Opioid Antagonists for the Treatment of Opioid-Induced Constipation

  1. medline abstracts: opioid antagonists for the treatment of opioid-induced constipation

    from medscape pharmacotherapy

    what's the latest in the treatment of opioid-induced constipation? find out in this easy-to-navigate collection of recent medline abstracts compiled by the editors at medscape pharmacotherapy.

    oral naloxone reverses opioid-associated constipation

    meissner w, schmidt u, hartmann m, et al
    pain. 2000; 84(1):105-9

    opioid-related constipation is one of the most frequent side effects of chronic pain treatment. enteral administration of naloxone blocks opioid action at the intestinal receptor level but has low systemic bioavailability due to marked hepatic first-pass metabolism. the aim of this study was to examine the effects of oral naloxone on opioid-associated constipation in an intraindividually controlled manner. twenty-two chronic pain patients with oral opioid treatment and constipation were enrolled in this study. constipation was defined as lack of laxation and/or necessity of laxative therapy in at least 3 out of 6 days. laxation and laxative use were monitored for the first 6 days without intervention ('control period'). then, oral naloxone was started and titrated individually between 3x3 to 3x12 mg/day depending on laxation and withdrawal symptoms. after the 4-day titration period, patients were observed for further 6 days ('naloxone period'). the wilcoxon signed rank test was used to compare number of days with laxation and laxative therapy in the two study periods. of the 22 patients studied, five patients did not reach the 'naloxone period' due to death, operation, systemic opioid withdrawal symptoms, or therapy-resistant vomiting. in the 6 day 'naloxone' compared to the 'control period', the mean number of days with laxation increased from 2.1 to 3.5 (p<0.01) and the number of days with laxative medication decreased from 6 to 3.8 (p<0.01). the mean naloxone dose in the 'naloxone period' was 17.5 mg/day. the mean pain intensity did not differ between these two periods. moderate side effects of short duration were observed in four patients following naloxone single dose administrations between 6 and 20 mg, resulting in yawning, sweating, and shivering. most of the patients reported mild or moderate abdominal propulsions and/or abdominal cramps shortly after naloxone administration. all side effects terminated after 0.5-6 h. this controlled study demonstrates that orally administered naloxone improves symptoms of opioid associated constipation and reduces laxative use. to prevent systemic withdrawal signs, therapy should be started with low doses and patients carefully monitored during titration.

    opioid antagonists in the treatment of opioid-induced constipation and pruritus

    friedman jd, dello buono fa
    ann pharmacother. 2001; 35(1):85-91

    objective: to describe the role of opioid antagonists in the treatment of opioid-induced constipation and pruritus.
    data sources: a medline search was performed (1966-february 2000) for narcotics and opioid antagonists. results were limited to english-language and clinical trials. background information was obtained from pharmacology and pharmacotherapy references and review articles. hand searching of selected bibliographies yielded several references.
    study selection and data extraction: studies were reviewed that examined the use of naloxone, naltrexone, and methylnaltrexone for opioid-related constipation and pruritus. selected citations included various clinical trials and case series.
    data synthesis: opioid agents are used for cancer and nonmalignant pain. peripheral opioid receptor stimulation due to endogenous (i.e., endorphins) or exogenous (i.e., morphine) stimulants may result in negative adverse effects, including constipation and pruritus. adjuvant agents, such as laxatives and antihistamines, are often used to treat these adverse effects, but are themselves associated with adverse effects and are sometimes ineffective. opioid antagonists have demonstrated reversal of peripheral opioid receptor stimulation. clinical trials show adequate maintenance of pain control, as well as decreases in opioid-induced constipation and pruritus.
    conclusions: opioid antagonists offer a therapeutic alternative to conventional adjuvant agents, with the risk of loss of analgesia at higher doses. methylnaltrexone offers the advantage of peripheral action only, therefore not reversing analgesia. results are promising; however, larger clinical trials are necessary before opioid antagonists become the standard of care for opioid-induced constipation and pruritus.

