Effects of Ibudilast on the Subjective, Reinforcing, and Analgesic Effects of Oxycodone in Recently Detoxified Adults with Opioid Dependence

Abstract

Ibudilast, a nonselective phosphodiesterase inhibitor, is used clinically in Asia for the treatment of asthma and poststroke dizziness. Recent preclinical studies have suggested that it also inhibits glial cell activation in rodents, and may alter opioid-mediated effects, including analgesia and withdrawal symptoms. The effects of ibudilast on the abuse potential of opioids in humans are largely unknown. The present study was designed to examine the influence of ibudilast on subjective (including drug craving), reinforcing, and analgesic effects of oxycodone in human volunteers diagnosed with opioid dependence (equivalent to moderate-severe opioid use disorder). Non-treatment-seeking opioid-dependent male volunteers (n=11) underwent an in-patient detoxification with morphine, followed by maintenance on placebo (0 mg b.i.d.) and active ibudilast (50 mg b.i.d.). Under each maintenance dose, six experimental sample and choice sessions were completed involving oral oxycodone administration (0, 15, and 30 mg/70 kg, p.o.). Subjective effects of oxycodone and drug craving were measured with visual analog scales (VAS) and a Drug Effects Questionnaire. The cold pressor test was used to produce pain, and a modified progressive-ratio choice procedure was used to measure the reinforcing effects of oxycodone. Under the active ibudilast condition compared with the placebo condition, ratings of drug liking following 15 mg of oxycodone were decreased significantly. The mean drug breakpoint value was also significantly lower in the active vs the placebo ibudilast condition under the 15 mg oxycodone condition, but not significantly lower under the 30 mg oxycodone condition. Heroin craving was significantly reduced under active ibudilast vs placebo, and similar effects were observed for tobacco and cocaine craving. Furthermore, mean subjective ratings of pain were lower in the active ibudilast condition. Our data suggest that ibudilast may be useful for treating opioid use disorders and it may enhance the analgesic effects of oxycodone.

Glial and neuroinflammatory targets for treating substance use disorders

“…Metz and colleagues (Metz et al, 2017) extended these findings by testing the effects of ibudilast on the subjective and reinforcing effects of OXY. Non-treatment seeking opioid users (n=11) first underwent inpatient detoxification followed by maintenance on placebo (0 mg ibudilast, BID) and active ibudilast (50 mg, BID).…”

Imaging Biomarkers of the Neuroimmune System among Substance Use Disorders: A Systematic Review

“…Recent studies have begun to investigate these medications in humans. A rigorous inpatient study among opioid-dependent subjects found ibudilast reduced opioid-seeking behavior and self-reported opioid craving, relative to placebo levels [15]. In separate studies, ibudilast reduced self-reported opioid withdrawal symptoms [254] and amplified oxycodone-induced analgesia [245] among opioid-dependent individuals.…”

“…Glial modulators, e.g. minocycline and ibudilast, may be effective medications for blocking the neuroimmune effects of abused substances [15, 245]. Minocycline is a tetracycline derivative that inhibits microglial activation and proliferation [246-248].…”

“…Further, disrupted neuroimmune signaling may also contribute to psychiatric symptoms [7, 11], alter medication response [12, 13], and/or increase likelihood of SUD relapse [14, 15]. For example, a rigorous inpatient study among opioid-dependent subjects found ibudilast, a glial modulator that suppresses proinflammatory glial responses [16], reduced opioid-seeking behavior and self-reported opioid craving, relative to placebo levels [15]. These studies illustrate the complex and important role of the neuroimmune system in SUDs.…”

Medications for substance use disorders (SUD): emerging approaches

“…Also, Recent studies show that the glial activation inhibitor ibudilast can decrease signs of withdrawal in opioid-dependent persons, and can also reduce the reinforcing effects of oxycodone [168,169]. …”