title: 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.
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.
  
  
  METHODS
  Randomized, double-blind, two-way crossover study.
  
  
  METHODS
  Single center.
  
  
  METHODS
  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).
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Pfizer Inc, Cary, NC, USA.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Setnik
authors.forename: Carl L
authors.initials: CL
authors.lastname: Roland
authors.forename: Veeraindar
authors.initials: V
authors.lastname: Goli
authors.forename: Kenneth
authors.initials: K
authors.lastname: Sommerville
authors.forename: Lynn
authors.initials: L
authors.lastname: Webster
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D001711:Biotransformation; D002214:Capsules; D002626:Chemistry, Pharmaceutical; D059350:Chronic Pain / Q000175:diagnosis / Q000188:drug therapy*; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D009271:Naltrexone / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D009293:Opioid-Related Disorders / Q000097:blood / Q000175:diagnosis / Q000209:etiology*; D013375:Substance Withdrawal Syndrome / Q000097:blood / Q000175:diagnosis / Q000209:etiology*; D013997:Time Factors; D014589:Utah
chemical_list: D000701:Analgesics, Opioid; D002214:Capsules; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D009292:Narcotic Antagonists; C550436:morphine, naltrexone combination; C010410:6 beta-hydroxynaltrexone; D009271:Naltrexone; D009020:Morphine