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Pain Management

Advances to Block the Adverse Side Effects of Opioid Analgesics on the Gastrointestinal Tract Without Blocking Their Beneficial Analgesic Effects

a report by

Jo h n B L e s l i e , M D , M BA

Professor of Anesthesiology, Mayo Clinic College of Medicine, Rochester, and Consultant in Anesthesiology, Mayo Clinic Arizona

Opioid-based analgesia is considered the standard of care for post-operative pain management and is widely used for the management of chronic pain.1­3 Opioids mediate analgesia by binding to mu-opioid receptors in the central nervous system (CNS);3 however, they also bind to mu-opioid receptors in the gastrointestinal (GI) tract, resulting in opioid-induced bowel dysfunction (OBD) or contributing to post-operative ileus (POI).3,4 The most commonly reported symptom of OBD, opioid-induced constipation (OIC), is considered an expected side effect of opioid therapy; it substantially reduces patient quality of life and may interfere with optimal opioid dosing.1,5,6 POI, a transient cessation of co-ordinated bowel motility, occurs after surgical intervention and may not resolve for more than five days.7 Currently, there are no consensus guidelines or US Food and Drug Administration (FDA)-approved pharmacological agents for the management of OBD, OIC, or POI. Laxatives are the mainstay of the pharmacological management of constipation associated with OBD; however, these agents may not address other symptoms of OBD (e.g. gastroesophageal reflux, nausea, and vomiting), must often be used in combination with other treatments, and may be associated with abdominal cramping, bloating, and gas.8,9 Moreover, a substantial proportion of patients continue to experience symptoms of OBD despite treatment with laxatives. Laxatives have also not consistently been successful in the management of POI.10 Many institutions have implemented multimodal care pathways intended to accelerate GI recovery after surgery. Some techniques or pathways are not feasible for all patients or available at all institutions, and patients may still experience POI even with implementation of these pathways.10 A new class of peripherally acting mu-opioid receptor (PAM-OR) antagonists target the mechanism underlying OBD and one of the primary causes of POI: opioid activation of mu-opioid receptors within the GI

John B Leslie, MD, MBA, is Professor of Anesthesiology at the Mayo Clinic College of Medicine and serves as a Consultant in Anesthesia at the Mayo Clinic in Scottsdale, Arizona. He has published numerous peer-reviewed articles in the fields of anesthesiology, cardiac anesthesiology, and opioid pharmacology, including primary research and review articles, and is currently participating in industry-sponsored multicenter trials evaluating peripherally acting mu-opioid receptor antagonists (PAM-OR) and the development of cost-effective clinical pathways. Dr Leslie received his medical degree from Duke University in Durham, North Carolina, where he also completed fellowships in anesthesiology, clinical pharmacology, and cardiac anesthesia; he also obtained a degree in healthcare management later in his career. E: [email protected]

tract.11­15 Two agents in this pharmacological class--alvimopan (Adolor Corporation, Exton, Pennsylvania, and GlaxoSmithKline, Philadelphia, Pennsylvania) and methylnaltrexone (Progenics Pharmaceuticals, Tarrytown, New York, and Wyeth, Madison, New Jersey)--have been investigated for the management of OBD (alvimopan), OIC (methylnaltrexone), and POI (alvimopan and methylnaltrexone). This brief report presents a short introduction to the PAM-OR antagonist class and its mechanism of action, as well as a description of the current clinical development of methylnaltrexone and alvimopan. Peripherally Acting Mu-opioid Receptor Antagonists The Peripherally Acting Mu-opioid Receptor Antagonist Class Naloxone, a mu-opioid receptor antagonist, administered orally accelerated GI transit in healthy volunteers and increased bowel movement (BM) frequency in patients receiving opioid therapy;16­18 however, naloxone crosses the blood­brain barrier, activates central mu-opioid receptors, and is associated with loss of analgesia18 or symptoms of opioid withdrawal.19 PAM-OR antagonists were designed to block the GI adverse effects of opioids without compromising analgesia.11­15,20 Methylnaltrexone, a quaternary N-methyl derivative of naltrexone, is a first-generation PAM-OR antagonist that was discovered in the 1980s but not immediately commercialized. It is derived from naltrexone, with the addition of a methyl ring to create methylnaltrexone. This compound has increased polarity and reduced lipid solubility, and limits the ability of the agent to cross the blood­brain barrier.21,22 Another member of the PAM-OR antagonist class, alvimopan, is a trans-3,4dimethyl-4-(3-hydroxyphenyl) piperidine.23 Alvimopan is expected to be excluded from the CNS because of its large molecular weight, zwitterionic form, and high polarity at clinically relevant concentrations.23,24 Both methylnaltrexone and alvimopan were generally well tolerated in patients with OBD and POI and did not appear to compromise centrally based opioid analgesia in numerous clinical trials.11,13­15,20,25­27 Mechanism of Action in the Gastrointestinal Tract The digestive tract is regulated by the enteric nervous system (ENS) and extrinsic neural pathways.28­30 The complex motor patterns in the GI tract responsible for mixing and propulsive movements and secretory function are co-ordinated by the ENS.29 Co-ordination of sensory and motor information within the ENS occurs through enteric sensory neurons, interneurons, and motor neurons within the intestinal plexuses, resulting in effective peristalsis through interaction and control of smooth-muscle cells, epithelial cells, glands, and blood vessels.30,31

