[Show abstract][Hide abstract] ABSTRACT: Opioid analgesics can be abused by crushing followed by solubilization and intravenous injection to attain rapid absorption. Morphine sulfate and naltrexone hydrochloride extended release capsules (EMBEDA, MS-sNT), indicated for management of chronic, moderate to severe pain, contain pellets of morphine sulfate with a sequestered naltrexone core. Should product tampering by crushing occur, the sequestered naltrexone is intended for release to reduce morphine-induced subjective effects.
This study compared self-reports of high, euphoria, and drug-liking effects of intravenous morphine alone versus intravenous morphine combined with naltrexone in a clinical simulation of intravenous abuse of crushed MS-sNT.
This single-center, randomized, double-blind, crossover study characterized subjective effects of naltrexone administered intravenously at the same ratio to morphine present in MS-sNT. Subjects were male and had used prescription opioids five or more times within the previous 12 months to get 'high' but were not physically dependent on opioids. The primary outcome was the response to the Drug Effects Questionnaire (DEQ) question #5, "How high are you now?" (100 mm Visual Analog Scale [VAS]). The secondary outcome was the response to a Cole/Addiction Research Center Inventory (ARCI) Stimulation-Euphoria modified scale. Additional outcomes included response to VAS drug liking, the remaining DEQ questions, and pupillometry.
Administration of intravenous naltrexone following intravenous morphine diminished mean high (29.8 vs 85.2 mm), Cole/ARCI Stimulation-Euphoria (13.7 vs 27.8 mm), and drug-liking (38.9 vs 81.4 mm) scores (all p < 0.0001) compared with intravenous morphine alone. No serious adverse events occurred as a result of the tested ratio of naltrexone to morphine.
Results in this study population suggest that naltrexone added to morphine in the 4% ratio within MS-sNT mitigates the high, euphoria, and drug liking of morphine alone, potentially reducing the attractiveness for product tampering. Assessment of the true clinical significance of these findings will require further study.
[Show abstract][Hide abstract] ABSTRACT: Although contraindicated, coingestion of alcohol and opioids by patients or drug abusers is a major health concern because of dangerous additive and potentially life-threatening sedative and respiratory effects. In addition, alcohol has been shown to disrupt the extended-release characteristics of certain extended-release opioid formulations, releasing a hazardous amount of opioid over a short time period. Morphine sulfate and naltrexone hydrochloride extended release capsules (MS-sNT), which contain naltrexone sequestered in each pellet core, are indicated for management of chronic, moderate to severe pain. Sequestered naltrexone is designed for release upon product tampering (crushing) to potentially mitigate morphine-induced subjective effects. This open-label, single-dose, 4-way crossover, pharmacokinetic drug interaction study compared the relative bioavailability of morphine and naltrexone when MS-sNT is administered (under fasting conditions) with increasing doses of alcohol. Thirty-two healthy, opioid-naive adults were randomized to MS-sNT administered with 240 mL of 4%, 20%, or 40% alcohol or water. No drug interaction was found between morphine in MS-sNT and 4% or 20% alcohol. Administration with 40% alcohol did not affect overall morphine exposure but was associated with a 2-fold increase in C(max) and reduction of t(max) from 9 to 4 hours versus MS-sNT taken with water. Naltrexone sequestering was successful in all treatment arms and not affected by coadministration with alcohol over the dose range tested.
The Journal of Clinical Pharmacology 05/2011; 52(5):747-56. · 2.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Morphine sulfate and naltrexone hydrochloride extended release capsules (EMBEDA®, King Pharmaceuticals®, Inc., Bristol, TN), indicated for the management of chronic, moderate to severe pain, contain extended release morphine pellets with a sequestered naltrexone core (MS-sNT). If the product is tampered with by crushing, naltrexone, a μ-opioid antagonist, is intended for release to mitigate morphine-induced subjective effects. The primary end point of this randomized 2-way crossover study in healthy fasted volunteers was evaluation of morphine bioequivalence between MS-sNT (treatment A) and morphine sulfate extended release capsules (KADIAN®, treatment B). Morphine pharmacokinetics were assessed predose to 72 hours postdose of single 100-mg doses of treatment A or B. Analysis of variance of ln-transformed ratios of least squares mean of the area under the concentration time curve (AUC) from time 0 to last measurable concentration (AUC0-t) and AUC from time 0 to infinity (AUCinf) and maximum serum concentration (Cmax) for treatments A versus B were performed. Ratios and 90% confidence intervals for least squares mean for AUC0-t (102.2%; 98.6-105.9%), AUCinf (97.4%; 91.2-104.1%), and Cmax (93.8%; 82.4-106.7%) indicated bioequivalence between the 2 formulations. When subjects who vomited during the 12-hour dosing interval were excluded, the confidence interval for AUC0-t and AUCinf fell within the 80%-125% range, but the lower limit for Cmax was 76.9%.
American journal of therapeutics 11/2010; 18(1):2-8. · 1.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Morphine sulfate and naltrexone hydrochloride extended release capsules, indicated for chronic moderate-to-severe pain, contain extended-release morphine pellets with a sequestered naltrexone core. If pellets are tampered by crushing, naltrexone is released to reduce morphine-induced effects that appeal to opioid abusers. The primary objective of this study was to assess single-dose relative bioavailability of morphine when morphine sulfate and naltrexone hydrochloride extended release capsules were taken under fed and fasting conditions and when pellets were sprinkled on apple sauce.
This was a single-center, randomized, open-label study in 36 healthy adult volunteers. Subjects took a 100-mg morphine sulfate and naltrexone hydrochloride extended release capsule intact with 240 mL water, under fed and fasted conditions, and when the capsule was opened and pellets were sprinkled over apple sauce and consumed without chewing; each treatment was separated by a 14-day washout. Plasma samples were collected just before dosing through 72 hours postdose for pharmacokinetic analyses of morphine, and through 168 hours postdose for naltrexone and its major metabolite 6-β-naltrexol.
Morphine bioavailability was similar for all treatments. There was a lack of sprinkle effect (sprinkle vs. whole, fasted); 90% confidence intervals (CIs) of ratios of log-transformed least squares means for area under the plasma concentration-time curve (AUC) and peak plasma concentration (C(max)) fell within 80%-125% boundaries. For the food effect, 90% CIs were within the boundaries for AUC, but C(max) was reduced and time to C(max) was delayed by 2.5 hours under fed conditions. Naltrexone remained sequestered under all treatment conditions with only trace systemic exposure.
Results indicated that morphine sulfate and naltrexone hydrochloride extended release capsules can be administered without regard to meals, and contents can be sprinkled over apple sauce and consumed without chewing by patients with difficulty swallowing.
Advances in Therapy 11/2010; 27(11):846-58. · 2.44 Impact Factor