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Pharmacodynamic profile of tramadol in humans: influence of naltrexone pretreatment

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Abstract

Rationale

Tramadol is a prescription analgesic that activates mu opioid and monoamine receptor systems. Tramadol is thought to have limited abuse potential compared to mu opioid agonists, but laboratory data indicate that it shares some of their pharmacodynamic effects.

Objectives

This study evaluated the effect of mu opioid receptor blockade with naltrexone on the pharmacodynamic action of tramadol in humans.

Methods

This inpatient, double-blind, randomized, within-subject study examined the effects of oral placebo, tramadol (87.5, 175, and 350 mg), and hydromorphone (4 and 16 mg; positive control) after 1 h pretreatment with oral naltrexone (0 and 50 mg). Ten recreational opioid users completed the study. Pharmacodynamic effects were measured before and for 7 h after initial drug administration.

Results

Lower doses of tramadol and hydromorphone were generally placebo-like. Hydromorphone (16 mg) produced prototypic mu opioid agonist-like effects that were blocked by naltrexone. Tramadol (350 mg) produced miosis and increased ratings of “Good Effects” and “Liking” but also increased ratings of “Bad Effects.” Naltrexone reversed tramadol-induced physiological effects and mydriasis emerged, but unlike results with hydromorphone, naltrexone only partially attenuated tramadol’s positive subjective effects and actually enhanced several unpleasant subjective ratings.

Conclusions

Naltrexone can be used to disentangle the mixed neuropharmacological actions of tramadol. High-dose tramadol produces a mixed profile of effects. These data suggest that both mu and non-mu opioid actions play a role in tramadol’s subjective profile of action.

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Acknowledgments

This research was supported by grant number R01DA025649 from the National Institute on Drug Abuse (PI: William W. Stoops) and by grant number UL1RR033173 from the National Center for Research Resources (PI: Philip A. Kern). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIDA, NCRR, or NIH. The authors declare no conflicts of interest relevant to this project. The authors wish to thank the staff at the University of Kentucky Center on Drug and Alcohol Research for technical and medical assistance.

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Authors and Affiliations

  1. Department of Behavioral Science, University of Kentucky College of Medicine, 140 Medical Behavioral Science Building, Lexington, KY, 40536-0086, USA

    William W. Stoops, Michelle R. Lofwall & Sharon L. Walsh

  2. Center on Drug and Alcohol Research, University of Kentucky, Lexington, KY, USA

    William W. Stoops, Michelle R. Lofwall, Paul A. Nuzzo, Lori B. Craig & Sharon L. Walsh

  3. Department of Psychology, University of Kentucky College of Arts and Sciences, Lexington, KY, USA

    William W. Stoops

  4. Department of Psychiatry, University of Kentucky College of Medicine, Lexington, KY, USA

    Michelle R. Lofwall, Anthony J. Siegel & Sharon L. Walsh

  5. Department of Pharmaceutical Sciences, University of Kentucky College of Pharmacy, Lexington, KY, USA

    Sharon L. Walsh

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  1. William W. Stoops
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  2. Michelle R. Lofwall
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Correspondence to William W. Stoops.

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Stoops, W.W., Lofwall, M.R., Nuzzo, P.A. et al. Pharmacodynamic profile of tramadol in humans: influence of naltrexone pretreatment. Psychopharmacology 223, 427–438 (2012). https://doi.org/10.1007/s00213-012-2739-4

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