1. Narcotic Bowel Syndrome

2. Definitions, history, how frequent?

3. Definition NBS Note: not yet defined in Int
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:

4. 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

5. 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

6. 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%
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 from UNC

7. 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 % prior meta: 80% at least 1 symp
nausea % (non ca pain) constip 41% nausea 32%
Talley et al, AJG V104 May

8. What is prevalence in pts on chronic narcotics?
146 subjects, on narcotics for CNCP (non GI origin)
CAP %, 19.4% daily
Constipation % correlated with duration , not dose
Nausea % Vomiting 9% no cor with dose/dur
GERD % HB 25%
NBS %
Neurogastro Motil V e Tuteja et al Univ of Utah

9. 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

10. 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

11. 5 Criteria for Dx
Chronic or frequently recurring GI pain treated with acute high dose or continual narcotics
Pain worsens or incompletely resolves with continued or increased dosages of narcotics
There is marked worsening when the narcotic dose wanes and improvement when reinstituted (“soar and crash”)
There is progression of the frequency, duration and intensity of GI pain episodes
The nature and intensity of the pain is not explained by a current or previous GI Dx *

12. When patients with abdominal pain are on
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

13. What causes NBS

14. 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

15. 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 mu-opioid receptor-selective agonists
Given the presence of delta and kappa receptors, selective opioid analgesics for these receptors would not help reduce GI SE….thus

16. Opioid Receptors delta (OP1) kappa (OP2) mu (OP3)
Selectively targeting peripheral mu opioid receptors has been a goal of pharmacological research
Methylnaltrexone non selective mu receptor preferring antagonist Alvimopan selective mu opioid receptor antagonist
ex. of peripheral mu receptor antagonists
Loperamide
ex. of peripheral gut selective mu receptor agonist

17. 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

18. 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

19. 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

20. Mechanisms for NBS
How does narcotic use cause and aggravate the pain being treated
4 mechanisms proposed:
bimodal opioid regulation system
counter regulatory mechanisms
glial cell activation
microglia (CNS macrophage) cell activation

21. 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

22. 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 Horn-
Low conc.----prolong AP and excitatory effects (enhance NT release)
High conc.----shorten AP and inhibit NT release **(typical therapeutic
doses of opioids)

23. 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

24. 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

25. 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

26. 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

27. Spinal cord glial cell activation- Newly 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

28. 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

29. 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

30. 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

31. 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

32. Treatment of NBS

33. The Basics

34. Overview of Therapy Post therapy issues:
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

35. 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 **

36. 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

37. 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

38. 3. Will address any flair ups or side effects as they occur
“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

39. 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

40. 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

41. 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

42. Inpatient vs Outpatient
Inpt: N/V, pseudo-obstruction, ileus
Limited motivation or social support
Outpt: Chronic narcotic use without acute
medical problems

43. 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

44. Components of therapy

45. Concomitant treatments
Prevent withdrawal
Reduce Anxiety
Treat psychological comorbidity
Provide long term central analgesia

46. 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 mg 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)

47. 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) mg 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

48. 2. Narcotic Withdrawal
Convert total daily dose to morphine equivalents
Inpt: use IV route:
- Continuous drip of MS with PCA pump
- Reduce dosage by % q24 hours
Use the slower taper for more extended user
Typical duration is 4-11 days

49. 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

50. Narcotic Withdrawal Outpatient regimen: - taper with oral medications
- reduce by one dose (about 10-20%) / wk

51. 10 to 33% per day using medium to long acting narcotic
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

52. Equivalent Dosages of Common Opioids
Drug SC/SQ/IV po
morphine
codeine
fentanyl
patch- careful as conversion data underestimate strength
hydrocodone
hydromorphone
meperidine
methadone *acute/op naive; for chronic- goes
down and depends on daily dose
oxycodone
Source: Epocrates- Opioid Equivalents

53. 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

54. 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

55. 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

56. 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

57. 6. Psychotherapy (Vital) part of comprehensive approach
CBT and other behavioral therapies
Dx and Rx rec of underlying psychopathology

58. Outcomes

59. 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

60. 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

61. 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

62. 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

63. Functional Abdominal Pain Syndrome

64. 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

65. 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

66. 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

67. 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

68. 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

69. 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

70. 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): Methadone Chronic dosing: 0-99 mg: 4:1   mg: 8: mg: 12: mg:  15:1 >1000 mg:  20:1

71. Opioid Conversion Data: Equi-Analgesic Dosing Guide Equivalency Table
                                                                                                                     

72. 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