Alvimopan

Alvimopan

PEP Topic 
Constipation
Description 

Alvimopan is a peripherally acting mu-opioid receptor (PAM-OR) antagonist that has been studied for the treatment of opioid-induced bowel dysfunction. Alvimopan counteracts the effects of opioids on gastrointestinal motility and secretion. The drug is available as a capsule to take by mouth and has been evaluated in opioid-induced constipation.

Likely to Be Effective

Systematic Review/Meta-Analysis

Ahmedzai, S.H., & Boland, J. (2010, April). Constipation in people prescribed opioids. Clinical Evidence, 2407.

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Purpose:

To answer the following questions: What are the effects of oral laxatives, rectal preparations, and opioid antagonists for constipation in people prescribed opioids?

Search Strategy:

Databases searched were MEDLINE, Embase, Cochrane Central Register of Controlled Trials and Library, NHS Centre for Reviews and Dissemination (CRD), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment, TRIP, and the National Institute for Health and Clinical Excellence (NICE) up to August 2009. Alerts from the U.S. Food and Drug Administration and the U.K. Medicines and Healthcare Products Regulatory Agency were included to identify any adverse effects.

Search keyword were constipation and opioids, Lactulose, macrogols, senna, bisacodyl, co-danthrusate/co-danthramer, docusate, ispaghula husk, liquid paraffin, magnesium salts, methylcellulose, arachis oil enema, glycerol suppository, phosphate enema, sodium citrate enema, and opioid antagonists.

Studies were included in the review if they

  • Were randomized controlled trials (RCTs), observational studies, or systematic reviews
  • Had a study sample of at least 20 participants
  • Had a maximum loss to follow-up of 30% per year in longitudinal studies.

Literature Evaluated:

The GRADE System was used to evaluate study quality. Full information is available online with a subscription.

Sample Characteristics:

The final sample comprised 23 systematic reviews, RCTs, or observational studies. This was an update of a previous review that added 1 systematic review and 5 RCTs, with no change in overall recommendations provided.

Results:

Oral Laxatives

  • Lactulose, polyethylene glycols (PEGs) plus electrolytes, and senna were identified as beneficial in this systematic review. Evidence in this area was graded as low-to-moderate quality. Lactulose appears to be as effective as PEG in reducing the number of hard stools, and as effective as senna in reducing the number of days without defecation.
  • Preparations identified as unknown effectiveness included bisacodyl, co-danthrusate and co-danthramer, docusate, ispaghula husk, liquid paraffin, magnesium salts, and methylcellulose.
  • Some oral laxatives such as bisacodyl often are prescribed in combination with other agents or rectal suppositories, but no evidence supports this use, particularly in people taking opioids.
  • Liquid paraffin may be harmful in patients who have difficulty swallowing.

Rectal Preparations

  • All of the rectal preparations studied were categorized as unknown effectiveness. The preparations included arachis oil enema, glycerol suppository, phosphate enema, and sodium citrate micro-enema.

Opioid Antagonists

  • Opioid antagonists, including alvimopan, methylnaltrexone, and naloxone, were categorized as beneficial.  Categorization was based on studies comparing those agents to no treatment or placebo.  The most common side effects reported were abdominal pain, nausea, and diarrhea, particularly with higher doses. 
  • A concern with these agents is the potential for use to reverse the therapeutic action of opioids.  Alvimopan and methylnaltrexone are considered safer than naloxone in this regard, as neither of those agents can cross the blood-brain barrier and a few small studies of acute pain have shown success in blocking the constipating effect of opioids without compromising pain relief.

Limitations:

  • Although various combinations of oral laxatives and rectal agents may be used clinically, their effectiveness for constipation in people taking opioids has not been evaluated. This area can benefit from continued well-designed study.
  • Opioid antagonists are considered effective for reducing constipation in people prescribed opioids. However, only a few studies with small groups of patients have examined the effect of these agents on pain relief with opioids. Use of opioid antagonists may also have implications for which type of opioid should be used for pain control.  Long-term use with chronic pain managed by opioids is not well researched.

Nursing Implications:

Nurses should be aware of potential implications related to the use of opioid antagonists in controlling constipation for opioid interactions and changes in pain control. In addition, nurses should routinely assess for pain relief, as well as symptoms of constipation, in this patient population.

