.g., mepivacaine) with few side effects in
doses up to 150 mcg but may not have an effect
on long-acting local anesthetics.25, 27 There has
been increasing interest in dexamethasone as an
adjuvant to local anesthetic solutions based on
clinical reports of extended duration when added to intermediate-acting local anesthetics. 28,
29 This effect may be less pronounced with
long-acting local anesthetics, with one study
demonstrating average durations of 22 hours
when dexamethasone is added to either ropivacaine or bupivacaine.30 Caution is warranted
when experimenting with adjuvants that have
not been specifically approved for peripheral
nerve block indications (i.e., “off-label” use)
as many of the usual safeguards have not been
performed, and these drugs may have additive
effects on local anesthetic-induced neurotoxicity.31
Novel Extended-Duration Local Anesthetics
There has been interest in liposomal formulations of extended-release bupivacaine for
regional anesthesia for over two decades.32, 33
A recent formulation consisting of bupivacaine encapsulated in multivesicular liposomes to
produce slow release is approved by the United
States Food and Drug Administration for local
infiltration but not yet for regional anesthesia.34
Initial nerve block studies in animals suggest
a lower maximum serum concentration with
the liposomal formulation compared to plain
bupivacaine 35 unless co-administered with lidocaine which facilitates release of liposomal
bupivacaine, 36 and epidural administration in
human volunteers more than doubles duration
of sensory block with a shorter duration of motor block. 37 Additional studies are underway to
further explore the efficacy and safety of this
drug for regional anesthesia.
In summary, there are currently few options
to extend the duration of regional analgesia at
home beyond the one day expected from most
single-injection nerve blocks. CPNB with local anesthetic perineural infusion is an effective method to provide acute postoperative pain
control for up to several days after surgery, but
training in insertion techniques and a system to
manage CPNB patients on an outpatient basis
are necessary. Adjuvants or liposomal formulations of local anesthetics offer potential options
for extended-duration pain control, but further
research regarding efficacy and safety for regional anesthesia indications is necessary.
References
1. Liu SS, Strodtbeck WM, Richman JM, Wu CL. A comparison of regional versus general anesthesia for ambulatory anesthesia: a meta-analysis of randomized controlled trials. Anesth Analg 2005;101:1634-42.
2. McCartney CJ, Brull R, Chan VW, Katz J, Abbas S,
Graham B et al. Early but no long-term benefit of regional compared with general anesthesia for ambulatory
hand surgery. Anesthesiology 2004;101:461-7.
3. Williams BA, Kentor ML, Vogt MT, Williams JP, Chelly
JE, Valalik S, Harner CD, Fu FH. Femoral-sciatic nerve
blocks for complex outpatient knee surgery are associated with less postoperative pain before same-day discharge: a review of 1,200 consecutive cases from the
period 1996-1999. Anesthesiology 2003;98:1206-13.
4. Williams BA, Kentor ML, Vogt MT, Vogt WB, Coley
KC, Williams JP, Roberts MS, Chelly JE, Harner CD,
Fu FH. Economics of nerve block pain management after anterior cruciate ligament reconstruction: potential
hospital cost savings via associated postanesthesia care
unit bypass and same-day discharge. Anesthesiology
2004;100:697-706.
5. Ilfeld BM. Continuous peripheral nerve blocks: a review
of the published evidence. Anesth Analg 2011;113:90425.
6. Ilfeld BM. Continuous peripheral nerve blocks in the
hospital and at home. Anesthesiol Clin 2011;29:193211.
7. Ilfeld BM, Enneking FK. Continuous peripheral nerve
blocks at home: a review. Anesth Analg 2005;100:182233.
8. Bingham AE, Fu R, Horn JL, Abrahams MS. Continuous peripheral nerve block compared with single-
51
ABSTRACT
injection peripheral nerve block: a systematic review
and meta-analysis of randomized controlled trials. Reg
9. Ilfeld BM, Esener DE, Morey TE, Enneking FK. Ambulatory perineural infusion: the patients’ perspective. Reg
10. Charous MT, Madison SJ, Suresh PJ, Sandhu NS, Loland
VJ, Mariano ER, Donohue MC, Dutton PH, Ferguson
EJ, Ilfeld BM. Continuous femoral nerve blocks: varying local anesthetic delivery method (bolus versus basal)
to minimize quadriceps motor block while maintaining
sensory block. Anesthesiology 2011;115:774-81.
11. Ilfeld BM, Moeller LK, Mariano ER, Loland VJ, Stevens-Lapsley JE, Fleisher AS, Girard PJ, Donohue MC,
Ferguson EJ, Ball ST. Continuous peripheral nerve
blocks: is local anesthetic dose the only factor, or do
concentration and volume influence infusion effects as
well? Anesthesiology 2010;112:347-54.
12. Feibel RJ, Dervin GF, Kim PR, Beaule PE. Major complications associated with femoral nerve catheters for
knee arthroplasty: a word of caution. J Arthroplasty
2009;24: 132-7.
13. Ilfeld BM, Duke KB, Donohue MC. The association
between lower extremity continuous peripheral nerve
blocks and patient falls after knee and hip arthroplasty.
Anesth Analg 2010; 111: 1552-4
14. Capdevila X, Pirat P, Bringuier S, Gaertner E, Singelyn
F, Bernard N, Choquet O, Bouaziz H, Bonnet F. Continuous peripheral nerve blocks in hospital wards after
orthopedic surgery: a multicenter prospective analysis of
the quality of postoperative analgesia and complications
in 1,416 patients. Anesthesiology 2005;103:1035-45.
15. Stojadinovic A, Auton A, Peoples GE, McKnight GM,
Shields C, Croll SM, Bleckner LL, Winkley J, Maniscalco-Theberge ME, Buckenmaier CC 3rd. Responding to challenges in modern combat casualty care: innovative use of advanced regional anesthesia. Pain Med
2006;7:330-8.
16. Mariano ER, Chu LF, Peinado CR, Mazzei WJ. Anesthesia-controlled time and turnover time for ambulatory upper extremity surgery performed with regional
versus general anesthesia. J Clin Anesth 2009;21:253-7.
17. Oldman M, McCartney CJ, Leung A, Rawson R, Perlas
A, Gadsden J, Chan VW. A survey of orthopedic surgeons’ attitudes and knowledge regarding regional anesthesia. Anesth Analg 2004;98:1486-90, table of contents.
18. Hadzic A, Vloka JD, Kuroda MM, Koorn R, Birnbach
DJ. The practice of peripheral nerve blocks in the United States: a national survey [p2e comments]. Reg Anesth
Pain Med 1998;23:241-6.
19. Salinas FV. Location, location, location: Continuous
peripheral nerve blocks and stimulating catheters. Reg
20. Casati A, Borghi B, Fanelli G, Cerchierini E, Santorsola
R, Sassoli V, Grispigni C, Torri G. A double-blinded,
randomized comparison of either 0.5% levobupivacaine
or 0.5% ropivacaine for sciatic nerve block. Anesth Analg 2002;94:987-90, table of contents.
21. Hickey R, Hoffman J, Ramamurthy S. A comparison
of ropivacaine 0.5% and bupivacaine 0.5% for brachial
plexus block. Anesthesiology 1991;74:639-42.
22. Klein SM, Greengrass RA, Steele SM, D’Ercole FJ,
Speer KP, Gleason DH, DeLong ER, Warner DS. A
comparison of 0.5% bupivacaine, 0.5% ropivacaine,
52
and 0.75% ropivacaine for interscalene brachial plexus
block. Anesth Analg 1998;87:1316-9.
23. Fanelli G, Casati A, Beccaria P, Aldegheri G, Berti
M, Tarantino F, Torri G. A double-blind comparison
of ropivacaine, bupivacaine, and mepivacaine during sciatic and femoral nerve blockade. Anesth Analg
1998;87:597-600.
24. Weber A, Fournier R, Van Gessel E, Riand N, Gamulin Z. Epinephrine does not prolong the analgesia of 20
mL ropivacaine 0.5% or 0.2% in a femoral three-in-one
block. Anesth Analg 2001;93:1327-31.
25. Murphy DB, McCartney CJ, Chan VW. Novel analgesic
adjuncts for brachial plexus block: a systematic review.
Anesth Analg 2000;90:1122-8.
26. Candido KD, Franco CD, Khan MA, Winnie AP, Raja
DS. Buprenorphine added to the local anesthetic for
brachial plexus block to provide postoperative analgesia
in outpatients. Reg Anesth Pain Med 2001;26:352-6.
27. McCartney CJ, Duggan E, Apatu E. Should we add clonidine to local anesthetic for peripheral nerve blockade?
A qualitative systematic review of the literature. Reg Anesth Pain Med 2007;32:330-8.
28. Movafegh A, Razazian M, Hajimaohamadi F, Meysamie
A. Dexamethasone added to lidocaine prolongs axillary
brachial plexus blockade. Anesth Analg 2006;102:263-7.
29. Parrington SJ, O’Donnell D, Chan VW, Brown-Shreves
D, Subramanyam R, Qu M, Brull R. Dexamethasone
added to mepivacaine prolongs the duration of analgesia
after supraclavicular brachial plexus blockade. Reg Anesth Pain Med 2010;35:422-6.
30. Cummings KC, Napierkowski DE, Parra-Sanchez
I, Kurz A, Dalton JE, Brems JJ, Sessler DI. Effect of
dexamethasone on the duration of interscalene nerve
blocks with ropivacaine or bupivacaine. Br J Anaesth
2011;107:446-53.
31. Williams BA, Hough KA, Tsui BY, Ibinson JW, Gold
MS, Gebhart GF. Neurotoxicity of adjuvants used in
perineural anesthesia and analgesia in comparison with
ropivacaine. Reg Anesth Pain Med 2011;36:225-30.
32. Boogaerts J, Lafont N, Donnay M, Luo H, Legros
FJ. Motor blockade and absence of local nerve toxicity induced by liposomal bupivacaine injected into
the brachial plexus of rabbits. Acta Anaesthesiol Belg
1995;46:19-24.
33. Boogaerts JG, Lafont ND, Declercq AG, Luo HC,
Gravet ET, Bianchi JA, Legros FJ. Epidural administration of liposome-associated bupivacaine for the management of postsurgical pain: a first study. J Clin Anesth
1994;6:315-20.
34. Chahar P, Cummings KC. Liposomal bupivacaine: a
review of a new bupivacaine formulation. J Pain Res
2012;5:257-64.
35. Richard BM, Newton P, Ott LR, Haan D, Brubaker AN,
Cole PI, Ross PE, Rebelatto MC, Nelson KG. The Safety of EXPAREL (R) (Bupivacaine Liposome Injectable
Suspension) Administered by Peripheral Nerve Block in
Rabbits and Dogs. J Drug Deliv 2012;2012:962101.
36. Richard BM, Rickert DE, Doolittle D, Mize A, Liu J,
Lawson CF. Pharmacokinetic Compatibility Study of
Lidocaine with EXPAREL in Yucatan Miniature Pigs.
ISRN Pharm 2011;2011:582351.
37. Viscusi ER, Candiotti KA, Onel E, Morren M, Ludbrook GL. The pharmacokinetics and pharmacodynamics of liposome bupivacaine administered via a single
epidural injection to healthy volunteers. Reg Anesth
Pain Med 2012;37: 616-22.
March 2013

ABSTRACT
Mechanisms of chronification of acute
into chronic pain
Mark A. Schumacher Ph.D., M.D.
UCSF School of Medicine and medical Center, San Francisco,
USA.
The development of chronic pain following
an acute injury, whether by unexpected trauma or following a planned operative procedure, remains a medical and scientific enigma.
On the one hand, we may consider that the
human nervous system was fundamentally
ill prepared to function normally following
acute painful events of extraordinary magnitude. Beyond signaling recognition of impending or real tissue injury, once activated, the
pain pathway may in fact be poorly designed
to subsequently limit or suspend its activity
once the noxious stimulus has been removed.
