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Home , Gabapentinoid, Pregabalin

THERAPY FOCUS ■

Guide to the management of misuse

GRAHAM PARSONS

In light of the SPL government’s proposals to reclassify and as Class C controlled due to the risk of misuse, this article examines the extent of the problem of gabapentinoid misuse and its effects, and provides practical advice to prescribers on reducing these harms.

regabalin was launched in the UK Pin 2004 while gabapentin was first authorised in the UK in 1997. Both drugs were originally licensed for dis­ orders but now have multiple licensed indications. In England during 2016, over current (licensed and unlicensed) indica­ 12 million prescription items were dis­ tions and the pharmacology of the two pensed for as a group.1 drugs, aspects of their misuse potential The Advisory Council on the Misuse of and effects of this misuse on the indi­ Drugs (ACMD) reported that pregabalin vidual. Finally, it provides advice for prescribing in the UK increased by 350% prescribers on managing the misuse of in the five years to 2012 while gabapen­ gabapentinoids and supporting patients tin prescribing increased by 150% during who are discontinuing a gabapentinoid. the same period.2 There has been growing concern Licensed uses about the misuse potential of the gaba­ The gabapentinoids have a wide range pentinoids as a group and in particular of licensed uses. Pregabalin and gaba­ pregabalin, as reported in the 2016 pentin are both licensed for neuropathic ACMD review of this class of drugs.2 This pain and .3,4 Pregabalin also has concern led to the government launch­ a licence for the treatment of generalised ing a consultation on the reclassification disorder (GAD).3 Pregabalin is of pregabalin and gabapentin as Class recommended by NICE as a second-line C controlled drugs under the Misuse of pharmacotherapy for GAD if a patient Drugs Act, which ended on 22 January cannot tolerate SSRIs or SNRIs.5 NICE 2018.1 recommends offering a choice of amitrip­ This article discusses both drugs but tyline, , gabapentin or pregab­ with a particular emphasis on pregaba­ alin as initial treatment for neuropathic lin, which presents with a greater misuse pain (except trigeminal ).6 Off- potential than gabapentin. It explores the label uses for gabapentinoids include

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the treatment of , use • Presenting intoxicated, impaired or dishevelled (especially if this is a change to disorders, and .7 the normal presentation) NICE recommends early and regu­ • Loss of interest in alternative pleasures or activities (the becomes lar assessments of patients prescribed the focus) pharmacotherapies for neuropathic • Early requests for prescriptions pain, including the gabapentinoids. The • ‘Lost’ prescriptions assessment should include dosage titra­ • Increasing use of current prescription due to unsanctioned dose increases tion, tolerability and adverse effects.6 • Concurrent misuse of related illicit drugs While markers for potential misuse (see • Acquisition of medication from other sources, eg out-of-hours services Table 1) may emerge later in treatment, • Subjective and objective withdrawals when the patient does not have the medication prescribers should always be alert to • No interest in the diagnosis (the medication becomes the focus) these even at the start of a treatment • Failure to keep appointments for further diagnostic tests or refusal to see episode so that misuse can be avoided. another practitioner for consultation • Worsening mental health presentation Pharmacology • Aggressive complaining Both gabapentin and pregabalin are • Reporting unintended psychotropic effects from prescription medication structurally similar to the inhibitory neu­ • Prescription forgery rotransmitter gamma-aminobutyric­ acid (GABA) and rapidly cross the blood- Table 1. Markers for potential misuse of gabapentinoids barrier. The gabapentinoids bind to the alpha-2-delta subunit of the voltage-de­ bility is reported as 60% for a 300mg needed to provide a similar psychoactive pendent calcium channels in the CNS capsule.4 Gabapentin is also eliminated effect. Mixed misuse with antipsychotic resulting in a decrease in the excitatory unchanged through renal with drugs can also be a problem – as demon­ glutamate, noradrena­ an elimination half-life of between five to strated in a case report describing the line, substance P and calcitonin gene-re­ seven hours.4 misuse of gabapentin and quetiapine.9 lated peptide. Both drugs produce Pregabalin and gabapentin have also pharmacological effects that are sim­ Why are gabapentinoids been used to enhance the effects of ilar in nature to those produced by the misused? alcohol and other prescribed and non-pre­ inhibitory GABA, ie they Gabapentinoids have been reported to scribed drugs including .7,8,10 exhibit GABA-mimetic properties. produce alcohol/gamma hydroxybutyrate Animal models also support the hypoth­ Pregabalin is rapidly absorbed on (GHB)/-type effects esis that the effects of and an empty stomach with peak plasma mixed with . Rates of euphoria pregabalin are potentiated when taken concentrations occurring within one have been reported at between 1 and together. hour. It has a high (≥90%) 12% but this has been for therapeutic The of the gabapenti­ and a mean elimination half-life of 6.3 doses.8 Other reported actions include noids ranges from between 10 minutes, hours and undergoes almost no metab­ effects, improved sociability, ie quick acting, and two hours depend­ olism with the parent being largely relaxation and sense of calm, and psy­ ing on the route of administration and excreted unchanged in the . The chedelic effects. both dependent and recreational use linear of pregabalin Schifano et al. reported that signifi­ has been reported. Rapid development (compared with the non-linear phar­ cant psychotropic effects are associated and extinction of tolerance to the effects macokinetics of gabapentin) allows with higher doses and “idiosyncratic (ie of gabapentinoids has also been docu­ straightforward dosing regimens and a IV, rectal, intranasal) drug intake modali­ mented.11 predictable response. Pregabalin also ties” but the most common route of mis­ The effects associated with pregab­ has a higher binding efficiency than gaba­ use remains oral.8 alin at increasing doses, as reported by pentin and higher (2.5 times Polydrug misuse remains a signifi­ users, is summarised in Box 1. greater than gabapentin). The higher cant concern with the cohort of service potency, quicker absorption and greater users that may misuse gabapentinoids Evidence for and prevalence of availability of pregabalin vs gabapentin and has been implicated in the recent gabapentinoid misuse makes pregabalin more attractive as a rise in drug-related deaths for the gaba­ There is now a rich source of anecdotal drug of misuse pentinoids. A recent review in the jour­ reports that support significant misuse of The absorption of gabapentin follow­ nal suggests that pregabalin gabapentinoids both in the UK and inter­ ing oral administration is less rapid than is used to enhance the effects of nationally, such as the user reports on pregabalin. Peak plasma concentrations but for some people it may also be used the Erowid website.12 Following the intro­ are observed within two to three hours to help support the reduction in use of duction of pregabalin to the UK in 2004, with oral bioavailability decreasing with heroin.7 This synergistic effect can also the and Healthcare products increasing dose. Absolute bioavaila­ be used to reduce the amount of heroin Regulatory Agency (MHRA) received its

