Gabapentinoids Attenuate Naloxone Reversal of Heroin‐Induced Ventilatory Depression

Abstract

A growing body of epidemiological evidence suggests increasing misuse of gabapentinoids (gabapentin and pregabalin, calcium channel inhibitors approved to treat some neuropathic pain conditions) in people with opioid use disorder. The number of prescriptions for gabapentinoids has risen rapidly over the past decade, with the majority of these prescriptions being for off‐label indications. Over the same period, gabapentinoids have become increasingly prevalent in opioid overdose deaths. Despite these trends little research has evaluated potentially harmful interactions between gabapentinoids and opioids. This study evaluated the effects of gabapentin and pregabalin on the ventilatory depressant effects of heroin, and the reversal of heroin‐induced ventilatory depression by naloxone. Five male Sprague Dawley rats were given pregabalin (1‐32 mg/kg), gabapentin (10‐100 mg/kg), or saline i.v. 30 minutes prior to receiving increasing doses of heroin while ventilation was monitored using whole‐body plethysmography. Sessions began with a 30‐minute baseline period followed by a test period during which rats received infusions of heroin or saline at minutes 0, 3, and 6 with heroin infusions resulting in cumulative doses of 0.1, 0.32, and 1 mg/kg (i.v.), respectively. Naloxone (0.0056‐0.01 mg/kg) or saline was administered i.v. 5 minutes following the final infusion of heroin. Minute volume, the product of tidal volume (mL/inspiration) and respiratory rate (breaths/minute), was the primary outcome of this study. Heroin dose‐dependently reduced minute volume with 1.0 mg/kg reducing minute ventilation on average to 42% of baseline. Neither pregabalin nor gabapentin altered the ventilatory depressant effects of heroin. When given 5 minutes following the 1.0 mg/kg cumulative dose of heroin, naloxone dose‐dependently reversed heroin‐induced decreases in minute volume with 0.0056 and 0.01 mg/kg naloxone restoring ventilation to 95 and 160% of baseline levels, respectively. Interestingly, pretreatment with gabapentin or pregabalin dose‐dependently attenuated the ability of naloxone to reverse heroin‐suppressed minute volume, with the largest dose of gabapentin and pregabalin almost completely blocking the effects of 0.0056 mg/kg naloxone. Both gabapentin and pregabalin attenuated the ability of naloxone to restore ventilation following administration of heroin in rats but did not alter the effects of heroin alone. These findings suggest that gabapentinoids might diminish the effectiveness of naloxone to reverse opioid overdose in humans, a possible explanation for the prevalence of these drugs in opioid overdose deaths. It will be important to determine whether similar interactions occur between gabapentinoids and naloxone for reversing the effects of other mu opioid receptor agonists such as fentanyl.