Therefore, from the nervous system’s point of
view, routine recovery from a thoracotomy or
treatment of invasive cancer may represent an
“unexpected” survival. Importantly, despite
the advent of anesthetics that render patients
insensate during or just following injury, the
eventual cessation of the anesthetic action
typically unmasks ongoing painful sensations
that can last days to weeks. Unfortunately, and
as reported by the Institute for Medicine, for
many patients the sensation of pain may continue for months to years. Moreover, how can
two individuals who sustain the “identical”
injury, disease process or operative procedure have dramatically different long-term pain
outcomes? In one case, the patient experiences
the expected gradual resolution of their pain
while the other has pain that fails to resolve
and that ultimately degrades their quality of
life. Classically, one may consider three predominant modalities that are considered to
underlie the chronification of acute to chronic
pain. They include 1) Peripheral Sensitization:
development of persistent dysfunction of the
peripheral nervous system including the dorsal root or trigeminal ganglion often typified
by lowering nociceptor activation thresholds
or spontaneous activation; 2) Central Sensitization: abnormalities of nociceptive signaling
and plasticity in the spinal cord dorsal horn
often described as arising from enhanced facilitation of nociceptive neurotransmission and
dependent on NMDA mediated signaling; 3)
Supraspinal Modulations: alterations in signal
processing above the spinal cord, especially
changes in plasticity dedicated to descending
inhibition of second-order dorsal horn neurons. Although these three modalities are often
represented as distinct neural systems, under
closer inspection they rely on a set of overlapping mechanisms that once initiated by injury or disease, drive the transition from acute
to chronic pain. Together, these mechanisms
may be broadly viewed as abnormalities in
injury–induced plasticity involving: Inflammation (eg: excessive cytokine production, sustained production of lipoxygenase products);
Post–translational modification (eg: activation of kinases with subsequent modification
and activation of nociceptive ion channels);
and Transcription – Gene expression (eg: activation or repression of gene promoters within the pain pathway that result in either an
overexpression of pain transducing channels
and/or a concomitant reduction of negative
regulatory elements or channel subunits). In
support of such a model, reports linking these
mechanisms to Peripheral Sensitization, Central Sensitization and Supraspinal Modulation
will be presented. Given its dominant role in
regulating cellular plasticity, a special focus on
transcriptional mechanisms of nociceptive plasticity will be undertaken. Emerging findings
from our laboratory have linked the expression of TRPV1 to the Sp1-like transcription
factor family. Subsequent findings support the
hypothesis that development of persistent inflammatory hyperalgesia is dependent on one
or more members of the Sp1-like transcription
factor family. We propose that multiple nociceptive genes are co-regulated by individual
transcription factors or a small subset of related transcription factor family members that
directs a nociceptive (pain) transcriptome. In
turn, we speculate that the emergence of transcription – based therapeutic targeting, such
that exists in cancer chemotherapy, could one
day be designed to prevent or reverse the deleterious effects of aberrant nociceptive plasticity whether arising from peripheral - central
sensitization or descending modulatory pathways. Therefore, future multimodal analgesic
therapies designed to abate or reverse the transition from acute to chronic pain, will require
the inclusion of compounds that will selectively block nociceptive transcriptional plasticity
possibly based on genetic predispositions.
53
ABSTRACT
Drug-drug combinations in the management of chronic pain
Robert B. Raffa, PhD
Department of Pharmaceutical Sciences,
Temple University School of Pharmacy and Department
of Pharmacology,
Temple University School of Medicine, Philadelphia, PA
(USA)
The evolution in understanding pain (patho)physiological processes in recent years has
brought into focus the fact that the optimal
treatment of pain is achieved only when the
mechanism of analgesic effect of the pharmacotherapeutic agent best addresses, that is
matches, the physiologic mechanisms that are
involved in the initiation and chronification
of specific pains. However, many if not most
persistent pain syndromes are initiated and
maintained by multiple underlying mechanistic processes, including nociception, central
sensitization, peripheral sensitization, phenotypic switches, ectopic excitability, structural
reorganization, and compromised inhibitory
systems. The relative contributions of each of
these various mechanisms are time- and intensity-dependent, such that clinical signs such as
hypersensitivity, allodynia, and hyperalgesia
evolve with pain duration. Primary afferent
and sensory neurons play an important role in
nociceptive pain processing, as do inflammation, altered sympathetic function, and changes in somatosensory function, neuropathic
components, along with psychological factors.
And the transition from acute to chronic pain
is not thoroughly understood, but it likely involves interaction among the immune, endocrine, and nervous systems. Other factors no
doubt play a role. Against this background of
complex physiology, it is no surprise that no
single mono-mechanistic analgesic agent can
universally address multi-mechanistic pain
(efficacy and safety). A muti-mechanistic analgesic approach for the management of multimechanistic pain is more likely to provide a
superior clinical outcome. This goal might
be accomplished by combining two analgesics that work through different mechanisms or
by administration of a single agent that works through multiple analgesic mechanisms.
Such combination analgesic products are theoretically more effective because they activate
multiple pain-inhibitory pathways and offer a
broader spectrum of relief. This might include
54
multiple afferents and other transmission pathways as well as multiple processes. Combining
two or more agents from different mechanistic
classes (e.g., opioid + non-opioid, opioid +
acetaminophen (paracetamol), etc.) can result
in an additive or even in a synergistic (greater
than additive) analgesic effect. The combining
of analgesics having different analgesic mechanisms might also allow the use of lower doses
of the individual agents, possibly low enough
doses to reduce the adverse effects below that
expected from the sum of each used alone at
the necessitated higher doses. However, not all
analgesic combinations are better than treatment with individual agents alone. The combination analgesic effect can be greater than,
the same as, or even less than the therapeutic
effects of the individual components. Furthermore, the combination adverse effects can be
the same as, or even greater than, the adverse effects of the individual components used
alone. Therefore, each combination product
– and each combination dose ratio – must be
rigorously evaluated. Such evaluation is mathematically based on the concept of dose
equivalence and the actual (experimental) vs
expected effects can be presented in graphical
representation (e.g., in an isobologram). The
literature provides examples of each of these
concepts.
Steroid injections in chronic spinal pain:
indications, effectiveness, and safety
Honorio T. Benzon, MD
Northwestern University Feinberg School of Medicine Chicago, Illinois USA
Low back with or without radicular pain is
the most common manifestation of back pain.
Radicular pain, or radiculitis, is pain along the
distribution of the spinal nerve root while radiculopathy implies neurologic conduction loss,
i.e. sensory numbness or muscle weakness. The
symptoms usually results from compression or
irritation of the nerve root from a herniated
disc, spinal stenosis, ligamentum flavum cyst
or hypertrophy, or other causes.1, 2 Mechanisms
involved in the production of pain have been
ascribed to the production of prostaglandins
and cytokines. It has been postulated that inflammatory changes in the nerve root cause the
March 2013

ABSTRACT
pain,1, 3 and nerve root edema has been demonstrated on CT scans of patients with herniated
discs.4 Inflammation, lymphocyte infiltration,
and edema were noted on histologic sections
of nerve roots biopsied during discectomy.5
Increased levels of inflammatory cytokines interleukin (IL)-6 and IL-8 were noted in disc
materials taken from patients with known disc
disease.6 Disc herniation results in the release of
phospholipase A2 (PLA2) resulting in the production of prostaglandins.7, 8 Elevated levels of
leukotriene B4 and thromboxane B2, which are
products of PLA2 activity, were noted on biopsies of patients who were operated on for disc
herniation.9 The injection of nucleus pulposus
in the epidural space of dogs resulted in inflammatory changes in the nerve root.10 Recently,
cytokines such as interleukins 1 and 6 (IL-1, IL6) and tumor necrosis factor alpha (TNF-alpha)
have been strongly linked to radicular pain.11, 12
IL-1 beta, IL-6, or TNF-alpha have been noted
to increase the discharge rates and mechanosensitivity of dorsal root ganglion and peripheral
receptive fields in rats.13 It has been noted that
discs express tumor necrosis factor-alpha (TNFalpha) which causes morphologic and functional changes when applied to spinal nerve roots.14 Levels of IL-6 in the CSF of patients with
radicular pain from spinal stenosis correlated
with the degree of spinal stenosis.15 The epidural injection of TNF-alpha inhibitor etanercept
has been shown to have salutary effects in patient with herniated disc 16 or spinal stenosis.17
The epidural injection of the anti-IL6 receptor
antibody tocilizumab decreased low back pain
and numbness in patients with spinal stenosis.18
These results should be contrasted with the
findings that intravenous infliximab had similar efficacy as placebo in relieving sciatica from
herniated disc.19 While these developments are
exciting, issues associated with epidural steroid
injections will be discussed.
Pain relief from epidural steroids are secondary
to their anti-inflammatory (1) and antinociceptive
effect. Steroids not only block cytokine synthesis,
but also interfere with their activity. Steroids have
been shown to suppress spontaneous ectopic neural discharge originating in experimental neuromas
and prevent the later development of ectopic impulse discharge in freshly cut nerves.20 The topical
application of methylprednisolone was noted to
block transmission of C fibers but not the A fibers.21
There have been several studies on the efficacy
of ESIs. Randomized placebo-controlled studies
on interlaminar ESIs showed short-term efficacy of
the ESIs. One study showed reduction in leg pain
at 6 weeks, without functional improvement; the
decrease in pain was not significant at 3 months.22
The other study showed better functional improvement in the steroid group at 3 weeks but not at 6
weeks.23 A placebo-controlled study on caudal ESI
showed better results in the ESI group at 4 weeks,
with no difference at 1 year.24 Epidural steroid injections (ESIs) are given either through the interlaminar (IL) approach or the transforaminal (TF)
approach. The rationale for the TF approach is to
deposit the steroid along the nerve root, through
the intervertebral foramina, and at the lateral and
ventral epidural spaces, i.e. at the interspace between the disc and the nerve root. Studies on TF ESI
showed either no difference when compared with
IL ESI,25-27 or superiority over IL ESI 28-33 and over
paravertebral local anesthetic.33 Non-particulate
steroids have been recommended to improve safety. A dose-ranging study on lumbar TF epidural
dexamethasone showed no differences in efficacy
between 4, 8, and 12 mg dexamethasone.34 The effectiveness of cervical TF epidural dexamethasone
was slightly less than that of triamcinolone, but the
difference was not statistically or clinically significant.35, 36
The safety of fluoroscopically-guided ESIs has
been confirmed in a retrospective study, most
complications were minor and involved pain and
numbness.37 The ASA closed claim study during
the years 1970 to 1999 revealed the increasing
occurrence reporting of injuries from chronic
pain procedures. Of the 5475 claims, ESIs accounted for 83% of the injections and 40% of
the claims.38 A follow-up closed claims study
for the years 2005-2008 was done for cervical
procedures.39 Of the cervical procedures, 59%
resulted in spinal cord damage, 31% of which
resulted from direct needle trauma. Sedation
or general anesthesia was more prevalent in the
claims associated with spinal cord injuries. Case
reports of CNS injury from TF ESIs are secondary to the proximity of the needle to arteries
in cervical TF ESIs 40 and to the steroid’s particle size.41 Methylprednisolone was noted to
have the largest particles, triamcinolone was intermediate, betamethasone was the smallest, and
dexamethasone non-particulate.41 The increased
CNS lesions with methylprednisolone were noted in animal studies.42, 43 Several cases of fungal
55
ABSTRACT
meningitis occurred recently in the U.S., this resulted from contaminated steroids from a single
compounding company. Compounding of steroids is done to eliminate the preservatives in the
steroid. However, an 8- 10-fold increase in the
concentration of the preservatives is necessary to
cause such changes.44 Compounding betamethasone also resulted in an increase in the size and a
change of the appearance of the steroid particle.
A Working Group of experts and the FDA Safe
Use Initiative are working on recommendations
to improve the safety of ESIs.
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24. Bush K, Hillier S. A controlled study of caudal epidural
injections of triamcinolone plus procaine for the management of intractable sciatica. Spine 1991;16:572-5.
25. Rados I, Sakic K, Fingler M et al. Efficacy of interlaminar
vs. transforaminal epidural steroid injection for the treatment of chronic unilateral radicular pain: prospective, randomized study. Pain Med 2011;12:1316-21.
26. Smith CC, Booker T, Schaufele MK, Weiss P. Interlaminar versus transforaminal epidural steroid injections for
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ABSTRACT
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Possibility of particulated steroids injection for selective root blocks in the cervical and lumbar regions: anatomical study
Miguel A. Reina a,b,* , José A. De Andrés c, José M. Hernández a, Andrés López a,b, Manuel Fernández Domínguez b,
Alberto Prats-Galino d
aDepartment of Anaesthesiology, Madrid-Montepríncipe University Hospital, Madrid, Spain
bDepartment of Clinical Medical Sciences and Applied Molecular Medicine Institute, CEU San Pablo University School
of Medicine, Madrid, Spain
cDepartment of Anaesthesiology, Valencia General University
Hospital, Valencia, Spain
dLaboratory of Surgical Neuro-Anatomy, Human Anatomy
and Embryology Unit, Faculty of Medicine, Universitat de
Barcelona, Barcelona, Spain
Selective root block by transforaminal approach
with radiological control allows selective deposition of an appropriate corticosteroid next to the
Figure 1.—Human in vitro anatomical model at cervical level.
Review unintentional possibility of arterial vessel injection
closed out sensitive spinal cervical ganglia with different needles. Needles: 22G Quincke needle and 22G Blunt nerve block
needles (Epimed International).
nerve root. This type of treatment is available since
many decades due to medical consensus and good
clinical results from open studies, but it has been
associated with major neurological complications.