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which increased to 15–22% within “opi­ According to pregabalin (mis)users, different doses are associated with a vast oid abuse samples”.18 range of effects: Drug-related deaths and 600mg: stumbling, disorientation, increased physical and psychological gabapentinoid misuse awareness, difficulty driving, slurred and broken speech, hearing and visual The CNS effects of the gaba­ alterations/hallucinations, double and blurred vision, uninhibited behaviours, pentinoids and (drowsiness, talkativeness, increased body energy, increased sexual performance respiratory depression and respiratory failure) are a significant risk and have 900mg: strong feelings of drunkenness, difficulty walking, alteration of colour been implicated in drug-related deaths. perception, little euphoria Deaths where gabapentinoids were men­ tioned on death certificates in England 1200mg: drowsiness, euphoria, entactogenic (empathetic) feelings, ie similar to and Wales have increased from less than Ecstasy one a year before 2009 to 137 deaths in 2015.7 In 79% of these deaths, opioids >1500mg (to 5g): uncontrollable drowsiness, frequent hallucinations, great were also mentioned. This increase in euphoria, frequent dissociative events (described as /DXM-like drug-related deaths was also shown to dissociative effects), behavioural inhibition, anxiety, and necessity to move correlate highly with prescribing data, ie increased prescribing of gabapentinoids Box 1. Online user accounts of pregabalin effects, according to dose8 (see Figure 1). first report of withdrawal symptoms in of patients with a history of drug or sub­ In summary, we have the “perfect 2005. Following this, the first report of stance abuse.3,4 storm” of the summation of CNS effects drug use disorder was reported in 2006 International reports from Finland, through polydrug misuse, an increase in and drug dependence in 2009.13 Germany and the USA suggest a global prescription numbers, and drug effects Evidence from UK secure settings problem with gabapentinoid misuse. In that cannot be reversed with an antidote suggests significant use of gabapenti­ Finland, a study of toxicology reports of (although naloxone will support the rever­ noids. Prescribing of gabapentin and drug-related deaths between 2010 and sal of the element of a drug over­ pregabalin occurs in 2.8% of the prison 2011 suggest a “substantial increase” dose), which all contribute to the risk of population, which is twice the rate found in drug-related deaths involving pregab­ drug-related death. in the general population. Category A alin and opioids, with opioids present in prisons having the highest rates and 47% 90% of deaths involving gabapentinoids. How can patients be supported of prisoners in this cohort are also pre­ The study also reported a seven times to discontinue gabapentinoids scribed opioid substitution treatments greater incidence of pregabalin misuse in safely? (OST).14 The ACMD has also noted that drug-related deaths compared with gaba­ Although there is insufficient evidence to the prescribing of the gabapentinoids pentin.7 In Germany, pregabalin misuse support practitioners in helping patients in secure environments often does not has been reported to the German med­ discontinue gabapentinoids, there are meet “best practice guidelines”.2 The ical regulatory body with an increasing some practical guidelines that provide Pain Management Formulary for Prisons frequency since 2008, while the USA a framework for the development of an classifies the gabapentinoids as drugs placed pregabalin under the Controlled appropriate recovery plan. Harm reduc­ for “limited use” and aims to challenge Substances Act in 2005, citing that mis­ tion also remains an important compo­ current practice and introduce a frame­ use may lead to “limited physical depend­ nent of the advice practitioners should work around the management of pain in ence or ”.2 provide to patients. secure settings.15 The prevalence of gabapentinoid Discontinuation symptoms of gaba­ The DrugScope 2014 street survey misuse has been assessed in two sys­ pentinoids are varied and will be depend­ highlighted the problem of misuse quot­ tematic reviews. An international sys­ ent on the dose consumed and the route ing “significant use… chiefly among tematic review of 59 studies indicates of administration. Table 2 summarises Britain’s -using and prison popu­ a gabapentinoid abuse prevalence of these symptoms for both gabapentin lation”.16 The effects of gabapentinoids 1.6% in the general population. This and pregabalin for patients reducing are described within the report as “hor­ prevalence increased to 3–68% among from therapeutic doses, as outlined in rendous and life threatening” with one opioid abusers. Risk factors for misuse the summaries of product characteris­ drug worker reporting the prevalence of were identified as a history of substance tics. The manufacturer of pregabalin has use in one homeless hostel at 70% of abuse (particularly opioids) and psychi­ noted that the severity of symptoms and residents.16 The manufacturers of both atric co-morbidities.17 Another system­ their incidence “may be dose-related”3 drugs have also warned prescribers of atic review looking at gabapentin only and prescribers should take this into the risk of abuse and dependence, high­ reported a 1.1% prevalence of gabap­ account when managing a pharmacologi­ lighting the need for a careful evaluation entin misuse in the general population, cal withdrawal episode. prescriber.co.uk Prescriber April 2018 ❚ 27 ■ THERAPY FOCUS l Gabapentinoid misuse

