Narcotic Bowel Syndrome

Narcotic Bowel Syndrome
Definitions, history, how frequent?
Definition NBS
Note: not yet defined in Int. Classification of diseases
or Rome Criteria of FGID
• Progressive and paradoxical increase in abdominal
pain despite continued or escalating doses of
narcotics prescribed to relieve the pain
• Less common than but may be associated with
opioid bowel disorder, a dose related dysmotility
Grunkemeier, Drossman, et al Clin Gast and Hep 2007;5:1126-39
Opioid Bowel Disorder or Dysfunction (OBD)
A Dysmotility Disorder
• Central effects also implicated, but interaction with opioid
receptors in the gut felt to be primary
•
•
•
•
•
•
•
•
Nausea
Bloating, distension
Ileus
Constipation
Abdominal Pain
GERD
Pseudo-obstruction
Interference with oral drug absorption
First described
• Narcotic Bowel Syndrome Treated with Clonidine:
CAP, Pseudo-obstruction, vomiting, wt loss- resolution after
discontinuing narcotics Annals of IM Sandgren et al U of KS 1984;101:334-8
• Editorial: The Narcotic Bowel Syndrome:
Pain and pseudo-obstruction described- “although helpful
initially, the pain returns requiring more and more narcotic for
control of symptoms” J Clin Gastro Michael Rogers and James Cerda U of Fl 1989;11:132-5
• A Case of Narcotic Bowel Syndrome Successfully Treated with
Clonidine: CAP worsening treated with narcotics and followed
by increasing doses need for pain relief, resolution of pain
upon withdrawal of narcotics aided by Clonidine Wong et al Postgrad Med J
1994;70:138-40
Opiate Use in the US
Study of Narcotic Use in IBD
• Estimated: 80% of world’s opioid used in USA (4.6%)
• Rx’s for methadone ↑ 1177% 1997-2006
• Estimated: ~5-13% IBD pts on chronic narcotics as opt
~ 8% IBS
“
“
• Estimated: Prevalence of IBS symptoms in IBD 2-3x
> general population
~57% CD ~33% UC report IBS-like symptoms
• Study result: 70% of hospitalized pts received narcotics
↑ CD, duration of IBD, prior psych dx, prior outpt use of
narcotics, smoking, prior IBD surgery, and prior dx of
IBD/IBS
*Not associated with disease severity on CT or endoscopy
Long et al, Inflamm Bowel Dis V 18 #5 May 2012 869-876 from UNC
OBD and NBS in the Mayo
Olmstead County Population
(~ 124,000 total, ~5000 participated in the study)
• Opioids mainstay of Rx in cancer pain and increasingly used as the main or
only source of pain relief for non cancer pain
• Few studies on GI effects in non cancer pain in outpts
• Results: 4% of population on prescription narcotics
8.5 % on narcotics were for cancer pain
.17% met criteria of NBS (5 cases)
Increased symptoms of abd pain, and laxative use
• OBD symptoms prevalence from previous studies:
(ca and non ca pain) constip 20-40% prior meta: 80% at least 1 symp
nausea 8-40% (non ca pain) constip 41% nausea 32%
Talley et al, AJG V104 May 2009 1199-1204
What is prevalence in pts on chronic narcotics?