These complications have occurred in small percentages, but the problem still continues. Several
reports revealed that corticosteroid injections performed at the cervical or lumbar spine could be
followed by severe spinal cord ischemic infarction
(Brouwers et al., 2001; Hodges et al., 1998; Ludwig and Burns, 2005; Muro et al., 2007; Rozin et
al., 2003; Suresh et al, 2007; Houten and Errico,
2002; Quintero et al., 2006; Somayaji et al., 2005;
Meyer et al., 2005; Furman et al., 2003), despite
the techniques being performed under radiological
control, trying to recognize the tip of the needle
and any vascular spreading of the solution injected.
Consequences were catastrophic, with neurologic sequelae including vertebrobasilar brain infarcts,
combined brain/spinal cord infarcts, cervical spinal
cord infarcts as well as thalamic, cerebellum, brainstem, or posterior cerebral artery territory infarcts
(Malhotra et al., 2009).These patients resulted in
tetraplegia or bilateral lower extremity paralysis,
with neurogenic bowel and bladder and some cases
associated with hemorrhagic complications and
hydrocephalus (Ludwig and Burns, 2005; Tiso et
57
ABSTRACT
Figure 2.—Human in vitro anatomical model at cervical
level. Review unintentional possibility of arterial vessel injection closed out sensitive spinal cervical ganglia. Needles: 22G
Quincke needle.
al, 2004; Ziai et al, 2006; Lyders and Morris, 2009;
Houten and Errico, 2002; Kennedy et al , 2009;
Scott et al, 2005).
Positive blood aspirate to predict intravascular
injections was 97.9% specific, but only 44.7% sensitive. This test to predict an intravascular injection
is not sensitive, and therefore a negative aspiration
is not reliable (Tiso et al, 2004).
Magnetic resonance examination, spinal cord
arteriography, or pathologic examination suggests
that spinal cord and cerebral infarction were of arterial origin. Vasospasm or arterial traumatic dissection might occur, however, the leading hypothesis until now was that inadvertent intra-arterial
injection of particulate corticosteroid that creates
an embolus causing a distal infarct in the anterior
spinal or vertebral arteries territory (Baker et al,
2003; Tiso et al, 2004; Scanlon et al, 2007).
Detail of arterial vascularization is necessary to
understand the origin of these complications, as
well as to know the size of arteries at intervertebral
foraminal level and possibility to introduce the tip
of needles used. Radicular arteries occupy a medial
place inside the intervertebral foramen, close to
nerve roots. Some reach the spinal cord and others
only the nerve roots. Branches of radicular arteries
are vertebral arteries, as well as ascending cervical,
deep cervical, ribs, lumbar and ilio-lumbar arteries.
Huntoon described the importance of the ascending and deep cervical arteries when performing
transforaminal cervical injections due to their criti-
58
Figure 3.—Human in vitro anatomical model at lumbar
level. Review unintentional possibility of arterial vessel injection closed out sensitive spinal lumbar ganglia. Needles: 22G
Quincke needle.
cal role in spinal perfusion (Huntoon, 2005). The
ascending and deep cervical arterial branches enter
the external opening of the posterior intervertebral
foramen near the target area for transforaminal injections. These branches occasionally supply anterior radicular and segmental medullary arteries to
the spinal cord (Furman, 2003; Hoeft, 2006). Cadaver dissection revealed ascending and deep cervical arterial branches entering the external opening
of the posterior intervertebral foramen.
At lumbar level, the artery radicularis magna
or artery of Adamckievich enters the left foramina
between D9 and L1 in 75% of the patients and
between D7-D9 in 15% and 10% of the cases in
L1-L4. The artery usually enters in the superior or
middle portion of the neural foramen, slightly ventral and superolateral to the dorsal root ganglion.
Injury to the artery of Adamkiewicz can result in
March 2013

ABSTRACT
Figure 4.—Human in vitro anatomical model at lumbar level.
Review unintentional possibility of arterial vessel injection
closed out sensitive spinal lumbar ganglia with different needles. Needles: 22G Quincke needle, 25G Whitacre needle and
22G Blunt nerve block needles (Epimed International).
devastating ischemia of the lower spinal cord causing the anterior spinal artery syndrome (Gillilan,
1958; Huntoon, 2005).
We found vessels next to the nerve root cuff.
Trying to improve our view, we dissected the dural
sac together with nerve root cuffs and plexus roots
in three cadavers. During dissection we kept vessels
close to nerve root cuffs and plexus roots. This area
is the target region for placement of needles during
selective root blocks.
The diameter of these arteries was 1-2 mm at
cervical, thoracic and lumbar level near the puncture zone. Commonly used needles with sharp and
blunt tips were introduced into these vessels (Figures 1, 2, 3 and 4). This study allowed us to verify
that the possibility of arterial injection during a selective root block technique is possible at cervical
level as well as thoracic and lumbar level.
Incidence of intravascular uptake in cervical and
lumbar transforaminal steroid injection procedures
by unintentional and unnoticed penetration of
radicular arteries was studied.
It occurs at different percentage; at cervical level
were 3.9% (Verrills et al., 2008), 11.2% (Furman
et al, 2000, 2003) 11.3% (Kim et al., 2009), at
thoracic level 0.7% (Verrills et al., 2008), at the
lumbar levels 0.9% (Kim et al., 2009), 3.7%(115)
8.1% (Furman et al, 2000, 2003), and at S1 21.3%
(Furman et al, 2000, 2003).
Another possibility could be simultaneous epidural and vascular injection during cervical transforaminal epidural injections. It occurs by partial
vascular penetration: at cervical level were 13.9%
(Smuck et al., 2009) and 52.1% (Furman et al.,
2000, 2003); at lumbar level was 9% (Furman et
al, 2000, 2003) and 32.8% (Smuck et al., 2009).
Steroid with particle sizes larger than 1,000 microns cannot theoretically enter the vessel. Because
the solution is usually shaken before it is injected,
it is possible that the steroid particles coalesce and
precipitate to form the large particles after the steroid has entered the blood vessel. The mediumsized particles (51-1,000 microns) can enter and
partially occlude the vessels. Smaller particles (1050 microns) may not be able to occlude the arteries (Benzon et al., 2007). However, these smaller
particles can occlude the arterioles and capillaries,
causing tissue damage. It is therefore possible that
any particulate steroid can occlude the distal portions of the arteries. In epidural steroid injections,
the steroids are usually diluted to decrease the concentration. Benzon et al., 2007 found that dilution
did not decrease the size of the particles except in
compounded betamethasone, in which increasing
dilutions with the local anesthetic decreased the
proportion of the larger particles.
Methylprednisolone, triamcinolone, and betamethasone have been associated with ischemic
complications reported while dexamethasone was
not (Derby, 2008)
Dexamethasone sodium phosphate particle size
was approximately 10 times smaller than red blood
cells and the particles did not appear to aggregate
(Derby, 2008; Reina, 2010; Gazelka, 2012). These
characteristics should significantly reduce the risk
of embolic infarcts or prevent them from occurring after intra-arterial injection. Triamcinolone
acetonide and betamethasone sodium phosphate
showed variable sizes; some particles were larger
than red blood cells, and aggregation of particles
was evident. Methylprednisolone acetate showed
uniformity in size and most of the particles were
smaller than red blood cells which were not aggregated, but the particles were densely packed (Derby, 2008; Reina, 2010; Gharibo, 2009; Gazelka,
2012)
We studied different particulate steroids with
scanning electron microscopy and observed crystals in normal conditions without dilution and
after dilution with local anaesthetic. Two solutions
were made, one with 1 cc of steroid and 1 cc of lidocaine 1%, used for transforaminal injection and
59
ABSTRACT
another with 1 cc of steroid and 10 cc of bupivacaine 0.25%, used for epidural administration;
both were filtered through a milipore filter of 0.2
microns.
In normal conditions, without dilution, triamcinolone particles piled on the filter. With betamethasone and dexamethasone there were few
particles and none with methylprednisolone.
When diluted with local anaesthetic, only the use
of triamcinolone appeared in different sizes in the
filter: 10-100 microns in the dilution 1:1 with lidocaine 1% and 10-60 microns when diluted 1:10
with bupivacaine 0.25%.
Sharp versus Blunt Needles could be used in this
technique. While some authors advocate to use
blunt needles (Heavner et al., 2003, Raghavendra and Patel, 2005), others (Helm et al., 2003;
Smuck and Leung, 2011) reported inadvertent
injection during cervical transforaminal injection.
Al¬though the use of blunt tip needles seems prudent, we lack clinical evidence that complications
with blunt needles would not occur.
When studying bevel implication, the incidence of vascular injections in the short-bevel needle
group was 15.6% compared with the long-bevel
needles group, 12.8% (Smuck et al., 2010). It did
not reduce the risk of inadvertent vascular injection in lumbosacral transforaminal epidural injections. Neither needle gauge used were no statistical
differences in the overall rates of vascular injection
(Smuck et al., 2010). We can see that introduction
of sharp type needles of 22G inside the artery was
possible. The point of blunt needle may push the
wall of artery and could be more difficult it. However, if that tip of needle perforated the artery,
steroid particles will be intravascular injected.
Conclusions
The size and location of radicular arteries requires us to put extreme precaution when we perform
transforaminal or selective root blocks at cervical
and lumbar regions. Radicular arteries perforation
and unintentional or unnoticed arterial injections
is possible and increases as the do more attempts.
It is necessary to restrict the attempts to a certain
number, especially at cervical level, due to a higherrisk. We should also avoid movement of the needle
with further manipulation after placement and we
should attach a syringe with therapeutic medication (Tiso et al., 2004).
Advices to avoid these complications have to include the use of nonparticulate steroids, test dose
of local anesthetic before injection of steroids, live
60
fluoroscopy, digital subtraction, not using light sedation, use of true lateral view to supplement frontal and oblique views in fluoroscopy, use of blunt
needles, and computed tomography guidance.
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ABSTRACT
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61
POSTERS
Survival on controlled-release (CR) morphine versus cr oxycodone in opioidnaïve patients with non-malignant pain:
data from Danish national health registers
Robin Christensen 1, - Henning Bliddal 1, Simon Tarp 1,
Peter Vestergaard 2
1The Parker Institute, Department of Rheumatology
Copenhagen University Hospital, Frederiksberg
Copenhagen F, Denmark
2Institute of Medicine and Health Technology,
Aalborg University, Aalborg, Denmark
Background and aims. Opioids provide one
treatment option for Chronic non-cancer pain
(CNCP). This study was conducted to compare
the risk of patients rotating opioid therapy from
either controlled-release (CR) morphine or CR
oxycodone in opioid-naïve patients with non-malignant pain.
Methods. By individual-level linkage of the Danish
nationwide administrative registries between 20052007, adult patients who were prescribed either
CR morphine or CR oxycodone, who had not previously been prescribed opioids (at least six months
prior to “baseline” defined as the first prescription
of CR morphine or CR oxycodone), were followed
up for as long as 3 years (maximally until December 31, 2007). Patients with a cancer diagnosis were
excluded from the study and subsequent analyses.
Adjusted for age, sex, comorbidity, calendar year,
concomitant pharmacotherapy, income and social status, Hazard Ratios (HR) for the association
between opioid treatment (CR-oxycodone vs. CRmorphine) and withdrawal from opioid therapy
were analysed by Cox proportional-hazard models.
The main outcome measure was the number of patients switching from one type of opioid to another;
secondary outcome was the number of patients who
were able to withdraw from opioid therapy (i.e., no
further need for opioid analgesics).
Results. Of the 101,635 patients assessed for inclusion, 75,587 (74%) had been prescribed opioids
6 months prior to enrolment and 4,818 (5%) had
a cancer diagnosis. In total, 21,230 patients were
enrolled, 16,553 (78%) were prescribed CR-oxy-
codone and 4,677 (22%) CR-morphine. Of these,
5,750 (35%) CR-oxycodone patients and 2,166
(46%) CR-morphine patients switched to another
opioid. After adjustment, CR-oxycodone was associated with a statistically significant reduced risk
for rotation (switch) to another opioid compared
to CR morphine; HR = 0.82 (95%CI: 0.78-0.87;
P<0.001). Among patients still on therapy at time
of censoring (possible drug addiction development), 4.5% (112) were still using CR-morphine
and 2.1% (231) were using CR-oxycodone.
Conclusions. This study demonstrates a significantly greater risk (18%) for opioid rotation using
CR-morphine compared with CR-oxycodone in
patients suffering from non-malignant pain.
The role of tramadol in labor analgesia
Teresa Letizia Di Gennaro 1, Maria Beatrice Passavanti 1,
Maria Caterina Pace 1, Francesco Coletta 1, Silvia D’arienzo
1, Raffaela Stumbo 1, Vincenzo Pota 1, Pasquale Sansone 1,
Caterina Aurilio 1
1Seconda Università degli Studi di Napoli, Aou S.u.n.,
Napoli, Italy
Introduction. Perineal trauma caused by episiotomy and lacerations occurring during vaginal delivery are often associated to female chronic pelvic
pain , whose etiopathogenesis is multifactorial. In
particular, one of the most important risk factors linked to pain chronicization is pain intensity during
labor. Coadministration of opiates and local anesthetics to get the pudendal nerve block could reduce
pain chronicization.
