Morphine Sulfate and Naltrexone Hydrochloride Extended-Release Capsules: Naltrexone Release, Pharmacodynamics, and Tolerability

Background: Morphine sulfate and naltrexone hydrochloride extended-release capsules (EMBEDA,King Pharmaceuticals, Inc., Bristol, TN), indicated for management of chronic, moderate-to-severe pain,contain pellets of extended-release morphine sulfate with a sequestered naltrexone core (MS-sNT).Taken as directed, morphine provides analgesia while naltrexone remains sequestered; if tampered withby crushing, naltrexone is released to mitigate morphine-induced euphoric effects. While it is necessaryto establish that formulations intended to reduce attractiveness for abuse are successful in doing so, it isalso necessary to demonstrate that product therapeutic integrity is maintained for patients.Objectives: Data were reviewed from 3 studies to determine: 1) the quantity of naltrexonereleased when MS-sNT pellets are crushed (MS-sNTC) for at least 2 minutes with mortar andpestle); 2) the extent to which the naltrexone released upon crushing mitigated morphine-inducedsubjective effects; and 3) whether sequestered naltrexone precipitates opioid withdrawal when MSsNT is taken as directed.Methods: The naltrexone bioavailability study compared naltrexone release from MS-sNTC with thatfrom whole intact MS-sNT capsules (MS-sNTW) and an equal naltrexone solution (NS) dose. Equivalentbioavailability was established if 90% confidence intervals (CIs) for geometric mean ratios (maximumplasma naltrexone concentration [Cmax] and area under the concentration-time curve extrapolated toinfinity [AUC∞]) fell between 80% and 125%. The oral pharmacodynamic study assessed drug likingand euphoria and pharmacokinetic properties of MS-sNTC and MS-sNTW compared with morphinesulfate solution (MSS) and placebo. The 12-month, open-label (OL) safety study evaluated safetyof MS-sNT administered orally as directed in patients with chronic, moderate-to-severe pain. Safetyassessments included withdrawal symptoms based on the Clinical Opiate Withdrawal Scale (COWS).Results: Naltrexone from MS-sNTC met criteria for equivalent bioavailability to NS. Although morphinerelative bioavailability was similar for MS-sNTC and MSS, mean peak (Emax) visual analog scale (VAS)scores for drug liking and Cole/Addiction Research Center Inventory Stimulation-Euphoria weresignificantly reduced for MS-sNTC vs MSS (P < 0.001). In these 2 studies, a total of 6 participants had onemeasurement of plasma naltrexone after MS-sNTW that was above the lower limit of quantification. Inthe OL safety study, 72/93 participants (77%) had no quantifiable naltrexone concentrations. There wasneither evidence of naltrexone accumulation for any participant nor any significant correlation with MSsNT dose, age, or sex. Of 4 participants with the highest naltrexone concentrations, none had COWSscores consistent with moderate opioid withdrawal symptoms. Only 5 participants had COWS scoresconsistent with moderate opioid withdrawal; all 5 had not taken MS-sNT as directed.Limitations: Study populations may not be fully representative of patients receiving opioidtherapy for the management of chronic, moderate-to-severe pain and of opioid abusers.Conclusions: When MS-sNT capsules are crushed, all of the sequestered naltrexone (relative tooral NS) is released and immediately available to mitigate morphine-induced effects. When MSsNT was crushed, the naltrexone released abated drug liking and euphoria relative to that from anequal dose of immediate-release morphine from MSS administration in a majority of participants.Naltrexone concentrations were low over a period of 12 months without evidence of accumulation,and there were no observable opioid withdrawal symptoms when MS-sNT was taken as directed.Key words: Chronic pain, drug liking, euphoria, extended-release opioids, morphine, naltrexone,opioid withdrawal, pharmacodynamics, pharmacokinetics