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© TOUCH BRIEFINGS 2007

Advances to Block the Adverse Side Effects of Opioid Analgesics on the Gastrointestinal Tract

ENS neurons release not only acetylcholine, substance P, nitric oxide, adenosine tri-phosphate (ATP), vasoactive intestinal polypeptide, and 5-hydroxytryptamine (5-HT), but also opioid peptides (i.e. met-enkephalin, leu-enkephalin, -endorphin, dynorphin, and others) as transmitters. Three primary opioid receptor types (mu, delta, and kappa) are ubiquitous in the CNS and the ENS.3 Opioid analgesic effects are primarily mediated by mu-opioid receptors in the CNS (brain and spinal cord); however, GI-related adverse effects are primarily mediated by mu-opioid receptors in the GI tract.3 Exogenous opioids (e.g. morphine), administered to mediate analgesia or manage chronic pain, can activate the peripheral mu-opioid receptors in the GI tract and may cause GI-related opioid side effects such as disruption of the migrating motor complex and propulsive motor activity, inhibition of intestinal ion and fluid secretion, nausea, vomiting, and increased GI transit time.3,22,32 PAM-OR antagonists bind to mu-opioid receptors in the GI tract without compromising centrally based opioid analgesia, thereby mitigating opioid-based GI-adverse events.11­15,26 PAM-OR antagonists have the potential to block GI-related opioid adverse effects without inhibiting the beneficial action of exogenous opioids administered to treat or control pain.11­15 Clinical Pharmacology Alvimopan binds with a higher affinity (alvimopan: Ki = 0.4nM; methylnaltrexone: Ki = 26­110nM) and has a slower dissociation rate (alvimopan: t1/2 = 30­44 minutes; methylnaltrexone: t1/2 = 0.46 minutes) from the mu-opioid receptor in vitro compared with methylnaltrexone.33 The half-life of intravenous (IV) or subcutaneous methylnaltrexone ranges from 2.5 to 3 hours, and the time to maximum concentration (Tmax) of oral methylnaltrexone is 116 minutes.25,27,34 Tmax of oral alvimopan is two hours.35,36 The volume of distribution is similar for both PAM-OR antagonists (methylnaltrexone: 1.8­2.6l/kg; alvimopan, 0.24­2.0l/kg).25,36 Methylnaltrexone can be metabolized to a centrally active precursor in rodents; however, this does not appear to occur following metabolism of methylnaltrexone in humans.37 An active primary amide hydrolysis metabolite of alvimopan is produced by GI microflora, but is not required for efficacy in the management of POI.35 The majority of methylnaltrexone is excreted in the urine (40­60% within 24 hours of IV administration),25,37 and the elimination of alvimopan occurs through biliary (65%) and renal (35%) excretion.38 Clinical Development Currently, three formulations of methylnaltrexone are being studied in clinical trials. Subcutaneous and oral methylnaltrexone are under investigation for OIC in patients with advanced medical illness or chronic pain. Recruitment for phase III trials of IV methylnaltrexone for the management of POI after bowel resection (BR) is currently under way. Oral alvimopan is currently under investigation by the FDA for the management of POI after BR, and phase III trials of oral alvimopan for the management of OBD were recently reported (see Table 1). Peripherally Acting Mu-opioid Receptor Antagonists for the Management of Opioid-induced Bowel Dysfunction and Opioid-induced Constipation In phase III OBD trials, subcutaneous methylnaltrexone (0.15 or 0.3mg/kg) significantly increased the proportion of patients with advanced illness who had a BM within four hours compared with placebo (50­62% compared with 13­16% for placebo; p<0.0001).39,40 Phase II OBD trials are currently ongoing to investigate the effects of oral methylnaltrexone in chronic opioid

Table 1: Clinical Development of Peripherally Acting Mu-opioid Receptor Antagonists

Clinical Development Phase Phase II Phase III Under FDA Investigation X ­ X X ­ X ­ X

R

Indication OBD/OIC

POI

Agent Methylnaltrexone Oral IV Subcutaneous Alvimopan Oral Methylnaltrexone Oral IV Subcutaneous Alvimopan Oral

Phase I X ­ X X ­ X ­ X

­ ­ X ­ ­ XR ­ X

= recruiting.