• 146 subjects, on narcotics for CNCP (non GI origin)
• CAP
58.2%, 19.4% daily
• Constipation
47%
correlated with duration , not dose
• Nausea
27%
Vomiting 9% no cor with dose/dur
• GERD
33%
HB 25%
• NBS
6.4%
Neurogastro Motil V22 424-e96 2010 Tuteja et al Univ of Utah
Features of NBS
• Increasingly recognized with increased use of
narcotics for non cancer pain over the last decade
• Initially narcotics relieve pain, but continued use in a
subset (?) with chronic use → NBS
• Pts first develop tolerance or tachyphylaxis followed
by hyperalgesia even with dose escalation
• Genetic or pharmacogenomic factors, vary pt to pt
Not specific to any disorder
• Not associated with any specific medical
condition
• Seen in a wide variety of disorders
• Can be seen when high dose narcotics are
used postoperatively
5 Criteria for Dx
1. Chronic or frequently recurring GI pain treated with acute
high dose or continual narcotics
2. Pain worsens or incompletely resolves with continued or
increased dosages of narcotics
3. There is marked worsening when the narcotic dose wanes
and improvement when reinstituted (“soar and crash”)
4. There is progression of the frequency, duration and intensity
of GI pain episodes
5. The nature and intensity of the pain is not explained by a
current or previous GI Dx *
Dx of NBS
• Dr. Drossman’s group recommends Dx of NBS be
strongly considered:
When patients with abdominal pain are on
narcotics and fulfill 3 of the other 4 criteria
• Dose of narcotic: equiv of 100mg MS/d
Talley et al report dosage of >10mg/d is “high”
Am J Surg 2001;182:11s-8s
What causes NBS
ENS Neurotransmitters
Largest collection of neurons outside the CNS
•
•
•
•
•
•
•
AcH (acetylcholine)
Serotonin (5-hydroxytryptamine)
Adrenergic
Tachykinins (substance P, neurokinin A)
NO (nitric oxide)
ATP
Opioid peptides- endorphins, endomorphins,
dynorphins, enkephalins, and nociceptin
• Neuropeptide Y
Opioid Receptors
delta (OP1) kappa (OP2) mu (OP3)
• All 3 contribute to opiate-induced inhibition of
muscle activity
• Symptoms of OBD are predominantly
mediated by mu-opioid receptors in humans
• Most effective opioid analgesics are muopioid receptor-selective agonists
• Given the presence of delta and kappa receptors,
selective opioid analgesics for these receptors would
not help reduce GI SE….thus
Opioid Receptors
delta (OP1) kappa (OP2) mu (OP3)
• Selectively targeting peripheral mu opioid receptors has been a
goal of pharmacological research
• Methylnaltrexone
Alvimopan
non selective mu receptor preferring antagonist
selective mu opioid receptor antagonist
ex. of peripheral mu receptor antagonists
• Loperamide
ex. of peripheral gut selective mu receptor agonist
Central Opioid Receptors
• OP1……………………OP4 (OPL-1, CNS only)
• OP4: Nociceptin Receptor: anxiety, depression, appt
tolerance to μ agonists
• Location in multiple locations in the brain and spinal
cord
• Effects multiple: analgesia, physical dependence,
euphoria, respiratory depression, anti-depressive,
are examples
Adverse effects of opioid analgesics on the GI
tract:
• Expression of opioid peptides and opioid receptors by distinct
enteric neurons and intestinal muscle cells
• When released from these neurons opioid peptides play a
transmitter role in enteric regulation of propulsive motility
and secretory processes
• Inhibitory effects on peristalsis primarily from interruption of
transmission ENS pathways governing muscle contractions via
pre and post synaptic modulation: AcH, other excitatory
neurotransmitters attenuated
Adverse effects of opioid analgesics on the GI
tract:
• Inhibit peristalsis- ↓AcH and other excitatory NT release,
and tonic contractions induced which block propulsive activity
• Tonic Spasms: depression of NO from inh neurons or direct
activation of muscles cells that express opioid receptors
• Alters intestinal fluid balance- ↓ ion and fluid secretion
↑ intestinal fluid absorption
• Constipation: stationary segmentations + inhibition of
peristalsis + depression of secretory activity
Mechanisms for NBS
• How does narcotic use cause and aggravate the pain
being treated
• 4 mechanisms proposed:
1.
2.
3.
