Boxed Warnings for Gabapentinoids

The Therapeutic Goods Administration (TGA) is adding boxed warnings to the product information and consumer medicine information of all products containing pregabalin or gabapentin. These warnings advise that pregabalin and gabapentin pose a risk of abuse and dependence, and pregabalin may be associated with misuse.

Pregabalin and gabapentin are known as gabapentinoids. These agents were originally developed for the treatment of epilepsy but have increasingly been used in the treatment of neuropathic pain. In the 2019-2020 financial year, over 3.2 million pregabalin prescriptions were supplied on the Pharmaceutical Benefits Scheme (PBS). This is a significant increase from the almost 1.4 million prescriptions dispensed in the 12 months after pregabalin was first listed on the PBS in March 2013.

Misuse and abuse of gabapentinoids appear to be increasing in line with their increased overall use. Misuse and abuse include the self-administration of higher than prescribed doses, combining with other central nervous system (CNS) depressants, and diversion. Euphoria is listed as a common side effect of pregabalin, which may explain why this agent is liable to misuse. This effect appears to be dose-dependent, with higher doses also associated with relaxation, uninhibited behaviour, improved sociability, dissociation, and hallucinations. Euphoria was not reported during pre-marketing trials for gabapentin. However, evidence now suggests that gabapentin can produce euphoria similar to pregabalin. These effects tend to be less potent with gabapentin and have a more delayed onset. Tolerance is reported to quickly develop to the euphoric effects of gabapentinoids. This can lead to recreational users increasing the dosage, often far beyond the recommended daily maximum dose.

The Therapeutic Guidelines advise that pregabalin and gabapentin cause minimal toxicity on their own, with sedation the most common effect in single-drug poisonings. However, morbidity and mortality are significantly higher when combined with other medications. Serious breathing difficulties can occur in people taking gabapentin or pregabalin who have any of the following respiratory risk factors:

• Use of other CNS depressants, such as opioids and benzodiazepines;
• Conditions that reduce lung function, such as chronic obstructive pulmonary disease (COPD); and
• Advanced age.

Gabapentinoids have also been associated with withdrawal symptoms when abruptly discontinued. Symptoms may include insomnia, headache, nausea, anxiety, hyperhidrosis, and diarrhoea. Withdrawal symptoms have been reported following discontinuation of both long-term and short-term treatment, and may be severe in people taking high doses. It is recommended that these agents be discontinued gradually over at least one week.

The TGA advice for healthcare professionals includes:

• Check for a history of substance use disorder before prescribing a gabapentinoid;
• Regularly monitor patients during treatment, particularly those with current or past use of opioids or benzodiazepines;
• If a gabapentinoid must be prescribed with another CNS depressant, the patient should be carefully monitored for signs of CNS depression; and
• When combined with another CNS depressant, the dosage and duration of therapy should be limited to the minimum required for therapeutic effect.

Gabapentinoids have become integral to the management of neuropathic pain. The appropriate use of these agents has the potential to improve pain and reduce the need for other analgesics such as opioids. However, if a gabapentinoid is not appropriate for a patient, alternatives such as a tricyclic antidepressant or a serotonin and noradrenaline reuptake inhibitor may be considered.