Effects of buprenorphine/naloxone in opioid-dependent humans.
BACKGROUND
Buprenorphine is a partial mu opioid agonist under development as a sublingual (SL) medication for opioid dependence treatment in the United States. Because buprenorphine may be abused, tablets combining buprenorphine with naloxone in a 4:1 ratio have been developed to reduce that risk. Low doses of injected buprenorphine/naloxone have been tested in opioid-dependent subjects, but higher doses (more than 2 mg of either medication) and direct comparisons to SL buprenorphine/naloxone have not been examined.


OBJECTIVE
To assess and compare the effects of intramuscular (i.m.) versus SL buprenorphine/naloxone in opioid-dependent volunteers.


METHODS
Opioid-dependent volunteers were maintained on 40 mg per day of oral hydromorphone while on a residential research ward. After safety testing in two pilot subjects, participants (n = 8) were tested with both i.m. and SL buprenorphine/naloxone (1/0.25, 2/0.5, 4/1, 8/2, 16/4 mg); i.m. hydromorphone (10 mg) and naloxone (0.25 mg); both i.m. and SL buprenorphine alone (8 mg); and placebo. Test sessions were twice per week; dosing was double-blind.


RESULTS
Intramuscular buprenorphine/naloxone produced dose-related increases on indices of opioid antagonist effects. Effects were consistent with naloxone-precipitated withdrawal, and were short-lived. As withdrawal effects dissipated, euphoric opioid agonist effects from buprenorphine did not appear. Sublingual buprenorphine/naloxone produced neither opioid agonist nor antagonist effects.


CONCLUSIONS
Intramuscular injection of buprenorphine/naloxone precipitates withdrawal in opioid dependent persons; therefore, the combination has a low abuse potential by the injection route in this population. Sublingual buprenorphine/naloxone by tablet is well tolerated in opioid dependent subjects, and shows neither adverse effects (i.e., precipitated withdrawal) nor a high abuse potential (i.e., opioid agonist effects).
Stoller
K B
KB
Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 5510 Nathan Shock Drive, Baltimore, MD 21224, USA. kstolle@jhmi.edu
Bigelow
G E
GE
Walsh
S L
SL
Strain
E C
EC
D000286:Administration, Sublingual; D000293:Adolescent; D000328:Adult; D000339:Affect / Q000187:drug effects / Q000502:physiology; D002047:Buprenorphine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D004091:Hydromorphone / Q000008:administration & dosage; D007273:Injections, Intramuscular; D008297:Male; D008875:Middle Aged; D009270:Naloxone / Q000008:administration & dosage*; D009292:Narcotic Antagonists / Q000008:administration & dosage*; D009294:Narcotics / Q000008:administration & dosage; D015588:Observer Variation; D009293:Opioid-Related Disorders / Q000188:drug therapy* / Q000523:psychology; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000523:psychology
D009292:Narcotic Antagonists; D009294:Narcotics; D009270:Naloxone; D002047:Buprenorphine; D004091:Hydromorphone