Becker, G., Galandi, D., & Blum, H.E. (2007). Peripherally acting opioid antagonists in the treatment of opiate-related constipation: A systematic review. Journal of Pain and Symptom Management, 34, 547-565.

doi: 10.1016/j.jpainsymman.2006.12.018
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Purpose:

To evaluate evidence on the effectiveness of the peripherally acting mu-receptor antagonists alvimopan and methylnaltrexone in the management of opioid-induced constipation.

Search Strategy:

Databases searched were Ovid MEDLINE, Biological Abstracts, BIOSIS Previews, CINAHL, Evidence-Based Medicine Reviews (EBMR) (Cochrane Database of Systematic Reviews, ACP [American College of Physicians] Journal Club, Database of Abstracts of Reviews of Effectiveness [DARE], and the Cochrane Central Register of Controlled Trials [1966-May 2005]), PubMed (1996-May 2005), CancerLit (1963-June 2005), and Embase (1980-May 2002). A hand search also was conducted on bibliographies of books about palliative care.  From that hand search, reference citations concerning constipation were identified to find additional clinical trials to include in the review.

Search keywords were constipation, intestinal obstruction, opioid bowel dysfunction, opioid related constipation, opioid-related disorders, peripherally acting opioid antagonist, opioid antagonist, opioid mu receptors, narcotic antagonists/naltrexone, methylnaltrexone, and alvimopan.

Studies were included in the review if

  • The trial population comprised adults with opioid-related constipation who (a) had chronic pain and were being treated with an opioid regimen, (b) were on methadone maintenance programs, or (c) were healthy volunteers used as models to reproduce the condition of real patients.
  • The sample size was at least 10 participants.
  • The intervention treatment was with methylnaltrexone or alvimopan.
  • The outcome measures of prevention or reduction of constipation and the incidence of adverse events were addressed.

Studies were excluded if they had a small sample size (fewer than 10 participants) or used the Rome Diagnostic Criteria to define constipation.

Literature Evaluated:

Ten studies were appropriate for this review. However, four of the 10 had two or three parts performed in different populations or using different dosing regimens. The differing parts were treated as different studies and assessed individually, yielding 15 studies (10 randomized controlled trials and five phase II studies addressing dose and toxicity).

Sample Characteristics:

  • Study groups ranged in size from 11 to 168 participants, for a total of 605 participants in all 15 studies.
  • Seven studies included healthy volunteers, two included members of methadone maintenance programs, and three included both members of methadone maintenance programs and patients with chronic pain.
  • One study looked at patients receiving opioids for acute pain and two included hospice patients.

Results:

This systematic review looked mainly at the efficacy of using the peripherally acting opioid antagonists methylnaltrexone (nine studies) and alvimopan (six studies) in managing opioid-induced constipation. Internal validity of the studies was high, indicating methylnaltrexone and alvimopan may be effective in relieving opioid-induced constipation. However, most study participants were healthy volunteers or members of methadone programs.

Limitations:

  • The studies in this review addressed the efficacy of methylnaltrexone and alvimopan. However, most study participants were healthy volunteers or members of methadone programs. The question arises as to whether the effectiveness of those drugs would hold true in other populations.
  • Additional research is needed to assess the effectiveness of methylnaltrexone and alvimopan in patients with cancer. Not all of the studies addressed the effects of those peripherally acting antagonists on pain control and withdrawal. Of the 15 studies, five reported no effect on pain and seven reported no withdrawal effects. The effects of those drugs on pain and withdrawal require additional study.

Research Evidence Summaries

Taguchi, A., Sharma, N., Saleem, R.M., Sessler, D.I., Carpenter, R.L., Seyedsadr, M., & Kurz, A. (2001). Selective postoperative inhibition of gastrointestinal opioid receptors. New England Journal of Medicine, 345, 935–940.

doi: 10.1056/NEJMoa010564
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Study Purpose:

To evaluate the effects of alvimopan on postoperative gastrointestinal (GI) function and length of hospitalization.

