Quantifying Catastrophizing About Pain Can Lead to

SATURDAY
Find even more news coverage online @ www.eMPR.com/PAINWeek
September 6
news
Quantifying Catastrophizing
About Pain Can Lead to More
Effective Patient Management
Higher catastrophizing is a risk factor for long-term pain and
for disproportionately negative consequences of pain
R
➤ There is No Pleasure Without PAIN
New acquaintances and old friends gather for one last hurrah at
the PAINWeek Exhibit Hall Closing Reception, bidding each other
farewell—until next year!
Nonopioid Analgesics: Anticonvulsants,
Antidepressants and Muscle Relaxants
Remain Important in Pain Management
More data is needed to better define the role of nonopioid
adjuvants and co-analgesics in pain
N
INSIDE
onopioid anticonvulsants, antidepressants and muscle relaxants
can serve as important painmanagement adjuvants and co-analgesics, according to Chris Herndon,
PharmD, CPE, Associate Professor
at Southern Illinois University
Edwardsville, in Edwardsville, Illinois.
“We really need to figure out which
of these medications we have a decent
amount of evidence to support their
use,” he said. “But more importantly,
how do we use these medications
safely—and how do we pick the patients
for whom they might work best?”
Dr. Herndon surveyed three categories of nonopioid adjuvants and
co-analgesics: anticonvulsants, antidepressants, and skeletal muscle relaxants.
New anticonvulsants continue to
arrive on the market; there’s a lot of
clinical research underway on anticonvulsants. The evidence base for
their use for pain management hasn’t
always kept pace, however, he noted.
Continues on page 6
esearch increasingly is focusing on whether negative cognitive and emotional factors,
such as catastrophizing, can predict patient response to pain, said
Robert R. Edwards, PhD, MSPH,
of Brigham and Women’s Hospital
Department of Anesthesiology,
Boston, Massachusetts.
The goal: by improving assessment
and targeting of pain-related catastrophizing, healthcare providers can offer
more effective pain management to
patients with many different persistent
pain conditions, such as fibromyalgia,
osteoarthritis, and postoperative pain.
“Variability in pain is the rule rather
than the exception,” he said, and this is
related to its biopsychosocial aspects.
Catastrophizing, considered one
of the most important psychological
factors that shape pain perception, is
defined as a set of negative cognitions,
emotions, attitudes, and beliefs related
to pain that include magnification,
rumination, and helplessness.
Catastrophizing can easily be
assessed in patients using the PCS, or
Pain Catastrophizing Scale, which asks
patients to rate 13 questions beginning with, “When I’m in pain…”, on
a scale of 0 (not at all) to 4 (all the
time). Examples include:
• I worry all the time about whether the
pain will end.
Catastrophizing is one of the most
important psychological factors that shape
pain perception, said Dr. Edwards.
• I feel I can’t stand the pain anymore.
• I wonder whether something serious
may happen.
Overall, Dr. Edwards said, higher
catastrophizing is a risk factor for
long-term pain and for disproportionately negative consequences of
pain, including worsening physical
disability, medication misuse, and
12 When Treatment for Orofacial Neuropathies Fail
20 Pain Coaching Helps Patients Achieve Goals
14 Understanding PK/PD Drug Interactions
21 The Undead Dead Nerve
16 Are You Ready for ICD-10?
24 How Extroverts and Introverts Manage Pain
18 PDMPs: ‘One Tool in the Toolbox’
30 Buprenorphine Promising for Chronic Pain
Continues on page 6
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PAINWEEK news
Saturday, September 6
death. With parenteral abuse, the inactive ingredients in OXYCONTIN can be
expected to result in local tissue necrosis, infection, pulmonary granulomas,
and increased risk of endocarditis and valvular heart injury. Parenteral drug
abuse is commonly associated with transmission of infectious diseases, such
as hepatitis and HIV. Summary The in vitro data demonstrate that OXYCONTIN
has physicochemical properties expected to make abuse via injection difficult.
The data from the clinical study, along with support from the in vitro data, also
indicate that OXYCONTIN has physicochemical properties that are expected
to reduce abuse via the intranasal route. However, abuse of OXYCONTIN by
these routes, as well as by the oral route, is still possible. Additional data,
including epidemiological data, when available, may provide further information
on the impact of the current formulation of OXYCONTIN on the abuse liability
of the drug. Accordingly, this section may be updated in the future as appropriate. OXYCONTIN contains oxycodone, an opioid agonist and Schedule II
controlled substance with an abuse liability similar to other opioid agonists,
legal or illicit, including fentanyl, hydromorphone, methadone, morphine, and
oxymorphone. OXYCONTIN can be abused and is subject to misuse, addiction,
and criminal diversion [see Warnings and Precautions (5.1) and Drug Abuse and
Dependence (9.1)]. 9.3 Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for
increasing doses of opioids to maintain a defined effect such as analgesia (in
the absence of disease progression or other external factors). Tolerance may
occur to both the desired and undesired effects of drugs, and may develop
at different rates for different effects. Physical dependence results in withdrawal
symptoms after abrupt discontinuation or a significant dose reduction of a
drug. Withdrawal also may be precipitated through the administration of drugs
with opioid antagonist activity, e.g., naloxone, nalmefene, mixed agonist/
antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists
(buprenorphine). Physical dependence may not occur to a clinically significant
degree until after several days to weeks of continued opioid usage. OXYCONTIN
should not be abruptly discontinued [see Dosage and Administration (2.4)].
If OXYCONTIN is abruptly discontinued in a physically-dependent patient, an
abstinence syndrome may occur. Some or all of the following can character-
Nonopioid Analgesics
Continued from page 1
Lacosamide has level 2 data both supporting and refuting its utility in pain,
for example. A Cochrane review concluded there was no difference between
lacosamide and placebo. Other drugs
have only animal data or ongoing clinical trials, he said.
“I feel much better prescribing a
medication, if I’ve burned through
other options, that has randomized
controlled trial data and I know the
adverse event rates,” he said.
On the other hand, evidence for some
anticonvulsant agents’ utility in pain is
sometimes neglected. Topiramate and
zonisamide are examples. “We have
positive randomized controlled trial
studies for both agents in radicular
low back pain—but we never use it.”
(That may partly be because of cognitive fogginess or renal stones, known
Catastrophizing
Continued from page 1
higher healthcare costs.
Catastrophizing appears to exert its
effects via numerous pathways, including amplifying pain processing in the
brain, increasing distress. For example,
a higher percentage of patients with
chronic pain who rated themselves
as “high catastrophizing” (versus low
or average), embraced active suicidal
ideation and intent.
In addition, studies in patients with
musculoskeletal pain conditions have
found catastrophizing to be the most
important pretreatment risk factor
that impairs the effectiveness of pain-
ize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration,
chills, myalgia, and mydriasis. Other signs and symptoms also may develop,
including: irritability, anxiety, backache, joint pain, weakness, abdominal
cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood
pressure, respiratory rate, or heart rate. Infants born to mothers physically
dependent on opioids will also be physically dependent and may exhibit
respiratory difficulties and withdrawal signs [see Use in Specific Populations
(8.1)]. 10 OVERDOSAGE Clinical Presentation Acute overdosage with
OXYCONTIN can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin,
constricted pupils, and in some cases, pulmonary edema, bradycardia,
hypotension, partial or complete airway obstruction, atypical snoring and death.
Marked mydriasis rather than miosis may be seen due to severe hypoxia in
overdose situations. Treatment of Overdose In case of overdose, priorities
are the reestablishment of a patent and protected airway and institution of
assisted or controlled ventilation if needed. Employ other supportive measures
(including oxygen, vasopressors) in the management of circulatory shock and
pulmonary edema as indicated. Cardiac arrest or arrhythmias will require
advanced life support techniques. The opioid antagonists, naloxone or
nalmefene, are specific antidotes to respiratory depression resulting from
opioid overdose. Opioid antagonists should not be administered in the absence
of clinically significant respiratory or circulatory depression secondary to
oxycodone overdose. Such agents should be administered cautiously to
persons who are known, or suspected to be physically dependent on
OXYCONTIN. In such cases, an abrupt or complete reversal of opioid effects
may precipitate an acute withdrawal syndrome. Because the duration of
reversal would be expected to be less than the duration of action of oxycodone
in OXYCONTIN, carefully monitor the patient until spontaneous respiration is
reliably reestablished. OXYCONTIN will continue to release oxycodone and add
to the oxycodone load for 24 to 48 hours or longer following ingestion necessitating prolonged monitoring. If the response to opioid antagonists is suboptimal or not sustained, additional antagonist should be administered as directed
in the product’s prescribing information. In an individual physically dependent
side effects for these drugs, he said.)
SNRIs (serotonin-norepinephrine
reuptake inhibitors) “are your friend,”
Dr. Herndon said, in introducing antidepressants for pain management.
on opioids, administration of the usual dose of the antagonist will precipitate
an acute withdrawal syndrome. The severity of the withdrawal symptoms
experienced will depend on the degree of physical dependence and the dose
of the antagonist administered. If a decision is made to treat serious respiratory
depression in the physically dependent patient, administration of the antagonist
should be begun with care and by titration with smaller than usual doses of
the antagonist.
CAUTION
DEA FORM REQUIRED
17 PATIENT COUNSELING INFORMATION Advise the patient to read
the FDA-approved patient labeling (Medication Guide). Addiction, Abuse and
Misuse Inform patients that the use of OXYCONTIN, even when taken as
recommended can result in addiction, abuse and misuse, which can lead to
overdose and death [see Warnings and Precautions (5.1)]. Instruct patients
not to share OXYCONTIN with others and to take steps to protect OXYCONTIN
from theft or misuse. Life-Threatening Respiratory Depression Inform patients
of the risk of life-threatening respiratory depression including information that
the risk is greatest when starting OXYCONTIN or when the dose is increased
and that it can occur even at recommended doses [see Warnings and
Precautions (5.2)]. Advise patients how to recognize respiratory depression
and to seek medical attention if breathing difficulties develop. Accidental
Ingestion Inform patients that accidental ingestion, especially in children, may
result in respiratory depression or death [see Warnings and Precautions (5.2)].
Instruct patients to take steps to store OXYCONTIN securely and to dispose
of unused OXYCONTIN by flushing the tablets down the toilet. Neonatal
Opioid Withdrawal Syndrome Inform female patients of reproductive potential
that prolonged use of OXYCONTIN during pregnancy can result in neonatal
opioid withdrawal syndrome, which may be life-threatening if not recognized
and treated [see Warnings and Precautions (5.3)]. Interactions with Alcohol
and other CNS Depressants Inform patients that potentially serious additive
effects may occur if OXYCONTIN is used with other CNS depressants, and
not to use such drugs unless supervised by a health care provider. Important
with NSAIDs, he warned.
Skeletal muscle relaxants can be very
useful in treating pain, said Dr. Herndon.
“We really like tizanidine,” he noted.
“There is some decent data looking
We really need to figure out which of
these medications we have a decent
amount of evidence to support their
use. But more importantly, how do we
use these medications safely?
“They’re great.” But, SNRIs and
SSRIs (selective serotonin reuptake
inhibitors) cause hyponatremia in up
to 32% of patients, frequently within
the first two weeks. They can also
increase the risk of upper GI bleeds
when administered in combination
at tizanidine in neuropathic pain syndrome. … if I’m going to add a muscle
relaxant, I’d much rather use something
I have some data for, at least—some
hypothesis that it’s going to work.”
“My favorite of all time is baclofen,”
another antispasticity agent, he added.
relieving interventions.
He described familial catastrophizing, a phenomenon in which early parent catastrophizing predicted chronic
postoperative pain in children undergoing major surgery.
In one study in which 83 children
were followed for 12 months, parent and child catastrophizing became
more strongly linked over time.
In a second study of 107 families
of children with chronic pain, after
controlling for children’s pain duration
and intensity, parental catastrophizing
was associated with parental stress,
parental anxiety, a child’s functional
disability, and school attendance.
Although to date no genetic factors
have been linked to catastrophizing,
emotional—but not physical—abuse
in childhood has been found to predict
adult catastrophizing.
One of the most effective nonpharmacological treatment approaches to
the treatment of catastrophizing is
cognitive behavioral therapy (CBT),
he said. Recently, a pilot study has
found that CBT reduces catastrophizing in patients with fibromyalgia and
high PCS scores, with a short-term
change in catastrophizing at posttreatment prospectively associated
with reduction in pain severity at 6
months.
Administration Instructions Instruct patients how to properly take OXYCONTIN,
including the following: • OXYCONTIN is designed to work properly only if
swallowed intact. Taking cut, broken, chewed, crushed, or dissolved
OXYCONTIN tablets can result in a fatal overdose. • OXYCONTIN tablets
should be taken one tablet at a time. • Do not pre-soak, lick or otherwise
wet the tablet prior to placing in the mouth. • Take each tablet with enough
water to ensure complete swallowing immediately after placing in the
mouth. Hypotension Inform patients that OXYCONTIN may cause orthostatic
hypotension and syncope. Instruct patients how to recognize symptoms of
low blood pressure and how to reduce the risk of serious consequences
should hypotension occur (e.g., sit or lie down, carefully rise from a sitting
or lying position). Driving or Operating Heavy Machinery Inform patients that
OXYCONTIN may impair the ability to perform potentially hazardous activities
such as driving a car or operating heavy machinery. Advise patients not to
perform such tasks until they know how they will react to the medication.
Constipation Advise patients of the potential for severe constipation, including
management instructions and when to seek medical attention. Anaphylaxis
Inform patients that anaphylaxis has been reported with ingredients contained
in OXYCONTIN. Advise patients how to recognize such a reaction and when
to seek medical attention. Pregnancy Advise female patients that OXYCONTIN
can cause fetal harm and to inform the prescriber if they are pregnant or plan
to become pregnant. Disposal of Unused OXYCONTIN Advise patients to flush
the unused tablets down the toilet when OXYCONTIN is no longer needed.
Healthcare professionals can telephone Purdue Pharma’s Medical Services
Department (1-888-726-7535) for information on this product.
Purdue Pharma L.P. Stamford, CT 06901-3431
©2014, Purdue Pharma L.P.
U.S. Patent Numbers 6,488,963; 7,129,248; 7,674,799; 7,674,800;
7,683,072; 7,776,314; 8,114,383; 8,309,060; and 8,337,888.
This brief summary is based on OXYCONTIN Prescribing
Information 302940-0E, Revised 04/2014 (K)
“It’s well tolerated. I can start at 10
mg 2 or 3 times a day; the smaller
patients, who tend to be so sedated
on everything else, tolerate it really
well. And then in my big macho guys,
we can go all the way up to 80 mg.”