4.
bimodal opioid regulation system
counter regulatory mechanisms
glial cell activation
microglia (CNS macrophage) cell activation
Summary of proposed mechanisms for opioid
induced hyperalgesia
• Activation of excitatory antianalgesia pathways in the
opioid regulatory system
• Descending facilitation of pain at the rostral ventral
medulla
• Dorsal Horn glial cell activation leading to morphine
tolerance via inflammatory pathways
• Microglia (CNS macrophages) that release
inflammatory factors and may upregulate neural
signals
Bimodal (Excitatory and Inhibitory) Opioid Modulation
in the Dorsal Horn & Afferent Neurons
• Inhibitory mode: analgesia- opioids activate proteins
(G1,G0) that inhibit neurotransmission
• Excitatory mode: hyperalgesia- opioids also activate
proteins (Gs) that activates neurotransmission----- antianalgesia
and tolerance
• Effects depend in part on concentration and duration
of the opioids acting on the action potential
• At the Dorsal HornLow conc.----prolong AP and excitatory effects (enhance NT release)
High conc.----shorten AP and inhibit NT release **(typical therapeutic
doses of opioids)
Bimodal Mechanism
• High concentration of opioids typical for pain relief
lead to high concentration of opioids and pain relief
initially (inhib effect > excit effect)
• Over time, Gs coupled excitatory opioid receptors
become sensitized with chronic exposure at the
DRG- & chronic use will thus lead to tolerance of
inhibitory pain effects and ultimately hyperalgesia
Narcotic antagonists, pain relief,
and bimodal modulation
• Also note: low doses of antagonists
selectively inhibit the excitatory (Gs) pathways
which can enhance opioid analgesia
• Examples- naltrexone, naloxone, buprenorphone
& is basis for the combination:
Suboxone- buprenorphine/naloxone
Note: combo meds can be used for detox as well
Counter regulatory Mechanisms
A CNS effect
• Specific areas of the brain modulate incoming pain
signals at the level of the spinal cord ↑ or ↓
•
cingulate and prefrontal cortex
rostral ventral medulla (RVM) **
periaqueductal gray
• Responses occur in part via activation or inactivation of
on and off cells in the RVM
• Chronic use may lead sensitization of the on signals
? Role in a rebound effect when opioid analgesia wears off
Counter regulatory mechanisms
• Endogenous neuromodulators in the
brainstem and spinal cord
dynorphin, CCK →
increase in excitatory NT’s from 1° afferents in
nociceptive tracts → hyperalgesia
Spinal cord glial cell activationNewly found mechanism of pain amplification
• Dorsal horn glia (astrocytes and microglia)
• When activated produce hyperalgesia in response to:
**drugs such as morphine
inflammation or infection
peripheral injury
signals from the CNS--- possibly stress
• When blocked can decrease pain
Glia and opioids
• Glia have μ (OP3) receptors **
(as well as other NT and NM receptors)
• Opioids can release dynorphin that also can activate glia **
• Glial cells produce and release NT’s, proinflammatory
cytokines (IL-1, IL-6, TNF) others e.g. NO, PG’s, excitatory aa’s,
growth factors → hyperalgesia
• Chronic (not acute) use of morphine increases spinal levels of
dynorphin → hyperalgesia
Microglia
Newer information
• CNS microglia- inflammatory cells that release
cytokines the upregulate neural signals
• Concept of Toll-like-receptor-mediated glial cell
activation:
- may be central to neuropathic pain
- and impairment in opioid analgesia
- as well as development of unwanted opioid
side effects
Opioids and Glial Cells
• Opioid agents possess Toll-like-receptor-4
agonist activity
• Opioids thus act not only at classical opioid
receptors but also via TLR4 to activate glial
cells to release cytokines and other
pronociceptive agents leading to a reduction
in analgesia and then increase in hyperalgesia
Narcotic induced hyperalgesia
• Possible new roads to pain management:
• These mechanisms may help to explain NBS first
described 20 years ago, and are avenues for
research.