Aim of the study. The aim of our study was to
compare the efficacy of tramadol, an opiate with local anesthetic properties, vs mepivacaine 2% and vs
the association of tramadol plus mepivacaine 2% to
get the pudendal nerve block during the expulsive
stage of delivery (with cervix dilatation > 7cm).
Materials and methods. In our cohort observational longitudinal 24 months long study were enrolled 75 ASA I or II , 20-32 aged primiparas sche-
63
POSTERS
duled for normal vaginal delivery. Patients, in fact,
were at 37th - 41st gestational week and reported
foetal growth within normal limits, vertex presentation, singleton pregnancy, negative obstetric
anamnesis, BMI < 30. Patients were randomly allocated in 3 groups according to the drug administered to get pudendal nerve block: GROUP T (n=25
pts) received tramadol 100 mg per nerve, GROUP
MT (n=25 pts) received tramadol 100 mg plus
mepivacaine 2% 7 mL per nerve and GROUP M
(n=25 pts) was administered mepivacaine 2% 7mL
per nerve. The total amount of injected drugs was
10 mL, variably reached by the addition of 0,9%
saline solution. Maternal- foetal strict monitoring
during delivery was assessed through foetal tocography, Apgar score at childbirth and 5 minutes later, uterine contractions intensity, continuous maternal heart rate and venous oxygen saturation and
arterial blood pressure every 5 minutes per patient.
Pain severity was assessed by VNRS (Verbal Numerical Rating Scale) 10 minutes after pudendal
nerve block (t0) , at childbirth (t1) , episiorraphy
(t2) , and 12 hours (t3) , 36hours (t4) , 2 and 6
months (t5 and t6 respectively) after delivery. Pelvic Pain Assessment Form (PPAF) was performed
too at anesthesiological visit and 2 and 6 months
after delivery. The length of labor stages was monitored too.
Results. In our cohort all patients presented similar demographic characteristics. As concerning
maternal- foetal monitoring and delivery stages
time, no statistically significant differences were observed among the three study groups. No PPAF administered at the anesthesiological visit was already
suggestive for chronic pelvic pain. As concerning
acute pain, in particular, at childbirth 48% of patients of group M reported moderate pain (VNRS
score: 6) which did not reduce until episiorraphy.
36% of patients of group M complained of weakmoderate pain (VNRS score: 4) at t1, increasing
at t2 time(VNRS score: 5). 16% of patients of
group M complained of weak pain (VNRS score:
2) both at t1 and t2 time. Furthermore only patients complaining of moderate pain (VNRS score:
6) continued to report moderate pain with VNRS
score 4 at t3 and t4 time and a VNRS score 0 at t5
and t6 except 4 patients still complaining of weak
pain with a VNRS score 3 at t5 and t6 time. Only
4 of the above mentioned patients were diagnosed chronic pelvic pain by PPAF administration.
In group T, moreover, 20 % of patients complained of weakmoderate pain with a VNRS score
4 at childbirth (t1) and at episiorraphy (t2). The
64
same patients registered a VNRS score 2 until t4
evaluation. Four patients vomited postoperatively
within 3 hours from the performance of the block.
No patient of group T was diagnosed with chronic
pelvic pain.
Patients of group MT resulted better satisfied of
the antalgic approach because of a weak pain report
(VNRS score 2 in 65% of patients, VNRS score 1
in 35% of patients) at t1 and t2 time. Subsequently
all except one of patients reported a VNRS score 0.
Just one patient complained of pain with VNRS
score 2 at t3 and t4 times and suffered of postoperative vomiting 2 hours after delivery. No patient
of group MT underwent pain chronicization.
Conclusions. Our study confirms local anesthetic properties of tramadol, also for definitely higher
pain intensity, such as that of childbirth. An effective
pain control at the expulsive stage of delivery deals
with a rarer pain chronicization such as assessed by
PPAF. Tramadol plus local anesthetic pudendal nerve block (Group MT) deals with more satisfactory
results. Statistically significant is the difference concerning moderate pain incidence in group MT vs
groups T and M, everytime. Local anesthetic and
analgesic properties make tramadol an atipic, handly and ductile opiate in parturients. Tramadol use
and indications could more and more widespread.
Female chronic pelvic pain post vaginal delivery
laceration is just one of the multiple pathologies
which could benefit from tramadol block by nerve
infiltration.
Efficacy of pain therapy and quality of life
in opioid-naïve patients treated with oxycodone/naloxone or other strong opioids
Sabine Hesselbarth 1
1Regional Pain And Palliative Care Centre, Group Practice,
Mainz, Germany
Background and aims. Patients treated with opioids often complain about a reduced quality of life
due to bowel dysfunction and other impairments
of daily life. This non-interventional study (NIS)
was designed to determine pain control, bowel
function, and quality of life (QoL) in patients treated with oxycodone/naloxone (OXN) prolongedrelease (PR) or other strong opioids.
Methods. In this 4-6-week prospective, multicenter, Ethics Committee-approved NIS, data were
recorded at three visits (baseline, after 1-2 weeks,
study end) in 141 centers. Efficacy was measured
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by changes in pain intensity (Numeric Rating Scale (NRS)). Opioid-induced bowel dysfunction was
assessed using the bowel function index (BFI). Health outcome parameters were measured by EuroQoL-5D.
Results. In total 588 patients were included in
this NIS. A subgroup of 263 patients with nonopioid pre-treatment was analyzed: 154 patients
were treated with up to 40mg/20mg OXN PR/day
and 6 patients with up to 80mg/40mg OXN PR/
day, 103 patients were treated with other strong
opioids. Mean pain intensity (MPI) was reduced
significantly in both OXN PR groups from NRS
7.2 to 3.8 and from NRS 7.0 to 3.0. In patients
treated with other strong opioids MPI decreased
from NRS 7.0 to 4.9. Mean BFI decreased from
NRS 25.8 to 13.7 and from NRS 41.1 to 26.9 in
both OXN PR groups, respectively, whereas BFI
increased from NRS 21.8 to 24.3 in patients receiving other strong opioids. Mobility (no problems in walking about) increased in both OXN
PR groups from 11.7% to 40.3% and from 0%
to 50.0% of patients, respectively. The increase in
the other strong opioid group was less remarkable
(11.7% to 18.4%).
Conclusions. In this NIS, patients with non-opioid pre-treatment treated with OXN PR benefited
from better efficacy, tolerability, and QoL compared to patients treated with other strong opioids,
supporting initiation of OXN therapy in opioidnaïve patients.
Low dose of lidocaine (ld) enhances in
vitro natural killer (nk) cell function
Maria F Ramirez 1, Lavinia Bergesio 2, Mark J. Truty MD
3, Juan P Cata 1
1Md Anderson Cancer Center, University of Texas, Houston,
United States
2Fondazione Irccs Policlinico San Matteo,
Universisty of Pavia,
Pavia, Italy
3Department of Gastroenterology and General Surgery.
Mayo Clinic. Rochester. Minnesota. USA
Background. The perioperative period represents a time of vulnerability for patients undergoing cancer surgery because there are a number of
factors, including blood transfusion, volatile anesthetics, opioids and surgical stress response that
have been suggested to impair the immune system.
(Cata, 2011) Natural killer (NK) cells are key players of the immune response because they are able
Figure 1.—The figure depicts the cytotoxic function of natural killer cells before and after surgery. It can be appreciated
that there is a significant postoperative decrease in the function
compared to preoperative levels. *, p<0.05.
to destroy cancer cells (Wu and Lanier, 2003). Experimental studies have demonstrated that the function of the NK killer cells is decreased by volatile
anesthetics, opioids and surgery.(Goldfarb, 2011;
Hogan, 2011; Vallejo, 2003) Importantly, the impairment in the function those cells correlate with
tumor growth. Similar results have been found in
humans with cancer who undergo cancer surgery.
(Espi, 1996) Our laboratory reported that the function of the NK cells is decreased immediately after
lung surgery (Accepted for publication, Journal of
Clinical Anesthesia, 2013). One of the means of
ameliorating the immunosuppression observed in
the perioperative period is by avoiding volatile anesthetics, opioids and modulation of stress response.
Local anesthetics when used intravenously or as
part of regional analgesia have the ability of block
the stress response and induce significant anesthesia and analgesia hence reducing the need of volatile anesthetics and opioids. Lidocaine is a widely
used local anesthetic. In vitro studies suggest that
lidocaine when used at doses found in peripheral
tissues during regional anesthesia decreases the function of NK cells (Krog, 2002; Mitsuhata, 1991).
However, the effect of lower doses of lidocaine on
NK cells cytotoxicity has so far not been studied.
The aim of the present study is therefore to investigate the in vitro effect of low doses of lidocaine on
the NK cell cytotoxicity of cancer patients.
Methods. This study was approved by the Institutional Board Review of our institution. Blood
samples were collected from patients with abdominal malignancies or osteosarcoma who underwent
tumor resective surgery under general balanced
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A
B
Figure 2.—The figure illustrates the effect of lidocaine on the
function of NK cells. It can be observed that lidocaine significantly improved the function of those cells.
anesthesia. Blood specimens were collected preoperatively and on days 1, 3 and 5 after surgery. Peripheral mononuclear cells (PBMC) were isolated
with Ficoll-paque (Ficoll plaque TM plus, GE Healthcare) gradient centrifugation technique. Natural killer cells (CD56+) were isolated through positive selection (MidiMACS TM starting kit, MACS
Miltenyi Biotec). The human myeloid cell line
K-562 was used as the target cell (ATCC). Cytotoxicty assays were performed at an effector: target
ratio of 1:1 and 10:1. After 20 hour of incubation
with and without lidocaine (20 nM), 100 µl of supernatant was collected from each well to measure
the levels of lactate dehydrogenase release and thus
calculate the function of NK cell (LDH cytotoxicity detection kit, Clontech). The effect of lidocaine
was tested at the lowest level of NK cell function. A
Kruskal-Wallis or paired T- tests were used. Values
66
are expressed in mean +/- sd. A p value lower than
0.05 was considered statistically significant.
Results. Data from a total of 12 patients were
included in the analysis. The mean percentage of
NK cells was comparable before and after surgery.
Briefly, the mean percentage of those cells preoperatively was 13.89% +/- 5.79 and that on days
1, 3 and 5 postoperatively was 12.12% +/- 4.62,
14.59% +/- 5.4 and 11.23% +/- 3.89, respectively
(p=0.419). The function of the NK cells was lower postoperatively than preoperatively (p=0.024)
(Figure 1). The addition of lidocaine enhanced
the function of NK killer cells. Figure 2 demonstrates that when lidocaine was added the cytotoxic activity of the NK cells increased significantly
(p=0.0424).
Discussion. In the present study we demonstrated for the first time that the addition of lidocaine at a dose of 20 nM enhances the function of
NK killer cells. This finding is clinically relevant
because the dose that we used is much lower to
that reported to cause systemic toxicity or even to
that that is clinically used when lidocaine is used
systemically. It is difficult to hypothesize the mechanism or mechanisms behind our findings. One
possible explanation is that the activity of NK cells is more efficient when cancer cells have started
apoptosis or mitotic arrest. This speculation is based on previous studies that demonstrated that local anesthetics are able to induce cancer cell death.
Preliminary data from our laboratory indicates that
at the dose of lidocaine used in this study this local
anesthetic is able to induce some cell death (data
not showed) which is much pronounced at larger
doses. We decided to use this dose of lidocaine due
to possibility that at higher doses would impair
the function of NK cells or induce death on them;
although this last statement is merely speculative.
In the present study, we also confirmed data from
previous studies from our group and others that
indicate that the function of NK cells that is impaired postoperatively. (Greenfeld, 2007)
Our study suffers from several limitations. First,
the small sample size and observational nature of
the study. Second, the in vitro model that we used.
Last, we did not test higher dose of lidocaine hence
we do not know if the effects on NK cells is dosedependent or not.
Conclusion: Our study indicates that at a low
dose lidocaine enhances the function of NK cells.
More studies are needed to confirm our findings
and to have an understanding on the potential mechanisms behind our findings.
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Neuropsychological effects of opioid
drugs in chronic pain patients: state of art
Valentina Caserio 1, Federica Rossi 1, Nicola Allegri 1,
Cristina E. Minella 2, Stefano Govoni 3, Davide Liccione 4
1Scuola Lombarda di Psicoterapia (slop),
Scuola Lombarda di Psicoterapia (slop), Retorbido, Italy
2Pain Therapy Service, Foundation Irccs Policlinico
San Matteo, Pavia, Italy
3Department of Drug Sciences, Pharmacology Section,
University of Pavia, Pavia, Italy
4Department of Psychology, University of Pavia, Pavia, Italy)
Background and aim. Lawlor (2002b) describes cognition as brain’s acquisition, processing, storage and retrieval of information. Cognitive functioning can be evaluated by means
of validated neuropsychological tests able to
assess several ability such as attention, learning
and memory, psychomotor ability and executive
functions (which include working memory, inhibition, planning and decision making skills).