    methylnaltrexone for reversal of constipation due to chronic methadone use: a randomized controlled trial

    yuan cs, foss jf, o'connor m, et al
    jama. 2000; 283(3):367-72

    context: constipation is the most common chronic adverse effect of opioid pain medications in patients who require long-term opioid administration, such as patients with advanced cancer, but conventional measures for ameliorating constipation often are insufficient.
    objective: to evaluate the efficacy of methylnaltrexone, the first peripheral opioid receptor antagonist, in treating chronic methadone-induced constipation.
    design: double-blind, randomized, placebo-controlled trial conducted between may 1997 and december 1998.
    setting: clinical research center of a university hospital.
    participants: twenty-two subjects (9 men and 13 women; mean [sd] age, 43.2 [5.5] years) enrolled in a methadone maintenance program and having methadone-induced constipation.
    main outcome measures: laxation response, oral-cecal transit time, and central opioid withdrawal symptoms were compared between the 2 groups.
    results: the 11 subjects in the placebo group showed no laxation response, and all 11 subjects in the intervention group had laxation response after intravenous methylnaltrexone administration (p<.001). the oral-cecal transit times at baseline for subjects in the methylnaltrexone and placebo groups averaged 132.3 and 126.8 minutes, respectively. the average (sd) change in the methylnaltrexone-treated group was -77.7 (37.2) minutes, significantly greater than the average change in the placebo group (-1.4 [12.0] minutes; p<.001). no opioid withdrawal was observed in any subject, and no significant adverse effects were reported by the subjects during the study.
    conclusions: our data demonstrate that intravenous methylnaltrexone can induce laxation and reverse slowing of oral cecal-transit time in subjects taking high opioid dosages. low-dosage methylnaltrexone may have clinical utility in managing opioid-induced constipation.

    effects of intravenous methylnaltrexone on opioid-induced gut motility and transit time changes in subjects receiving chronic methadone therapy: a pilot study

    yuan cs, foss jf, o'connor m, et al
    pain. 1999; 83(3):631-5

    in this preliminary study, we evaluated the effects of methylnaltrexone, a peripheral opioid-receptor antagonist, on chronic opioid-induced gut motility and transit changes in four subjects with chronic methadone-induced constipation. subjects participated in this single blind, placebo controlled study for up to 8 days. we gave placebo the first day; for the remainder of the study, we gave intravenous methylnaltrexone (0.05-0.45 mg/kg) twice daily. during the study period, we recorded oral-cecal transit time and opioid withdrawal symptoms, as well as laxation response based on the frequency and consistency of the stools. subjects 1 and 2 who were administered methylnaltrexone 0.45 mg/kg, a dose previously administered in normal volunteers, showed immediate positive laxation. subject 2, after positive laxation response, had severe abdominal cramping, but showed no opioid systemic signs of withdrawal. the subject was discontinued due to the cramping. in subjects 3 and 4, we reduced the methylnaltrexone dose to 0.05-0.15 mg/kg. the latter two subjects also had an immediate laxation response during and after intravenous medication without significant side effects. the stool frequency of these four subjects increased from 1-2 times per week before the study to approximately 1.5 stool per day during the treatment period. oral-cecal transit times of subjects 1, 3, and 4 were reduced from 150, 150 and 150 min (after placebo) to 90, 60 and 60 min (with methylnaltrexone), respectively. our preliminary results demonstrate that low dose intravenous methylnaltrexone effectively reversed chronic methadone-induced constipation and delay in gut transit time. thus, we anticipate that cancer patients receiving chronic opioids may also have increased sensitivity to methylnaltrexone, and that low dose methylnaltrexone may have clinical utility in managing opioid-induced constipation in chronic-pain patients.

    medscape pharmacotherapy 3(1), 2001. 2001 medscape
  2. 5 Comments

  3. by   fab4fan
    OK, I'm confrazzled here...why aren't these pts. being put on stool softeners proactively? You know, like, lets not let them get constipated to begin with. We do this for hospice pts. all the time; why should people with CNMP be any different?

    Am I missing something? (I did spend the better part of the day on a plane, so I may be short on critical reading skills.)
  4. by   fab4fan
    PS-The day I give a cancer/hospice pt IV Narcan for constipation...
  5. by   Dave ARNP
    This is something I would absoultely never due (less we're talking life or death).

    You get long acting narcs, or are at high risk for constipation... you're started on bowel regimine DAY ONE!!!

    We're talking Docusate, Fiber, and orders for agressive lax's PRN.

  6. by   fab4fan
    Do the people who write this stuff actually practice ITRW, or do they just sit around and think this stuff up?

    As you said, from day one of starting a narcotic regimen you start the pt on a bowel regimen. In my little corner of PA, people are obsessed with bowel function; they think they're constipated if it's been 8h since the last BM.
  7. by   Dave ARNP
    They try it out on defenseless animals who can't say "HEY! Thanks for burning off my pain meds you FREAK!", then they tell us it's good clinical practice