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.

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.