Narcotic Bowel Syndrome

1. Narcotic Bowel Syndrome

2. Definitions, history, how frequent?

3. Definition NBSNote: 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

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 ClonidineWong et al Postgrad Med J 1994;70:138-40

6. Opiate Use in the USStudy 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

7. OBD and NBS in the MayoOlmstead 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

8. 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% • NBS6.4% Neurogastro Motil V22 424-e96 2010 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. 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 NeurotransmittersLargest 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 Receptorsdelta (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 GISE….thus

16. Opioid Receptorsdelta (OP1) kappa (OP2) mu (OP3) • Selectively targeting peripheral mu opioid receptors has been a goal of pharmacological research • Methylnaltrexonenon selective mu receptor preferring antagonist Alvimopanselective 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 NTrelease) 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 MechanismsA 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. MicrogliaNewer 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 • 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. “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 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)

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) 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

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 10-33% 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