Background

In Europe, concerns about the potential risk for misuse of or dependence on the prescription drugs pregabalin and gabapentin have been raised for at least a decade. This article brings together a brief overview of some of the main international and national literature to date. In 2009, pregabalin and its potential involvement in drug-related deaths in Finland, Sweden and the United Kingdom (UK) was reported to the EMCDDA Early Warning System.1 A retrospective analysis of German data showed that as early as 2008 cases of pregabalin misuse/dependence were reported in that country.2 However, several years earlier in 2005, the United States (US) made pregabalin a controlled drug due to the recognition of the potential risk of misuse and/or dependence.3

What is pregabalin?

Pregabalin is a prescription-only drug, licensed to treat a number of serious conditions: epilepsy (antiseizure), neuropathic pain, e.g. caused by shingles (pain relief) and also for generalised anxiety disorder (antianxiety). A common brand name for pregabalin is Lyrica®. Pregabalin and gabapentin are frequently discussed together in the literature, usually under their group name ‘gabapentinoid’. This is because they are a similar type of drug, both cited as having a risk of misuse or dependency. A common brand name for gabapentin is Neurontin®. There has been a 23% increase in the number of GMS prescriptions for pregabalin in Ireland between 2008 and 2016 (unpublished data from the Primary Care Reimbursement Service).

What is gabapentin?

Gabapentin is a prescription-only drug, similar to pregabalin, and prescribed for epilepsy (anticonvulsant) and neuropathic pain (pain relief). Literature referring to pregabalin and gabapentin often refers to their ‘off label’ use. This means the drugs are being prescribed (or used) for a condition outside the terms of its original product authorisation (or in different doses or to patient groups not specified in the authorisation).4 Over the past decade there has been a massive increase in Europe in the number of prescriptions for pregabalin and gabapentin.5, 6 Analysis of UK data showed that there was a 24% increase in the number of gabapentinoid prescriptions between 2004 and 2015.6

Risk of misuse/dependence

The drugs are reported to give feelings of euphoria and relaxation.5,7 Studies have shown that people do experience tolerance and subsequent withdrawal symptoms on stopping pregabalin and gabapentin; however, this is less common for those who use gabapentin. There are a very small number of documented cases of dependence (rather than misuse) in Europe.5 Pregabalin appears to have a greater potential for misuse or dependency because of its more rapid absorption and potency.5 This is supported by the available evidence which suggests that dependence is more common for those who misuse pregabalin rather than gabapentin.5,7

However, it is clear from the literature reviews that individuals who misuse pregabalin and gabapentin are taking (often much) higher than recommended doses and the vast majority have a history of misuse of or dependence on other drugs, in particular, opioids.5,7 This is supported by studies that show prevalence of gabapentinoid misuse among opioid substitution treatment clients varied from 3% to 68%.7

The literature states that people who misuse opioids appear to use gabapentinoids, in particular pregabalin, to achieve a quicker euphoric high and reduce withdrawals.5 This close association with this high risk population is most likely to be influencing the increased prevalence of misuse/dependence and serious side-effects, including fatal overdose, rather than pregabalin or gabapentin solely as primary drugs of misuse or dependence.5 Some studies show higher prevalence of misuse among psychiatric patients and within prisons.7 It is not clear if this is directly related to drug misuse/dependence or a separate concern.

In Ireland, the National Drug Treatment Centre (NDTC) tested 425 opioid substitution clients for pregabalin in 2014 following requests from health professionals concerned about misuse of this drug.8 In all, there were 498 samples across seven different clinics: 8.8% of samples tested positive, equivalent to 39 of 425 clients (9.2%) testing positive. Only 10 (10/39, 25.6%) clients were known to have been prescribed pregabalin.

Of those clients who tested positive for pregabalin, the average age was 38 years and the majority (59%) were female. Also published in 2014 was a case study of an individual with a history of drug misuse and dual diagnosis of mental illness who misused pregabalin.9

Risks associated with overdose

A known side-effect of pregabalin and gabapentin is central nervous system depression (ranging from sleepiness and drowsiness to difficulty breathing, coma and death). The literature suggests that potential risks of serious side-effects are greater for pregabalin than for gabapentin, although fatal overdose from either alone is thought to be very rare.5,7 However, users prescribed the drugs are specifically advised not to take them with other drugs that may also negatively affect the central nervous system, such as opioids, benzodiazepines or alcohol. This is because they may interact together and have an additive effect, which in turn may increase the risk and severity of the serious side-effects, including death.

In Ireland, a recent study (see page 00) found that the annual number of intentional drug overdoses involving gabapentinoids, mainly pregabalin, increased year on year from 0.5% in 2007 to 5.5% in 2015.10 The majority were women (59.9%), with a median age of 37 years (74.6% were aged 24‒54 years). Over one-half (52.4%) involved multiple drugs, while over one-third (37.2%) involved alcohol. However, history of drug misuse or dependence was unknown.

