Evaluation of the effects of lofexidine and clonidine on naloxone-precipitated withdrawal in opioid-dependent humans.
OBJECTIVE
To examine the efficacy of lofexidine, an alpha2 adrenergic agonist, to suppress opioid withdrawal symptoms in opioid-dependent humans under in-patient laboratory conditions by using a naloxone challenge procedure.


METHODS
Randomized, within-subject, cross-over design with drug administration taking place under double-blind and triple-dummy conditions.


METHODS
A 14-bed in-patient hospital research unit dedicated to the conduct of behavioral pharmacology studies.


METHODS
Eight healthy adult volunteers (two female/six male) with histories of polysubstance abuse and current physical dependence on opioids.


METHODS
Participants were stabilized onto methadone and maintained on 30 mg/day, p.o. throughout the study. Oral placebo, lofexidine (0.4, 0.8 and 1.6 mg, p.o.) and clonidine (0.1 and 0.2 mg, p.o.) were each tested as pre-treatments once in combination with each of three intramuscular naloxone doses (0, 0.1 and 0.3 mg, i.m.) during 18 separate experimental sessions.


METHODS
An array of physiological indices (e.g. heart rate, blood pressure, pupil diameter) as well as a number of subjective and observer-rating scales sensitive to opioid withdrawal effects.


RESULTS
As expected, lofexidine and clonidine both produced dose-related decreases in blood pressure and heart rate but few subjective effects; naloxone increased opioid withdrawal signs and symptoms in a dose- and time-dependent fashion. Although both lofexidine and clonidine reduced the cardiovascular response to naloxone challenge, close inspection of the data reveal that this occurred only to the extent that baseline physiological parameters were reduced, while neither drug significantly modified the overall magnitude of the response to naloxone. Moreover, neither lofexidine nor clonidine suppressed the subjective discomfort of opioid withdrawal or significantly reduced other autonomic signs of opioid withdrawal, such as lacrimation or rhinorrhea.


CONCLUSIONS
These data suggest that lofexidine is well tolerated even at supratherapeutic acute doses. However, its failure to modify most signs and symptoms of opioid withdrawal suggest that its effective use in spontaneous withdrawal will require concomitant medications for improved therapeutic response.
Walsh
Sharon L
SL
Behavioral Pharmacology Research Unit, Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD 21224, USA. swalsh@jhmi.edu
Strain
Eric C
EC
Bigelow
George E
GE
D000316:Adrenergic alpha-Agonists / Q000627:therapeutic use; D000328:Adult; D003000:Clonidine / Q000031:analogs & derivatives / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D009270:Naloxone / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000627:therapeutic use*; D009294:Narcotics / Q000009:adverse effects*; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*
D000316:Adrenergic alpha-Agonists; D009292:Narcotic Antagonists; D009294:Narcotics; D009270:Naloxone; D003000:Clonidine; C025655:lofexidine