Dr. Herndon was quick to add
though, that the problem with
baclofen is that “sometimes these
patients don’t tolerate coming off of
that drug abruptly very well.” “They
get some pretty serious side-effects,
almost like a withdrawal syndrome.
You have to tell these patients, OK,
we’ll go up to 80 mg, but you’ve got
to make sure you’re not missing doses
or losing the pills and that you take
it regularly.”
“I’d love to see more information
on these drugs,” Dr. Herndon said of
muscle relaxants. But most of them
are generic now, so new research is
limited, he noted.
CORRECTIONS
In the previous stories “Pharmacogenomic
Testing Helps Personalize Pain Medicine,
Improving Outcomes” (Thursday edition)
and “Nurse Practitioners Should Not Feel
Pressured to Prescribe Pain Medicines”
(Friday edition), Brett B. Snodgrass, MSN,
APRN, and FNP-C was inadvertently
referred to as “he.” We sincerely apologize
for the error.
In Thursday’s story “Promoting Mind-Body
Approaches to Pain Self-Management”
the Chronic Pain and Addiction Treatment
Center at Silver Hill Hospital has changed
their name to the Chronic Pain and
Recovery Center.
PAINWEEK news
Saturday, September 6
PREVIEWS IN BRIEF
Today’s PAINWeek sessions not to be missed.
Prescription Opioid Use After Surgery: Who’s at Risk
for Delayed Opioid Cessation?
A TOTAL OF 45 MILLION AMERICANS undergo surgery each year with
obligatory prescription opioid use. Through surgery, “we can study how
patients respond to injury, resulting pain, and prescription opioid exposure,”
said Jennifer Hah, MD, MS, instructor in the Department of Anesthesiology,
Perioperative, and Pain Medicine at Stanford University, Stanford, California.
During her course, Dr. Hah will review the adverse effects of prescription
opioids, discuss the current approaches to postoperative pain management,
review measures to reduce persistent postoperative opioid use and chronic
postsurgical pain, and present risk factors for delayed opioid cessation after
surgery.
Also explored will be the standard of care, which is to advise patients to
discontinue opioids when they no longer have pain, focusing on analgesic
management after surgery.
7
SATURDAY SCHEDULE OF EVENTS
7:00 am–8:00 am
● Fear and Loathing in the Exam Room: Your Addicted Patient is Waiting in Room 4
● Chronic Pelvic Pain in Women: Translating Research Into Clinical Practice
● Prescription Opioid Use After Surgery: Who’s at Risk for Delayed
Opioid Cessation?
● Virtual Education and Consulting in Chronic Pain in the VA and
Department of Defense (DoD)
8:10 am–9:10 am
● Medical Marijuana in the Treatment of Central Nervous System Disorders
● Repetitive Stress Injuries
● Corresponding Responsibility or Mother May I Prescribe?
8:10 am–10:10 am
● Facilitating Treatment Adherence in Pain Medicine
9:20 am–10:20 am
● Interventional Pain Management: What it Is and When to Refer
● Evidence-Based CAM for Low Back Pain
● The VA/Department of Defense (DoD) SCAN/ECHO
10:20 am–10:50 am BREAK
What Constitutes Best Medical Practice With
Medical Marijuana?
PHYSICIANS AND THE GENERAL PUBLIC agree that marijuana shows promise in combating diverse medical problems; however, little about cannabis is
straightforward, and evidence-based guidelines are lacking.
Questions include, what are the risks and benefits of prescribing marijuana?
How is risk stratified? What is the dosage? Should medical marijuana be used at
work, when driving, or during pregnancy? How should such use be monitored?
In his presentation, Gilbert J. Fanciullo, MD, MS, Director, Pain Management
Center; Fellowship Director, Pain Medicine Program, and Professor of
Anesthesiology, Geisel School of Medicine, Dartmouth, New Hampshire, will
review the endocannabinoid system and the use of phytocannabioids in epilepsy,
multiple sclerosis, Parkinson’s disease, depression, and neuropathic pain. The
safety of prescribing medical marijuana will also be addressed.
10:50 am–11:50 am
● Overview of Interventional Procedures
● The Changing Face of Canabis in America: Medical vs Recreational Use
● Medical Errors in 3D: What PAs Can Do Before, During, and After to
Enhance Patient Safety
● Pain and Addiction: Phenotypic and Genotypic Characteristics of
Opioid Use Disorder
● Calling in the Marines: Methadone, Ketamine, and Lidocaine
12:00 pm–1:30 pm
● Sponsored lunch program (Please check PAINWeek mobile for details
at m.painweek.org)
1:40 pm–2:40 pm
● Risk Managment, Complications, Options, and Outcomes of Interventions
● Medicinal Canabis: How Do You Distinguish Appropriate From
Inappropriate Use?
● Mirror Mirror on the Wall: Reframing Diagnosis and Treatment of Chronic Pain
1:40 pm–3:40 pm
● Sailing to Byzantium: Geriatric Pain Management
Sailing to Byzantium: Geriatric Pain Management
ELDERLY ADULTS are a fast-growing patient population for whom pain management can be challenging, if not downright byzantine.
Physiological and psychological changes in late adulthood mean that these
patients are not simply a “chronologically older version of younger patients
with chronic pain,” cautions Debra K. Weiner, MD, Professor of Medicine,
Anesthesiology, Psychiatry & Clinical and Translational Science at the University
of Pittsburgh.
“Low back pain in older adults is typically a syndrome with multiple sources
of pathology,” Dr. Weiner says. This course will introduce the principles of
aging and normal lumbar deterioration with age, identifying perpetuating
factors, conducting comprehensive assessments that include functional reach
testing and mobility screening of older adults with chronic low-back pain,
other sources of chronic pain, and treatment planning, with case studies and
audience participation. Both pharmacologic and non-pharmacological management options will be discussed, including cardiovascular exercise and cognitive
behavioral therapy.
2:50 pm–3:50 pm
● New Trends in Interventional Pain Control
● What Constitutes Best Medical Practice With Medical Marijuana?
4:00 pm–5:00 pm
● Cannabis Point of Care Testing
● My Aching Feet!
● The VA/Department of Defense (DoD) SCAN/ECHO Experience:
Addiction and Chronic Pain
4:00 pm–6:00 pm
● Critical Documentation Skills (Encore)
5:10 pm–6:10 pm
● Clinical Conundrum: Nightmares
● TheUseofInflammatoryandHormoneBiomarkersinPainManagement
● The Power of Groups
8
PAINWEEK news
Saturday, September 6
PREVIEWS IN BRIEF
Today’s PAINWeek sessions not to be missed.
Repetitive Stress Injuries
REPETITIVE STRESS INJURIES—more commonly known as cumulative trauma
disorders—are on the rise with the increased use of computers and mobile
devices. There is significant pain and functional limitations associated with
nerve entrapment, tendonitis, and muscle sprains. In this course, Srinivas
Nalamachu, MD, of the International Clinical Research Institute, Overland
Park, KS, will review with attendees etiology, standard as well as new diagnostic
tools, and treatment approaches.
The Use of Inflammatory and Hormone Biomarkers
in Pain Management
SINCE PAIN, per se, cannot be numerically measured like a glucose or cholesterol
level, there have been numerous attempts to find markers or “tracers” that will
determine the presence of pain and its severity. This course will describe the
historical attempts to identify markers, discuss currently available biomarkers,
and present clinical situations for their use. It is now known that abnormal
serum levels of some hormones and by-products of neuroinflammation indicate the presence of uncontrolled pain. Although somewhat imprecise, the
biomarkers that have currently been identified should have an expanded role
in the diagnosis and management of chronic pain.
Medical Errors in 3D: What PAs Can Do Before, During,
and After to Enhance Patient Safety
MUCH HAS BEEN WRITTEN about the impact of errors on patients. Most of the
literature examines how they occur, the variety of ways that they are viewed, how
to prevent them, and error disclosure. But after an error, then what happens to
those who made it? This presentation examines the emotional impact of errors
on those who make them, when the provider becomes what has been described as
the “second victim.” Using a case based scenario, the talk explores the commonly
complex and multifactorial nature of medical errors, describes the predictable
post error trajectory of events, and examines the challenge of self-forgiveness
for providers following participation in potentially catastrophic medical errors.
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Calling in the Marines: Methadone, Ketamine,
and Lidocaine
THE VAST MAJORITY of patients with an advanced illness can achieve adequate
pain control with commonly used analgesics. Occasionally patients have “difficult” pain syndromes that require the use of more advanced therapies, which
practitioners are often not familiar with. Participants in this session will learn
about the pharmacology, therapeutics, and evidence supporting the use of
methadone, ketamine, and lidocaine. Vignettes will be used to illustrate the
appropriate use of these agents with suggestions for protocol development
including appropriate monitoring parameters.
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10
PAINWEEK news
Saturday, September 6
PARTICIPATING ORGANIZATIONS
AMERICAN SOCIETY OF INTERVENTIONAL PAIN PHYSICIANS
Interventional Pain Medicine:
What it Is and When to Refer
Overview of Interventional
Procedures
and Hans Hansen, MD, DABPP,
FIPP
Time: 9:20 am – 10:20 am
Location: Level 3/Castellana
Ballroom
Interventional Pain Medicine (IPM)
is undergoing “explosive growth,”
according to Hans C. Hansen,
MD, DABPP, FIPP, and Sanford
M. Silverman, MD.
“Interventional pain management
techniques are minimally invasive
procedures, including percutaneous precision needle placement with
placement of drugs in targeted areas
or ablation of targeted nerves and
some surgical techniques, such as
laser or endoscopic discectomy,
intrathecal infusion pumps and spinal
cord stimulators, for the diagnosis
and management of chronic, persistent and intractable pain.”
“IPM is a solid choice solution to
avoid escalation of controlled substances and assist in diagnosis and
treatment of painful conditions,”
they report. “Ultimately, function
and quality of life may be restored.”
Their introductory panel on IPM
will introduce diagnostic and therapeutic interventions, such as epidural injections and nerve blocks,
facet joint interventions; outcomes;
evidence-based guidelines; algorithmic approaches to low back pain
diagnosis; rising costs in health
care; the cost effectiveness of surgery and spinal cord stimulation;
and the growth and economics of
pain medicine and IPM.
and Hans Hansen, MD, DABPP,
FIPP
Time: 10:50 am – 11:50 am
Location: Level 3/Castellana
Ballroom
Thirty percent of patients who
develop low back pain will develop
chronic pain or frequent occurrences
of back pain. Low back pain affects
40% to 70% of adults at some point
in their lifetimes, with an annual
prevalence of 10% to 30% of the
population and an annual estimated
cost of $100 billion, they report.
Low back pain is a leading cause of
disability in adults age 45 years and
younger.
This lecture will provide an overview of the epidemiology, neurobiology and anatomy, function and
pathophysiology of pain and pain
pathways in the spine; analgesia, steroid and prostaglandin interactions
and the pain pathway; and interventional procedures for spinal pain.
The roles of disc herniation, nerve
fiber deformation, inflammation, stenosis, radiculopathy, and post lumbar laminectomy syndrome will be
discussed, and the history, rationale,
clinical presentation, indications,
evidence and complications of epidural steroid injections are reviewed.
Cervical epidural techniques and
positioning will be detailed, as well.
Presenters: Sanford Silverman, MD
Presenters: Sanford Silverman, MD
New Trends in Interventional
Pain Control
Presenters: Sanford Silverman, MD
and Hans Hansen, MD, DABPP, FIPP
Time: 1:40 pm – 2:40 pm
Location: Level 3/Castellana Ballroom
Autologous stem cell implantation
represents a promising treatment for
a variety of orthopedic conditions.
An expert panel will review an
emerging evidence base for stem
cell and mesenchymal precursor cell
therapies; diagnosis and treatment
of spinal pain stemming from spinal stenosis and failed back surgery;
joint pain; headache, neuropathy,
central pain states and depression;
and tendonopathies.
Ketamine’s role in inducing
synaptogenesis and restoration
of neurons’ synaptic connections
will be described, as will the spinal pain applications of spinal cord
stimulation, facetectomy, discectomy, decompression and fusion,
and percutaneous interventional
procedures.
“Bone marrow appears to have
the greatest evidence of efficacy
and safety” as a source for stem
cells, the presenters note. “Thus
far, there have been no significant
adverse events directly related to
bone marrow stem cell implantation. The evidence for the efficacy of
stem cell therapies remains limited
but is evolving.”
Risk Management, Complications,
Options and Outcomes of
Interventions
Presenter: Sanford Silverman, MD
Time: 2:50 pm – 3:50 pm
Location: Level 3/Castellana
Ballroom
Interventional pain management
procedures can benefit patients and
Pain is not just a physical symptom -- it also affects mental health.
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prevent surgery, but also involve
risks and complications that must
be managed.
“Factors associated with treatment
outcome include neuropathic spinal
pain; disease burden and comorbidities; psychosocial factors; Waddell’s
signs; multiple prior procedures
and catastrophic thinking,” noted
Sanford M. Silverman, MD.
Dr. Silverman’s presentation will
review the history, indications,
techniques, and evidence base for
interventional pain management
procedures such as epidural steroid injections, and prevention of
surgery; evidence and indications
for spinal cord stimulation; factors
associated with treatment outcomes;
complications; local anesthetic toxicities and risks; neurotoxicity and
injury; epidural hematoma and
abscess.
Complications can include sometimes-lethal fungal and bacterial
infections, nerve injury, brain damage, headache, increased pain or no
relief, Dr. Silverman reports. Overall,
the complication rate for interventional procedures is 2.4%.
The evidence base varies for different interventional procedures, Dr.
Silverman notes. Evidence is strongest for short-term benefits of medial
branch nerve block and neurotomy,
caudal epidural steroid injection,
and short- and long-term benefits
from transforaminal epidural steroid
injection. Evidence is weaker for
epidural adhesiolysis, percutaneous
disc decompression, and long-term
benefits from interlaminar epidural
steroid injections.
12
PAINWEEK news
Saturday, September 6
In Patients with Orofacial Neuropathies,
Suspect Central Pain When Treatment Fails
For orofacial pain, the site of the pain is not always its source
W
hether called “atypical” facial
pain, or “phantom tooth pain,”
if edentulous—which Peter
Foreman, DDS, consultant, Orofacial
Pain, New Zealand, called “useless
terms”—clinicians should be alert
to pain that may precede or follow
dentistry.
The signs and symptoms of oral
neuropathies are aching, stabbing,
burning, and throbbing, mostly in
the upper molar/premolar region.
