Overview of disorders of pregabalin and gabapentin use

Pregabalin and gabapentin (gabapentinoids) are gamma amino butyric acid (GABA analogues) but do not interact significantly with GABA receptors; they act primarily by inhibiting voltage-gated calcium channels, indirectly reducing neuronal excitability and firingEvoy, 2021. Both are often overprescribed and used for unapproved indications, but nonmedical use is more common with pregabalin because gabapentin absorption becomes saturated at higher doses, reducing the effect of escalating dosesBockbrader, 2010. Nonmedical use describes use that does not align with the directed useAustralian Institute of Health and Welfare (AIHW)McNeely, 2014. For example, a person may use pregabalin or gabapentin to treat a symptom other than the clinician intended, or to become intoxicated.

The spectrum of substance use in these guidelines is described by the terms ‘hazardous use’, ‘harmful use’ or ‘substance dependence’, outlined in Terminology describing the spectrum of substance use.

Nonmedical use of pregabalin (in particular) and gabapentin is increasing in Australia and overseasBonnet, 2017Crossin, 2019Lyndon, 2017. In 2019, an estimated 4.3% of people taking any pain medication reported nonmedical use of pregabalin or gabapentin within the last 12 monthsAustralian Institute of Health and Welfare (AIHW), 2020.

Case reports describe dependence with chronic use of very high doses of pregabalin (up to 9 g per day). Other substance use is a risk factor for pregabalin or gabapentin dependenceBonnet, 2017.

The harms of nonmedical use of pregabalin and gabapentin include:

  • enhanced toxicity, including fatal sedation, especially when taken with opioids, benzodiazepines or alcoholCrossin, 2019
  • seizures in acute withdrawal
  • delirium following dose increases or in withdrawal.

Pregabalin and gabapentin lower the threshold at which opioid overdoses are fatal. While any combination of these drugs may be problematic, risk of toxicity is particularly high if pregabalin doses more than 300 mg daily or opioid doses more than the oral morphine equivalent of 100 mg daily are used. Risk of toxicity escalates markedly if pregabalin or gabapentin is used with 2 or more sedative drugs (eg opioids, benzodiazepines, alcohol)Gomes, 2018. Risk of death is lower for patients using pregabalin or gabapentin with prescribed buprenorphine or methadone than for those who use other opioidsGomes, 2018. For advice on managing pregabalin or gabapentin toxicity, see Pregabalin and gabapentin poisonings.

Note: Combination of pregabalin or gabapentin and an opioid lowers the threshold at which opioid overdose is fatal.

Significant withdrawal symptoms, similar to benzodiazepine and selective serotonin reuptake inhibitor (SSRI) withdrawal syndromes, have been reported with both tapering and abruptly stopping pregabalin or gabapentinBonnet, 2017.