Cocaine dependence in opioid addicts is associated with less severe naloxone-precipitated opioid withdrawal compared to opioid addicts who are not cocaine dependent, suggesting that cocaine may reduce opioid withdrawal severity. The present study examines this effect further by comparing withdrawal severity in these two groups of opioid addicts. To control for dose, length of exposure, and time of administration of drugs, we also studied this effect in rats. Cocaine reduced the overall severity of opioid withdrawal in both human and rat. This drug-drug interaction may occur through alpha-2 adrenergic neurons in the locus coeruleus, similar to the effect of clonidine on opioid withdrawal.