Intervention Characteristics/Basic Study Process:

Alvimopan is an investigational opioid antagonist with limited oral absorption that does not readily cross the blood-brain barrier and, therefore, acts on the peripheral opioid receptors in the GI tract without affecting analgesia in patients taking opioids. Doses used in the study were 1 mg and 6 mg by mouth. On the day of surgery, patients were randomly assigned in equal proportions to one of three arms using computer-generated randomization stratified according to type of surgery. The three arms were 1 mg of alvimopan, 6 mg of alvimopan, or an identical appearing placebo. Patients took the drug or placebo two hours before surgery and then twice daily postoperatively until the first bowel movement, until discharge from the hospital, or for a maximum of seven days. Patients were seen twice daily by the research team, from 6 am to 8 am and then from 4 pm to 6 pm.  At each visit, patients were asked about time of first passage of flatus and first bowel movement. Oral intake was measured until patients could tolerate regular meals. Subjects were considered ready for discharge if they had adequate oral intake to discontinue IV fluids, GI function had returned (defined as passage of flatus), they were afebrile, and they were free of major complications.

Sample Characteristics:

  • The study reported on a sample of 78 patients who were generally healthy or had well-controlled systemic disease.
  • Patient age ranged from 18 to 78 years.
  • Patients were undergoing abdominal surgery (partial colectomy: n = 15; total abdominal hysterectomy: n = 63) with general anesthesia.
  • Patients were included in the study if they were receiving opioids postoperatively for pain.
  • Patients were excluded if they had received epidural administration of analgesia, had used corticosteroids or immunosuppressive drugs concomitantly within two weeks or opioid analgesics within four weeks before surgery, were likely to receive nonsteroidal anti-inflammatory drugs (NSAIDs) after surgery, had Crohn disease, or had a history of abdominal radiation therapy or treatment with vinca alkaloids. 

Setting:

  • Washington University in St. Louis, MO
  • January 4 to July 22, 2000

Study Design:

This was a randomized, placebo-controlled study.

Measurement Instruments/Methods:

  • Enrollment of 26 patients per group provided 95% power to identify a significant difference of one day in time to fitness for discharge between the 6-mg dose group and the placebo group at an alpha level of 0.05 with a two-tailed logrank test.
  • Time to events (time in hours since end of surgery) was compared among groups using the logrank test. Other statistical analyses were described in detail.
  • For patients who withdrew, administration of the drug or placebo was stopped; however, evaluation of the patients continued and all available data were entered into the analysis.
  • Demographic data and type and duration of surgery were recorded.
  • Primary efficacy outcomes were time to first passage of flatus, time to first bowel movement, and time until patient was ready for discharge.
  • Secondary outcomes were time to first ingestion of solids, time until actual discharge, and visual analog scores (VAS) for nausea, abdominal cramping, itching, and pain.
  • Severity of nausea, abdominal cramping, pain, and itching were also recorded using 100 mm VAS.
  • Total daily use of opioids was also recorded.

Results:

  • Twelve patients withdrew from the study (four in the placebo group and eight in the 1-mg dose group); however, none were from the 6-mg arm of the study.
  • Time to recovery of GI function was significantly shorter in the 6-mg dose group than the placebo group.
  • Median time to first passage of flatus decreased from 70 to 49 hours (p = 0.03), time to first bowel movement decreased from 111 to 70 hours (p = 0.01), and the time until patients were ready for discharge decreased from 91 to 68 hours (p = 0.03).
  • Oral consumption and actual discharge occurred significantly earlier for the 6-mg dose group.
  • VAS scores for pain, itching, and abdominal cramping were similar in the three groups. In contrast, nausea scores were significantly reduced in the 6-mg dose group compared with the 1-mg dose and placebo groups (p = 0.003).
  • No vomiting occurred in the 6-mg dose group compared with 23% and 26% in the placebo and 1-mg dose groups, respectively (p = 0.03).

Conclusions:

The 6-mg dose of alvimopan improved all major outcomes, with or without correction for the type of surgery. Analgesic efficacy of opioids was not affected by the study drug, and no adverse events occurred.

Limitations:

  • The study was funded by the pharmaceutical company Adolor Corporation, a grant from the National Institutes of Health (NIH), and two other local funds.
  • Two authors were employees of Adolor Corporation and contributed to the study design and statistical analysis.

