A clinical trial to determine if corelease of morphine and naltrexone from crushed extended-release capsules induces withdrawal in opioid-dependent patients: A descriptive analysis of six patients

Beatrice Setnik, PhD; Carl L. Roland, PharmD; Veeraindar Goli, MD; Kenneth Sommerville, MD; Lynn Webster, MD

doi:10.5055/jom.2013.0155

Authors

Beatrice Setnik, PhD
Carl L. Roland, PharmD
Veeraindar Goli, MD
Kenneth Sommerville, MD
Lynn Webster, MD

DOI:

https://doi.org/10.5055/jom.2013.0155

Keywords:

opiate, opioid, pharmacokinetics, withdrawal, opioid dependent, naltrexone

Abstract

Objective: To evaluate whether intact or crushed doses of an extended-release formulation of morphine sulfate surrounding an inner core of sequestered naltrexone (MSN) induces signs and symptoms of withdrawal in opioid-dependent patients.

Design: Randomized, double-blind, two-way crossover study.

Setting: Single center.

Patients: Fourteen patients with chronic moderate-to-severe noncancer pain receiving opioids were enrolled into the study; six completed the maintenance and treatment phases prior to early study discontinuation for issues with manufacturing; eight discontinued: adverse effects (4), noncompliance (1), patient decision (1), study termination (2).

Interventions: Patients were titrated to a stable dose of MSN (ranging from 30/1.2 to 100/4.0 mg of morphine/naltrexone) that was used in the single-dose crossover evaluation of crushed and intact MSN.

Main outcome measures: Clinical Opiate Withdrawal Scale (COWS).

Results: Clinically significant withdrawal (COWS ≥ 13) was observed with rapid onset (≥ 0.8 hours postdose) in three patients (50 percent) following treatment with crushed MSN at the highest doses administered of ≥ 60/2.4 mg. Although naltrexone exposure was negligible following exposure to intact MSN, increasing plasma levels of naltrexone and 6-β-naltrexol were associated with COWS score ≥ 13 in patients who received crushed MSN. COWS ≥ 13 was observed in one patient receiving intact MSN without quantifiable naltrexone concentrations.

Conclusion: Crushing the MSN capsule may precipitate moderate-to-severe signs and symptoms of opioid withdrawal in opioid-dependent individuals. The negligible exposure to naltrexone following exposure to intact MSN supports that intact capsules may be taken safely without precipitating withdrawal in opioid-dependent individuals.

Author Biographies

Beatrice Setnik, PhD

Pfizer Inc, Cary, North Carolina

Carl L. Roland, PharmD

Pfizer Inc, Cary, North Carolina

Veeraindar Goli, MD

Pfizer Inc, Cary, North Carolina; Duke University Medical Center, Durham, North Carolina

Kenneth Sommerville, MD

Pfizer Inc, Cary, North Carolina; Duke University Medical Center, Durham, North Carolina

Lynn Webster, MD

CRI Lifetree, Salt Lake City, Utah

References

Rosenblum A, Marsch LA, Joseph H, et al.: Opioids and the treatment of chronic pain: Controversies, current status, and future directions. Exp Clin Psychopharmacol. 2008; 16(5): 405-416.

King Pharmaceuticals: EMBEDA (morphine sulfate and naltrexone hydrochloride) [package insert]. Bristol, TN: King Pharmaceuticals, Inc; 2009. Available at http://www.kingpharm.com/products/product_document.cfm?brand_name_Embeda&product_specific_name_CII&document_type_code_PI. Accessed January 27, 2012.

Katz N, Hale M, Morris D, et al.: Morphine sulfate and naltrexone hydrochloride extended release capsules in patients with chronic osteoarthritis pain. Postgrad Med. 2010; 122(4): 112-128.

Katz N, Sun S, Johnson F, et al.: ALO-01 (morphine sulfate and naltrexone hydrochloride) extended-release capsules in the treatment of chronic pain of osteoarthritis of the hip or knee: Pharmacokinetics, efficacy, and safety. J Pain. 2010; 11(4): 303-311.

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 nondependent opioid users: A randomized, double-blind, placebo-controlled, crossover study. Clin Drug Investig. 2009; 29(12): 777-790.

Webster LR, Johnson FK, Stauffer J, et al.: Impact of intravenous naltrexone on intravenous morphine-induced high, drug liking, and euphoric effects in experienced, nondependent male opioid users. Drugs R D. 2011; 11(3): 259-275.

Tompkins DA, Bigelow GE, Harrison JA, et al.: Concurrent validation of the Clinical Opiate Withdrawal Scale (COWS) and single-item indices against the Clinical Institute Narcotic Assessment (CINA) opioid withdrawal instrument. Drug Alcohol Depend. 2009; 105(1-2): 154-159.

Badalamenti VC, Buckley JW, Smith ET: Safety of EMBEDA (morphine sulfate and naltrexone hydrochloride) extended-release capsules: Review of post-marketing adverse events during the first year. J Opioid Manag. 2012; 8(2): 115-125.

Johnson FK, Stark JG, Bieberdorf FA, et al.: Relative oral bioavailability of morphine and naltrexone derived from crushed morphine sulfate and naltrexone hydrochloride extended-release capsules versus intact product and versus naltrexone solution: A single-dose, randomized-sequence, open-label, three-way crossover trial in healthy volunteers. Clin Ther. 2010; 32(6): 1149-1164.