The purpose of this pilot study was to validate a methodology for testing the opioid withdrawal-attenuating effects of new medications using clonidine as a positive control. Seven heroin-dependent subjects stabilized on levorphanol received naloxone challenge tests on 4 consecutive days in a 2 x 2 design with placebo or clonidine (0.4-0.5 mg) pretreatment, followed by 0.2 or 0.4 mg of i.v. naloxone. The change in the area-under-the-curve from the preclonidine base line for various measures of withdrawal was analyzed in a two-factor (naloxone dose and clonidine condition) analysis of variance. Clonidine significantly (P < .05) attenuated systolic and diastolic blood pressure, pulse, lacrimation, nasal congestion and plasma cortisol, but not subject-rated withdrawal severity. There was a robust dose-dependent adrenocorticotropic hormone response to naloxone that was not changed by clonidine pretreatment. The consistency between these results and prior studies of clonidine's antiwithdrawal efficacy suggests the validity of the methodology for testing medications to treat opiate withdrawal. Studies with larger samples are needed to refine this methodology.