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.

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

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.

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).

• 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.

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.

• 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.