Fatal overdose

Fatal overdoses related to gabapentinoids, mostly pregabalin, have been reported from the US, Finland, Sweden, Germany and the UK in the literature.5,6,7 These deaths appear to be almost always in combination with other drugs. The numbers of fatal overdoses reported have increased over the past decade. Of note, in the US where pregabalin has been controlled since 2005, gabapentin is more commonly implicated in fatal overdoses.5

The National Drug-Related Deaths Index is a census of all drug-related deaths in Ireland. Pregabalin has been implicated in fatal overdoses since 2009, although initially in small numbers (less than five per year).11 The first significant increase was observed in 2013, with 14 deaths recorded where pregabalin was implicated. However, between 2014 and 2015, the number of deaths where pregabalin was implicated had increased by 69%, from 26 to 44. Of note, pregabalin has only been routinely screened for in postmortem toxicology in Ireland since 2013.

Summary

The evidence from Ireland, however limited, does mirror the available international literature on the risks of pregabalin and gabapentin. A factsheet12 has been produced and there has been a call to consider making pregabalin a controlled drug.13

In 2014, the UK government issued advice for prescribers on the potential risk of misuse of both pregabalin and gabapentin.14 It advises caution in particular when considering prescribing a gabapentinoid to a person with a known history of drug misuse or dependence. However, this should not preclude them prescribing the medication if the benefit outweighs the risk. In Ireland, the patient factsheet on pregabalin, under warnings and precautions, urges patients to inform their doctor if they have a history of alcohol or drug dependence, or misuse of drugs before starting the medication.15 In 2017, the UK government commenced the process to make both pregabalin and gabapentin controlled drugs in response to concerns raised.16, 17

1    European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) (2010) Annual report 2010: the state of the drugs problem in Europe: new drugs and emerging trends. Available online at: https://www.drugsandalcohol.ie/14182/2       Gahr M, Freudenmann RW, Hiemke C, Kölle MA and Schönfeldt-Lecuona C (2013) Pregabalin abuse and dependence in Germany: results from a database query. Eur J Clin Pharmacol, 69(6): 1335‒42.

3    Federal Register (2005), Vol. 70, No. 144 / Thursday, July 28, 2005 / Rules and Regulations 43633. Washington DC: Office of the Federal Register. Available online at: https://www.gpo.gov/fdsys/pkg/FR-2005-07-28/pdf/05-15036.pdf

4    Irish Medicines Board (2003) Guidance note for medical professionals, June 2003. Dublin: Irish Medicines Board. Available online at: https://www.hpra.ie/docs/default-source/publications-forms/newsletters/drug-safety-newsletter-issue-no-17-june-2003-(guidance).pdf?Status=Master&sfvrsn=2

5    Bonnet U and Scherbaum N (2017) How addictive are gabapentin and pregabalin? A systematic review. Eur Neuropsychopharmacol, 27(12): 1185‒215.

6    Lyndon A, Audrey S, Wells C, Burnell ES, Ingle S, Hill R, et al. (2017) Risk to heroin users of polydrug use of pregabalin or gabapentin. Addiction 112: 1580‒589.

7    Evoy KE, Morrison MD and Saklad SR (2017) Abuse and misuse of pregabalin and gabapentin. Drugs, 77(4): 403‒26.

8    McNamara S, Stokes S, Kilduff R and Shine A (2015) Pregabalin abuse amongst opioid substitution treatment patients. Ir Med J, 108(10): 309‒10. https://www.drugsandalcohol.ie/24965/

9    Osman M and Casey P (2014) Pregabalin abuse for enhancing sexual performance: case discussion and literature review. Ir J Psychol Med, 31(4): 281‒86. https://www.drugsandalcohol.ie/22563/

10  Daly C, Griffin E, Ashcroft DM, Webb RT, Perry IJ and Arensman E (2018) Intentional drug overdose involving pregabalin and gabapentin: findings from the National Self-Harm Registry Ireland, 2007‒2015. Clin Drug Investig, 38(4): 373‒380. https://www.drugsandalcohol.ie/28436/

11  Health Research Board (2017) National Drug-Related Deaths Index 2004 to 2015 data. Dublin: Health Research Board. https://www.drugsandalcohol.ie/28086/

12  Ana Liffey Drug Project (2018) Pregabalin fact sheet. Dublin: Ana Liffey Drug Project. Available online at: http://www.drugs.ie/pregabalin

13  Corrigan D (2016) Concern increasing over the emergence of pregabalin as a drug of abuse. Irish Pharmacist, 18(3): 20. https://www.drugsandalcohol.ie/26786/

14  Public Health England and NHS England (2014) Pregabalin and gabapentin: advice for prescribers on the risk of misuse. Available online at: https://www.gov.uk/government/publications/pregabalin-and-gabapentin-advice-for-prescribers-on-the-risk-of-misuse

15 Wockhardt UK Ltd (2017) Package leafl­et: information for the user: pregabalin. Available online at: https://www.hpra.ie/img/uploaded/swedocuments/PIL-2192445-31082017145017-636397878185312500.pdf

16  Advisory Council on the Misuse of Drugs (2016) Letter to Minister for Preventing Abuse and Exploitation re pregabalin and gabapentin advice. London: Advisory Council on the Misuse of Drugs. Available online at: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/491854/ACMD_Advice_-_Pregabalin_and_gabapentin.pdf

17  UK Home Office (2017) Closed consultation: pregabalin and gabapentin: proposal to schedule under the Misuse of Drugs Regulations 2001. London: Home Office. Available online at: https://www.gov.uk/government/consultations/pregabalin-and-gabapentin-proposal-to-schedule-under-the-misuse-of-drugs-regulations-2001