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 non-dependent opioid users: a randomized, double-blind, placebo-controlled, crossover study.
OBJECTIVE
Given the dual public health challenges of undertreated pain and opioid abuse, there is a need to reduce attractiveness of opioid analgesics to drug abusers. ALO-01 (morphine sulfate and naltrexone hydrochloride) extended-release capsules, indicated for treatment of chronic, moderate to severe pain, contain polymer-coated pellets of morphine, each with a core of sequestered naltrexone intended for release only upon tampering (crushing). The purpose of this study was to assess the pharmacodynamic effects (including drug-liking and euphoria) of whole and crushed ALO-01 versus morphine sulfate solution (MSS) and placebo.


METHODS
This was a randomized, double-blind, placebo-controlled, triple-dummy, four-way crossover study carried out at a clinical research centre. Participants were experienced non-dependent opioid users. Subjects were given either two ALO-01 60 mg capsules, crushed pellets from two ALO-01 60 mg capsules, MSS 120 mg or placebo; there was a 14- to 21-day washout between treatments. The primary endpoints were drug-liking visual analogue scale score, scores on items from the Addiction Research Center Inventory (ARCI) and Cole/ARCI scales characterizing abuse potential and euphoria, and pupil diameter as measured by pupillometry.


RESULTS
Morphine plasma concentrations were similar after ALO-01 crushed and MSS, with a median time to reach maximum plasma concentration (t(max)) of 1.1 and 1.2 hours, respectively; the plasma naltrexone median t(max) was 1.1 hours after ALO-01 crushed. By comparison, the median t(max) for morphine with ALO-01 whole was 8.1 hours. The maximum effect (E(max)) of MSS was significantly greater than placebo on pupillometry and the subjective measures (all p < 0.001). ALO-01 whole and crushed produced lower E(max) values and flatter effect-time profiles for subjective measures and caused less pupillary constriction than MSS.


CONCLUSIONS
The results of this study demonstrated that ALO-01, whether taken orally whole as intended or tampered with by crushing and taken orally, had reduced desirability compared with MSS.
Stauffer
Joseph
J
Alpharma Pharmaceuticals LLC, a wholly owned subsidiary of King Pharmaceuticals, Inc., Bridgewater, New Jersey, USA. beatrice.setnik@kingpharm.com
Setnik
Beatrice
B
Sokolowska
Marta
M
Romach
Myroslava
M
Johnson
Franklin
F
Sellers
Edward
E
D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D002214:Capsules; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D004338:Drug Combinations; D005059:Euphoria / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D009271:Naltrexone / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D019999:Pharmaceutical Solutions; D011680:Pupil / Q000187:drug effects; D013997:Time Factors; D055815:Young Adult
D000701:Analgesics, Opioid; D002214:Capsules; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D009292:Narcotic Antagonists; D019999:Pharmaceutical Solutions; D009271:Naltrexone; D009020:Morphine