Pain may be intermittent or prolonged, and worse with temperature
changes. Hyperesthesia and allodynia
may occur.
Neuropathic pain can follow deafferentation, defined as elimination
or interruption of sensory nerve
transmission due to nerve injury. For
example, exodontia, third molar surgery, and endosseous dental implants
can all create nerve injuries and neuropathic pain.
“Posterior mandibular implants
may result in 5% to 15% of postoperative problems, with permanent
neurosensory disorders occurring in
approximately 8%,” he said. “‘Nerve
lateralization’ risks perineural damage
from ischemic stretching. Implant
compression and drill punctures may
result in neuroma formation, which
TABLE. Common Dentist
Responses to Chronic Orofacial
Pain Complaints
That leaky filling needs replacement
It must be a “cracked tooth syndrome”
You need a root canal filling
I’ll have to do an apicectomy
Sorry, I’ll have to extract the tooth
Let’s explore that “bone cavity”
You’ve got “TMJ syndrome”
Your occlusion needs adjustment
You need a bite splint
You need an arthrogram
I’ll have to refer you to an oral surgeon
can result in permanent pain.”
Orofacial pain occurs more often
in females (at a 2:1 ratio to males)
and in those primarily older than 40
years of age. Incidence of neuropathy
following endodontia ranges from
3% to 6%. Some patients appear to
be at risk of whenever endodontia is
performed. What remains unknown,
however, is whether there is a genetic
predisposition.
There are few pathological or radiographic signs; for that reason, patients
may see many physicians without
success.
“Patients with unrelenting pain
often visit numerous dentists, dental
and medical specialists, and others in
search of relief,” Dr. Foreman said.
“Many undergo multiple extractions
and/or irreversible and often harmful
procedures, yet they still have pain.” In
fact, he added, many patients continue
to suffer but avoid further treatment
due to fear of more pain and treatment costs.
He said few dentists and maxillofacial surgeons consult with colleagues such as pain specialists or
neurologists. On the contrary, “69.7%
rated the efficacy of their procedures
highly, despite ongoing problems.”
Oral surgeons and endodontists are
more likely to see persistent pain
patients due to referrals. “Caution is
wise if the pain history is long standing. It is a warning that diagnosis and
management may prove difficult,” he
advised.
Some common responses of dentists
to complaints of chronic orifacial pain
are summarized in the Table.
In addition, diagnostic and treatment errors are common, which
can increase pain and problems. He
pointed to one study of 64 patients
that found prior to a diagnosis of
atypical odontalgia, they collectively
visited 16 different specialists, from
a dentist to an oncologist to a psychiatrist. In fact, “frustrated clinicians
may refer patients to a psychiatrist
if no apparent cause for pain can be
identified.”
Dr. Foreman said statistics show
psychiatric morbidity often results
from persistent pain; however, “it
is seldom the cause. One common
dental example is “burning mouth
syndrome,” which is often labeled psychogenic. Yet, evidence now shows a
neurological etiology is more likely,
he said.
A thorough history is essential in
diagnosing and managing atypical odontalgia. Patients should be
Instead, clinicians should place their
emphasis on management.
Preemptive analgesia may be used to
try to prevent atypical odontalgia. For
example, effective long-acting local
anesthesia, supported centrally with
perioperative NSAIDs, can help block
events that lead to onset of central
sensitization as well as development of
“If there are no clear signs indicating a dental
origin for pain, why so do many dentists stubbornly continue to search for one, and carry
out harmful and futile attempts to impose
a dental solution on a non-dental problem?”
—David Hay, Head of Oral Health Unit,
Green Lane Hospital, New Zealand
asked about the duration of pain and
its cause (eg, caries, injury) and the
nature of the pain. For example, deep,
dull, aching, intermittent pain of variable intensity suggests myofascial
pain, which is often due to muscle
overuse, such as bruxism and work
habits. Relief is often achieved after
the cause is controlled. Conversely,
sharp, burning, tingling, or stabbing pain that is constant or intermittent suggests neuropathic pain.
Relief is often difficult to achieve and
may follow deafferentation, such as
extractions, surgery, endodontia, or
implants.
“Dental neuropathies are difficult
to diagnose and treat,” he said. The
“smoking gun” in the process of complex events that lead to the development of central sensitization—and,
eventually, atypical odontalgia—may
well be prolonged C-fiber activity, he
said, because approximately 87% of
dental pulp fibers are type C.
Since atypical odontalgia is a central
sensitization disorder, invasive procedures that could further exacerbate
the situation “should be avoided.”
Once central sensitization has developed, pain is likely to continue despite
treatment, Dr. Foreman said, adding,
“this is a trap for the unwary dentist.”
postoperative rebound pain, reducing
analgesic needs. General anesthesia
alone will not block C-fiber activity,
he pointed out.
Postsurgery, “pain medications
should be time contingent, not pain
contingent,” he said. “This maintains
optimal drug levels and helps prevent
breakthrough pain.” Tricyclics such
as amitriptyline and nortriptyline are
useful. He recommended starting with
a low dose (10 mg), increasing gradually for the best effect with minimal side
effects. Patients should be warned that
such agents are not a cure but can help
reduce discomfort. Acetaminophen has
a mild effect on central pain if used
as an adjunct; however, high dosages
should be avoided.
Anti-neuropathic drugs such as clonazepam, gabapentin and pregabalin
may provide relief, Dr. Foreman said;
however, carbamazepine is seldom
prescribed due to significant side
effects. Ketamine acts on the NMDA
receptor site but also has “major side
effects.”
What’s important to understand,
he said, is that for orofacial pain of
nondental origin, “the site of the pain
is not always its source. Where the
diagnosis is in doubt and the patient
is insistent, proceed with caution.”
14
PAINWEEK news
Saturday, September 6
Understanding PK/PD Drug Interactions Essential
to Effective Pain Management
Drug interactions common in pain management must be anticipated judiciously
T
he “ABCs” of pharmacokinetics—
absorption, distribution, metabolism, and excretion—are what
guide all medication prescribing. Yet,
pharmacokinetic and pharmacodynamic
properties of medications are multifactorial, with patient-specific variables
playing a large role in the pharmacodynamic response to medications, said
Chris Herndon, PharmD, CPE, an
Associate Professor in the Department
of Pharmacy Practice at Southern
Illinois University, Edwardsville, Illinois.
He began by describing the types of
drug interactions: drug-drug, drugfood, drug-disease, and, perhaps,
drug-genetics. “Drug-drug interactions are extremely common in pain
management and must be anticipated
judiciously,” he said.
The next consideration is absorption. For example, controlled release
or long-acting formulations have
the potential to decrease efficacy in
hypovolemia/dehydration, increase
absorption with a high-fat meal, and
decrease efficacy in patients with a
history of malabsorptive or mixed
bariatric procedures. Transdermal
formulations can decrease efficacy of
fentanyl TTS in cachectic patients or
increase absorption of fentanyl with
heat or iontophoresis, while agents
administered sublingually may actu-
TABLE 1. Common Inhibitors / Inducers (Strong or Moderate Only)
CYP 2D6
CYP 3A4/5
CYP 2C9/19
CYP 1A2
CYP 2B6
INHIBITORS
• Bupropion
• Fluoxetine
• Paroxetine
• Duloxetine
• Sertraline
• Fluconazole
• PPIs
• Sertraline
• Paroxetine
• Modafinil
• Topiramate
• Clarithromycin
• Buprenorphine
• Aprepitant
• Erythromycin
• Verapamil
• Diltiazem
• Ciprofloxacin
• Fluvoxamine
• Inducers
• Insulin
• Modafinil
• Omeprazole
• Tobacco
• Clopidogrel
• Ticlopidine
INDUCERS
• Dexamethasone
• Carbamazepine
• Norethindrone
• Prednisone
• Carisoprodol
• Carbamazepine
• Prednisone
• Dexamethasone
• Oxcarbazepine
ally be absorbed via slow swallowing
(eg, sublingual morphine) compared
with true transmucosal products.
Gabapentin exerts its effect via saturable active transport systems.
There is usually poor patient preference for rectal administration, he said;
however, this route is reasonable to consider for patients in which other alternative delivery methods are unavailable.
Drugs are metabolized through three
phases in order to convert these substanc-
es into increasingly polar metabolites for
ease in elimination from the body. Phase
1 comprises oxidation (affecting the
cytochrome P450 system), reduction,
and hydrolysis; phase 2, glucuronidation
(UDP-glucuronsyltransferase, or UGT);
and phase 3, acetylation, transpeptidases,
and dipeptidases.
Drug metabolism is multifactorial, he
pointed out. Concurrent patient conditions, such as inflammation, liver disease,
and pregnancy, can all affect metabolism.
• Carbamazepine
Drugs may be excreted/eliminated via
the kidney, liver (feces, bile), skin lungs,
and salivary/lacrimal glands.
Approximately 15% of the population lacks the CYP-2D6 enzyme,
restricting ability to metabolize certain
agents. More than 100 drugs inhibit
or induce CYP-2D6, CYP-2C19, or
CYP-2B6, and data are emerging on
UGT. Common strong or moderate
inhibitors/inducers are summarized
in Table 1.
TABLE 2. Opioids Metabolism
Substance
Phase I Enzyme(s)
Metabolite (s)
Phase II Enzyme/Metabolite
Tramadol (Prodrug)
CYP2D6 (major)
CYP 3A4
O-desmethyltramadol(M1)
N-desmethyltramadol
Glucuronidation and/or sulfation
Hydromorphone
N/A
N/A
UGT/Glucuronides
Codeine (Prodrug)
CYP 2D6, CYP 3A4
Morphine, Norcodeine
UGT/ Glucuronides
Fentanyl
CYP3A4
Norfentanyl
N/A
Hydrocodone
CYP 2D6
CYP 3A4
Hydromorphone
Norhydrocodone
UGT/Glucuronides
Methadone
CYP 3A4, 2D6, 2C19, 2C8, 2C9, 2B6
EDDP
N/A
Morphine
N/A
N/A
UGT/Glucuronides (A)
Oxycodone
CYP 2D6
CYP 3A4
Oxymorphone
Noroxycodone
UGT/Glucuronides
Oxymorphone
N/A
N/A
UGT/Glucuronides
Tapentadol
CYP2D6, 2C9 & 2C19 (all minor)
Inactive metabolites
UGT/Glucuronides
Buprenorphine
CYP 3A4
Norbuprenorphine
UGT/Glucuronides
PAINWEEK news
Saturday, September 6
15
Test Your Knowledge of PK/PD Drug Interactions
To illustrate the multifactorial complexity of the pharmacokinetic and pharmacodynamic properties of medications , Dr. Herndon presented five
case studies, each of which addressed a specific question as it related to a patient requiring medication (see Cases 1–5). Participants helped
design individualized treatment regimens, given unique patient-specific and drug-specific parameters. Test your knowledge to see if you can
identify the drug interaction(s) in each of these case studies. See bottom of page for answers.
CASE 1
A 45-year-old male with type 2 diabetes mellitus being treated for
painful peripheral neuropathy is stable on metformin, fentanyl patches
75 mcg/hr, and lisinopril, with his pain well controlled on the current
regimen. He is prescribed a course of clarithromycin for suspected
rhinosinusitis. What pharmacodynamic effect do you expect?
Following a positive Myoview stress test and subsequent catheterization, J.R. receives a drug-eluting stent and is discharged on aspirin and
clopidogrel. What pharmacodynamic effect would you expect?
CASE 4
A.H. is a 54-year-old female with a past medical history of osteoarthritis
of the knee, hip, and hand as well as gastroesophageal reflux disease
CASE 2
(GERD), and generalized anxiety disorder. Her pain and anxiety sympJ.W. is a 42-year-old female with a past medical history of fibromy- toms are well controlled on scheduled nabumetone, PRN hydrocodone/
algia, hypertension, asthma, and depression. While her fibromyal- acetaminophen, and paroxetine. Her primary care manager initiates
gia symptoms are well-controlled on tramadol, her Patient Health omeprazole for GERD symptoms and advises her to quit smoking. What
Questionnaire-9 scores have increased and she reports worsening pharmacodynamic effect do you expect on her follow-up visit?
of depressive symptoms, despite counseling. The team decides to initiate bupropion for antidepressant therapy. What pharmacodynamic CASE 5
effect do you expect?
B.O. is a 46-year-old roofer with osteoarthritis of the right shoulder
and both hands. He has trialed numerous NSAIDs and reports the
CASE 3
meloxicam you recently started works very well, but only for 1-2 hours
J.R. is a 68-year-old male with a past medical history of coronary artery each dose. You decide to order pharmacogenetic testing. Which isodisease, type 2 diabetes mellitus, hypertension, and phantom limb pain. enzyme do you request and what result do you expect based on the
He is currently taking methadone, lisinopril, metformin, and simvastatin. pharmacodynamics of meloxicam?
CASE 1 ANSWER: Clarithromycin is a CYP 3A4/5 inhibitor (see Table 1). Inhibitors of CYP 3A4, such as clarithromycin, may inhibit the metabolism of fentanyl. This may increase the blood
levels of fentanyl and could potentially result in increased risk of respiratory depression or other dose-dependent toxicity. CASE 2 ANSWER: Bupropion is a CYP 2D6 enzyme inhibitor.
Tramadol is rendered active (ie, converted to O-desmethyltramadol) via the CYP 2D6 pathway. Therefore, bupropion will reduce levels of the active metabolite, O-desmethyltramadol,
and reduce the analgesic effect of tramadol. CASE 3 ANSWER: Methadone is a racemic mixture of (S)-methadone and (R)-methadone, with its analgesic effect primarily attributed to
the R-enantiomer. (S)-methadone is demethylated via the CYP 2B6 pathway to its major inactive metabolite, EDDP, whereas (R)-methadone is rendered inactive via the CYP 1A2, CYP 2D6,
and CYP 3A4 enzymes. Clopidogrel is a CYP 2B6 enzyme inhibitor. Therefore, clopidogrel will inhibit metabolism of (S)-methadone and increase its level or effect of (S)-methadone, but will
not affect (R)-methadone. (S)-methadone is considered to exert a greater effect on cardiac conductance and therefore, theoretically, selective increases in this enantiomer may result in a
prolongation of QTc intervals. CASE 4 ANSWER: Both omeprazole and tobacco are CYP 1A2 enzyme inducers. Nabumetone is rendered to its active form (6’-methylnabumetone) via
the CYP 1A2 pathway; therefore, omeprazole will increase the levels of 6’-methylnabumetone and increase the analgesic effects or potential toxicity of nabumetone; however, reduction in
her tobacco use may correspondingly decrease metabolism to the active metabolite. CASE 5 ANSWER: Meloxicam is metabolized by CYP 2C9 and CYP 3A4 to inactive metabolites. You
order pharmacogenetic testing for both CYP 2C9 and CYP 3A4. Based on these results, B.O. is predicted to be an extensive metabolizer for CYP 3A4 and an ultra-rapid metabolizer for
CYP 2C9, resulting in a shorter duration of action for meloxicam for B.O. Patients may be extensive metabolizers, with “normal” function; intermediate metabolizers, with “reduced” function;
poor metabolizers, with significantly “reduced” or “absent” function; or ultra-rapid metabolizers, with significantly “increased” function.