­ ­ ­ ­ ­ ­ ­ X

FDA = US Food and Drug Administration; OBD = opioid-induced bowel dysfunction; OIC = opioid-induced constipation; IV = intravenous; POI = post-operative ileus;

users. Thus far, data indicate that patients who received oral methylnaltrexone (1 or 3mg/kg; n=10) had BMs within 12 and five hours of dosing, respectively.41 Results of phase II trials of alvimopan for the treatment of OBD in patients receiving opioid therapy for chronic pain or methadone for opioid addiction were reviewed by Schmidt.42 In these trials, a single dose of oral alvimopan (0.5, 1.5, or 3mg) significantly increased stool weight (p<0.05) and the proportion of patients with a BM within 12 hours (p<0.001) compared with placebo.42 In another phase II OBD trial in patients with chronic opioid therapy for non-malignant pain or opioid dependence, alvimopan (0.5mg or 1mg) also significantly increased the proportion of patients having at least one BM within eight hours of dosing on each day of a 21-day cycle compared with placebo (alvimopan: 43­54%; placebo: 29%; p<0.001).43 In a subsequent phase IIb dose-finding study, patients (n=522) experiencing OBD and receiving opioid treatment for chronic non-cancer pain were treated with alvimopan (0.5mg twice daily, 1mg once daily, or 1mg twice daily) or placebo for six weeks.44 Alvimopan (all dose regimens) significantly increased spontaneous BM frequency and relieved constipation-related symptoms of straining, incomplete evacuation, and dry, hard stools.44 Patients also reported improvements in symptoms such as abdominal pain and bloating.44 Based on the results of this dose-finding study, two phase III studies of approximately 1,000 patients with chronic non-cancer pain receiving the 0.5mg twice-daily dosing regimen were recently completed. Results of a phase IIb trial in patients with cancer-related pain are also expected to be published soon. Peripherally Acting Mu-opioid Receptor Antagonists for the Management of Post-operative Ileus IV methylnaltrexone has been studied in a phase II pilot trial for the management of post-operative bowel dysfunction after segmental colectomy.12 Although complete results of this trial have yet to be published, methylnaltrexone (0.3mg/kg) accelerated time to first BM by 20 hours compared with placebo.12 Recruitment of patients for phase III trials of IV methylnaltrexone for the management of POI after laparotomy for segmental colectomy is under way.

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Pain Management

Five phase III trials of alvimopan for the management of POI after BR have been completed.11,13­15,45 In these trials, oral alvimopan 12mg in conjunction with a standardized accelerated post-operative care pathway significantly accelerated recovery of upper (toleration of solid food) and lower (first BM) GI function in patients undergoing BR via laparotomy by 11­26 hours compared with patients who received a standardized accelerated post-operative care pathway alone.11,13­15,45 Alvimopan is currently under review by the FDA for the management of POI after BR, based on the positive results of these trials in the BR population. Discussion Agents in this new PAM-OR antagonist class have the potential to mitigate the GI-related adverse effects often seen with both acute and chronic opioid-based pain management. Both agents in this class accelerate GI function after BR, reduce time to BM, increase the proportion of patients with BMs after chronic opioid therapy, and do not appear to compromise central opioid-based analgesia. These agents are at different stages of

development, and further study is needed to sufficiently compare the safety and efficacy of alvimopan and methylnaltrexone in patients with OBD, OIC, and POI. If approved, these agents could allow clinicians the option of safely treating their patients' pain with the necessary doses of opioids without many of the currently expected GI-related adverse side effects. Conflict of Interest Dr Leslie has received research funding and served as an advisor for Adolor Corporation, Exton, Pennsylvania; GlaxoSmithKline, Philadelphia, Pennsylvania; Progenics Pharmaceuticals, Tarrytown, New York; and Wyeth, Madison, New Jersey. Acknowledgements The author would like to thank Kerry A O'Connor, PhD, ProEd Communications, Inc., for her medical editorial assistance with this manuscript, and Amy Rachfal, PhD, ProEd Communications, Inc., for her review and constructive help with the final draft.

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