Current Scheduling Status
Year(s) and type of review / ECDD meetings
Drug Class
ECDD Recommendation
Placed under surveillance
Recommendation (from TRS)
Substance identification
Chemically, pregabalin is (3S)-3-(aminomethyl)-5-methylhexanoic acid, a white to off-white crystalline solid. It is the (S)-(+)-isomer of 3-isobutyl-gamma- aminobutyric acid. Pregabalin is produced in various formulations including capsules, solution and extended-release tablets available as pharmaceutical products to be taken orally.

WHO review history
Pregabalin was pre-reviewed by the ECDD at its thirty-ninth meeting in November 2017 and it was recommended that a critical review be undertaken.

Similarity to known substances and effects on the central nervous system
Pregabalin is an inhibitor of alpha-2-delta subunit-containing voltage- gated calcium channels. Through this mechanism it decreases the release of neurotransmitters such as glutamate, noradrenaline and substance P. It has been suggested that pregabalin exerts its therapeutic effects by reducing the neuronal activation of hyper-excited neurons while leaving normal activation unaffected. The mechanism(s) by which pregabalin produces euphoric effects or induces physical dependence is unknown.

Despite being a chemical analogue of the neurotransmitter gamma- aminobutyric acid (GABA), pregabalin does not influence GABA activity via either GABA receptors or benzodiazepine receptors. However, pregabalin has been found to produce effects that are similar to those produced by controlled substances, such as benzodiazepines, that increase GABA activity.

Dependence potential
Tolerance has been shown to develop to the effects of pregabalin, particularly the euphoric effects. A number of published reports have described physical dependence associated with pregabalin use in humans. The withdrawal symptoms that occur following abrupt discontinuation of pregabalin include insomnia, nausea, headache, anxiety, sweating and diarrhoea. Current evidence suggests that the incidence and severity of withdrawal symptoms may be dose-related and hence those taking doses above the normal therapeutic range are most at risk of developing withdrawal symptoms. At therapeutic doses, withdrawal symptoms may be minimized by gradual dose-tapering.

Actual abuse and/or evidence of likelihood of abuse
While some preclinical research using self-administration and conditioned place preference models has shown reinforcing effects of pregabalin, overall, the results from such research are contradictory and inconclusive.

In clinical trials, patients have reported euphoria, although tolerance to this effect develops rapidly. Laboratory research on humans is very limited and only a relatively low dose of pregabalin has been tested in a general population sample; the results indicated low abuse liability. However, when a higher dose of pregabalin was administered to users of alcohol or sedative/hypnotic drugs, it was rated similar to diazepam, which is indicative of abuse liability.

Pregabalin is more likely to be abused by individuals who are using other psychoactive drugs (especially opioids) and there is a significant potential for adverse effects among these subpopulations. The adverse effects of pregabalin include dizziness, blurred vision, impaired coordination, impaired attention, somnolence, confusion and impaired thinking. Other reported types of harm associated with nonmedical use of pregabalin include suicidal ideation and impaired driving. Users of pregabalin in a number of countries have sought treatment for dependence on the drug.

While pregabalin has been cited as the main cause of death in more than 30 documented cases of fatality following overdose, very few cases of fatal intoxication have resulted from pregabalin use alone and the vast majority of instances involve other central nervous system depressants such as opioids and benzodiazepines.

Only limited information is available regarding the illicit trade in pregabalin, but there is evidence of illicit marketing through online pharmacies.

Pregabalin has been placed under national control in many countries in different regions of the world.

Therapeutic usefulness
Pregabalin is used for the treatment of neuropathic pain, including painful diabetic peripheral neuropathy and postherpetic neuralgia, fibromyalgia, anxiety and the adjunctive treatment of partial seizures. The exact indications for which pregabalin has received approval vary across countries. Pregabalin has also been used to treat conditions such as substance use disorders, alcohol withdrawal syndrome, restless legs syndrome and migraine.

The Committee noted that there has been increasing concern in many countries regarding the abuse of pregabalin. Cases of dependence have been reported and there are increasing numbers of reports of adverse effects. While these problems are concentrated in certain drug-using populations, there are limited data on the extent of the problems related to pregabalin abuse in the general population. The Committee also noted that pregabalin has approved therapeutic uses for a range of medical conditions, including some for which there are few therapeutic options. Given the limitations of the available information regarding the abuse of pregabalin:

■■ Recommendation: The Committee recommended that pregabalin ((3S)-3-(aminomethyl)-5-methylhexanoic acid) should not be scheduled but should be kept under surveillance by the WHO Secretariat.
MS Questionnaire Report