A recent review by Hart and colleagues (2000)
identifies a series of clinical evidences suggesting neuropsychological impairment in patients
with chronic pain: decrements in test performance have been found especially on memory,
attentional and executive tasks, associated with
reduced psychomotor speed.
Opioid analgesics are widely used to treat
moderate to severe persistent pain. Their role in
the long-term treatment of chronic noncancer
pain is controversial. Side effects such as constipation, nausea and sedation often limit the
effectiveness of opioids, leading to early discontinuation, under-dosing and inadequate analgesia. Among the most well-known adverse effects,
cognitive and psychomotor impairment are particularly worrisome and often hinder clinicians
and patients from initiating or optimizing therapy, despite analgesic effectiveness. Many patients report a subjective feeling of mental dullness, fuzziness, slow reactions time and problem
solving difficulties after drug use (Moriarty et
al., 2011; Erseck et al., 2004). Theoretical explanation for such effects is suggested by the
presence of opioid receptors in many areas of
the brain that are involved in attention, memory, learning and executive functions (Chapman
et al. 2002). Given the clinical importance of
this topic, many researchers have recently examined the relationship between pain and cognition in relation to the effects of pharmacological opioid treatment. Opioids may be associated
with cognitive dysfunction and may exacerbate
already existing neuropsychological difficulties.
On the other hand, the analgesic relief, derived
from the assumption of medication, can reverse
the pain-induced cognitive impairment. The
aim of this review is to define the state of art of
the latest studies that have investigated the relationship between chronic pain, opioids drugs
and cognitive functions.
Method. We reviewed relevant English language publications available from 2000 and
2012 in which neuropsychological effects of
opioids in chronic pain patients have been investigated. Electronic databases were searched,
such as Pubmed, and selected articles were
cross-checked for other relevant publications.
Keywords included were chronic pain, opioid,
cognitive impairment and neuropsychological
functions. Since we wanted to focus on information relevant to patients with chronic nonmalignant pain, our review exclude studies
that addressed the cognitive effects of opioids
therapy in cancer pain patients. We also omitted
papers that examined data obtained from opioid
administration in healthy volunteers and nonclinical pain populations as well as those from
preclinical samples. The exclusion of these last
studies is due to the difficulty in generalizing
the findings to the clinical setting.
Results. Findings do not allow the definition
of a clear relationship among pain, opioids and
cognitive deficits; while some studies found that
opioids cause a significant decrease in mental
status (Sjogren et al.2000; Kamboj et al. 2005),
others fail to demonstrate such impairment
(Dagtekin et al. 2007; Agarwal et al.), or even
show that opioid have beneficial effects on cognition (Tassain et al. 2003; Jamison et al. 2003).
This discrepancy is likely due to methodological
differences among studies: first of all, many studies adopted dissimilar operational definitions of
psychological constructs (i.e. “memory”) and
used different neuropsychological tests (memory
can be conceptualized as working memory, short
or long term memory; recall can be immediate
or delayed, free or with cueing and for each of
these meanings specific tools are available) Several studies examined one or just a few cognition
dimensions and failed to assess the complete
neuropsychological profile of patients, because
they didn’t include other abilities (such as high
language skills) not necessary associated with
pain but potentially compromised since related
to attention and executive functions. Secondary,
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few works controlled adequately the potential
confounding effects of variables related to analgesic medication. There was a great variability
about type and doses of drugs (i.e. morphine,
oxycodone, fentanyl, buprenorphine, tramadol), time of treatment. Moreover, experimental
samples differed for type of pain-disease, illness
duration, location and intensity of pain. Comorbidity with psychopathologies (i.e. depression,
anxiety) and the contribution of relevant demographic variables, as age and level of education,
were not always considered.
Conclusion. Chronic pain is recognized as a
biopsychosocial phenomenon in which biological, psychological and social factors dynamically
interact with each other (Gathchel 2007).Attentive, mnestic and executive abilities represents a
fundamental corollary of the model, given the
role they play in physical functioning and in
emotional pain modulation. Indeed, for people
with chronic pain illnesses efficient neuropsychological abilities are critical for performing
daily activities such as driving and for achieving
compliance to therapeutic treatment. Negative
effects on cognition can intensify pain, anxiety, depression and constrain communication
of pain symptoms to clinicians. Moreover, complementary non-pharmacological interventions,
such as supportive psychotherapy or patient psycho-education, demand intact cognitive functioning to be effective. At the present, the great
variability of experimental conditions among
studies evaluating effects of opioid therapy on
cognition limits the generalizability of findings: further methodological ad hoc researches,
including comprehensive neuropsychological
battery, longitudinal follow up, adequate sample size and proper chronic pain non-medicated
control groups, are needed. Other studies are
necessary in order to compensate the paucity
of experimental trials about adverse opioid effects in older patients with or without neurodegenerative impairment. Since the successful of
drug therapy depends on achieving a subjective
balance between analgesic efficacy and possible
side effects, proper patient screening, education,
and preventive treatment of potential side effects may aid in maximizing effectiveness while
reducing the severity of side effects and adverse
events. Finally, advanced knowledge about the
cognitive impact of opioid treatment may explain brain mechanisms that mediate both pain
and cognition.
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Analgesia nociception index: a new system
of monitoring of pain of patient under
general anesthesia
Eleonora Schiappa (1) - Christian Compagnone (1) Fernanda Tagliaferri (1) - Marco Berti (1) - Guido Fanelli (1)
Azienda Ospedaliero-Universitara Parma,
Università di Parma, Parma, Italy (1)
Background and aims. There are no specific indicators of intraoperative pain. Currently, pain is measured using indirect parameters, such as heart rate and
blood pressure, in adjustment of drugs in anesthesia.
Unfortunately, many factors can alter these parameters which, although useful, are not neither specific
nor sensitive indicators of pain and analgesia.
Several authors have repeatedly used the Heart
Rate Variability (HRV) in order to characterize the
activity of the autonomic nervous system (ANS)
during anesthesia to find a parameter that could be
reliable and helpful for the proper management of
intraoperative pain. The pain may alter the HVR,
so its analysis could be used as a target parameter
of the degree of pain. The hemodynamic reactivity
(increase in HR and SBP of 20%) can be expected
by measuring the reaction of the ANS to nociception using HRV. Unfortunately, the study of HRV
is complex, not allowing the use and systematic interpretation in an operating room.
In the last years, as an alternative, a new system
of monitoring (Physiodoloris) has been developed.
This system provides a new index defined ANI
(Analgesia nociception Index) for the assessment
of the balance nociception / analgesia during general anesthesia. The monitor Physiodoloris is able
to measure pain by analyzing the patient’s heart
rhythm. The monitor is connected to the ECG and
provides a real-time index, ANI that is the result of
the analysis of the variability of the RR series. ANI
is expressed on a scale from 0 to 100 % and gives a
continuous reading of the proportion of parasympathetic tone in ANS. In fact, the sinus node of
the heart, that induces the regulation of the heart
rhythm, is connected with the sympathetic and
parasympathetic branches of the autonomic nervous system (ANS).
In presence of a parasympathetic tone, each
respiratory cycle influences the RR range, causing
a slight reduction in the cardiac cycle that corresponds to a small increase in heart rate, known as
Respiratory Sinus Arrhythmia (RSA). In case of a
decrease of the parasympathetic tone, the influence
of each respiratory cycle is damped. This explains
why the area of influence in the respiratory RR
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series can be used to evaluate the activity of the
parasympathetic tone, hence the balanced analgesia / nociception. In presence of a painful stimulus
surgery, or when the analgesic effect is reduced, the
parasympathetic tone decreases with a corresponding increase in sympathetic activity, which will
ultimately lead to a reduction of the Index. Consequently, the mathematical analysis of these variations provides a snapshot image of the activity of
the ANS, the adjustment of the heart rate and thus
the regulation of pain. Considering a ANI cut-off
of 50, we can assume that an ANI value lower than
50 may be indicative of pain / agitation.
The aim of this study was to evaluate the effectiveness of ANI for the evaluation of pain in patients undergoing general anesthesia.
Methods. Patients undergoing elective lobectomy were recruited. Exclusion criteria were patients younger than 18 years, ASA status greater
than 3, inability to consent, inability to assess pain,
known hypersensitivity to any of the drugs used in
the study.
The study involved the use of the monitor Phisiodoloris in patients undergoing thoracic surgery
without changes to the standard protocol used in
these patients. The protocol consists in the placement of an epidural catheter. After a test bolus with
lidocaine 2%, infusion bolus of ropivacaine 3% to
5% were allowed. All patients underwent TIVA
(Total Intravenous Anesthesia). In the operating
room, patients were subjected to continuous monitoring of mean arterial pressure (invasive), ECG,
heart rate, respiratory rate, BIS and ANI.
The parameters were collected before induction
(base), during the positioning of the epidural catheter, after induction, before and after each bolus injection of local anesthetic into the epidural catheter
and during any potential nociceptive stimulus. At
the end of surgery patients were asked to rate their
pain on a numerical rating scales (NRS).
Results. 8 patients were enrolled, 7 males
(87.5%) and 1 female (12.5%) with a median ASA
of 2 (IQR 1). The mean age was 73.6 + 11.7 years.
Two patients reported intensive pain with the insertion of epidural catheter, 100% associated with
an ANI lower than 50 and a difference from baseline ANI statistically significant (p =0.04). Four
patients (57%) had an ANI less than 50 during the
incision.
The patient, who had a mean ANI < 50 during
surgery (100%), reported pain at emergence from
anesthesia (p=0,008).
A significant correlation was found between
the value of ANI at baseline (79 (IQR 30)) and
the value of ANI at bolus (32 (IQR 33)) of local
anesthetic/opioid into the epidural space was performed (p = 0.004).
Conclusions. The intra-operative management
of pain in patients under general anesthesia remains a challenge because there are no standardized models for its evaluation. We found an association between pain episodes and ANI values of less
than 50. Our study aims to lay the groundwork for
further investigation into the new index of nociception which we believe has potential clinical utility in the intraoperative management of patients,
especially in the administration of medications to
avoid over-or under-dosing. Further studies by increasing the number of patients and reducing the
covariates in the study will increase the knowledge
of this new index.
Treatment of disk herniation by intradiscal oxygen-ozone (O2-O3) injection technique
Marcella Sacco (1) - Guido Fanelli (1) - Fabrizio Micheli (2)
Scuola di Specializzazione in Anestesia,
Rianimazione e Terapia Antalgica,
Azienda Ospedaliero-Universitaria,
Parma, Italy (1) - U.o.c di Terapia del Dolore,
Ospedale G. Da Saliceto, Piacenza, Italy (2)
Background and aims. Disk herniation chronic pain is a very common disease and percutaneous
treatment with intradiscal oxygen-ozone (O2-O3)
could be considered as an alternative approach before major neurosurgery.
Aim. Assessment of long-term effectiveness (1
year) of this technique by monitoring the pain relief in patients with back and neck disk herniation.
Methods. 88 medical records of patients treated
with percutaneous O2-O3 intradiscal injection
(January 2004-December 2006, Pain Therapy
Centre, Piacenza Hospital) were retrospectively
reviewed. The follow up examinations, succeeding the treatment, were recorded at one week, one
month, six months and, one year. Pain was measured with the numeric scale (NRS). For the clinical outcome, the quality of life and the therapeutic
success the modified MacNab method was used.
The statistical analysis, for both NRS and MacNab
scale, was performed with non-parametric Wilcoxon test.
Results. 79 patients were enrolled (9 patients did
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not meet inclusion criteria). According to the modified MacNab score the treatment was “successful”
(disappearance of symptoms, complete recovery in
working and sports activities, occasional episodes of
low back pain/sciatica, no limitations of occupational activities) in 55% of patients with low back pain.
Therefore, patients with cervical disk herniation
had no benefit from the treatment. Considering the
lumbar chronic pain subgroups, among the patients
with lumbar iatrogenic or degenerative canal stenosis, complicated by disk herniation, the success was
achieved for 52.3% of subjects; in disk herniation
at L4-L5 or L5-S1 the success was for the 51.85%
of cases; in patients with multiple herniated disk
the rate of success was 57.10%. Statistical analysis
showed a significant reduction of pain (p < 0.00).
Fourteen patients with lower back pain underwent to major surgery for relapsed symptoms after
1 month.
Conclusion. We confirm the efficacy of percutaneous O2-O3 intradiscal injection for the majority of patients with lumbar disk herniation pain.
