Correspondence

Methylnaltrexone for Opioid-Induced Constipation in Advanced Illness

N Engl J Med 2008; 359:1070-1071September 4, 2008

Article

To the Editor:

In their article on methylnaltrexone for opioid-induced constipation in patients with advanced illness, Thomas et al. (May 29 issue)1 point out that the effectiveness of methylnaltrexone appeared to be undiminished throughout the 2-week, double-blind trial, as well as during the 3-month, open-label extension phase. However, during the trial, the percentage of positive responses to the drug decreased from 48% after the first dose to 38% after the dose received on day 13. Although this decrease was not significant (P=0.13 by the chi-square test for trend), it becomes more relevant if we recognize that there may have been attrition bias, since one of every four patients who received the first dose was lost to follow-up by the 13th day. Furthermore, the response rates for methylnaltrexone and placebo differed by 3% during the first month of the open-label extension phase, 10% during the second month, and 5% during the third month. On the basis of these data, it would seem that a caveat concerning the possible loss of activity of methylnaltrexone over time is in order.

Alvaro Sanz Rubiales, M.D., Ph.D.
Hospital Universitario del Río Hortega, 47010 Valladolid, Spain
asrubiales@hotmail.com

María Luisa del Valle Rivero, M.D., Ph.D.
Hospital Clínico Universitario de Valladolid, 47005 Valladolid, Spain

1 References

1. 1

   Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med 2008;358:2332-2343
   Full Text | Web of Science | Medline

To the Editor:

In their study involving 133 patients with advanced illness who had laxative-resistant opioid-induced constipation, Thomas and colleagues showed that subcutaneous methylnaltrexone rapidly induced laxation within several hours after treatment. Furthermore, this μ-opioid–receptor antagonist had no influence on the overall incidence of adverse events, nor did it affect central analgesia. However, oral administration of methylnaltrexone is more convenient than injections, and since oral methylnaltrexone acts directly in the bowel, it would appear to be potentially safer and more efficient than subcutaneous methylnaltrexone.1

Daniel Chappell, M.D.
Markus Rehm, M.D.
Peter Conzen, M.D.
Ludwig-Maximilians University, 80336 Munich, Germany
daniel.chappell@med.uni-muenchen.de

1 References

1. 1

   Yuan CS, Foss JF. Oral methylnaltrexone for opioid-induced constipation. JAMA 2000;284:1383-1384
   CrossRef | Web of Science | Medline

Author/Editor Response

Our study showed that treatment with subcutaneous methylnaltrexone rapidly induced laxation in patients with advanced illness. Rubiales and del Valle Rivero note that the rates of laxation response within 4 hours after each of the seven doses over the course of 13 days (from 48% after the first dose to 38% after the seventh dose) suggested a loss of activity over time. Although there appeared to be a numerical decrease in the laxation response in the methylnaltrexone group, this decrease also occurred in the placebo group. The statistical difference between the response rates in the methylnaltrexone and placebo groups remained strongly significant (P<0.005) for each of the seven doses.

With regard to the interpretation by Rubiales and del Valle Rivero of the response rates during open-label treatment, all study medication administered during this 3-month extension period consisted of open-label methylnaltrexone. Thus, the response rates of 48% in month 1 to 52% in month 3 (shown in Table 4 of our article) correspond to the open-label administration of methylnaltrexone in the patients who had previously received placebo during the double-blind period. The response rates of 45% in month 1 to 57% in month 3 correspond to the open-label administration of methylnaltrexone in the patients who had previously received methylnaltrexone during the double-blind period. These efficacy response rates showed that the laxation response observed during the double-blind period was maintained with open-label treatment for 3 months. In aggregate, these data from the 2-week, double-blind period and the 3-month, open-label period suggest that the laxation response persisted without evidence of a diminished effect.

Chappell and colleagues comment on the potential oral administration of methylnaltrexone. Although we agree that an oral formulation is generally more convenient than injections, the use of oral methylnaltrexone for the treatment of opioid-induced constipation has not been evaluated in large, randomized, placebo-controlled trials.

Jay Thomas, M.D., Ph.D.
San Diego Hospice and Palliative Care, San Diego, CA 92103
jthomas@sdhospice.org

Sloan Karver, M.D.
Gulfside Regional Hospice, New Port Richey, FL 34653

Robert J. Israel, M.D.
Progenics Pharmaceuticals, Tarrytown, NY 10591

Citing Articles (1)

Citing Articles

1. 1

   Michael Iskedjian, Shrividya Iyer, S. Lawrence Librach, Mike Wang, Bechara Farah, Jade Berbari. (2011) Methylnaltrexone in the Treatment of Opioid-Induced Constipation in Cancer Patients Receiving Palliative Care: Willingness-to-Pay and Cost-Benefit Analysis. Journal of Pain and Symptom Management 41:1, 104-115
   CrossRef