TABLE 3. NSAIDs Metabolism
Drug
Phase I / II
Metabolite
Activity
Celecoxib
2C9 / 3A4 (m)
Carboxycelecoxib
Parent only
Diclofenac
2C9
5-hydroxydiclofenac
Parent ~ Eff
Metab ~ Tox
Diflunisal
- / UGT
DAG, DAS, DPG
Parent only
Etodolac
s-etodolac ~ 2C9
r-etodolac ~ UGT
EAG, EHM, 7-hydroxyetodolac
sE > rE ~ Eff
Ibuprofen
2C8,9 / UGT 2B7
IAG
sIbu > rIbu ~ Eff
Indomethacin
2C9 / 2C19
ODM-Indomethacin
Parent only
Ketorolac
Unknown
p-hydroxyketorolac
sKet > rKet ~ Eff
Meloxicam
2C9 > 3A4
5’-carboxymelox
Parent Only
Nabumetone
1A2
6-MNA
Metabolite only
Naproxen
2C9 / 2C8 / 1A2
ODM-naproxen
Parent only
Oxaprozin
CYP (unknown)
Ox-glucuronides
Parent only
16
PAINWEEK news
Saturday, September 6
Easing the Transition to ICD-10-CM Implementation
Improving documentation is essential to the success of ICD-10, to better patient care
O
ctober 1. 2015. That’s the projected date of implementation
of the ICD-10-CM.
Currently, the version used is ICD-9CM, which is maintained by the Centers
for Medicare & Medicaid Services and
the National Center for Health Statistics.
Marvel J. Hammer, RN, CPC,
CCS-P, ACS-PM, CPCO, of MJH
Consulting, Denver, Colorado, asked,
“Why change” to ICD-10?
“First, the ICD-9 code set is almost
40 years old, based on the state of
medical knowledge of the late 1970s,
with periodic updates applied,” he
said. ICD-9 “includes outdated and
obsolete terminology, is inconsistent
with current medical practice, and
inadequately described 21st century
diagnoses. This hampers the ability
to compare costs and outcomes of
different medical technologies, both
within the US and globally, and cannot
support the transition to interoperable
health data exchange.”
Most importantly, ICD-9 is simply “running out of space,” Hammer
said. The limited structural design of
ICD-9 cannot accommodate advances
in medicine and medical technology and the growing need for data.
Compared with ICD-9-CM’s ~14,000
codes, ICD-10-CM has ~70,000 codes,
incorporating much greater clinical
detail and specificity.
Use of ICD-10-CM is required
by all covered entities under the
Health Insurance Portability and
Accountability Act (HIPAA) and, after
implementation, the ICD-9-CM code
set “will not be maintained,” he said.
Covered entities include physicians
and other healthcare providers, health
insurance companies (payers, including Medicare and Medicaid), clearinghouses, third-party billing services,
and software vendors.
Hammer provided a detailed overview of the differences between ICD-9CM and ICD-10-CM codes for many
diagnoses currently encountered in
pain management, including complex
regional pain syndrome, pain in spinal regions, trigger points, radiculitis/
radiculopathy, spondylosis, spinal stenosis, disc displacement, disc degeneration, disc disorder with radiculopathy,
osteoporosis, and sprains and strains.
ICD-10-CM uses new “7th character extensions” to provide additional
information about the characteristic of
the encounter for episode of care for
obstetrics, injuries, and external causes
of injuries. For example:
• S43.422A Sprain of left rotator
cuff capsule, initial encounter
Steps to Meet October 1, 2015 ICD-10-CM
Implementation Goal
1
2
3
4
Educate providers about the detail required in their documentation for specific conditions and symptoms they treat
Review and update electronic health records and procedure
templates for ICD-10 documentation requirements
Build an ICD-9-CM to ICD-10-CM “hot list” of your most
popular codes. Every month, print out a list of 10 or more
diagnosis codes for each provider and try to code them.
Keep a list of those that are causing questions and problems
For detailed information, consult the 2015 ICD-10-CM
website: http://www.cdc.gov/nchs/icd/icd10cm.htm
• S43.422D Sprain of left rotator
cuff capsule, subsequent encounter
• S43.422S Sprain of left rotator
cuff capsule, sequela
He also provided a list of steps to ease
the transition to ICD-10-CM (box).
Hammer said one myth is that “the
increased number of codes will make
ICD-10-CM impossible to use.”
Only Seconds to Care!
Safety Recalls
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to the pertinent prescribing information
and resources you need so you can spend
more time with your patients.
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eMPR.com/app
HOURS
However, “just as the size of a dictionary doesn’t make it more difficult to
use, a higher number of codes doesn’t
necessarily increase the complexity
of the coding system. Because ICD10-CM is much more specific, it is
more clinically accurate and uses a
more logical structure, making it much
easier to use than ICD-9-CM.”
News & Alerts
Interactions
MINUTES
00:00:
SECONDS
Drug
Information
Calculators
18
PAINWEEK news
Saturday, September 6
PDMPs: ‘One Tool in the Toolbox’ for Tracking
Controlled Substance Prescriptions
Prescription drug monitoring programs impact opioid prescribing and clinical decision making
D
rug-induced deaths are now the
leading cause of injury death
in 17 states and the District of
Columbia. In response to this crisis,
49 states and one territory had passed
legislation authorizing Prescription
Drug Monitoring Programs (PDMPs)
as of January 2013, and 43 states had
an operating PDMP.
What does this mean for the practicing clinician?
“PDMPs are tools that can potentially help track how medications
are being prescribed and dispensed,”
said Kevin L. Zacharoff, MD, FACIP,
FACPE, FAAP, a clinical instructor at
the State University of New York Stony
Brook School of Medicine, Stony
Brook, New York, and Vice President
of Medical Affairs at Inflexxion, Inc.,
Newton, Massachusetts. “They are, at
best, one tool in the toolbox.”
In essence, “a PDMP is a state-wide
electronic database that gathers information from pharmacies on dispensed
prescriptions for controlled substances,” he said, adding that states that
permit practitioners to dispense also
require them to submit prescription
information to the PDMP. Although
prescription data are made available
upon request from end users and are
sometimes distributed via unsolicited
reports, “states vary widely in which
categories of users are permitted to
request and receive prescription history reports and under what conditions.”
Additional recipients of data may
also include licensing boards, law
enforcement and drug control agents,
medical examiners, drug courts, criminal diversion programs, addiction
scriptions for Schedule II, III, and IV
controlled substances, he said.
“The registry provides practitioners
with direct, secure access to view dispensed controlled substance prescription histories for their patients,” he said,
adding the PMP is available “24/7”
(https://commerce.health.state.ny.us).
The reports include all controlled substances dispensed in New York State
and reported by the pharmacy/dispenser for the past 6 months, allowing
Studies of PDMP use found that 41% of
cases had altered prescribing after
the clinician reviewed the PDMP data.
treatment programs, public and private
third-party payers, and other public
health and safety agencies.
On August 27, 2013, the State of
New York mandated use of its free
program, I-STOP (Internet System
for Tracking Over-Prescribing),
requiring most prescribers to consult
the Prescription Monitoring Program
(PMP) Registry when writing pre-
practitioners to evaluate their patient’s
treatment with controlled substances
“and determine whether there may be
abuse or nonmedical use.”
Studies of PDMP use, for example, in
an emergency department, found that
41% of cases had altered prescribing
after the clinician reviewed the PDMP
data: 61% of patients received fewer
or no opioid pain medications than
Collaboration is Key to Deterring Drug Diversion
without Chilling Appropriate Prescribing
Most prescribers are responsible and lawful; fewer than 2% behave criminally
P
roviders and law enforcement
must work closely together to
prevent drug abuse while ensuring adequate treatment for patients with
pain, according to Stephen J. Ziegler,
PhD, JD, of Indiana University-Purdue
University, in Fort Wayne, Indiana, and
Marc Gonzalez, PharmD, President of
the NADDI of California.
Providers need to work with the DEA
in a spirit of collaboration to foster a quid
pro quo relationship of “how can we help”
rather than “leave us alone,” they said. And
law enforcement, in turn, needs to work to
deter overprescribing, prescription drug
diversion and illicit use without chilling
the appropriate prescribing of medicallynecessary medications, they said.
Most prescribers behave reasonably
and lawfully, Dr. Gonzalez was quick
to note. Fewer than 2% of prescribers
behave criminally. But those 2% are
responsible for more than 90% of law
enforcement activity on prescription
drug diversion, he said.
Most prescribers are “reasonable,”
Drs. Ziegler and Gonzalez said. But
“even the best can be duped by those
with substance abuse or those motivated by profit,” they warned.
They called for new interactive
approaches that encourage regulators and prescribers to collaborate on
a continual basis. Part of that approach
involves distinguishing between criminal and negligent prescribing.
As opposed to criminal prescribers,
negligent providers are those who
do not profit from over-prescribing
medications. These providers still contribute importantly to the drug diversion and illicit prescription painkiller
use epidemics, but negligence cases
are best handled administratively or
civilly, Drs. Ziegler and Gonzalez said.
originally planned, with “39% receiving
more opioid medication than previously planned because the physician
was able to confirm the patient did
not have a recent history of controlled
substance use,” Dr. Zacharoff said.
A survey in Oregon found typical
PDMP users to be emergency medicine and primary care clinicians and
pain/addiction specialists. Among
users, 95% reported accessing the
PDMP “when they suspected a patient
of abuse or diversion.” Fewer than half
checked it for every new patient or
every time they prescribed.
“Nearly all users reported that
they discuss worrisome PDMP data
with patients,” Dr. Zacharoff said,
with 54% reporting making mental
health/substance abuse referrals and
36% reporting sometimes discharging patients from the practice. Those
surveyed reported “frequent patient
denial or anger.”
He concluded that more research
on PMDPs is needed, including how
they are incorporated into workflow
and clinical decision making, what
barriers exist, and how clinicians share
results with patients
Investigations can focus on rogue
doctors or clinics, nurses, organized
criminal groups, supply chains, insurance fraud, theft, doctor shopping, and
unlicensed practices, Dr. Gonzalez said.
Red flags for bad actors – the very
small minority of providers who run
“pill mills” practices – include those
who have multiple patients in each exam
room, who diagnose patients in fewer
than four minutes, tell patients where to
fill their prescriptions (often at a nearby, small pharmacy), whose patients
request specific drugs, and who perform
no good-faith exams, Dr. Gonzalez
reported. Another warning sign is when
every patient “gets the same thing”
prescribed to them, he added.
When it comes to patients, drug
enforcement agencies must focus on
distinguishing between people with
substance abuse problems and “criminal
profiteers,” concluded Dr. Gonzalez.
20
PAINWEEK news
Saturday, September 6
Pain Coaching Helps Patients Achieve Goals
Coaches can help patients learn active coping skills
C
oaching can provide ongoing
support to help patients achieve
active-coping strategies for contending with pain and recovering or
improving function.
Pain-management coach Rebecca
L. Curtis, ACC, of Take Courage
Coaching, stated “just as coaching
has become a proven method to aid
in management of other chronic con-
The rates of discontinuation due to adverse events during the
double-blind, placebo-controlled clinical trials (Study 1 and
Study 2) were comparable between RELISTOR (1.2%) and
placebo (2.4%).
The following is a brief summary only. See complete
Prescribing Information on www.Relistor.com or request
complete prescribing information by calling 1-800-508-0024.
INDICATIONS AND USAGE
RELISTOR is indicated for the treatment of opioid-induced
constipation in patients with advanced illness who are
receiving palliative care, when response to laxative therapy
has not been sufficient.
Limitation of use: Use of RELISTOR beyond four months has
not been studied in the advanced illness population.
CONTRAINDICATIONS
RELISTOR is contraindicated in patients with known or
suspected mechanical gastrointestinal obstruction.
WARNINGS AND PRECAUTIONS
Gastrointestinal Perforation
Cases of gastrointestinal (GI) perforation have been reported
in adult patients with opioid-induced constipation and
advanced illness with conditions that may be associated with
localized or diffuse reduction of structural integrity in the wall
of the GI tract (i.e., cancer, peptic ulcer, Ogilvie’s syndrome).
Perforations have involved varying regions of the GI tract
(e.g., stomach, duodenum, or colon).
Use RELISTOR with caution in patients with known or
suspected lesions of the GI tract. Advise patients to
discontinue therapy with RELISTOR and promptly notify
their physician if they develop severe, persistent, or
worsening abdominal symptoms.
Severe or Persistent Diarrhea
If severe or persistent diarrhea occurs during treatment,
advise patients to discontinue therapy with RELISTOR and
consult their physician.
ADVERSE REACTIONS
Clinical Trial Experience
Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in the clinical
trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates
observed in clinical practice.
The majority of patients had a primary diagnosis of incurable
cancer; other primary diagnoses included end-stage
COPD/emphysema, cardiovascular disease/heart failure,
Alzheimer’s disease/dementia, HIV/AIDS, or other advanced
illnesses. Patients were receiving opioid therapy (median
daily baseline oral morphine equivalent dose = 172 mg),
and had opioid-induced constipation (either <3 bowel
movements in the preceding week or no bowel movement
for 2 days). Both the methylnaltrexone bromide and placebo
patients were on a stable laxative regimen for at least
3 days prior to study entry and continued on their regimen
throughout the study.
The safety of RELISTOR was evaluated in two, double-blind,
placebo-controlled trials in patients with advanced illness
receiving palliative care: Study 1 included a single-dose,
double-blind, placebo-controlled period, whereas Study 2
included a 14-day, multiple-dose, double-blind, placebocontrolled period.
The most common adverse reactions (>5%) in patients
receiving RELISTOR are shown in the table below.