Intra-articular pulsed radiofrequency
treatment in chronic knee osteoarthritis
pain with ultrasound-guided tecnique
Giuliano De Carolis 1, Lara Tollapi 1, Franca Bondi 1,
Mery Paroli 1, Antonella Ciaramella 1, Paolo Poli 1
Pain Therapy Unit - Dept. of Oncology,
Santa Chiara University Hospital, Pisa, Italy (1)
Background. Chronic osteoarthritis (OA) pain
of the knee is often not effectively managed with
conservative treatments models and some of them
have serious adverse effects. Pulsed Radiofrequency
(PRF) is a therapeutic alternative for chronic pain.
We investigated short- and mid-term effectiveness
of intra-articular PRF applied with ultrasound
(US) guided technique in patients with chronic
knee pain due to OA.
Methods. This study was carried out in the pain
unit of Santa Chiara University hospital between
January 2011 and June 2011.Twenty-one female
patients who received intra-articular PRF were retrospectively reviewed. Intensity of pain and activity were evaluated by a VAS (0=no pain/activity;
10=worst possible pain/activity). Patients were
evaluated at baseline and after 1, 2, 3 mths from
PRF. Changes in pain medications were noted.
Results. Mean sample age was 78, 2 yrs. Before PRF mean intensity of pain was 8.9. During
70
3 months follow-up period all patients showed a
significant reduction of pain during activity. Pain
intensity was 3,8 after 1 mth; 4,2 after 2mths and
5 after 3mths. Pain was absent at rest that resulted
in an improvement in quality of sleep. Activity improved but not in significant way probably due to
the high average age. All patients decreased drugs
rescue dose.
Conclusion. PRF applied to the knee joint appears to be effective in pain reduction and functional improvement in a subset of elderly chronic
knee OA pain. Further trials with larger sample size
and longer follow-up are warranted.
Pain relief and quality of life after spinal
cord stimulation for fbss: a comparison
between paddle and cylindrical lead
Giuliano De Carolis 1, Mery Paroli 1, Lara Tollapi 1, Franca
Bondi 1, Antonella Ciaramella 1, Paolo Poli 1
Pain Therapy Unit- Dept. of Oncology,
Santa Chiara University Hospital, Pisa, Italy (1)
Introduction. In FBSS patients is difficult to
manage low back pain with spinal cord stimulation (SCS). The performance between paddle and
cylindrical shaped SCS lead was evaluated collecting data on pain relief and quality of life improvement in patients with FBSS.
Materials and methods. 81 patients with FBSS
being eligible for SCS. 32 patients have been implanted a paddle lead (S8 seriesTM leads, St Jude
Medical) and 49 a singular cylindrical lead (OctrodeTM leads, St Jude Medical). Outcome measures included pain scores assessed by visual analog
scale (VAS) and the Italian version of McGill Pain
Questionnaire (IPQ), pain medication, and patient quality of life assessed by SF-36 questionnaire. These scores were assessed before and at regular
intervals after 3, 6, 12, 18, 24 mths after implantation.
Results. Two groups did not differ in mean age
and onset of pain. After 24 months VAS and all dimensions of IPQ decreased in significant way (p<.
001). Paddle and cylindrical leads did not show
any significant difference both in VAS and IPQ
dimensions. At the last follow-up 65% of paddle
sub-group stopped their pain medications against
only the 57% of the cylindrical lead. The variation
(ΔT) of all SF-36 dimensions is higher in paddle
subgroup (p<.05). Regarding the body area coverage, in the axial-lumbar area it was in a range of
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90-100% for the paddle and 60-70% for the cylindrical; in the radicular and lower limbs was in a
range of 80-90% for both leads. No adverse events
occurred during the surgical procedure. During
the observation period no displacement occurred
for paddle leads and 4 displacements occurred for
the cylindrical ones.
Conclusion. Paddle leads seemed to be an efficient alternative for patients with FBSS. Despite of
the fact that there were non-significant differences
in pain relief, more paddle patients reduced their
disability and stopped their pain medications.
Ultrasound guided tap block as part of
fast-track multimodal rehabilitation after
cesarean section
Vito Torrano 1, Costantino Bolis 2,
Ermenegildo Santangelo 3, Gianluca Russo 4
1U.O. Anestesia, Rianimazione e Terapia del Dolore,
Azienda Ospedaliera della Provincia di Lodi, Lodi, Italy
2U.O. Anestesia, Rianimazione e Terapia del Dolore
Azienda Ospedaliera della Provincia di Lodi, Lodi,
3Scuola di Specializzazione in Anestesia,
Rianimazione e Terapia Antalgica
Università Magna Graecia, Catanzaro
Background and aims. Postoperative pain
management of caesarean delivery should provide
an adequate analgesia with minimal or no side effects for mother and her child. An effective postoperative analgesic regimen is important to facilitate
the early ambulation, infant care (breast feeding,
maternal-infant bonding) and prevention of postoperative morbidity (thromboembolic events).
The transversus abdominis plexus provides sensory innervations to the anterolateral abdominal
wall and it could be block as part of a multimodal
pain treatment of caesarean section.
Methods. Thirty patients (ASA I-II) undergoing caesarean deliveries at term were randomized
to receive, at the end of surgery, epidural infusion
(patient controlled epidural analgesia, PCEA, continuous 4ml/h of 0.125% levobupivacaine, , 2ml
bolus with 15 min lockout) or bilateral Us-guided
TAP Block (levobupivacaine 0.375% 20 ml for
each side). All patients received standard spinal
anaesthesia with levobupivacaine 10 mg and sufentanyl 2.5 mcg.
We evaluated as our primary outcome the ambulation ability at 6 hours after surgery (walk test)
and as secondary outcomes pain control at rest and
on movement (NRS score at 6h, 12h, 18h, 24 h),
side effect and patient satisfaction.
Exclusions criteria included regular opioids use,
BMI>35 (at the time of enrolment), a prepregnancy weight (<50 kg).
Postoperative acetaminophen (1 gr every six
our) was given in TAP group as part of multimodal
pain management and tramadol (100 mg iv) was
the rescue pain therapy.
Results. US-guided Tap Block allow an earlier recovery after caesarean section compared to
PCEA and provide similar adequate postoperative
analgesia with less side effect. No patient required
rescue drug.
Conclusions. Tap block could be an effective
tool as part of a multimodal analgesia treatment
for caesarean section. Further research is essential
to establish the optimal use of this relatively new
technique.
Lumbar intra-articular facet joint injections in the treatment of facet mediated
low back pain
Sameh Badran 1, Mohamed Madkor 2, Amr Abd Alkader 3,
Ahmed Khatab 4, Tamer Mewida 5
1Department of Neurosurgery, Cairo University, Cairo, Egypt
2Department of Radiology, Ain Shams University,
Cairo, Egypt
3Department of Orthopedics, Cairo University, Cairo, Egypt
4Department of Anesthesia, Ain Shams University,
Cairo, Egypt
5Department of Anesthesia, Alazhar University, Cairo, Egypt
Background. Facet joints are considered to
be a common cause of chronic spinal pain. Facet
joint interventions, including medial branch nerve
blocks, intraarticular injections and neurotomies
(radiofrequency and cryoneurolysis) are used to
manage facet-mediated spinal pain; there is moderate evidence that injection of local anesthetic and
steroids into the facet joint is diagnostic and potentially therapeutic. Appropriate use of fluoroscopic
guidance can potentially reduce catastrophic complications and help in confirmation of needle location thus to improve the outcome .The purpose of
this prospective study was to compare the effectiveness of image guided lumbar intrarticular facet
injection of Hylan G-F 20 (Synvisc) versus steroids
in the management of low back pain due to facet
arthrosis and to evaluate patients’ satisfaction in
each group.
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Methods. This prospective, randomized, study
included twenty four adult patients; with American
Society of Anesthesiologists physical status (ASA) I
or II, who presented with low back pain due facet
arthrosis, after failure of conservative and medical
treatment . Patients were allocated into 2 groups:
The first group (Group I = 12 patients) had been
treated with lumbar intrarticular facet injection of
1.0-1.5 ml of 0.5 % bupivacaine mixed with 40 mg
methylprednisolone with needle position confirmation by computerized tomography guidance; while
the second group ( Group II = 12 patients)had lumbar intrarticular facet injection of 1.0 ml of Hylan
G-F 20 (Synvisc) under computerized tomography
guidance. Using the 5-Points verbal Pain Scale, severity of back pain was rated and recorded before
and after each procedure at intervals of 1 week, 3
months, and 4 months. AT six months after treatment patients’ satisfaction regarding the selected
management were graded as per Modified MacNab’s
outcome assessment of patient’s satisfaction.
Results. There was statistical significant difference between the pre- and post- injection pain
score at 1week, 3 months and 4 months within the
same group (p<0.05).While there was no statistical
significant difference between both groups, comparing the number of patients post injection, 7out of
the twelve (58%) of group I, versus ten out of twelve (83%) of group II had no pain) P>0.05) with no
complications recorded in both groups. Regarding
the overall patients’ satisfaction; at the time of final assessment; seven patients (58%) of group I,
whereas 9 patients (75%) of group II had complete
satisfaction. Two patients in the first group and one
patient in the second group were not satisfied by
the treatment because of persistence of symptoms
at 1 week and 4 weeks in group I; and the recurrence of symptoms at 17 weeks in Group II.
Conclusion. Lumbar intrarticular facet injections with Hylan G-F 20 (Synvisc) or methylprednisolone performed under intermittent fluoroscopic visualization should be considered as a
treatment option for patients with low back pain
due to facet arthrosis. Neither the use of Hylan
G-F 20 (Synvisc) nor methylprednisolone demonstrated any benefit over the other; both are effective and safe with considerable patient satisfaction
up to 6 months post treatment. However samplesize restrictions preclude any definitive comment
and blinded controlled studies with larger patient
population are encouraged to evaluate the clinical
safety and effectiveness of Hylan G-F 20 (Synvisc)
injection into facet joints.
72
Ultrasound-guided alcohol injection in
the treatment of Morton’s neuroma
Gianluca Russo 1, Costantino Bolis 1,
Ermenegildo Santangelo 2, Vito Torrano 1
2Scuola di Specializzazione in Anestesia, Rianimazione
e Terapia Antalgica
Università Magna Graecia, Catanzaro, Italy
Background. The purpose of our retrospective
study is to evaluate the efficacy of ultrasound guided alcohol injection as a treatment of Morton’s
neuroma, a common cause of neuralgia. Morton’s
neuroma is an benign neuroma of an intermetatarsal plantar nerve, second and third intermetatarsal
spaces.
Methods. Twenty seven patients with ultrasound diagnosis of Morton’s neuroma were treated in the past year. Ultrasound was even used to
guide the alcohol injection (20% alcohol) causing
toxicity to the fibrous nerve tissue. All this patients
received other conservative treatment as corticosteroid injection or orthotics before alcohol ablation
of the nerve.
Results and conclusion. Partial or total symptom
improvement was reported after the first injection
and all patient becoming totally pain-free after three
injection. Therefore ultrasound alcohol injections
are an reliable treatment for Morton’neuroma, alternative to the surgery (neurectomy). Usually injections must be performed 2-3 times, with 1–3 weeks between interventions. The injections are well
tolerated by the patients with low procedural pain.
Compared with surgical neurectomy this technique
has almost no serious complications or side effects
and less significant recovery. However other well designed studies are needed.
Comparison of analgesic effect of paracetamol and morphine infusion after elective laparotomy surgeries
Peyman Yazdkhasti, Saeid Safari, Mahsa Motavaf
Department of Anesthesiology and Pain Medicine,
Rasoul Akram Medical Center,
Tehran University of Medical Sciences, Tehran, Iran
Background and aim. Introduction of the newest short-acting analgesic drugs for intraoperative
pain control and widespread acceptance of them
in anesthesia practice, has made the postoperative
pain control a new dilemma to anesthesiologist,
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especially in more painful surgical procedures (like
laparotomy). Opioid narcotics had been traditionally used for this purpose but because of their
side effect (like nausea, vomiting, and respiratory
depression) have made us decrease their use. Scientists are still seeking for new analgesic agents with
less side effects. Paracetamol-intravenously form
of acetaminophen-is a new compound which has
been studied for postoperative pain control. The
aim of our study is to compare the analgesic effect
of paracetamol and morphine infusion after elective laparotomy surgeries.
Materials and methods. this is a double-blind
study which was carried out on 150 ASA (American
Society of Anesthesiology) class I-II patients between 27-85 years that were scheduled for elective laparotomy. The subjects were divided accidentally into
two groups, each of which included 75 patients.
Technique of anesthesia was similar in all of them
(TIVA technique).Then we administered paracetamol (4 gr/24hr) in group 1 and morphine (maximum dose 10mg) in group2.after the end of surgery the visual analog scale(VAS) for postoperative
pain evaluation in several time was performed. This
evaluation was performed by a member of research
team not involved in the study. Any patient complaining of pain or VAS≥ 4, 0.03 mg of pethidine
was injected and if needed, the same dose was repeated till the patient was free of pain. The total dose
and number of doses injected was recorded.