• May lead to improved pharmacologic treatment of
chronic pain and NBS
Treatment of NBS
The Basics
Overview of Therapy
• Physician –Patient Relationship:
Accept pain as real
Provide information to the pat and family- basis of pain in
NBS, effect of narcotics on pain and GI function
Present the rationale of and plan for withdrawal
Elicit pt concerns and gauge willingness to proceed
Review with family
• NBS withdrawal protocol
• Post therapy issues:
Pt negotiates to go back on narcotics
Pt seeks drugs elsewhere
Treatment- Psychobiological
• Effective physician patient relationship
• Consistent plan for narcotic withdrawal
• Effective alternative treatments to manage pain and bowel
symptoms
• Initiate treatment when dx of NBS made and no other dx
explains symptoms
• NBS is a positive Dx
• Does not exclude existing inactive abd pathology **
Physician-patient relationship
• Validate pain is real, empathize with impact
• Dialogue- not lecture or written materials
• Discuss the physiologic basis
It’s not in your head *
Visceral hypersensitivity
Brain-gut dysfunction & filter mechanism
Effects of narcotic- slowing the bowel:
Constip, bloating, N/V, narcotics sensitize
nerves and make the pain worse
Review the plan and rationale with the
patient
•
•
•
•
•
Assess patient concerns
Expectations
Willingness to participate in the program **
Review with family
Review the therapeutic plan
“You could you be missing something”
“What are you going to do for the pain”
• 1. NBS is a Dx that needs treatment but that
the doctor will stay vigilant to eval new
findings
• 2. Withdrawal is gradual, other treatments
will be started, will not abandon pt with their
pain
• 3. Will address any flair ups or side effects as
they occur
Expectations
• Be realistic in explaining expectations
• Some pts become pain free
• More likely pts will feel better off narcotics
than on and this may improve with time as
other treatments are added
• Review plan with family
• Treatment is an ongoing process and not a
cure- there will be ups and downs
Follow up
• Emotional support with continuity of care
• Psychologist, psychiatrist, pain management,
other ancillary personnel
• Visits in q 1-2 wks, then monthly x 2-3 months
Basics of Medical therapy
• Gradual withdrawal of narcotics
• Substituting other treatments to reduce the
immediate withdrawal symptoms
• Treat psychological comorbidity
• Other treatments for pain control
• **Note: not intended for habitual users of
recreational narcotics or those with drug
seeking behaviors
Inpatient vs Outpatient
• Inpt:
N/V, pseudo-obstruction, ileus
Limited motivation or social support
• Outpt: Chronic narcotic use without acute
medical problems
Time Frame
• Developed over a shorter time frame:
e.g. NBS in the postoperative setting
• Developed over a longer time frame
e.g. former IV narcotics user on
accelerated doses of methadone
Components of therapy
Concomitant treatments
• Prevent withdrawal
• Reduce Anxiety
• Treat psychological comorbidity
• Provide long term central analgesia
1. Antidepressants to assist with pain control
and treat depression when present
• Start optimally 1 week before withdrawal (start at lower doses)
(can ↑ over time)
• Continue indefinitely for pain management
• Provides improved well being and reduces abd pain
• TCA’s favored- use 2°amines over 3°
(desip, nortr over imip, amitrip)
desipramine, nortriptyline 25-150mg qhs (higher doses for depression)
SNRI can be substituted, e.g. duloxetine 30-90mg/d
**SSRI’s- less benefit in pain management
(norepinephrine- import in pain Rx)
Other Psychotropic Medicines to treat pain and
depression
• Mirtazapine 15-30mg hs:
- consider instead of or better in addition to a TCA or SNRI if
nausea is a prominent feature
• Quetiapine (Seroquel) 25-100mg hs:
- adjunctive treatment for pain either in hospital or
add after several weeks as opt if the antidepressant
is not sufficient for pain management
- also helpful for sleep problems, anxiety, and pain Rx
2. Narcotic Withdrawal
• Convert total daily dose to morphine equivalents
• Inpt: use IV route:
- Continuous drip of MS with PCA pump
- Reduce dosage by 10-33% q24 hours
• Use the slower taper for more extended user
• Typical duration is 4-11 days
Starting Dose
• Start with maximal dose that will achieve pt
comfort
• Those receiving IV should continue the IV
route for a few days and can switch to an
equivalent oral dose
• Those on oral narcotics continue same
Narcotic Withdrawal
• Outpatient regimen:
- taper with oral medications
- reduce by one dose (about 10-20%) / wk
Withdrawal Rate
3-10 days
• 10 to 33% per day using medium to long
acting narcotic
• Given in equal divided regular doses
• For shorter acting agents e.g. oxycodone,
hydrocodone: Convert to long term narcotic
such as methadone when pt is
or
Give more frequently e.g. q 3 hours
Equivalent Dosages of Common Opioids
Drug
SC/SQ/IV
po
morphine
10.