Adverse Reactions from all Doses in Double-Blind, PlaceboControlled Clinical Studies of RELISTOR in Adult Patients
with Opioid-Induced Constipation and Advanced Illness*
Adverse
Reaction
RELISTOR
N = 165
Placebo
N = 123
Abdominal Pain
47 (28.5%)
12 (9.8%)
Flatulence
22 (13.3%)
7 (5.7%)
Nausea
19 (11.5%)
6 (4.9%)
Dizziness
12 (7.3%)
3 (2.4%)
Diarrhea
9 (5.5%)
3 (2.4%)
Hyperhidrosis
11 (6.7%)
8 (6.5%)
* Doses: 0.075, 0.15, and 0.30 mg/kg/dose
019604_salrep_anchor2_pain_wk_conf_fa2.indd 2
Postmarketing Experience
The following additional adverse events have been identified
during post-approval use of RELISTOR. Because they are
reported voluntarily from a population of unknown size,
estimates of frequency cannot be made. These events have
been chosen for inclusion due to either their seriousness,
frequency of reporting or causal connection to RELISTOR,
or a combination of these factors.
Gastrointestinal
Perforation, cramping, vomiting
General Disorders and Administrative Site Disorders
Diaphoresis, flushing, malaise, pain. Cases of opioid
withdrawal have been reported.
DRUG INTERACTIONS
Drugs Metabolized by Cytochrome P450 Isozymes
In healthy subjects, a subcutaneous dose of 0.30 mg/kg
of methylnaltrexone did not significantly affect the
metabolism of dextromethorphan, a CYP2D6 substrate.
In vitro methylnaltrexone did not significantly inhibit or induce
the activity of cytochrome P450 (CYP) isozymes CYP1A2,
CYP2A6, CYP2B6, CYP2C9, CYP2C19, or CYP3A4.
In vitro, methylnaltrexone did not induce the enzymatic
activity of CYP2E1.
Drugs Renally Excreted
Methylnaltrexone is actively secreted in the kidney. The
potential of drug interactions between methylnaltrexone
bromide and other drugs that are inhibitors of transporters
in the kidney has not been fully investigated.
Cimetidine
Cimetidine given 400 mg three times daily did not significantly
affect the systemic exposure to methylnaltrexone. The effect
of a higher cimetidine dose (e.g., 800 mg) on the systemic
exposure of methylnaltrexone has not been evaluated.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category B
Reproduction studies have been performed in pregnant rats
at intravenous doses up to about 14 times the recommended
maximum human subcutaneous dose of 0.3 mg/kg based on
the body surface area and in pregnant rabbits at intravenous
doses up to about 17 times the recommended maximum
human subcutaneous dose based on the body surface
area and have revealed no evidence of impaired fertility or
harm to the fetus due to methylnaltrexone bromide. There
are no adequate and well-controlled studies in pregnant
women. Because animal reproduction studies are not always
predictive of human response, methylnaltrexone bromide
should be used during pregnancy only if clearly needed.
Labor and Delivery
Effects of RELISTOR on mother, fetus, duration of labor, and
delivery are unknown. There were no effects on the mother,
labor, delivery, or on offspring survival and growth in rats
following subcutaneous injection of methylnaltrexone bromide
at dosages up to 25 mg/kg/day.
Nursing Mothers
Results from an animal study using [ 3H]-labeled
methylnaltrexone bromide indicate that methylnaltrexone
bromide is excreted via the milk of lactating rats. It is not
known whether this drug is excreted in human milk. Because
many drugs are excreted in human milk, caution should be
exercised when RELISTOR is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of RELISTOR have not been
established in pediatric patients.
ditions, pain management coaching
works to help clients live well with the
condition of chronic pain.”
When pain is related to particular
movement, such as reaching or walking,
not identified differences in responses between the elderly
and younger patients, but greater sensitivity of some older
individuals cannot be ruled out.
Based on pharmacokinetic data, and safety and efficacy data
from controlled clinical trials, no dose adjustment based on
age is recommended.
Renal Impairment
No dose adjustment is required in patients with mild or
moderate renal impairment. Dose reduction by one-half
is recommended in patients with severe renal impairment
(creatinine clearance less than 30 mL/min as estimated by
Cockcroft-Gault).
In a study of volunteers with varying degrees of renal
impairment receiving a single dose of 0.30 mg/kg
methylnaltrexone bromide, renal impairment had a marked
effect on the renal excretion of methylnaltrexone bromide.
Severe renal impairment decreased the renal clearance of
methylnaltrexone bromide by 8- to 9-fold and resulted in a
2-fold increase in total methylnaltrexone bromide exposure
(AUC). Cmax was not significantly changed. No studies were
performed in patients with end-stage renal impairment
requiring dialysis.
Hepatic Impairment
No dose adjustment is required for patients with mild or
moderate hepatic impairment. The effect of severe hepatic
impairment on the pharmacokinetics of methylnaltrexone
has not been studied.
Patient Counseling
Instruct patients not to continue taking RELISTOR and to
promptly notify their physician if they experience severe,
persistent, or worsening abdominal symptoms because
these could be symptoms of gastrointestinal perforation
[see Warnings and Precautions].
Instruct patients not to continue taking RELISTOR if they
experience severe or persistent diarrhea. Inform patients that
common side effects of RELISTOR include abdominal pain,
flatulence, nausea, dizziness, and diarrhea.
Advise patients to be within close proximity to toilet facilities
once the drug is administered.
Instruct patients with opioid-induced constipation and
advanced illness to administer one dose subcutaneously
every other day, as needed, but no more frequently than
one dose in a 24-hour period.
Instruct patients to discontinue RELISTOR if they stop taking
their opioid pain medication.
Instruct patients to use the RELISTOR single-use vial with a
27 gauge x ½-inch needle and 1 mL syringe.
You are encouraged to report negative side effects
of prescription drugs to the FDA. Visit www.fda.gov/
medwatch or call 1-800-FDA-1088.
To report adverse events, a product complaint, or for
additional information, call: 1-800-508-0024.
Manufactured for:
Salix Pharmaceuticals, Inc.
Raleigh, NC 27615
Under License from:
Progenics Pharmaceuticals, Inc.
Tarrytown, NY 10591
REL-RALAB6-062013
Geriatric Use
In the phase 2 and 3 double-blind studies, a total of 77 (24%)
patients aged 65-74 years (54 methylnaltrexone bromide,
23 placebo) and a total of 100 (31.2%) patients aged 75 years
or older (61 methylnaltrexone bromide, 39 placebo) were
enrolled. Pharmacokinetics of methylnaltrexone was similar
between the elderly (mean age 72 years old) and young adults
(mean age 30 years old). No overall differences in safety or
effectiveness were observed between these patients and
younger patients, and other reported clinical experience has
8/7/14 4:30 PM
patient avoidance and reduced activity can impede his or her recovery of
function. Anxiety can also worsen pain,
Curtis noted.
Coaching can help overcome fear of
movement and break down resistance
and create bridges for the patient to
master self-management strategies,
improving adherence and outcomes,
she said. Understanding pain physiology
and the brain-body loop’s information
feedback system can help patients retain
and understand information about their
situation, and become more active in
their coping strategies, she added.
Active copers are
patients who learn
about their pain, explore ways to move,
“explore and nudge
the edges of pain.”
With coaching support, passive copers can adopt active coping strategies.
Active copers are patients who learn
about their pain, explore ways to move,
“explore and nudge the edges of pain,”
while staying positive and making
plans for recovery, she said. Passive
copers, in contrast, avoid activity and
tend to wait for their situations to
improve, believing others have answers
and solutions. They are “waiting for
something to happen” instead of
actively working to improve function
and cope with pain, Curtis explained.
Encouraging active coping involves
positive psychology, cognitive behavioral therapy and motivational interviewing to draw the patient into
helping identify personalized solutions, she said. The coaching toolkit
involves guidance and encouragement
for patient participation in exercise
plans, healthy sleep schedules and
habits, and relaxation, she said.
The pain coach and patient “co-develop strategies, which are personalized
for each individual’s specific needs,”
she said. “By participating in consistent
weekly sessions, the client is provided
with a source of support and accountability. The client begins with very small
steps to increase self-efficacy, and as
the self-efficacy grows so does the goal
accomplishment. This allows the passive client become an active participant
in the recovery process, which ultimately allows the patient to once again
become an active participant in life.”
PAINWEEK news
Saturday, September 6
21
Use and Development of NSAIDs Should Consider
More Than Just a Single Feature
Thinking beyond just COX-1 vs COX-2 inhibition can inform clinical practice and open new opportunities for drug development
I
t’s time to refocus on NSAIDs
beyond only COX-1 versus COX-2
inhibition.
That’s the conclusion of Robert B.
Raffa, PhD, of the School of Pharmacy
and School of Medicine, Temple
University, Philadelphia, Pennsylvania,
who said reemphasis on pharmacokinetic and pharmacodynamic concepts
“beyond just COX-1 versus COX-2
might hold promise for NSAID discovery, development, and clinical use.”
Although discovery of the cyclooxygenase (COX) enzyme advanced
understanding of arachidonic acid
metabolism, prostaglandin physiology, and pain-modulating pathways—
which was further advanced with the
discovery of COX-2—“arguably,
COX-2 inhibitors did not provide
significant new insight into painmodulating pathways or analgesic
mechanisms of action and may have
inadvertently resulted in a hiatus in
NSAID analgesia research,” he said.
This hiatus is due, in part, to the
time spent (lost?) in the almost exclusive interest in developing potentially
revolutionizing COX-2 inhibitors
and the unfortunate recognition of
increased risk of heart attacks and
stroke observed after several COX-2
agents were approved, which resulted in
rofecoxib being withdrawn in 2004 and
valdecoxib in 2005. Celecoxib remains
on the market, and all NSAIDs now
carry a warning of the potential for cardiovascular and gastrointestinal risks.
Other NSAIDs that may be prescribed
include ibuprofen, naproxen, indo-
methacin, diclofenac, and meloxicam.
Even inhibitor “selectivity” needs
a better measure, he argued, noting
that the commonly used ratio of IC50/
IC50, which measures the concentrations that inhibit both COX-1 and
COX-2 equally (50%), is not a good
measure; rather, the ratio IC80/IC50,
is both more biochemically accurate
and clinically relevant.
Other factors can be equally or more
important. For example, non-acidic
NSAIDs distribute almost equally
throughout the body, while acidic
NSAIDs have high plasma protein
binding, predominantly to albumin
and NSAIDs have varying access to
synovial fluid and the brain. Such
pharmacokinetic properties suggest
that peripheral tissue or CNS may be
targeted with newer agents.
Animal studies have shown evidence
of central action, with indomethacin,
ibuprofen, and diclofenac depressing
C fiber-evoked activity in the rat thalamus and spinal cord, while sodium
salicylate was found to inhibit GABAA
current in rat spinal cord neuron cells.
Dr. Raffa noted that “it is important
to recognize that there can be other
than COX activity.” For example, the
antinociceptive effect of one newer
NSAID, a ‘preferential COX-2 inhibitor’, actually also includes bradykinininduced effects on AMPA currents via
inhibition of protein kinase C.
Thinking beyond just COX-1 vs
COX-2 can inform clinical practice
and suggest possible drug development directions, he said.
The UNDEAD DEAD Nerve: Neuropathic Pain Has Diverse Causes
Damaged nerve and residual nociceptor activity may complicate the picture
U
nrecognized nerve damage and
residual function can be a “spontaneous pain generator,” said
Gary W. Jay, MD, DAAPM, FAAPM,
Medical Director of The DNA Center
in Daytona Beach, Florida.
“There is substantial evidence that
abnormal nerve activity is an important mechanism underlying the spontaneous pain typical of neuropathic
pain states,” Dr. Jay said. “It is hypothesized that sites of ectopic foci include
developing on injured or regenerating
nerves in the periphery, at the level
of the nociceptor, neuromas, or segments of injured nerves; at the dorsal
root ganglion, and in the dorsal horn
laminae of the spinal cord.”
These abnormal ectopic foci can be
considered “spontaneous pain generators,” that result in paroxysmal and spontaneous pain, he said.
Neuropathic pain is typically thought
of as painful peripheral neuropathy,
such as that suffered among patients
with severe diabetes. In contrast, the
pain caused by shingles (herpes zoster)
and inflammatory involvement of the
trigeminal nerves, are usually considered to be focal neuralgias.
Abnormal activity in damaged nerves
is just part of the picture, however.
Residual pain nerve activity in damaged tissues can create a more complex
situation, he suspects.
nociceptors at the site of the original
injury, creating a mixed nociceptiveneuropathic pattern,” Dr. Jay said.
Low back pain is one of the most
common disorders, affecting about
two-thirds of the adult population
in the US at some time in their lives.
“Viral, bacterial, aseptic inflammation,
pressure due to neoplasm or other structural
lesions, degenerative, ischemic, autoimmune,
toxic, traumatic, and endocrine/metabolic
mechanisms have all been implicated in the
production of pain.”
“While neuropathic pain has become
operationally defined as an abnormal
pain state that arises from a damaged
peripheral nervous system or central nervous system, there is supporting evidence suggesting that several
disease states within this category
have active residual involvement of
Degeneration of intervertebral discs
has long been considered to be the
primary etiology of low back pain, but
there is reason to suspect it is more
complicated than that, he said.
“Degeneration or deterioration of a
disc can influence the central nervous
system by nociceptor stimulation in
the annulus fibrosus, which can induce
nociceptive pain which is considered to
be discogenic pain,” explained Dr. Jay.
“This stimulation may be secondary to
mechanical or inflammatory factors.”
“In the normal intervertebral disc, only
the outer aspect of the annulus fibrosus
receives sensory innervation,” he said.
But when discs degenerate, extensive
nerve fiber growth is found in the middle
and inner third of the diseased annulus.
The degenerating disc releases inflammatory neuropeptides that, when combined with mechanical pressure, “can
induce chemical and mechanical sensitization and stimulation of the nociceptive
nerve fibers,” he surmised.
“In theory, almost any of the pathological processes known to create damage or dysfunction to neural tissue can
be considered as potential causes for
neuropathic pain,” Dr. Jay said. “Viral,
bacterial, aseptic inflammation, pressure
due to neoplasm or other structural
lesions, degenerative, ischemic, autoimmune, toxic, traumatic, and endocrine/
metabolic mechanisms have all been
implicated in the production of pain.”
22
PAINWEEK news
Saturday, September 6
e e
PAINWEEK CROSSWORD CHALL NG
An expert in pain
management news
and terminology?
Check your answers to see
how you scored in the
PAINWeek Crossword challenge!
1
3
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Opioid dependence treatment (brand)
Hard to control pain
Area of discomfort in coccydynia
Opium-dense island
Needles are needed for this alternative
therapy
Hydromorphone brand
Postherpetic neuralgia Rx (brand)
Fruitthataffectsmetabolismof
medications
Chronic, involuntary contraction of
neck muscles
____ cord stimulation
Opioids can cause this
A medication guide can be a
component (abbrv.)