Results. The analysis was performed on the complete data of 150 patients (75 in paracetamol group
and 75 in morphine group). Mean age of the study
population was 54±15.45 years, which was comparable 150 between groups.
The data analysis showed both groups were similar in regard to age, sex, duration of surgery.
The pain score in paracetamol group and morphine group was meaningful in first 8 hours after
operation (p value=0.00).but after 12 hours of the
study, the evaluations of pain were similar in both
groups (p value=0.14).
In both groups the Visual analog scale pain intensity scores were lower than 3 after 8 hour. The
total dose of rescue drug (pethidine) and number
of doses injected shown a meaningful difference in
the above group (p value =0.00).
The cumulative doses of pethidine were significantly differences in both groups (morphine versus
paracetamol) over the study period but degree of
sedation of all patients was generally mild in both
groups.
During the 24 hours of the study, the evalua-
tions of pain were similar in both groups, except
at 8 hours. This showed that pain scores were significantly lower for patients receiving morphine.
(P=0.00)
The nausea, vomiting and itching showed a meaningful difference in two groups (P value =0.034,
p value =0.00). No patient had a respiratory rate
<10 breaths/ min during the study period and no
late complications were reported.
Postoperative interviews with both patient
groups before hospital discharge showed a high
level of satisfaction. More patients in the paracetamol group felt that their postoperative analgesia
was excellent or good as compared with that of the
morphine group.
Percutaneous disc decompression for lumbar pain, what is new?
Al-Ali Salah
Dubai Bone and Joint Center, Sheikh Mohammed Bin Rashid
Al Maktoum Academic Medical Centre
Dubai, United Arab Emirates
Chronic low back pain is a major public health
problem in industrialized societies and ranks first
among all musculoskeletal disorders resulting in serious morbidity and financial loss. Approximately
70%-85% of all humans experience back pain at
some point in their lives.
Lumbar disc bulging, protrusion, or extrusion account for less than 5% of all low back problems, but
are the most common causes of nerve root pain and
surgical interventions .
Although surgical correction was made possible
to some extent, the high incidence of complications frustrates both patients and physicians.
To avoid risk and complications from open surgery, a number of techniques have been developed
that are applicable to the treatment of lumbar disc
herniation.
Most techniques for disc decompression utilize
coblation, laser, and physical aspiration, chemical
or thermal methods. These approaches have been
designed either to shrink or remove disc material
believed to be causing lumbar pain and/ or radiculopathy.
Generally, these procedures are proven to have
low complication and high success rates and it seems to be very cost effective.
We will review the literature to find out the
most recent applicable disc decompression proce-
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POSTERS
dures and its evidence based clinical usability, limitations and efficacy. Also we will highlights the
current ongoing studies in this field, like cell based
therapies using mesenchymal stem cells (MSCs) to
produce nucleus pulposus cells and matrix.
Epidural steroid use in Northern Ireland.
Are we missing the point?
ter selective transforaminal block: the role of corticosteroids. Spine J 2004;4:468-74.
4. Fitzgibbon DR et al. Chronic pain management: American Society of Anesthesiologists Closed Claims Project.
Anesthesiology 2004;100:98-105.
Radiofrequency pain treatment in hip and
knee osteoarthritis patients unsuitable for
surgery
Rory Maguire
Belfast Trust, Mater Hospital, Belfast, United Kingdom
Claudio Baldi, Vincenzo Tagariello)
Background. Epidural steroids are commonly
used to help manage chronic and subacute spinal
pain. Recent guidelines have recommended tenets
of good practice when administering such injections.1 The use of fluoroscopic guidance has been
advocated to ensure correct needle placement and
spread of injectate. Incorrect needle placement rate
is unacceptably high with standard loss of resistance techniques.2 Furthermore, particulate steroids
have been associated with rare but catastrophic side
effects with inadvertent intravascular injection.3
Methods. All consultants working in NHS pain
management clinics across Northern Ireland were
surveyed with regard to their practice of epidural
steroid injection.
Results. In total, 16 consultants were surveyed.
A response rate of 13/16 (81%) was achieved. All
5 hospital trusts were represented. The majority of
consultants (69%) do not use fluoroscopy routinely for epidural steroid placement. Particulate
steroids are the main therapeutic agent (92%). Almost 40% of consultants do not consent patients
for the off label use of this medication.
Conclusions. Epidural steroid administration
is common practice. Incorrect steroid placement
denies therapeutic benefit and may confer serious
risk. High litigation rates are associated with this
procedure4. Fluoroscopic guidance and/or use of
non-particulate steroids should be considered by
practitioners to protect their patients, and themselves.
Background. Osteoarthritis (OA) is a major cause of pain in hip and knee joints, the most effective
treatment being surgical joint replacement. The majority of these Pts are in older age groups, so that
is not infrequent in this setting to face individuals
with severe organ failure (i.e. cardiac, respiratory,
metabolic) who are unsuitable for surgery, due to
unacceptable high risk. Conventional medical pain
therapies (i.e. opioids, NSAIDs, steroids) have also
the risk of worsening ,in such fragile Pts, an already
unstable condition and, moreover, are often given
so cautiously to become substantially useless. RF
use has been postulated as effective in treating pain
arising in hip joint (1).Initial reports have been published about RF in these conditions (2,3,4)- We
therefore decided to apply Radiofrequency (RF) treatment at knee or hip joint in a small number of Pts
suffering from severe pain and who had been judged
unfit for replacement surgery.
Methods. During the period Jan-Jun 2012 we
have treated 10 ASA IV Pts with painful OA of
the hip or knee joint. The mean age was 76.4 y.o.
(range 68-87). 4 were Male and 6 Female; 4 had
their hip affected and 6 the knee). All had a VAS>7
when enrolled, showing a poor efficacy of medical
therapy (all of them had NSAIDs and paracetamol,
4 were also on chronic opiates, 2 were taking additional steroids).
RF for the hip was done as follows: Pt supine,
fluoroscopy in A-P projection, POE 1-2 cm lateral
to the femoral artery, needle advanced in an oblique external direction; targets were: sensitive branches of obturator and femoral nerves innervating
respectively the inferior and the superior border of
the hip joint(1). Following positive sensitive and
negative motor stimulation, 2 ml of 0.5% ropivacaine were injected. Then a continuous RF lesioning was applied at 80°C for 72 sec on each nerve.
RF for knee was done as follows: Pt supine, knee
flexed at 45°, Ultrasound guide; Targets were: geni-
References
1. Faculty of Pain Medicine (RCOA). Recommendations for
good practice in the use of epidural injection for the management of pain of spinal origin in adults. April, 2011.
2. Bartynski WS et al. Incorrect needle position during lumbar epidural steroid administration: Inaccuracy of loss of
air pressure resistance and requirement of fluoroscopy and
epidurography during needle insertion. American Journal
of Neuroradiology 2005;26:502-5.
3. Tiso RL et al. Adverse central nervous system sequelae af-
74
Ospedale S Pietro, Fatebenefratelli, Rome, Italy
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colate branch of common peroneal nerve(GBCP)
and terminal sensitive branches of the femoral nerve(
TBFN) innervating the patella. GBCP was treated
with 4 cycles of pulsed RF at 42°C for 120 sec. TBFN
were treated by ablative RF at 80°C for 72 sec on 1 or
2 points, following sensitive stimulation and patient’s
response.
Results. Follow-up was made at 2 weeks and 3
months. VAS was reduced from an average of 7.2 to
4.0 (2wks) and to 3.0 (3 mo) in the knee Pts. VAS
for hip Pts was 9.0 at starting, and fell to 6.0 (2 wks)
and to 3.5 (3 mo) when considering only 3 Pts, the
fourth reporting no benefit at all.
Discussion. RF, both pulsed and ablative, showed
to improve VAS on 9/10 Pts we enrolled and the results were maintained for at least 3 months. As all
were high surgical risk Pts, RF gave them the chance
of a better QoL, without the hazards associated with
an aggressive medical management. Should these
very initial results be confirmed by larger studies and
RCTs , RF lesioning of the peripheral sensitive rami
on the hip/knee joint, could also serve as a bridge
therapy for those waiting surgery or who want to
postpone it.
Non-contact optical photoplethysmography imaging technique make safe decisions before neurotomy or neurolysis
Iveta Golubovska 1, Aleksejs Miscuks 1, Mikhails Arons 2,
Uldis Rubins 3
University of Latvia, Faculty of Medicine
1Hospital of Traumatology and Orthopaedics, Riga, Latvia
2Pain Clinics Dap, Riga Stradina University, Riga, Latvia
3Institute of Atomic Physics and Spectroscopy
University of Latvia, Riga, Latvia
Background and aims. The goal of our research
was to find safe quantitative method for monitoring the quality of sympathetic block during the
invasive treatment of neuropathic pain: lumbar radiofrequency neurotomy or neurolysis.
Methods. The sympathetic block at lumbar III
level under X-ray control in AP and LL views with
a contrast was performed. Local anaesthetic (LA)
Lidocaine 100 mg/8 ml was injected. The photoplethysmography (PPG) have used green spectral band of backscattered radiation for detection
of amplitude of blood volume pulsations in skin
upper layers. The data of modification amplitude
of blood volume pulsations was analyzed “online”.
After increasing of PPG signal more than two times
we considered the sympathetic block is successful.
Results. The blood flow obtained by reflection
PPG increases immediately after LA injection.
Changes of PPG amplitude confirm it. Verification of changes in the skin blood flow and PPG
signal amplitude after LA input on 16 patients was
averaged (R = 0.96, P< 0.0001); on each patient
(R=0.8±0.14, P< 0.0001).
The sympathetic block absence was detected
when the PPG signal amplitude not increased or
was inside of a region of +/- standard deviation evaluated in one minute interval.
In the case of “successful” sympathetic block the
average PPG amplitude before the start of the manipulation is 0.25±0.04; with a -95% confidence
interval it is 0.17; with a +95% confidence interval
it is 0.33; the ±95% average feasibility interval is
0.08. In the case of “successful” sympathetic block
the average PPG amplitude at the end of the measurement is 0.86±0.07; with a -95% confidence
interval it is 0.71; with a +95% confidence interval
it is 0.99; the ±95% average feasibility interval is
0.14.
Conclusions. The new imaging phothopletismograpy technique, based on inexpensive components gives additional quantitative, online, contactless, radiation free method which may be used
for sympathetic block confirmation at any conditions.
Ultrasound guided costovertebral canal
block: a novel approach for ipsilateral
analgesia of the trunk
Satoh Yutaka
Department Of Anesthesia, Tsugaru Seihokugo Region Union
Seihoku Chuo Hospital, Goshogawara, Japan
Background and aims. There is increasing interest on thoracic paravertebral block for ipsilateral
analgesia for breast or thoracic endoscopic surgery.
However, this procedure has several limitations:
The risk of pneumothorax, epidural or subarachnoid block, and the patients under anticoagulant
therapy. The aim of this study is to investigate the
spread of local anesthetics injected in the costovertebral canal (CVC) just above the lamina of thoracic vertebra.
Methods. With written informed consent,
ten patients who underwent ipsilateral breast
surgery were scheduled to receive CVC block
for postoperative analgesia. Patients with any
degenerative or pathological change in vertebral
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POSTERS
column on admission were excluded from the
study. The patients are laid in lateral decubitus
position, under ultrasound guidance, a mixture of 10ml of 0.375% Ropivacaine and 10ml of
contrast media was injected just above the midpoint of lamina of 3rd thoracic vertebra. Radiographic studies were conducted at after 5ml,
10ml, 15ml and 20ml of cumulative volume injections. In two cases, Rt. to Lt. view image were
taken in spine position.
Results. In all ten cases, the injected fluid were
distributed within the costovertebral canal, mean
average 3:7, dominantly caudad. In two cases in
Rt. to Lt view image, contrast media suggested
spread into paravertebral space after 30 minutes of
injection.
Conclusions. This preliminary results suggest
that the spread of anesthetics to intercostal nerves,
hence ipsilateral analgesia of the trunk may be expected. Further anatomical and clinical studies are
warranted to compare the quality of analgesia with
conventional thoracic paravertebral block.
Relevance of Cytochrome p450 determination (genotype and phenotype) for
analgesic efficacy or resistance in a multidisciplinary pain center
Victoria Rollason 1, Kuntheavy Ing Lorenzini 1, Caroline
Samer 1, Youssef Daali 1, Marie Besson 2, Valérie Piguet 2,
Monica Escher 2, Pierre Dayer 1, Jules Alexandre Desmeules
1
1Clinical
Pharmacology and Toxicology
University Hospitals of Geneva, Geneva, Switzerland
2Clinical Pharmacology and Toxicology,
Multidisciplinary Pain Center,
University Hospitals of Geneva, Geneva, Switzerland
Background. Since 2005, the Geneva University Hospitals offer the possibility of several genotyping and/or phenotyping tests. The Multidisciplinary Pain Center offers an assessment of intractable
and chronic pain where patients are evaluated by
different experts. Individualised multidisciplinary
therapeutic programs are provided, including medication treatments adapted to specific phenotype
and/or genotype. The results of these tests are systematically interpreted by our Division of Clinical
Pharmacology and Toxicology.
