Animal models of spontaneous opioid withdrawal

Preclinical experiments have revealed much about opioid withdrawal, but have failed to discover novel treatments. The preclinical literature is dominated by experiments examining naloxone-precipitated withdrawal from morphine in male rats. These studies report a number of putative treatments for opioid withdrawal, none of which have become clinically approved. A major problem, supported by both human and animal research, is that antagonist-precipitated withdrawal is distinct from the spontaneous opioid withdrawal experienced by most opioid users. A second problem is the widespread focus in animal research on somatic symptoms (e.g., wet dog shakes). Although somatic symptoms can be disruptive, anxiety, anhedonia, and aches are the symptoms that cause distress and drive relapse. Somatic symptoms are also problematic because they are easily suppressed by treatments that produce sedative or motor effects. A potential solution to these problems is the use of voluntary home cage wheel running as a more general measure of opioid withdrawal. Wheel running provides a continuous and objective measure ideal for assessing changes in the magnitude and duration of spontaneous withdrawal over time. The decrease in wheel running caused by opioid withdrawal changes the definition of an effective treatment from suppressing behavior (somatic symptoms) to restoring behavior (wheel running), thereby avoiding confounds produced by sedative or motor effects. This review provides a detailed analysis of rodent experiments on opioid withdrawal, highlighting potential problems with external validity and describing wheel running experiments that align animal experiments with the clinical manifestation of opioid withdrawal to enhance the development of novel treatments.