Background Despite a decade-long reduction in opioid prescriptions, opioid misuse remains a major health crisis causing most drug overdose fatalities. Meanwhile, gabapentin (Neurontin®) prescriptions have doubled. Gabapentin is present in over 10% of drug overdose fatalities, 90% of which involve opioids. Although reports show gabapentin is prescribed off-label for opioid withdrawal, empirical evidence is lacking regarding its efficacy in mitigating opioid withdrawal symptoms or modulating opioid dependence. It is hypothesized that gabapentin attenuates expression of opioid withdrawal.

Methods Opioid dependence was established in male Sprague-Dawley rats administered escalating morphine doses (10-40 mg/kg) twice daily for four days. Morphine withdrawal was measured using food-maintained responding, withdrawal signs, and body weight loss in six rats trained to lever press for a sucrose pellet (fixed-ratio 5-response schedule of reinforcement). The operant session comprised five cycles: a 5-minute post-saline timeout and a 10-minute response period. Gabapentin doses (3.2-320 mg/kg) were cumulatively administered for testing and dependence was maintained with a morphine dose (40 mg/kg) after daily operant experiments.

In a separate experiment, seven groups of rats (N=8/group; Groups A - G) were observed for 14 somatic withdrawal signs, and changes in body weight. Opioid dependence was established in Groups A, B, D, and F with morphine doses (10-40 mg/kg), while Group C, E, and G received saline. Subsequently, Group A, the morphine-dependent control group, received saline injections at 7 AM and 5 PM, whereas the rest of the groups received gabapentin (32, 100, or 320 mg/kg) at 7 AM and saline at 5 PM daily. Body weight and rotarod performance were used to quantify effects following morphine discontinuation.

Results Following opioid dependence, response rates stabilized just below 35% of baseline, and body weight loss was 20 g greater at 7 AM (14 hours after administration of saline) than at 5PM (10 hours after administration of 40 mg/kg morphine). Morphine and gabapentin significantly increased rate of responding. Only 32 mg/kg gabapentin significantly attenuated body weight loss and withdrawal signs on days 1 and 2. Enhancement of rotarod performance and hypothermia were significantly attenuated by 320 mg/kg gabapentin. No dose of gabapentin significantly attenuated mechanical allodynia.

Conclusion These results fail to support the view that gabapentin attenuates opioid withdrawal in male rats. Further research is needed to clarify its role in mitigating opioid withdrawal and dependence, considering potential influences from other factors or perceived benefits.