The objective of this analysis was to evaluate the
data obtained after genotyping and/or phenotyping the patients seen in our pain consultations as
to the type of patients, the reasons leading to these
76
consultations, the drugs involved and the relevance
of these tests.
Methods. Since 2005, 345 patients were evaluated by our division after being genotyped and/or
phenotyped, of which 145 (42%) where pain patients. Genotyping tests relevant for analgesic treatments were CYP2C9, CYP2C19, CYP2D6, Pgp
and COMT and were available either by traditional
PCR or Amplichip® CYP450 (Roche, Basel). Phenotyping tests were done using a cocktail specific
probe approach and allowed simultaneous testing
of CYP1A2, 2C9, 2C19, 2D6 and 3A4/5. This approach was developed by our clinical pharmacology laboratory and uses caffeine as a probe to test
the activity of CYP1A2, flurbiprofen for CYP2C9,
omeprazole for CYP2C19, dextromethorphan for
CYP2D6 and midazolam for CYP3A4/5. Except
for omeprazole, all of these probes were given in
microdoses.1
Results. Mean age of patients was 57 years old
(from 11 months to 99 years old) and 66% were females. The main reason for geno and/or phenotyping was the occurrence of an unexpected adverse
drug reaction in 69% of patients. Other reasons
were analgesic resistance (19%) and exploration
of the genotype and/or the phenotype as a prediction before prescribing an analgesic (10%). Some
of these tests were also done to try and explain an
infra- ou supratherapeutic drug concentration, especially for antidepressants. Fifty-one percent of
the drugs in these evaluations were those that need
to be bioactivated by CYP2D6 into an active metabolite (tramadol, codeine and oxycodone). Other
drugs were opioids (21%), antidepressants (15%)
and NSAIDs (8%). Patients evaluated had complaints with more than one analgesic drug in 54%
of the cases. Twenty-seven percent of these patients
were simultaneously geno- and phenotyped. The
primary reason for evaluation by our consultation
was explained by geno and/or phenotype in the
majority (65%) of the cases.
Conclusion. Pain patients often suffer from adverse drug reactions and/or inefficacy of their analgesic treatment. Geno- and/or phenotyping tests
can help to explain the adverse drug reactions or
the resistance to treatment that occur when trying to treat these patients. Patients taking “prodrug” analgesics, that need to be bioactivated by
CYP2D6 to exert their efficacy, take benefit from
genotyping and phenotyping tests because they
seem especially prone to adverse drug reactions and
inefficacy of their treatment and sometimes even
experience both.
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This analysis highlights the potential usefulness
of both genotype and phenotype tests to better
understand adverse drug reactions or unexplained
resistance to analgesic treatment.
Impacts of high concentration of ropivacaine in second stage of labour during
epidural analgesia
Silvia Poma, Federica Broglia, Maria Ciceri,
Elisa Domenegati, Marinella Fuardo, Silvano Noli,
Simona Pellicori, Filippo Repossi, Debora Sportiello,
Silvia Zizzi, Marcella Ilardi, Dario Bugada,
Barbara Pistone, Maria Paola Delmonte, Giorgio Iotti
Anestesia e Rianimazione 2,
IRCCS Policlinico San Matteo, Pavia, Italy
Background and aims. Maternal pain changes
throughout labor especially during the second stage
where higher concentration of local anesthetic for
epidural analgesia are required. The aim of this study
was to assess how epidural analgesia with high ropivacaine concentration affects obstetric outcomes
(second stage duration and mode of delivery), maternal outcomes (free mobility during labor, satisfaction) and neonatal outcomes (apgar, arterial ph).
Methods. A total of 213 [Group A (107);
Group B (96)] singleton uncomplicated pregnancies above 36 weeks of gestational age during second stage of labor were retrospectively compared.
Ropivacaine 0.1% and 0.15-0.2% (top up) were
respectively administered to Group A and Group
B. Maternal, obstetric characteristics and dose of
ropivacaine (Group A mean: 20,9 mg, Group B
mean: 21,5 mg) did not differ among the groups.
Obstetric and neonatal outcomes were reviewed
from hospital database. Maternal satisfaction and
mobility during labor have been investigated with
a questionnaire after delivery.
Results. The results are summarized in Table I.
Conclusions. High concentrations of Ropivacaine during epidural analgesia seem to increase duration of second stage of labor but don’t affect obstetric
outcomes and reduce the rate of inadequate maternal
pain relief, appearing to be safe for neonates.
Ayx1: a single-dose intrathecal dna-decoy for the prevention of acute and chronic postsurgical pain
Julien Mamet Mamet 1, Donald Manning 1, Scott Harris 1,
William Schmidt 2, Klukinov Michael 3, David Yeomans 3
1Adynxx, Inc, N/a, San Francisco, United States
2Northstar Consulting, N/a, Davis, United States
3Stanford University, Stanford University, Stanford, United
States
Background and aims. Persistence of pain
following surgery compromises clinical recovery.
AYX1 is a DNA-decoy drug candidate designed to
prevent post-surgical pain with a single intrathecal
dose. Following an injury, the transcription factor
EGR1 rapidly triggers broad and ongoing waves
of pain-related gene regulation in the dorsal root
ganglia and dorsal horn, leading to long-term sensitization and pain. AYX1 is an EGR1-decoy (an
Table I.
Duration of ii stage
Minutes (mean;sd)
Limited mobility during ii stage (%)
Mode of delivery
Vaginal delivery rates (%)
Operative vaginal delivery rates (%)
Cesarean section rates (%)
Maternal satisfaction
Good (%)
Sufficient (%)
Inadequated (%)
Apgar score
1 Minute (mean;sd)
5 Minute (mean;sd)
Neonatal arterial ph (mean;sd)
Ropivacaine 0,1%
Group a (107)
Ropivacaine 0,15%- 0,2%
Group b (96)
P
53,35 (33,42)
20
67,48 (43,48)
13
0.009
Ns
80,5
17,7
1,8
88,6
8,3
3,1
Ns
Ns
Ns
81,4
11,1
7,5
84,8
15,2
0
0,01
9,24 (1,16)
9,77 (1,04)
7,29 (0,09)
9,13 (1,63)
9,85 (0,57)
7,28 (0,08)
Ns
Ns
Ns
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oligonucleotide and potent, specific inhibitor of
EGR1 activity) working by mimicking the genomic EGR1-binding sequence. These studies evaluate (1) AYX1 spectrum of efficacy across animal
models of pain representing the range of injuries
associated with surgery, (2) its pharmacokinetics
and (3) safety in animals.
Methods. AYX1 was delivered as a 0.02mL (rat,
Sprague Dawley) or 1mL (dog, Beagle) bolus intrathecal injection. Efficacy was measured using von
Frey hairs, weight bearing incapacitance or spontaneous rearing. Models of inflammatory (CFA),
incisional (Brennan), neuropathic (spared nerve)
injury or knee surgery in rats were performed as
previously described. CSF and plasma were collected via catheter or percutaneously for pharmacokinetic measures. N ~ 5-10 for efficacy, N ~ 3 for
pharmacokinetics and N ~ 6-16 for toxicity.
Results. AYX1 dose-dependently prevents ongoing mechanical hypersensitivity with no observed
effects upon motor function. Analysis of spontaneous
pain-related behaviors demonstrated that AYX1 also
accelerated functional recovery. AYX1 exposure was
high in lumbar CSF and low in plasma (~3-5 orders
of magnitude lower) with a half-life of ~3 hours in
CSF and <10 min in plasma. There was an absence
of toxicity up to maximum feasible dose.
Conclusion. This work illustrates AYX1 therapeutic potential for improving acute and preventing persistent pain and accelerating recovery after
surgery or trauma. These data and excellent safety
results in a recent Phase 1 clinical study in healthy
volunteers allow the initiation of a proof-of-concept Phase 2 study in surgical subjects.
Magnesium sulphate as a novel treatment
in resistant tic douloureux
paroxysmal facial pain. TN pain typically remits
and relapses, even when patients are on conventionally used treatments, resulting in a major source
of disability and poor quality of life. In this study
we present a patient with TN who was intractable
to carbamazepine, and was treated successfully by
intravenous magnesium sulphate.
Case presentation. We describe a 65-year-old
man who was admitted to Emergency medicine Department suffering from typical TN pain on the right
side of his face for 7 years. He used medications, including baclophen (10 mg per day) and carbamazepine (1200 mg per day). The pain was triggered by
speaking, eating or touching. The pain was evaluated
using a visual analog scale (VAS), which ranged from
0 (no pain) to 10 (worst pain imaginable). According
to the VAS, the patient rated his pain as 10.We administered intravenous magnesium sulphate 30 mg /
kg over 30 min (the required amount was added as
a 50% magnesium sulphate solution to 100 ml of
saline). The severity of pain was recorded using a numeric VAS at baseline and at 10, 20 and 30 min during the infusion. The VAS score obviously decreased
from 10 to 2 before and 30 minutes after receiving
the mentioned treatment, respectively.
Conclusion. We have presented a short-lived
but simple, inexpensive, low-risk, and effective
technique for treating pain associated with intractable TN. Magnesium could be expected to modulate neuropathic pain by blocking the NMDA receptor calcium ionophore. Parenteral magnesium
sulphate can reduce pain dramatically or subtly.
The effect of low level laser therapy on
knee osteoarthritis: prospective, descriptive study
Hassan Soleimanpour 1, Rouzbeh Rajaei Ghafouri 1,
Dawood Aghamohammadi 1, Saeid Safari 2, Karim Marjani
3,
Maryam Soleimanpour 4 , Mahsa Motavaf 2
1Emergency Medicine Department
Tabriz University of Medical Sciences, Tabriz, Iran
2Department of Anesthesiology and Pain Medicine
3Nikookari Hospital, Tabriz University of Medical Sciences
Tabriz, Iran
4Gastroenterology Research Center
Hassan Soleimanpour 1, Khosro Gahramani 2,
Reza Taheri 2, Saeid Safari 3, Samad Ej Golzari 4,
Robab Mehdizadeh Esfanjani 5, Mahsa Motavaf 3
1Emergency Medicine Department
2Iranian Medical Laser Association
Iranian Medical Laser Association, Tehran, Iran
3Department of Anesthesiology and Pain Medicine
4Cardiovascular Research Center
Tabriz University of Medical Sciences, Tehran, Iran
5Neurosciences Research Center
Tabriz University of Medical Sciences,, Tabriz, Iran
Background and aim. Trigeminal neuralgia
(TN), also called tic douloureux is a neuropathic
pain syndrome characterized by severe unilateral
Background and aims. Osteoarthritis is one
of the most common joint disorders in the elderly
which could be associated with considerable phy-
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March 2013

POSTERS
Table II.—VAS (Visual Analogues Scale).
1st session
6th session
12th session
P-value
VAS
7.39±1.68 3.61±1.91 2.22±1.7 <0.0001
Knee
41.5±4.03 40.63±3.37
40±3.63 <0.0001
Circumference
(cm)
Distance
19.83±9.26 13.83±9.33 12.8±8.61 <0.0001
Between Hip
And Heel
(cm)
Distance
5.23±1.92 4.00±1.26 3.5±0.94 <0.0001
Between Knee
And Heel
(cm)
sical disability. Although non-steroid anti-inflammatory drugs are broadly used for the treatment
of the pain and rigidity caused by osteoarthritis,
their undesirable gastrointestinal complications
have contributed to numerous limitations in their
administration. To reduce or eliminate these complications different approaches including ultrasound, transcutaneous electrical nerve stimulation
(TENS) and physical exercises have been utilized.
Methods. In a prospective, descriptive study,
33 patients enrolled in the study from which 15
people were excluded due to incomplete course of
treatment, leaving the total number of 18 patients
with knee osteoarthritis. Gal-Al-As diode laser device was used as a source of low power laser. Patients were performed laser therapy with a probe of
LO7 with a power output of 80 watts, and also a
probe of MLO1K with a power output of 50 watts,
wave length of 890 nm and frequency of 3000
Hz. patients were given Low Level Laser Therapy
(LLLT) three times a week with a total number of
10 sessions. Data were analyzed using SPSS ver. 15
and the obtained data were reported as mean ± SD
and frequency (%). To analyze the data Repeated
Measurement and Marginal Homogeneity approaches were used.
Results. In the current study, a significant reduction was observed regarding the nocturnal
pain, pain on walking and ascending the steps,
knee circumference, the distance between hip and
heel and the distance between knee and heel at the
end of treatment course (Table I).
Conclusions. In brief, the current study focuses
on the fact that LLLT is effective in reducing pain
in knee osteoarthritis.
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