30.
codeine
120.
180.
fentanyl
0.1
--patch- careful as conversion data underestimate strength
hydrocodone
--30.
hydromorphone
1.5
7.5
meperidine
75.
300.
methadone
5.
10. *acute/op naive; for chronic- goes
down and depends on daily dose
oxycodone
Source: Epocrates- Opioid Equivalents
---
20.
3. Block withdrawal symptoms
The role of clonidine
• Reduces sympathetic activation:
anxiety, restlessness, muscle pain, chills
• CNS: reduces anxiety (locus ceruleus)
• Intestinal effects: ↓ Ach release presynaptic terminals
reduces gut motor activity- cramps
• Relieves pain & diarrhea
Clonidine in NBS
• Dosage:
- start at 0.1 BID or TID
- can titrate to 0.6mg/day
- alternative is patch: same daily dose
- begin when dose ↓ 50% or 1st sign of withdrawal
• Can be tapered off rapidly or maintained for several
weeks, even indefinitely depending on perceived risk of
relapse & overall clinical benefit
May have independent effects on FGID symptoms
e.g. pain and diarrhea
4. Benzodiazepines
• Temporary use of medium to long acting benzo’s:
Clonazepam or lorazepam
• Start at beginning of withdrawal and give at regular
intervals throughout
• Addresses sympathetic activation of withdrawal
• Taper off when withdrawal is complete
• Example: Lorazepam 1 mg q 6-8 hours
5. Constipation
• PEG based preferred 1-3 glasses/day
• Avoid PO4, Mg based, stimulant types
• Colonoscopy prep for complete flush if severe
constipation and KUB reveals large stool burden
• Methylnaltrexone if constipation is severe and
not initially responsive to PEG solution
6. Psychotherapy
• (Vital) part of comprehensive approach
• CBT and other behavioral therapies
• Dx and Rx rec of underlying psychopathology
Outcomes
Prospective study of 3 month outcomes after
Detox in 39 Pts with NBS
• Pts: 92% F
• Dx: 21% IBS
37% IBD
29% FM/functional somatic/orthopedic
13% post op/other
• MS equivalent 75mg +/- 78mg with pain scores severe
• Common psychosocial problems: catastrophizing, anxiety,
depression, poor daily function scores
Drossman et al AJG 107 Sept 2012
Patient’s Clinical Features
• Mostly young to middle age females
• Variety of functional, structural, GI disorders and post operative
status
• Pain avg ~ 15 yrs, narcotic use ~ 5 yrs
• Despite MS equiv of 75mg/d, abd pain rated as more severe
than labor or post op pain
• Other severe symptoms: N, fatigue, bloating, sleep disturbances
• 1/3 signif anxiety, depression, high catastrophizing scores
• 80% out of work, > 6 hosp/2yrs, mult MD’s seen, high H.C. costs
Outcomes
• Detox successful 89.7%
side effects 81%- narcotic withdrawal: anxiety, n, HA, sleep disturbances
• Abdominal pain reduced by 35% post detox
• Nonabdominal pain reduced by 42%
• Catastrophizing improved
• At 3 months: 45.8% returned to using narcotics
For those who remain off- pain score at 3 mo ↓ 75% from pretreatment
compared to those back on narcotics
Why did pts resume narcotic if most had
reduced abd pain
•
•
•
•
•
¼ in 1 wk, ½ by ~3 mo, ¾ by ~8 mo
Reasons postulated other than pain relief:
Some report being “numb from life issues”
Some value being high
Other acknowledge some desire to stay off narcotics
but can’t resist taking them again when prescribed
by their doctors
• Higher COMM scores (Current Opioid Misuse Measure)
• Successful detox and good clinical response assoc
with low abuse potential
Functional Abdominal Pain Syndrome
Functional Abdominal Pain Syndrome (FAPS)
• Present for at least 3 mo, onset at least 6 mo
before dx of:
• 1. Continuous or nearly continuous abd pain
• 2. No or only occ relationship with physiologic
events (e.g. eating, defecation, or menses) and
• 3. Some loss of daily functioning and
• 4. The pain is not feigned (e.g. malingering)
• 5. Insufficient symptoms to meet criteria for
another dx of GI function that would explain the
pain
Clues on PE
• Paradoxical “closed eyes” sign- acute pain of
intestinal origin eyes open- anxious, FAP may
close eyes to communicate pain
• Carnett’s sign or test- Pain increases with raising
the head and contracting the rectus abdominus
muscle, with visceral pain it decreases.