Webster, L., Jansen, J.P., Peppin, J., Lasko, B., Irving, G., Morlion, B., . . . Carter, E. (2008). Alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist for the treatment of opioid-induced bowel dysfunction: Results from a randomized, double-blind, placebo-controlled, dose-finding study in subjects taking opioids for chronic non-cancer pain. Pain, 137, 428–440.

doi: 10.1016/j.pain.2007.11.008
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Study Purpose:

To assess the effectiveness and safety of alvimopan, a peripherally acting mu-opioid receptor antagonist, in patients with noncancer pain and opioid-induced bowel dysfunction.

Intervention Characteristics/Basic Study Process:

Patients were randomized to one of four groups: oral alvimopan 0.5 mg twice daily (n = 130), oral alvimopan 1 mg daily (n = 133), oral alvimopan 1 mg twice daily (n = 130), or placebo capsules (n = 129).

Patients were instructed to discontinue laxative use. Rescue laxative medication (bisacodyl 10-30 mg) could be taken if the patient experienced discomfort with no bowel movement (BM) for four consecutive days. An interactive voice response system via touch-tone telephone was used for number of BMs, associated symptoms, rescue laxative use, opioid consumption, and pain intensity.

Sample Characteristics:

  • The study reported on a final sample of 333 patients aged 18 years or older.
  • Mean patient age was 49.7 years in the alvimopan 0.5-mg twice daily group, 51.5 years in the alvimopan 1-mg daily group, 48.6 years in the alvimopan 1-mg twice daily group, and 51.3 years in the placebo group. 
  • The sample was 64% female and 36% male.
  • Patients had noncancer pain and an opioid regimen equivalent to at least 30 mg of oral morphine for at least one month prior to screening.
  • Back pain was the primary pain condition.
  • Patients with neuralgia, fibromyalgia, arthritis, joint pain, and headache were also included.

Setting:

  • Multi-site
  • Patients' homes and 113 centers in 9 countries

Study Design:

This was a phase IIb, randomized, double-blind, placebo-controlled, parallel-group study.

Measurement Instruments/Methods:

  • Patient Assessment of Constipation Symptoms (PAC-SYM)
  • Patient Assessment of Constipation Quality of Life (PAC-QOL)
  • Numeric Pain Scale (0 = no pain; 10 = worse possible pain)
  • Modified Himmelsbach Withdrawal Scale to measure signs of withdrawal

Results:

  • Change in frequency of spontaneous bowel movements (SBMs) during the first three weeks of the treatment period was greater in all alvimopan groups versus the placebo group (p < 0.001).
  • Mean weekly frequency of SBMs was significantly greater during the treatment period for all alvimopan groups versus the placebo group (p ≤ 0.01), as was the overall mean change in SBMs (p < 0.001).
  • On the first day of treatment, 31% of patients in each alvimopan group had at least one SBM, compared with 18% in the placebo group (p < 0.05).
  • Seventy-seven percent of patients in the alvimopan 0.5-mg twice daily group and 75% in both the 1-mg daily group and the 1-mg twice daily group had an increase from baseline of at least one SBM per week, compared with 55% in the placebo group (p ≤ 0.001).
  • Individuals in the alvimopan treatment groups versus the placebo group reported moderate or substantial opioid-induced bowel dysfunction global improvement during the treatment period (p ≤ 0.003).
  • All alvimopan groups reported improvement in bowel  evacuation throughout the treatment period (p ≤ 0.009).
  • Reports of pain or total daily dose of opioid did not change significantly throughout the study.
  • All groups had stable scores on the Himmelsbach Withdrawal Scale.

Conclusions:

Oral alvimopan increases the frequency of SBMs and improves symptoms in adults on opioid pain regimens.

Limitations:

  • The study did not include patients with cancer; therefore, the results cannot be generalized to that population.
  • The amount of opioid taken by participants was only the equivalent of at least 30 mg of oral morphine daily.
  • After withdrawals, the treatment groups were below the calculated sample size of 125 to achieve 90% power. For patients who withdrew from the study and did not have complete data sets, the last recorded observations for each endpoint were carried forward.

Nursing Implications:

Oral alvimopan may be effective for the treatment of opioid-induced constipation in patients taking opioids for chronic pain and may improve opioid-induced bowel dysfunction symptoms. Use of alvimopan does not appear to compromise analgesia or induce opioid abstinence. Additional study is necessary to look at efficacy with an oncology population and determine long-term efficacy, as well as an optimal dosing regimen.


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