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Methylnaltrexone: its pharmacological effects alone and effects on morphine in healthy volunteers

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Abstract

Rationale

Methylnaltrexone bromide (MTNX) is a peripherally acting mu-opioid receptor antagonist, prescribed for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care. Studies have used this drug to determine if other opioid-induced effects besides constipation are altered by MTNX in humans and have suggested, based on their results, that these other effects are altered by peripheral opioid actions.

Objective

The primary objective of this report is to present results that provide indirect evidence that MTNX has centrally mediated effects, albeit slight, and secondarily to describe the effects of MTNX on psychopharmacological effects of morphine.

Methods

In a crossover, randomized, placebo-controlled, double-blind study, 29 healthy volunteers received 0.45 mg/kg MTNX or saline subcutaneously, followed by saline intravenously. In three other conditions, 0.143 mg/kg of morphine sulfate administered intravenously was preceded by subcutaneous administration of 0, 0.225, or 0.45 mg/kg MTNX. Before and after drug administration, subjective and physiological measures, including pupil diameter, were assessed.

Results

Two separate analyses confirmed that 0.45 mg/kg MTNX alone induced a slight degree of miosis, a centrally mediated opioid agonist effect. This dose had minimal subjective effects. MTNX at either or both the 0.225 and 0.45 mg/kg dose reduced some subjective effects of morphine without altering miosis.

Conclusions

We present indirect evidence that MTNX crosses the blood–brain barrier in humans. Therefore, whether the reductions in subjective effects of morphine by MTNX that were observed in past studies and in this study can be attributed to peripheral mechanisms is open to question.

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Acknowledgments

Research was supported in part by grant R21 DA031318 from the National Institute on Drug Abuse. We wish to thank Drs. Ravi Singh, William (Scott) Jones, Joseph Enayati, Michael Esposito, Hasan Chowdhury, Kelly Eaton, Amy Gruber, Annie Amin, and Keith Rodriguez for administering the drugs and monitoring the physiological status of the research volunteers; Karin Kirulis for screening potential subjects and conducting the structured interviews; Katarzyna Zoszak, Sean M. Apfelbaum, and Sandra Gutierrez for assistance in conducting the experimental sessions; and for the research volunteers who participated in the study. We also wish to thank an anonymous reviewer who offered critical and valuable comments on earlier iterations of this manuscript that resulted in a more coherent and parsimonious representation of the findings of the study.

Conflicts of interest

The authors have no conflicts of interest to report.

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Authors and Affiliations

  1. Department of Anesthesia and Critical Care, The University of Chicago, Chicago, IL, 60637, USA

    James P. Zacny & Dennis W. Coalson

  2. Department of Health Studies, The University of Chicago, Chicago, IL, 60637, USA

    Kristen Wroblewski

  3. Cancer Center (M/C 713), University of Illinois Hospital and Health Sciences System, 909 S. Wolcott Avenue, 5141 COMRB, Chicago, IL, 60612, USA

    James P. Zacny

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  1. James P. Zacny
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Correspondence to James P. Zacny.

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Zacny, J.P., Wroblewski, K. & Coalson, D.W. Methylnaltrexone: its pharmacological effects alone and effects on morphine in healthy volunteers. Psychopharmacology 232, 63–73 (2015). https://doi.org/10.1007/s00213-014-3637-8

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  • DOI: https://doi.org/10.1007/s00213-014-3637-8

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