• Leads to harmful use or dependence, other complications including death

Prescribers must be aware and vigilant of the high potential for the misuse of pregabalin in Sri Lanka, which may increase, as it is a medication that can be legally prescribed, and since certain pharmacists tend to dispense medications without a valid prescription, and which may also lead to harmful use or dependence, and other complications including death.

These observations were made in a brief report on ‘Pregabalin misuse: A silent epidemic’ which was authored by A. Hapangama and K.A.L.A. Kuruppuarachchi (both attached to the Kelaniya University's Medical Faculty's Psychiatry Department) and published in the Sri Lanka Journal of Psychiatry's 10th Volume's Second Issue in December 2019.

Pregabalin has, as mentioned in S.M. Stahl's ‘Stahl’s essential psychopharmacology: Prescriber’s guide’, been approved by the United States Food and Drug Administration for diabetic peripheral neuropathy (a type of nerve damage that affects the feet and legs first, followed by the hands and arms), postherpetic neuralgia (causes burning pain in the nerves and skin), fibromyalgia (characterised by widespread musculoskeletal pain accompanied by fatigue, sleep, and memory and mood-related issues), and neuropathic pain associated with spinal cord injury and partial seizures in adults, while it is however also used off label for generalised anxiety disorder, panic disorder and social phobia. A large number of cases of pregabalin misuse have been reported in European countries (a German study) and a similar trend seems to be appearing in Sri Lanka. 

Case one 

A 17-year old school-boy presented with the worsening of anxiety-related symptoms, poor sleep, agitation and increased craving for pregabalin. He had been prescribed pregabalin 100 milligrams (mg) a day by a medical practitioner, for social phobia, three months prior. The patient had started to use more than the prescribed dose and had purchased it without a valid prescription, as he had found that increasing the dose made him feel “happy and less anxious about others when doing presentations in front of the class”. However, recently, he had not been able to obtain the same number of capsules.

Case two

A 56-year-old female on treatment for diabetic neuropathy was referred to the psychiatry clinic as she had been repeatedly requesting prescriptions for the above therapeutic doses of pregabalin. It was found out that she had been using the above therapeutic doses without a prescription for more than three months, in order to lessen her pain and to feel happier. She reported that she had been commenced on pregabalin 50 mg thrice a day about one year prior, and that after about two months, the dose had been increased to 100 mg thrice a day on her request. The patient herself had increased the dose during the last few months and on presentation to the psychiatry clinic, she was on a total daily dose of 800 mg a day.

Case three

A 65-year-old female who was ataxic (a neurological sign consisting of the lack of voluntary coordination of muscle movements that can include gait related abnormalities, speech changes, and abnormalities in eye movements, that indicate dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum) was found to be using more than the prescribed doses of pregabalin. She had been followed up at a medical clinic for peripheral neuropathy. She had been started on pregabalin 50 mg thrice a day a few months prior, however, she had kept increasing the dose herself without medical advice as she felt that ‘she needed more of the medication to relieve the pain’. She was found to be taking 600 mg a day of pregabalin. She was not on any other medication and the computed tomography scan of her brain was normal.

Case four 

A 35-year old male, who was in remand prison at the time of referral to the psychiatry clinic, presented with a three-day history of persecutory delusions. It was noted that he had been misusing pregabalin above 500 mg a day for the previous one year. He gave a previous history of heroin use, but denied a history of psychotic symptoms in the past. He stated that his pregabalin or ‘bud’ (as is commonly known in the street) use was less stigmatised by his family and friends, as he was obtaining it over the counter from a pharmacy for the treatment of ‘aches and pains’. His last dose of pregabalin had been on the day prior to him being arrested.

Discussion

Pregabalin is reported to reduce excessive neuronal activity and neurotransmitter release. Pregabalin, according to the World Health Organisation's (WHO) Expert Committee on Drug Dependence's ‘Critical review report: Pregabalin’ is reported to be well-absorbed after oral administration, with a bioavailability (the extent and rate to which the active drug ingredient or active moiety [a part of a molecule that is given a name because it is identified as a part of other molecules as well] from the drug product is absorbed and becomes available at the site of drug action) of about 90% or more. It is known to reach peak plasma concentrations within 1.5 days after oral administration, and has a half life of about six hours. Pregabalin is reported to achieve a steady state within about 24-48 hours after repeated administration.

The recommended therapeutic dose of pregabalin is 150-600 mg a day. Sedation, dizziness, ataxia, diplopia (double vision), blurred vision, tremors, confusion, impaired attention, euphoria, asthenia (abnormal physical weakness or lack of energy), dry mouth and constipation are some of the side effects of the therapeutic doses of pregabalin.

The aforementioned WHO Expert Committee report, in 2018, warned of tolerance and withdrawal symptoms and behavioural dependence caused by pregabalin. Even though pregabalin is not known to directly act at receptor sites associated with drugs of abuse, reports suggest evidence of it producing euphoria, which may explain its potential for abuse. O. Schjerning, M. Rosenzweig, A. Pottegård, P. Damkier and J. Nielsen's ‘Abuse potential of pregabalin: A systematic review’ mentions that the abuse potential is more in people with a history of substance abuse or psychiatric disorders.

The routes of abuse of pregabalin include oral, intravenous, nasal insufflation, rectal (‘plugging’), smoking and ‘parachuting’ (emptying the content of the capsule into a pouch).

The WHO report describes diaphoresis (sweating, especially to an unusual degree as a symptom of a disease or a side effect of a drug), tachycardia (increased heart rate for any reason), hypertension, tremors, diarrhoea, anxiety, and auditory hallucinations as symptoms of pregabalin withdrawal. I. Gundogmus, A. Karagöz and A. Algül's ‘First episode psychosis induced by pregabalin withdrawal: A case report’ described the development of psychotic symptoms including persecutory delusions on the rapid discontinuation of pregabalin.

All four of the patients had been misusing pregabalin, in doses between 300-800 mg a day. After referral, they were treated assertively for their underlying conditions (some patients needed to be continued on pregabalin) and were followed up without incident. The doctors also used behaviour therapy techniques in all four patients to change their respective lifestyles.