Diabetic peripheral neuropathic pain
treatment
Investigational drug for opioid-induced
constipation
Pain in the back
____ Elbow (medial epicondylitis)
Selective 5-HT1B/1D receptor agonist
Little ___ Shoulder
Cambia ingredient
IV ibuprofen brand
Duragesic dosage form
Indication for Relistor (abbrv.)
Jaw pain (abbrv.)
Also known as paramorphine
A Janus kinase inhibitor (brand)
Serotonin and norepinephrine
____ inhibitor
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EclipseCrossword.com
61. Creeping, crawling sensation in
legs (abbrv.)
62. ____ Elbow (lateral epicondylitis)
66. It can be slipped or ruptured
67. Alprazolam is one
68. Neck pain
69. Painkiller
71. Hydrocodone bitartrate/APAP brand
72. Postherpetic neuralgia follows this
73. Pain drug that went from Rx to CIV
in 2014
74. Type of pain that comes from an
injured organ
DOWN
1. Its caused by uric acid
2. Trigeminal neuralgia target
3. Migrainesufferersmayexperience
these
5. Good for cervical dystonia or
hyperhidrosis (brand)
6. Generic for Dolophine
7. Capsaicin patch for neuropathic pain
8. To manipulate the muscles
9. Tumor ____ factor blockers
11. Substance ____
15. Overprescribing of these is a big
problem
17. Autoimmune disorder
19. A corticosteroid
21. Muscle-bone connector
22. They may up CV risk
23. Small ____ neuropathy
24. Commonly associated with car
accidents
26. COX-2 inhibitor (brand)
29. Vaginal pain problem
30. Oxycodone HCl ext-rel tablets (brand)
32. Acetaminophen for short
34.
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It’s legal in Colorado
Joint pain
TRPV1 channel agonist
Fioricet component
Plantar fasciitis location
Type of pain caused by mental
disturbances
Potent opioid antagonist
Pain medicine organization (abbrv.)
____-of-life pain
S-Adenosylmethionine for short
24
PAINWEEK news
Saturday, September 6
Managing ‘Difficult’ Patients Starts with Understanding
their Personalities—and Your Own
Introverts and extraverts manage pain differently.
U
nderstanding why some patients
can be more “difficult” than others can involve understanding
personality differences. “Who are the
difficult patients who are not doing
well, who are taking a lot of your time?
One of the reasons for why things may
not be going well is that you don’t
fully appreciate the personality or
temperament of that patient,” said
Michael R. Clark, MD, MPH, MBA,
of Johns Hopkins University School
of Medicine in Baltimore, Maryland.
Of personality traits, understanding
the “introversion/extraversion” set
is particularly important for easing
clinical interactions and improvingpatient compliance. “Some people are
more outgoing, more dramatic, more
emotion-expressing and others are
introverted, shy and reserved,” he said.
Providers need to develop strategies for dealing with difficult patients
“without getting caught up in labeling
people as having a personality disorder, in cases when it’s just a matter of
understanding what personality traits
they possess and what strengths and
weaknesses are, of those personality
traits,” he explained.
How you approach treatment adherence can’t be a cookie-cutter affair for
different patients because noncom-
and get paralyzed by their own worry.”
Consider the “benign example” of
the obsessional introvert who is very
details-focused, he said.
“It’s not good or bad to be an obsessional introvert,” he noted. “You might
“We have our own strengths and weaknesses.
If we are not careful and self-aware as
clinicians, our own vulnerabilities can
be provoked and we won’t be as effective.”
pliance could be rooted in different
personality traits.
“A patient who is care-free, happygo-lucky is not always the best about
taking their medications on a day-in,
day-out fashion,” he explained. “If
they feel good, they don’t take it. On
the other end of the spectrum, the
obsessional patient worries about side
effects and can torture you with questions about toxicity and side-effects,
be a fantastic accountant but not a
very good car salesman. If somebody’s
asking you to be a car salesman, that’s
going to generate distress and poor
performance. But if you notice he loves
numbers and pays attention to detail,
well, that’s the guy you want keeping
books in the back office.”
It’s much the same with the pain
patient, Dr. Clark said. “You want the
patient to do well, and when it’s not
Major Depression and Pain are a Major Treatment Challenge
Each can reduce the efficacy of treatment for the other
M
ajor depression is pervasive
among pain clinic patients,
with reported rates varying
from clinic to clinic but commonly
exceeding 50%, compared to 4%
among the general population. But
treating major depression in the context
of pain is a complex challenge, said
Mark D. Sullivan, MD, PhD, Professor
of Psychiatry at the University of
Washington.
Worldwide and across cultures, the
WHO reports that patients with persistent pain (>6 months) are 4.14 times
more likely than others to have anxiety
or depressive disorder. Pain can cause
depression but treatment of pain does
not necessarily make depression vanish, Dr. Sullivan reported.
Among patients receiving chronic
opioid therapy, depression was the
strongest predictor of ambivalence
about opioids. “Depression reduces
response to pain treatment,” he said.
“Acute pain is lessened with opioid
treatment but depression is associated
with reduced response to acute opioid
treatment. Depression complicates
pain treatment, but the converse is also
true: chronic pain reduces responses
to depression treatment, further complicating treatment.
The risk of poor SSRI (selective
serotonin reuptake inhibitor) treatment response in those with mild pain
is 25%, he noted; 30% among patients
with moderate pain, and 14% among
patients with severe pain.
Antidepressants with norepinephrine reuptake inhibition like TCAs
(tricyclic antidepressants) and SNRIs
(serotonin–norepinephrine reuptake
inhibitors) are better analgesics than
other antidepressants, Dr. Sullivan
said. These are “clearly preferred
for neuropathic pain and probably
preferred for musculoskeletal pain,”
he noted.
Depression with chronic pain is frequently complicated by post-traumatic
stress disorder (PTSD) or anxiety,
substance abuse, and occasionally,
borderline personality disorder, Dr.
Sullivan said. Antidepressants with
serotonin blockade, like trazodone,
nefazodone, or mirtazapine, are associated with better sleep and anxiety, and
are better tolerated among patients
with PTSD or panic symptoms.
Patients suffering from depression
and pain also frequently have trauma
issues, often from childhood. “This
trauma needs to be recognized and
going well, you have to figure out why.
If it’s because of their personality traits,
you can change how you interact, and
change how the encounters go.”
A patient who is an obsessional introvert “wants to know as much as possible
about their care,” he said. “They’re
constantly calling the office to ask for
more information, asking to speak with
the doctor or nurse practitioner. What’s
really driving that behavior is that they
are not spending enough time with
their clinicians, and they don’t have a
good method for feeling calm and reassured. If you understand that person’s
personality, then that might be the
patient you give scientific articles to
read, or spend more time educating.”
It is also important for providers to consider their own personality, and how it affects relationships
with patients. “All of us are people,”
Dr. Clark said. “We have our own
strengths and weaknesses. If we are not
careful and self-aware as clinicians, our
own vulnerabilities can be provoked
and we won’t be as effective.”
addressed before depression treatment
can succeed,” he emphasized.
“Emphasize that depression treatment will help other pain treatments
work better.” If patients report that
antidepressants make them feel worse,
providers should carefully explore
what that means rather than dismissing—or accepting—such statements
at face value, he said. “It can mean
‘I felt the clinician was ignoring my
pain, or ignoring me, and writing the
prescription to get me out the door’,”
he explained. Or it might mean “the
antidepressant made me more anxious,
more angry, more depressed.”
“Don’t oversell antidepressants”
to patients, he concluded. “They
are imperfect medications with side
effects.” Instead, providers should
encourage patients to “put their nickel
down” by participating in the selection
of a treatment from among the available options. “If they are invested in
the choice of treatment, they are less
likely to reject the treatment,” he said.
26
PAINWEEK news
Saturday, September 6
CURRENT RESEARCH AND CLINICAL FINDINGS
Less Peripheral Edema and Weight Gain with Gabapentin Enacarbil
Therapy for Painful DPN
Overall, gabapentin enacarbil (GEn) was associated with lower incidences
of peripheral edema and weight gain than pregabalin, according to authors
of a multicenter, randomized, placebo-controlled Phase 2 study of adult
patients with painful diabetic peripheral neuropathy (DPN), reported lead
author Anne M. Calkins, MD, of New York Spine and Wellness Center,
North Syracuse, NY, and colleagues. “The weight gain in GEn-treated
patients appeared to be dose-dependent.”
The differences are clinically significant because they may improve patient
tolerance and treatment adherence, the coauthors said.
A total of 420 adult patients with type 1 or 2 diabetes mellitus with DPNattributed painful distal symmetric sensorimotor polyneuropathy were
randomly assigned to receive GEn 1200 mg/day, GEn 2400 mg/day, GEn
3600 mg/day, pregabalin 300 mg/day, or placebo, for 20 weeks.
Compared with pregabalin, patients administered gabapentin enacarbil
experienced less peripheral edema and weight gain. Peripheral edema
occurred in 11% of patients in the GEn 3600 mg and the pregabalin groups,
0% of the GEn 2400 mg-group patients, and 2% of GEn 1200 mg-group
patients, and 5% of placebo-group patients, the authors reported.
Worsening grade in pedal edema relative to baseline occurred in 8% of
patients in the placebo group, 11% of GEn 1200 mg, 16% of GEn 2400 mg, and
10% of GEn 3600 mg, compared to 28% of patients in the pregabalin group.
Mean change from baseline for weight gain at week 13 or at last observation
in early termination was -0.55 kg for placebo; +1.22 kg for GE 1200 mg; +1.71
kg GEn 2400 mg; +1.85 kg GEn 3600 mg; and +2.65 kg GEn pregabalin.
“Across treatment groups, the majority of patients reported at least one
TEAE [treatment-emergent adverse event],” the coauthors noted. “The
most common TEAEs that occurred in ≥5% of patients in either the GEn
or pregabalin treatment groups included dizziness, somnolence, nausea,
and peripheral edema. All of the most common TEAEs occurred more
frequently in at least one active treatment arm than in the placebo arm.”
Gabapentin enacarbil has been approved by the FDA for postherpetic
neuralgia in adults and moderate-to-severe primary restless legs syndrome;
it is not approved for the treatment of DPN.
Poster and Podium Presentation #: 17
Title: Peripheral Edema and Weight Gain in Adult Patients with Painful
Diabetic Peripheral Neuropathy Receiving Gabapentin Enacarbil or
Pregabalin Enrolled in a Randomized Phase 2 Trial
Authors: Anne M. Calkins, MD1, Joseph Shurman2, Mark Jaros3, Richard
Kim4, and Gwendoline Shang4
1
New York Spine and Wellness Center, North Syracuse, New York; 2Scripps
Memorial Hospital, La Jolla, California; 3Summit Analytical, LLC, Denver,
Colorado; 4XenoPort, Inc., Santa Clara, California.
Physical Therapy Increases Functional Gain in Patients with
Spine-Related Disorders
Patients with a spine-related disorder who adhered to recommended physical therapy required fewer visits, interventions, and/or prescription drugs,
a retrospective chart review has found.
Noting that little is known about the value of physical therapy interventions for spine care, Yung Chen, MD, of the San Mateo Spine Center in San
Mateo, California, hypothesized that such intervention would be associated
with decreases in subsequent rates of lumbar surgery, lumbosacral spinal
injections, and oral pain medication needs.
The charts of 1600 patients diagnosed with lumbar sacral radiculopathy,
spinal stenosis, and radiculitis who visited the center over a 24-month period
for treatment were reviewed for functional improvement, repeated spinal
injections, and oral medication usage at 6-month follow-up. Mean age of
the 782 female patients was 66 years and, the 818 male patients, 62 years.
In patients who underwent physical therapy, compared with those who
did not, 92% (vs 52%) had functional gain, 68% (vs 30%) had a repeat
spinal injection, and use of oral medication decreased approximately 60%.
Patients received a customized physical therapy program that included
manual therapy techniques (joint and soft tissue mobilizations, passive
stretching) modalities (interferential stimulation, cold laser, ultrasound),
therapeutic exercises (lumbosacral stabilization and LE strengthening) and
home exercises, including ergonomics and postural training.
“This study supports the importance of physical therapy after spinal injections for patients suffering back pain,” Dr. Chen stated. “Prospective trials
of physical therapy in spine-related patients are needed to better define
response rates and predictors of response.”
Poster #: 25
Title: Physical Therapy Utilization and Recovery After Lumbar Spinal
Injections for 1600 Patients with Spine Related Disorder
Authors: Yung Chen, San Mateo Spine Center, San Mateo, CA
Fixed-Dose Methylnaltrexone Alleviates Opioid-Induced Constipation in
Patients with Advanced Illness
Fixed-dose methylnaltrexone, a peripherally restricted mu-opioid receptor antagonist, demonstrated robust and durable efficacy in patients with
opioid-induced constipation and advanced illness, Janet Bull, MD, from
Four Seasons, Flat Rock, North Carolina, and colleagues have found.
Similar to weight-based dosing, fixed-dose methylnaltrexone was generally
well tolerated for up to 12 weeks.
The Phase 4 trial randomly assigned adults with opioid-induced constipation receiving stable doses of opioids to methylnaltrexone 8 mg or 12 mg
by body weight (38 kg to <62 kg or ≥62 kg, respectively; n=116) or placebo
(n=114) every other day for 2 weeks.
The most common underlying advanced illness was cancer (66.1%). Median
daily morphine equivalent dose was 176.8 mg/day and mean duration of
opioid-induced constipation, 76.6 weeks.
Patients treated with fixed-dose methylnaltrexone were significantly more
likely to have a rescue-free bowel movement, the primary end point, within
4 hours after 2 or more of the first 4 doses in the first week of treatment;
this rate was 62.9% and 9.6% for methylnaltrexone and placebo groups,
respectively (P< 0.0001). The time to rescue-free bowel movement after the
first methylnaltrexone dose was rapid, a median time of 0.8 hours versus
23.6 hours in the placebo group (P< 0.0001).
The most common adverse events (methylnaltrexone versus placebo,
respectively) were abdominal pain (33.6% vs 16.7%), nausea (11.2% vs
15.8%), and disease progression (8.6% vs 14.9%).
