Jonathon LaValley , MPH University of Oklahoma PA Program, PAS3 October 25, 2013

1. Among adult patients with opioid induced bowel dysfunction (OBD), is the administration of oral or parenteralµ-receptor antagonists more effective than oral laxatives in increasing intestinal transit time, relieving constipation and associated symptoms? Jonathon LaValley, MPH University of Oklahoma PA Program, PAS3 October 25, 2013

2. Disclosure • Jonathon LaValley, MPH • Current student • OU College of Medicine, PA Program • UNLV, School of Public Health • No other affiliations • No financial or non-financial disclosures

3. Objectives • Describe disease course, prognosis, pathophysiology and epidemiology of: • Opioid Induced Bowel Dysfunction (OBD) • Opioid Induced Constipation (OIC) • Describe current therapy modalities • Compare current therapies to µ-receptor antagonist treatments for OIB/OIC

4. OIC: Clinical Features • Reduced gastrointestinal motility • Constipation • Hard and painful stools • Incomplete bowel evacuation • Abdominal distension, bloating • Abdominal cramps and pain* • Biliary colic and increased gastroesophageal reflux*

5. OIC: Complications • Fecal impaction • Fecal incontinence • Urinary incontinence • Pseudo-obstruction of the bowel • Interference with drug administration and absorption

6. OIC: Pathophysiology • Bind to opioid receptors in myenteric plexus • Reduced circular and longitudinal muscle contractions • Decreased peristalsis • Increased sequestration • Increased rectal sphincter tone • Decreased colonic mucosal secretion • Decreased sensitivity to rectal distention • Centrally mediated effects

7. Pathophysiology

8. Increase in Therapeutic Opioid Use in the US, 1997 - 2006 Reproduced from Manchikanti and Singh, 2008. Data from US DEA

9. Epidemiology • Prevalence of OIC • 10-40% of Chronic opioid users in US, Britain • 35-45% of Opioid users with chronic non-malignant pain (musculoskeletal, neurologic, HA) • 80-90% of Opioid users with pain associated with malignancy • Patients with OIC find less resolution with laxatives than patients with chronic constipation for all other reasons • 46% vs. 84%; p=0.001

10. Epidemiology • OIC impacts • Opioid use patterns • Resource utilization • Total healthcare costs • Quality of life

11. Current Treatment Modalities

12. Current Treatment Modalities • Most commonly used • Stool softener (e.g. docusate 100mg po BID) • Cathartic (e.g. Senna 2 tabs poqHS) • In randomized trials comparing laxative treatments in OIC, no significant difference between types was observed • Cathartics did not outperform osmotic laxatives, humectants or other stool softeners

13. µ-Receptor Antagonists • Act directly on pathophysiology of OIC • Central acting (non-selective) • Naloxone PO, Nalmiphene PO • Alone or in combination with opioid analgesics • Targin, Targinact (EU only) • Have potential to cross BBB and reverse analgesia • Peripheral acting (selective) • Methylnaltrexone IM/IV, Alvimopan PO* • Manipulated to prevent crossing of BBB

16. Comparison of Laxatives to µ-Receptor Antagonists

17. Non-Selective µ-Receptor Antagonists • Oral IR Naloxone • Safe over wide range of dosages • Relieved constipation • 65.1% naloxone vs. 18.0% laxative; p=0.001 • Reversed analgesia or opioid withdrawal • 18% of study participants • 2mg PO qday then titrate up to reverse constipation without analgesia reversal

18. Non-Selective µ-Receptor Antagonists in Combination with Opioid Analgesics • Oxycodone PR 10 mg/ Naloxone PR 5 mg • 2:1 ratio is key • Relieved OIC • Improved Bowel Function Index (median BFI 13.0 vs. 3.0; p<0.001) • Increase in spontaneous BM per week (Median BM 3.0 vs. 1.0; p<0.001) • Fewer SE • nausea (16.3% versus 10.9%, p<0.001) • vomiting (1.39% versus 4.3%, p=NS), and dyspepsia (0.6% versus 2.5%; p =NS) • slightly higher incidence of diarrhea (5.2% versus 2.6%, p<0.001) • No significant reversal of opioid analgesia vs. placebo

19. Selective µ-Receptor Antagonists • Methylnaltrexone • dosed 8-12 mg (0.15 mg/kg) subcutaneously every other day for seven days • Reduced constipation • Improved stool transit time • Reported reduction in all types of laxative use • Daily enemas (5.3% treatment versus 35.2% placebo) • Low SE • Abdominal cramps and flatulence. • No reduction in analgesia or opioid withdrawal symptoms was observed

20. Amitiza (Lubiprostone) • Approved for OIC • Also used to treat IBD, idiopathic chronic constipation • No study directly assesses efficacy on OIC • No comparisons available with µ-Receptor Antagonists • Chloride channel activator • Increases intestinal fluid secretion and motility • Bypasses anti-secretory action of opiates • Does not alter serum Na, K • Dosing • Start 16 mcg po BID advance to 24 mcg po BID • Hepatic impairment dosing (Child-Pugh B and C)

21. Amitiza (Lubiprostone) • Contraindication • Mechanical Bowel Obstruction • Adverse Reactions • Nausea: 8% to 29% • Diarrhea: 7% to 12% • Abdominal Pain: 4% to 8% • Flatulence: 4% to 6% • HA: 2% to 11% • COST • 8mcg (60) $312.60 • Soonercare: Prior Authorization Required

22. Conclusion • OIC is a significant SE of opioid analgesia • OIC is a growing problem in the US • Current treatment modalities offer some resolution of symptoms • Stool softener + cathartic • Caution with bulking agents

23. Conclusion • µ-Receptor Antagonists outperform laxatives among patients with chronic malignant and non-malignant pain • Combinations outperformed oral naloxone • Not yet available in US • Methynaltrexone is effective in moderate to severe cases • Realistor (methylnaltrexone) • Covered by Soonercare • Cost: $336 for 7 dose kit • Amitiza efficacy in OIC not yet clear

24. Questions? • Full paper and references provided upon request: jonathon-lavalley@ouhsc.edu