Evaluation of the effects of lofexidine and clonidine on naloxone-precipitated withdrawal in opioid-dependent humans
Authors: Walsh, Sharon L.; Strain, Eric C.; Bigelow, George E.
Source: Addiction, Volume 98, Number 4, April 2003 , pp. 427-439(13)
To examine the efficacy of lofexidine, an α2 adrenergic agonist, to suppress opioid withdrawal symptoms in opioid-dependent humans under in-patient laboratory conditions by using a naloxone challenge procedure. Design
Randomized, within-subject, cross-over design with drug administration taking place under double-blind and triple-dummy conditions. Setting
A 14-bed in-patient hospital research unit dedicated to the conduct of behavioral pharmacology studies. Participants
Eight healthy adult volunteers (two female/six male) with histories of polysubstance abuse and current physical dependence on opioids. Intervention
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. Measurements
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. Findings
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.
Document Type: Research Article
Affiliations: Behavioral Pharmacology Research Unit, Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, USA
Publication date: 2003-04-01