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Subjective Effects and Safety of Whole and Tampered Morphine Sulfate and Naltrexone Hydrochloride (ALO-01) Extended-Release Capsules versus Morphine Solution and Placebo in Experienced Non-Dependent Opioid Users

A Randomized, Double-Blind, Placebo-Controlled, Crossover Study

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An Erratum to this article was published on 01 August 2011

Abstract

Background and Objective: Given the dual public health challenges of under-treated pain and opioid abuse, there is a need to reduce attractiveness of opioid analgesics to drug abusers. ALO-01 (morphine sulfate and naltrexone hydrochloride) extended-release capsules, indicated for treatment of chronic, moderate to severe pain, contain polymer-coated pellets of morphine, each with a core of sequestered naltrexone intended for release only upon tampering (crushing). The purpose of this study was to assess the pharmacodynamic effects (including drug-liking and euphoria) of whole and crushed ALO-01 versus morphine sulfate solution (MSS) and placebo.

Methods: This was a randomized, double-blind, placebo-controlled, triple-dummy, four-way crossover study carried out at a clinical research centre. Participants were experienced non-dependent opioid users. Subjects were given either two ALO-01 60 mg capsules, crushed pellets from two ALO-01 60 mg capsules, MSS 120 mg or placebo; there was a 14- to 21-day washout between treatments. The primary endpoints were drug-liking visual analogue scale score, scores on items from the Addiction Research Center Inventory (ARCI) and Cole/ARCI scales characterizing abuse potential and euphoria, and pupil diameter as measured by pupillometry.

Results: Morphine plasma concentrations were similar after ALO-01 crushed and MSS, with a median time to reach maximum plasma concentration (tmax) of 1.1 and 1.2 hours, respectively; the plasma naltrexone median tmax was 1.1 hours after ALO-01 crushed. By comparison, the median tmax for morphine with ALO-01 whole was 8.1 hours. The maximum effect (Emax) of MSS was significantly greater than placebo on pupillometry and the subjective measures (all p < 0.001). ALO-01 whole and crushed produced lower Emax values and flatter effect-time profiles for subjective measures and caused less pupillary constriction than MSS.

Conclusions: The results of this study demonstrated that ALO-01, whether taken orally whole as intended or tampered with by crushing and taken orally, had reduced desirability compared with MSS.

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Acknowledgements

This study and writing and editorial support for the manuscript were funded by King Pharmaceuticals®, Inc., Bridgewater, NJ, USA. Employee-authors from the study sponsor provided input into study design, analysis and interpretation of data, writing of the manuscript and the decision to submit the paper for publication.

The authors of this article are current or former employees of the funding source (Joseph Stauffer, Beatrice Setnik, Franklin Johnson) or clinical research site (Marta Sokolowska, Myroslava Romach, Edward Sellers, Beatrice Setnik). Joseph Stauffer has previously owned stock in Alpharma Pharmaceuticals LLC, a wholly owned subsidiary of King Pharmaceuticals®, Inc., and has a patent pending with Alpharma Pharmaceuticals LLC. Beatrice Setnik has stock options in King Pharmaceuticals®, Inc. Franklin Johnson held stock in Alpharma Pharmaceuticals LLC and is a co-inventor of the EMBEDA™ technology. Edward Sellers, Marta Sokolowska and Myroslava Romach have no conflicts of interest that are directly relevant to the content of this study.

Joseph Stauffer and Franklin Johnson were responsible for the study design, analysis and interpretation of data, and planning, critical review and approval of manuscript drafts. Marta Sokolowska, Beatrice Setnik, Myroslava Romach (chief investigator) and Edward Sellers (chief scientific advisor) were responsible for protocol development and implementation, study assessments, data entry and transfer, analyses and interpretation of data, writing the clinical study report and critical review of outlines and manuscript drafts. All authors had full access to all data, including statistical reports and tables, and take responsibility for the integrity of the data and the accuracy of the data analysis. Beatrice Setnik is guarantor.

The authors gratefully acknowledge the scientific contribution of Dr James B. Jones to this project. Writing and editorial support for this manuscript was provided by Innovex Medical Communications, Parsippany, NJ, USA; however, the context and text are those of the authors.

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Authors and Affiliations

  1. Alpharma Pharmaceuticals LLC, a wholly owned subsidiary of King Pharmaceuticals®, Inc., Bridgewater, New Jersey, USA

    Joseph Stauffer & Franklin Johnson

  2. Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicin, Baltimore, Maryland, USA

    Joseph Stauffer

  3. King Pharmaceuticals®, Inc., 4000 Centre Green Way, Suite 300, Cary, North Carolina, 27513, USA

    Beatrice Setnik

  4. Kendle Early Phase Toronto, formerly DecisionLine Clinical Research Corporation, Toronto, Ontario, Canada

    Beatrice Setnik, Marta Sokolowska, Myroslava Romach & Edward Sellers

  5. University of Toronto, Ontario, Canada

    Myroslava Romach & Edward Sellers

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  1. Joseph Stauffer
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  4. Myroslava Romach
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Correspondence to Beatrice Setnik.

Additional information

An erratum to this article is available at http://dx.doi.org/10.2165/11533600-000000000-00000.

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Stauffer, J., Setnik, B., Sokolowska, M. et al. Subjective Effects and Safety of Whole and Tampered Morphine Sulfate and Naltrexone Hydrochloride (ALO-01) Extended-Release Capsules versus Morphine Solution and Placebo in Experienced Non-Dependent Opioid Users. Clin. Drug Investig. 29, 777–790 (2009). https://doi.org/10.2165/11530800-000000000-00000

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