• Abd wall contraction leads to increased pain,
central sensitization due to viscerosomatic
referral
FAPS
• If exam is negative and with a history of
extensive negative testing, avoid ordering
further tests.
• This reinforces concept something has been
missed
• Further tests may aggravate pt’s visceral
hypersensitivity
Background factors with FAPS
Severe and disabling pain without a structural Dx
• Confluence of factors
• Brain-gut interactions
• Peripheral measures e.g. intestinal inflam and altered immune
function
• Central effects of stress on neural signaling
• Background: Family distress, emotional, physical sexual abuse
Often h/o of recurrent abd pain in childhood
• Perhaps post infectious IBS in a setting of emotional distress
• Prior surgeries that can lead to abd-pelvic nerve injury, mucosal
inflam from infection that can activate mucosal mast and immune
cells that secrete proteases, cytokines, and other mediators that
activate sensory neurons, and promote visceral hypersensitivity
Central mechanisms
• Activation of certain brain regions e.g. mid-cingulate cortex
• This leads to disinhibition- an inability to down regulate
incoming sensory input from the viscera
• Pain + noxious experiences can encode a linkage of emotional
distress with the pain in this part of the brain
• In chronic and severe pain peripheral factors e.g. visceral
hypersensitivity may become secondary to central
sensitization, the alteration of central pain control centers
• Therefore management must include centrally mediated
treatments
Effective doctor patient relationship
• Challenges for the physician:
- frustration, anger, perception of decreased effectiveness in the
absence of a treatable disorder, failure of pt improvement
perceived as failure by the physician, stress of the pt demands for
narcotics for pain relief, realities of large time commitments needed
and low reimbursement rates
• Physician to treat himself or herself first:
- Accept that FAPS is a + dx and further studies not needed
- Accept chronicity
- Reduce expectations for cure or rapid recovery
- Understand role: to provide support, guidance, and hope,
facilitate pt acceptance of the as a chronic disorder requiring
personal responsibility for management
Equianalgesic dosage table
Buprenorphine
(IM/IV): 0.4
Butorphanol
(IM/IV): 2.0
Codeine (IM/IV):
120
Codeine (PO): 200
Fentanyl (IM/IV):
0.1
Fentanyl
(Transdermal): 0.2
Hydrocodone (PO):
30
Hydromorphone
(IV/IM/SC): 1.5
Hydromorphone
(PO): 7.5
Levorphanol (acute
PO): 4.0
Levorphanol
(chronic PO): 1.0
Meperidine
(IV/IM/SC): 75
Meperidine (PO):
300
Methadone (acute
IV): 5.0
Methadone (acute
PO): 10
Morphine (IV/IM/SC): 10
Morphine (acute PO): 60
Morphine (chronic PO): 30
Nalbuphine (IV/IM/SC): 10
Oxycodone (PO): 20
Oxymorphone (IV/IM/SC): 1.0
Oxymorphone (PO): 10
Tapentadol (PO): 75-100
Methadone Chronic dosing:
0-99 mg: 4:1
100-299 mg: 8:1
300-499 mg: 12:1
500-999 mg: 15:1
>1000 mg: 20:1
Mechanism of Glial cell activation and pain
• Glial cells express receptors for NT’s and NM’s
• This can enhance pain transmission and counter pain
inhibitory effects of morphine
• Fractalkine: neuron to glial cell chemokine- may be
involved in exaggerated nociceptive pain response to
visceral stimuli