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Assessment of the Abuse Liability of a Dual Orexin Receptor Antagonist: A Crossover Study of Almorexant and Zolpidem in Recreational Drug Users

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Abstract

Background

Dual orexin receptor antagonists (DORAs) enable initiation and maintenance of sleep in patients with primary insomnia. Blockade of the orexin system has shown reduction of drug-seeking behavior in animal studies, supporting the role of orexin antagonism as a novel approach for treating substance abuse. Since hypnotics are traditionally associated with misuse, a lack of abuse liability of DORAs would offer significant benefits over current therapies for sleep disorders.

Methods

In this randomized, crossover, proof-of-concept study, single oral doses of the DORA almorexant (200, 400, and 1,000 mg) were administered to healthy subjects with previous non-therapeutic experience with central nervous system depressants and were compared with placebo and single oral doses of zolpidem (20 and 40 mg), a benzodiazepine-like drug. Subjective measures of abuse potential (visual analog scales [VAS], Addiction Research Center Inventory, and Subjective Drug Value) and objective measures (divided attention [DA]) were evaluated over 24 h post-dose in 33 evaluable subjects.

Results

Drug Liking VAS peak effect (E max; primary endpoint) was significantly higher for all doses of almorexant and zolpidem compared with placebo (p < 0.001). Almorexant 200 mg showed significantly less ‘Drug Liking’ than both zolpidem doses (p < 0.01), and almorexant 400 mg had smaller effects than zolpidem 20 mg (p < 0.05), while almorexant 1,000 mg was not different from either zolpidem dose. Results were similar for other subjective measures, although almorexant generally showed smaller negative and perceptual effects compared with zolpidem. Almorexant also showed less cognitive impairment compared with zolpidem on most DA endpoints.

Conclusion

This study in humans investigating single doses of almorexant is the first to explore and show abuse liability of a DORA, a class of compounds that is not only promising for the treatment of sleep disorders, but also of addiction.

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Acknowledgments

The authors thank the subjects and investigators who took part in this study. The authors received administrative support from Jorge Campos (Actelion Pharmaceuticals Ltd) for preparing the manuscript.

Funding

This study was sponsored by Actelion Pharmaceuticals Ltd, Switzerland, which provided payments to investigators or their institutions to perform the study.

Conflicts of Interest

Hans Cruz, Petra Hoever, and Jasper Dingemanse are full-time employees of, and own stock options in Actelion Pharmaceuticals Ltd. Edward M. Sellers, the principal investigator of the study, Bijan Chakraborty, the study statistician, and Kerri Schoedel, the scientific advisor, were full-time employees of INC Research Toronto Inc. (previously Kendle Early Stage, Toronto, ON, Canada) at the time of the study. Payments were received from their institutions and from Actelion Pharmaceuticals Ltd for performing the study and for data analysis.

Author Contributions

Hans Cruz wrote the manuscript, designed research, and analyzed data. Petra Hoever wrote the manuscript, designed research, and analyzed data. Jasper Dingemanse wrote the manuscript, designed research, and analyzed data. Edward M. Sellers wrote the manuscript, designed and performed research, analyzed data, and contributed new reagents/analytical tools. Bijan Chakraborty wrote the manuscript, designed research, and analyzed data. Kerri Schoedel wrote the manuscript, designed research, and analyzed data.

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Authors and Affiliations

  1. Actelion Pharmaceuticals Ltd, Clinical Pharmacology, Gewerbestrasse 16, 4123, Allschwil, Switzerland

    Hans G. Cruz, Petra Hoever & Jasper Dingemanse

  2. INC Research Toronto, Inc., Toronto, ON, Canada

    Bijan Chakraborty

  3. Altreos Research Partners, Inc., Toronto, ON, Canada

    Kerri Schoedel

  4. DL Global Partners, Inc., Toronto, ON, Canada

    Edward M. Sellers

Authors
  1. Hans G. Cruz
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  2. Petra Hoever
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  3. Bijan Chakraborty
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  5. Edward M. Sellers
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  6. Jasper Dingemanse
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Corresponding author

Correspondence to Jasper Dingemanse.

Additional information

ClinicalTrials.gov registration number: NCT01987739.

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Cruz, H.G., Hoever, P., Chakraborty, B. et al. Assessment of the Abuse Liability of a Dual Orexin Receptor Antagonist: A Crossover Study of Almorexant and Zolpidem in Recreational Drug Users. CNS Drugs 28, 361–372 (2014). https://doi.org/10.1007/s40263-014-0150-x

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  • DOI: https://doi.org/10.1007/s40263-014-0150-x

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