Poster #: 76
Title: Fixed-Dose Subcutaneous Methylnaltrexone in Patients With
Advanced Illness and Opioid-Induced Constipation: Results of a
Randomized, Placebo-Controlled Study and Open-Label Extension
Authors: Janet Bull1, Charles Wellman2, Robert Israel3, Andrew Barrett4,
Craig Paterson4, William Forbes4
1
Four Seasons, Flat Rock, Arkansas, USA, 2Hospice of the Western Reserve,
Cleveland, Ohio, USA, 3Progenics Pharmaceuticals, Inc., Tarrytown, New
York, USA, 4Salix Pharmaceuticals, Inc., Raleigh, North Carolina, USA
PAINWEEK news
Saturday, September 6
27
CURRENT RESEARCH AND CLINICAL FINDINGS
Once-Daily, Single-Entity Hydrocodone Provides Relief from Chronic Pain
Long-term use of once-daily, single-entity hydrocodone bitartrate, formulated
with abuse-deterrent properties (HysinglaTM ER), was safe and effective in
the treatment of patients with moderate to severe chronic pain, results of
an open-label study have found.
Warren Wen, PhD, Purdue Pharma, LP, Stamford, Connecticut, and colleagues evaluated long-term safety and effectiveness of hydrocodone bitartrate
20 mg, 40 mg, 60 mg, 80 mg, and 120 mg tablets for the treatment of controlled or uncontrolled, moderate to severe, chronic pain in 922 patients who
were both opioid-naive and opioid-experienced. The core study comprised
a screening period (up to 14 days), a dose titration period (up to 45 days),
and a maintenance period (52 weeks); patients also had the option to enter
a 24-week extension period with an optional taper period (up to 14 days).
Hydrocodone bitartrate improved mean pain intensity scores and lowered
Brief Pain Inventory interference scores, both of which were maintained for up
to 76 weeks without a dose increase or need for supplemental opioid analgesics.
The agent was generally well tolerated. During the core study, the most
frequently reported treatment-emergent adverse events included nausea,
constipation, vomiting, fatigue, dizziness, somnolence, and headache, typical
of systemic mu-opioid agonist analgesics.
The agent is currently under development for the management of pain
severe enough to require daily, around-the-clock long-term opioid treatment for which other treatment options are inadequate.
Poster #: 92
Title: Long-term Safety and Effectiveness of Once-daily, Single-entity
Hydrocodone, Formulated with Abuse Deterrent Properties (HysinglaTM ER)
in Chronic Nonmalignant and Nonneuropathic Pain: Results of an Openlabel Study
Authors: Warren Wen1, Louise Taber2, Shau Yu Lynch1, Catherine
Munera1, Steven Ripa1
1
Purdue Pharma L.P., Stamford, CT, USA, 2Arizona Research Center, Phoenix,
AZ, USA
Twitter Posts, Online Media Highlight Patients’ Ignorance of OpioidInduced GI Side Effects
Increasing utilization of social media by patients to create health communities
can offer insights to providers into patient concerns surrounding treatment.
Analysis of message content from Twitter and other health-related online
forums spotlighted patients’ “lack of knowledge about opioid-induced GI
side effects and their attempts to minimize them whilst maintaining effective pain management regimens,” reported authors.
“Qualitative analysis revealed that patients modify medication regimens
with and without medical advice,” said lead author Cynthia B. Whitman,
MPH, of the Cedars-Sinai Center for Outcomes Research and Education
in Beverly Hills, California, and coauthors. Patients were also found to be
“unprepared” to treat opioid-induced side effects, and to “feel unable to
communicate with their doctors about altering opioid regimens or addressing opioid-induced GI side effects.”
Using automated keyword-driven data collection algorithms, the researchers
were able to obtain 10,645 Twitter posts and 446 relevant e-forum posts at
health-related sites like www.PatientsLikeMe.com, yielding a total of 1342
relevant quotes on opioid therapy for automated and manual investigator
content analysis.
The most common themes of posts were GI side effects (1214 patient mentions, including 845 mentions of constipation, 258 descriptions of nausea,
and 118 mentions of vomiting), balancing continued opioid therapy against
side effects, and doctor-patient communication, including patients’ questioning doctors’ decisions or knowledge about side effects, difficulty talking
to doctors, and doctors’ listening or awareness about side-effects concerns.
“These data from social media platforms reveal a need for increased communication between patients and doctors regarding opioid-induced GI side
effects,” coauthor Justin L. Scopel, MD, MBA, reported.
Poster and Podium Presentation #:113
Title: Balancing Pain Relief and Opioid-Induced Gastrointestinal Side
Effects: Insights from a Structured Review of Social Media Platforms
Authors: Cynthia B. Whitman, MPH1, Corey Arnold, PhD2, Haridarshan
Patel, PharmD3, Justin L. Scopel, MD, MBA4, Mark W. Reid, PhD1,5, Brennan
M.R. Spiegel, MD, MSHS1,5,6
1
Cedars-Sinai Center for Outcomes Research and Education (CS-CORE),
Beverly Hills, California; 2David Geffen School of Medicine at UCLA, Los
Angeles, California; 3Immensity Consulting, Inc., Chicago, Illinois; 4US
Medical Affairs, Takeda Pharmaceuticals International, Inc., Deerfield, Illinois;
5
VA Greater Los Angeles Healthcare System, Los Angeles, California; 6UCLA
Fielding School of Public Health, Los Angeles, California.
Pregabalin Reduces Pain Severity in Patients with Fibromyalgia and
SSRI/SNRI-Treated Depression
Pregabalin shows promise as a possible treatment option for fibromyalgia
patients who are taking antidepressant medication, according to authors
of an international multicenter Phase 3b, randomized, two-way crossover,
double-blind, placebo-controlled study of pregabalin in fibromyalgia patients
who are taking a SSRI (selective serotonin reuptake inhibitor ) or a SNRI
(serotonin-norepinephrine reuptake inhibitor) for comorbid depression.
Pregabalin significantly reduced pain severity compared with placebo in
patients with fibromyalgia who were taking either a single SSRI or SNRI
for comorbid depression, reported lead author Richard Vissing, PharmD,
of Pfizer Inc. in Louisville, Kentucky, and a team of Pfizer coauthors.
Mean pain scores (0-10 NRS) were significantly lower among patients
administered pregabalin compared with those receiving placebo (P=0.0001),
“irrespective of the type of antidepressant used,” reported Dr. Vissing.
“In addition, pregabalin reduced pain severity irrespective of the type of antidepressant taken,” the coauthors reported. “Pregabalin also significantly improved
anxiety and depressive symptoms, patient function and global status. Sleep
quality measures were also significantly better,” (P< 0.0001), Dr. Vissing noted.
A total of 193 adult patients were randomized 1:1 and received ≥1 dose of
pregabalin or placebo (intent-to-treat population). Treatment was for two 6-week
periods separated by a 2-week, single-blind taper/washout phase, he reported.
For patients assigned to the pregabalin group, starting twice-daily dose was
150 mg/d, “optimized to 300 mg/d or 450 mg/d during the first 3 weeks of
each treatment period and then maintained at this level for the remaining
3 weeks,” he reported.
Discontinuation rates were very similar for pregabalin and placebo groups
(12.2% and 12.4%, respectively).
Poster #:139
Title: Pregabalin in Fibromyalgia Patients Taking Antidepressant
Medication for Comorbid Depression
Authors: Richard Vissing, PharmD1, Jaren Landen, PhD2, Pritha
Bhadra Brown, PhD3, Joseph Scavone, PharmD2, Andrew Clair, PhD3,
and Lynne Pauer2
1
Pfizer Inc, Louisville, Kentucky, 2Pfizer Inc, Groton, Connecticut, USA, 3Pfizer
Inc, New York, New York
28
PAINWEEK news
Saturday, September 6
PAiN ReLieF FROM LAUGHTeR?
It’s No Joke.
And the winning caption is...
Thanks to all those
who submitted
entries! Here are
a few honorable
mentions:
Outta my way! I need
my shot of Novo-canine!
—Thomas Winkler
They told me I was
catastrophizing but
I know a dog when I
see one.
—Ted Jones
They’ve gone too far with these doggone
abuse deterrent delivery systems!
—Frank M. Yuen, PA-C
I was delivering a
package from a rogue
internet pharmacy when
McGruff decided to
take a bite out of crime.
—Stephen Ziegler
OUR WINNER
Frank M. Yuen, PA-C, the
winner of the PAINWeek
Cartoon Caption Contest,
sponsored by Haymarket
Media, accepts his
$300 gift card. When
not attending PAINWeek,
Frank is the Treasurer
of the Society of
Physician Assistants in
Addiction Medicine.
30
PAINWEEK news
Saturday, September 6
PAINWEEK
NEWS
PAINWEEK
ADMINISTRATION
Redza Ibrahim
Satellite Events and Exhibit Hall
Darryl Fossa
Art Direction and Graphic Design
Sean Fetcho
Steve Porada
Corporate Relations
Debra Weiner
Course Development
Holly Caster
Keith Dempster
Editorial Services
Wanda Tarnoff
Finance
Keith Dempster
Media Relations
Acetaminophen, NSAIDs and Opioids
All Pose Underappreciated Risks
I
n a stimulating panel discussion,
Tanya Uritsky, PharmD, BCPS,
of the Hospital of the University
of Pennsylvania in Bryn Mawr,
Pennsylvania; Mary Lynn McPherson,
PharmD, MA, BCPS, FASPE, CPE,
Professor at the University of
Maryland School of Pharmacy in
Baltimore, Maryland; and James B.
Ray, PharmD, CPE, Clinical Assistant
Professor at Virginia Commonwealth
University in Richmond, Virginia,
take turns making the case that acetaminophen, NSAIDs, or opioids represent potentially the most dangerous
analgesics.
Acetaminophen: Dr. Uritsky highlighted acetaminophen’s dangers. It
is widely used in high-risk patients—
those with asthma, peptic ulcer disease,
hemophilia, salicylate sensitization,
children younger than age 12 years,
and pregnant or breastfeeding women.
There is evidence that prenatal
exposure may increase the risks of
asthma, ADHD, and cryptorchidism.
Unintentional overdoses are common;
in 38% of unintentional acetaminophen overdoses, patients were taking
2 or more over-the-counter products.
“Liver toxicity is what we’re worried about,” she said. “Forty percent
of acute liver failure cases are due to
acetaminophen.”
Hepatotoxicity risk factors include
acute ingestion—“large amounts
over a short amount of time”—and
concurrent use of other hepatotoxic
drugs. Preexisting liver disease, poor
nutritional intake and chronic alcohol
ingestion are also risk factors.
NSAIDs: Ironically, news coverage
of acetaminophen and opiate dangers may leave providers prescribing
NSAIDs more now than in the past,
noted Dr. McPherson.
“NSAIDs can double your risk of cardiovascular death,” she noted. Clinically
significant upper GI complications are
seen in up to 2% of the >30 million
Americans who use NSAIDs daily.
More than 16,500 people are estimated to die from NSAID-related
GI adverse effects annually, she said.
“And we tend to forget about renal
adverse effects.”
Opioids: More than 17,000 people
die of opioid-associated overdoses
annually, noted Dr. Ray. But he pointed
to less widely-appreciated risks as well,
from immunosuppression, osteoporosis, and structural changes in patients’
brains, to a possible correlation with
tumor progression and androgen deficiency at “nearly castrate levels.”
Mu receptors “don’t just sit in a
vacuum, affecting pain,” he said. “I
think we’ve grossly underestimated the
danger of how we’re using opioids.”
Jeffrey Tarnoff
Operations and Technology
Patrick Kelly
Web and Print Production
Gregory Hazel
Photography
Charles Caster-Dudzick
Video
HAYMARKET MEDIA
Jenny Ko, PharmD
Editor-in-Chief
Jennifer Dvoretz
Group Art Director,
Haymarket Medical
Bryant Furlow
Contributing Editor
Debra Hughes, MS
Contributing Editor
Dominic Barone
Publisher
John Pal
Senior Vice President
Lee Maniscalco
Chief Executive Officer,
Haymarket Media, Inc.
Suboxone’s Buprenorphine is
Promising for Treating Chronic Pain
Naloxone may improve Suboxone’s analgesia, discourages abuse
S
uboxone is a “first choice” longacting opioid for treating chronic pain among the frail elderly,
according to Gregory T. Carter, MD,
MS, Medical Director of the University
of Washington School of Medicine and
St. Luke’s Rehabilitation Institute in
Spokane, Washington.
Suboxone is a combination of two
medications: the semi-synthetic partial
mu-opioid receptor agonist buprenorphine, which is an analgesic, and naloxone, which is a competitive CNS
mu-opioid receptor antagonist.
Buprenorphine, the opioid in
Suboxone, is moderately bioavailable
sublingually, but has poor oral bioavailability. It is safer than other long
term medications like methadone or
Oxycontin, Dr. Carter reported. And
unlike hydrocodone, buprenorphine
gives patients steady relief, he added.
“Buprenorphine has a long effect, 6-8
hour analgesic duration, so it can be
dosed less frequently,” he explained. “It
is also a partial opioid receptor agonist,
which builds in a measure of safety.” But
“it may still be fatal in overdose, especially if mixed with benzodiazepines
and alcohol,” he cautioned.
The use of opioid
antagonists, such
as naloxone and
naltrexone, to treat
pain, is a very, very
new field.
Buprenorphine is not recommended for patients with dehydration,
renal failure or severe hepatic failure.
“Buprenorphine is highly bound to plasma proteins,” he noted. “It is metabolized by the liver via the cytochrome
P450 3A4 enzyme system into norbuprenorphine and other metabolites.”
Norbuprenorphine is an active metabolite. It crosses the blood-brain barrier
and contributes to buprenorphine’s
effects. Because buprenorphine has a
ceiling effect, it limits abuse and people
“chasing the dragon,” he said.
A long-acting C-III opioid, buprenorphine is a partial agonist that appears to
have less abuse potential than methadone. But patients can become physically dependent on buprenorphine, Dr.
Carter warned.
The naloxone component of
Suboxone might possibly also enhance
its analgesic effects.
“The use of opioid antagonists, such as
naloxone and naltrexone, to treat pain, is
a very, very new field,” he cautioned. “In
animal models of pain, administration of
naloxone has shown an anti-nociceptive
effect without the induction of tolerance,
dependence. Thus I would say that
there is emerging evidence that naloxone may have therapeutic potential,
particularly for treating chronic neuropathic pain. Naloxone avoids the risk
of development of dependence as well.
“Ultimately, safe and effective management of chronic pain will likely
require “combining the specific effects
of all opioid receptors, (and) taking
simultaneous advantage of other analgesic pathways,” he said.
PAINWEEK news
Saturday, September 6
31
LIVIN’ LA VIDA VEGAS
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isn’t your average Ferris wheel. There’s nothing
average about it. And it’s not really a Ferris
wheel; it’s an observation wheel — the biggest
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360-degree views of Las Vegas, in-cabin video,
and music shows during this 30-minute ride.”
Las Vegas attractions offer something for everyone. From solving crimes to sky diving to the Bellagio’s worldfamous fountains and the Mandalay Bay Beach, experiencing all of Las Vegas’ attractions is like riding a
roller coaster, which you can do because we have those, too.
GRALISE® (gabapentin) tablets
BRIEF SUMMARY: For full prescribing information, see package insert.
INDICATIONS AND USAGE
GRALISE is indicated for the management of Postherpetic Neuralgia (PHN). GRALISE is not interchangeable
with other gabapentin products because of differing pharmacokinetic profiles that affect the
frequency of administration.
DOSAGE AND ADMINISTRATION
Postherpetic neuralgia
• GRALISE should be titrated to an 1800 mg dose taken orally once daily with the evening meal. GRALISE tablets
should be swallowed whole. Do not split, crush, or chew the tablets.
• If GRALISE dose is reduced, discontinued, or substituted with an alternative medication, this should be done
gradually over a minimum of one week or longer (at the discretion of the prescriber).
• Renal impairment: Dose should be adjusted in patients with reduced renal function. GRALISE should not be used
in patients with CrCl less than 30 or in patients on hemodialysis.
• In adults with postherpetic neuralgia, GRALISE therapy should be initiated and titrated as follows:
Table 1 GRALISE Recommended Titration Schedule
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Daily dose
Day 1
Day 2
Days 3-6
Days 7-10
Days 11-14
Day 15
300 mg
600 mg
900 mg
1200 mg
1500 mg
1800 mg
CONTRAINDICATIONS
GRALISE is contraindicated in patients with demonstrated hypersensitivity to the drug or its ingredients.
Table 2 GRALISE Dosage Based on Renal Function
Once-daily dosing
Creatinine clearance (mL/min)
≥ 60
30-60
< 30
Patients receiving hemodialysis
GRALISE dose (once daily with evening meal)
1800 mg
600 mg to 1800 mg
GRALISE should not be administered
GRALISE should not be administered
WARNINGS AND PRECAUTIONS
GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles
that affect the frequency of administration. The safety and effectiveness of GRALISE in patients with epilepsy has
not been studied. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including gabapentin, the active
ingredient in GRALISE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any
indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening
of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Table 3 Risk by Indication for Antiepileptic Drugs (including gabapentin, the active ingredient
in Gralise) in the Pooled Analysis
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Bodies…The Exhibition: “Not for the
squeamish, Bodies…The Exhibition features
real human bodies preserved through a
process called polymer preservation, in which
all body tissue water has been replaced with
silicone rubber. Come see 21 whole-body
specimens as well as more than 260 organs
and partial body specimens.”
Indication
Epilepsy
Psychiatric
Other
Total
Placebo patients with events per 1000 patients
Drug patients with events per 1000 patients
Relative risk: incidence of events in
drug patients/incidence in placebo patients
Risk difference: additional drug patients
with events per 1000 patients
1.0
3.4
5.7
8.5
1.0
1.8
2.4
4.3
3.5
1.5
1.9
1.8
2.4
2.9
0.9
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for
psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric
indications. Anyone considering prescribing GRALISE must balance the risk of suicidal thoughts or behavior with the
risk of untreated illness. Epilepsy and many other illnesses for which products containing active components that are
AEDs (such as gabapentin, the active component in GRALISE) are prescribed are themselves associated with morbidity
and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may
be related to the illness being treated. Patients, their caregivers, and families should be informed that GRALISE contains
gabapentin which is also used to treat epilepsy and that AEDs increase the risk of suicidal thoughts and behavior and
should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression,
any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about
self-harm. Behaviors of concern should be reported immediately to healthcare providers. Withdrawal of Gabapentin
Gabapentin should be withdrawn gradually. If GRALISE is discontinued, this should be done gradually over a minimum
of 1 week or longer (at the discretion of the prescriber). Tumorigenic Potential In standard preclinical in vivo lifetime
carcinogenicity studies, an unexpectedly high incidence of pancreatic acinar adenocarcinomas was identified in male,
but not female, rats. The clinical significance of this finding is unknown. In clinical trials of gabapentin therapy in
epilepsy comprising 2,085 patient-years of exposure in patients over 12 years of age, new tumors were reported
in 10 patients, and preexisting tumors worsened in 11 patients, during or within 2 years after discontinuing the
drug. However, no similar patient population untreated with gabapentin was available to provide background tumor
incidence and recurrence information for comparison. Therefore, the effect of gabapentin therapy on the incidence
of new tumors in humans or on the worsening or recurrence of previously diagnosed tumors is unknown. Drug
Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction
with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported
in patients taking antiepileptic drugs, including GRALISE. Some of these events have been fatal or life-threatening.
DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with
other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis,
sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its
expression, other organ systems not noted here may be involved. It is important to note that early manifestations of
hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or
symptoms are present, the patient should be evaluated immediately. GRALISE should be discontinued if an alternative
etiology for the signs or symptoms cannot be established. Laboratory Tests Clinical trial data do not indicate that
routine monitoring of clinical laboratory procedures is necessary for the safe use of GRALISE. The value of monitoring
gabapentin blood concentrations has not been established.
ADVERSE REACTIONS
Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug
and may not reflect the rates observed in practice. A total of 359 patients with neuropathic pain associated with
postherpetic neuralgia have received GRALISE at doses up to 1800 mg daily during placebo-controlled clinical
studies. In clinical trials in patients with postherpetic neuralgia, 9.7% of the 359 patients treated with GRALISE
and 6.9% of 364 patients treated with placebo discontinued prematurely due to adverse reactions. In the GRALISE
treatment group, the most common reason for discontinuation due to adverse reactions was dizziness. Of
GRALISE-treated patients who experienced adverse reactions in clinical studies, the majority of those adverse
reactions were either “mild” or “moderate”. Table 4 lists all adverse reactions, regardless of causality, occurring in at
least 1% of patients with neuropathic pain associated with postherpetic neuralgia in the GRALISE group for which the
incidence was greater than in the placebo group.
Table 4 Treatment-Emergent Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain
Associated with Postherpetic Neuralgia (Events in at Least 1% of all GRALISE-Treated Patients and
More Frequent Than in the Placebo Group)
Body system—preferred term GRALISE N = 359, %
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Ear and Labyrinth Disorders
Vertigo
Gastrointestinal Disorders
Diarrhea
Dry mouth
Constipation
Dyspepsia
General Disorders
Peripheral edema
Pain
Placebo N = 364, %
1.4
0.5
3.3
2.8
1.4
1.4
2.7
1.4
0.3
0.8
3.9
1.1
0.3
0.5
Infections and Infestations
Nasopharyngitis
2.5
2.2
Urinary tract infection
1.7
0.5
Investigations
Weight increased
1.9
0.5
Musculoskeletal and Connective
Tissue Disorders
Pain in extremity
1.9
0.5
Back pain
1.7
1.1
Nervous System Disorders
Dizziness
10.9
2.2
Somnolence
4.5
2.7
Headache
4.2
4.1
Lethargy
1.1
0.3
In addition to the adverse reactions reported in Table 4 above, the following adverse reactions with an uncertain
relationship to GRALISE were reported during the clinical development for the treatment of postherpetic neuralgia.
Events in more than 1% of patients but equally or more frequently in the GRALISE-treated patients than in the
placebo group included blood pressure increase, confusional state, gastroenteritis viral, herpes zoster, hypertension,
joint swelling, memory impairment, nausea, pneumonia, pyrexia, rash, seasonal allergy, and upper respiratory
infection. Postmarketing and Other Experience with other Formulations of Gabapentin In addition to the
adverse experiences reported during clinical testing of gabapentin, the following adverse experiences have been
reported in patients receiving other formulations of marketed gabapentin. These adverse experiences have not been
listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is
alphabetized: angioedema, blood glucose fluctuation, breast hypertrophy, erythema multiforme, elevated liver function
tests, fever, hyponatremia, jaundice, movement disorder, Stevens-Johnson syndrome. Adverse events following the
abrupt discontinuation of gabapentin immediate release have also been reported. The most frequently reported events
were anxiety, insomnia, nausea, pain and sweating.
DRUG INTERACTIONS
Coadministration of gabapentin immediate release (125 mg and 500 mg) and hydrocodone (10 mg) reduced
hydrocodone Cmax by 3% and 21%, respectively, and AUC by 4% and 22%, respectively. The mechanism of this
interaction is unknown. Gabapentin AUC values were increased by 14%; the magnitude of this interaction at other
doses is not known. When a single dose (60 mg) of controlled-release morphine capsule was administered 2 hours
prior to a single dose (600 mg) of gabapentin immediate release in 12 volunteers, mean gabapentin AUC values
increased by 44% compared to gabapentin immediate release administered without morphine. The pharmacokinetics
of morphine were not affected by administration of gabapentin immediate release 2 hours after morphine. The
magnitude of this interaction at other doses is not known. An antacid containing aluminum hydroxide and magnesium
hydroxide reduced the bioavailability of gabapentin immediate release by about approximately 20%, but by only 5%
when gabapentin was taken 2 hours after antacids. It is recommended that GRALISE be taken at least 2 hours following
antacid administration. There are no pharmacokinetic interactions between gabapentin and the following antiepileptic
drugs: phenytoin, carbamazepine, valproic acid, phenobarbital, and naproxen. Cimetidine 300 mg decreased the
apparent oral clearance of gabapentin by 14% and creatinine clearance by 10%. The effect of gabapentin immediate
release on cimetidine was not evaluated. This decrease is not expected to be clinically significant. Gabapentin
immediate release (400 mg three times daily) had no effect on the pharmacokinetics of norethindrone (2.5 mg) or
ethinyl estradiol (50 mcg) administered as a single tablet, except that the Cmax of norethindrone was increased by
13%. This interaction is not considered to be clinically significant. Gabapentin immediate release pharmacokinetic
parameters were comparable with and without probenecid, indicating that gabapentin does not undergo renal
tubular secretion by the pathway that is blocked by probenecid.
USE IN SPECIFIC POPULATIONS
Pregnancy Pregnancy Category C: Gabapentin has been shown to be fetotoxic in rodents, causing delayed
ossification of several bones in the skull, vertebrae, forelimbs, and hindlimbs. There are no adequate and
well-controlled studies in pregnant women. This drug should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus. To provide information regarding the effects of in utero exposure
to GRALISE, physicians are advised to recommend that pregnant patients taking GRALISE enroll in the North
American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number
1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at
the website http://www.aedpregnancyregistry.org/. Nursing Mothers Gabapentin is secreted into human milk
following oral administration. A nursed infant could be exposed to a maximum dose of approximately 1 mg/kg/
day of gabapentin. Because the effect on the nursing infant is unknown, GRALISE should be used in women
who are nursing only if the benefits clearly outweigh the risks. Pediatric Use The safety and effectiveness of
GRALISE in the management of postherpetic neuralgia in patients less than 18 years of age has not been studied.
Geriatric Use The total number of patients treated with GRALISE in controlled clinical trials in patients with
postherpetic neuralgia was 359, of which 63% were 65 years of age or older. The types and incidence of adverse
events were similar across age groups except for peripheral edema, which tended to increase in incidence with
age. GRALISE is known to be substantially excreted by the kidney. Reductions in GRALISE dose should be made
in patients with age-related compromised renal function. [see Dosage and Administration]. Hepatic Impairment
Because gabapentin is not metabolized, studies have not been conducted in patients with hepatic impairment.
Renal Impairment GRALISE is known to be substantially excreted by the kidney. Dosage adjustment is necessary
in patients with impaired renal function. GRALISE should not be administered in patients with CrCL between
15 and 30 or in patients undergoing hemodialysis [see Dosage and Administration].
DRUG ABUSE AND DEPENDENCE
The abuse and dependence potential of GRALISE has not been evaluated in human studies.
OVERDOSAGE
A lethal dose of gabapentin was not identified in mice and rats receiving single oral doses as high as 8000 mg/kg.
Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, sedation, hypoactivity, or excitation.
Acute oral overdoses of gabapentin immediate release in humans up to 49 grams have been reported. In these
cases, double vision, slurred speech, drowsiness, lethargy and diarrhea were observed. All patients recovered with
supportive care. Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in
the few overdose cases reported, it may be indicated by the patient’s clinical state or in patients with significant renal
impairment.
CLINICAL PHARMACOLOGY
Pharmacokinetics Absorption and Bioavailability Gabapentin is absorbed from the proximal small bowel by a
saturable L-amino transport system. Gabapentin bioavailability is not dose proportional; as the dose is increased,
bioavailability decreases. When GRALISE (1800 mg once daily) and gabapentin immediate release (600 mg three
times a day) were administered with high fat meals (50% of calories from fat), GRALISE has a higher Cmax and lower
AUC at steady state compared to gabapentin immediate release. Time to reach maximum plasma concentration
(Tmax) for GRALISE is 8 hours, which is about 4-6 hours longer compared to gabapentin immediate release.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility Gabapentin was given in the diet to mice at 200,
600, and 2000 mg/kg/day and to rats at 250, 1000, and 2000 mg/kg/day for 2 years. A statistically significant
increase in the incidence of pancreatic acinar cell adenoma and carcinomas was found in male rats receiving the
high dose; the no-effect dose for the occurrence of carcinomas was 1000 mg/kg/day. Peak plasma concentrations
of gabapentin in rats receiving the high dose of 2000 mg/kg/day were more than 10 times higher than plasma
concentrations in humans receiving 1800 mg per day and in rats receiving 1000 mg/kg/day peak plasma
concentrations were more than 6.5 times higher than in humans receiving 1800 mg/day. The pancreatic acinar cell
carcinomas did not affect survival, did not metastasize and were not locally invasive. The relevance of this finding
to carcinogenic risk in humans is unclear. Studies designed to investigate the mechanism of gabapentin-induced
pancreatic carcinogenesis in rats indicate that gabapentin stimulates DNA synthesis in rat pancreatic acinar cells
in vitro and, thus, may be acting as a tumor promoter by enhancing mitogenic activity. It is not known whether
gabapentin has the ability to increase cell proliferation in other cell types or in other species, including humans.
Gabapentin did not demonstrate mutagenic or genotoxic potential in 3 in vitro and 4 in vivo assays. No adverse
effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg (approximately 11 times the
maximum recommended human dose on an mg/m2 basis).
© December 2012, Depomed, Inc. All rights reserved. GRA-410-P.1