• Tight chest 120 160 • Sweating with alternate chills Gabapentinoid prescriptions (100,000s) • Inability to think or concentrate properly 140 100 Deaths mentioning pregabalin • “No energy”.

or gabapentin - related deaths Drug 120 Deaths mentioning gabapentinoids Both service users describe their with­ 80 and opioids 100 drawals from therapeutic doses of pre­ gabalin (450mg and 600mg respectively) 60 80 as “hellish”.12 60 The summaries of product character­ 40 istics suggest that both pregabalin and 40 gabapentin should be discontinued over prescriptions per 100,000 Pregabalin and gabapentin 20 at least one week. However, this is pri­ 20 marily to minimise the risk of increased 0 0 seizure frequency where they are being 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 used for patients with a seizure disorder. Year Public Health England (PHE) recommends a more gradual reduction to reduce with­ drawal symptoms.14 Considering the 5 link between dose and symptoms sug­ gested by the manufacturers, a collabo­ 4 rative and more conservative approach seems a pragmatic response. Patients on supratherapeutic doses of gaba­ 3 pentinoids should have a reduction plan discussed that allows for an illicit reduc­ 2 tion in the community. If the prescriber decides to prescribe above the maximum dose in the summary of product charac­ Log number of deaths 1 teristics, this should be for a short period of time with an aim to reduce the patient 0 to below the licensed maximum dose in a short period of time and within the 0 20 40 60 80 100 guidance provided by PHE. The maximum Gabapentinoid prescriptions (per 100,000) reduction rates suggested for the gaba­ pentinoids within the PHE guidelines are: • 50mg to 100mg a week for pregabalin Figure 1. Gabapentinoid drug-related deaths and correlation with increase in gabapentinoid and prescribing in England and Wales7 • 300mg every four days for gabapentin. A more varied presentation of with­ with akathesia, catatonia and .19 drawal symptoms has been reported in Where gabapentin was reintroduced the There is insufficient evidence to suggest the medical literature for both gabapentin withdrawal symptoms resolved. what adjuvant medication could be used and pregabalin. A review of gabapentin A case study from Grosshans et al. to support patients, so no recommenda­ misuse case studies by Mersfelder et presents the withdrawal symptomology tions can made. Nevertheless, a reduc­ al. reported withdrawal symptoms begin­ associated with pregabalin at supra­ tion in the pharmacological agent used ning between 12 hours and seven days therapeutic doses. The authors report to manage the primary indication should after cessation of use with the majority the case of a 47-year-old male consum­ necessitate a review. For example, the of cases occurring between 24 and 48 ing the equivalent of 7500mg pregabalin treatment of GAD may necessitate a hours. Agitation was reported in more daily. On reduction, the patient experi­ transition to an SSRI. This should also than half of the cases with confusion and enced sweating, unrest, arterial hyperten­ include a review of the psychosocial inter­ disorientation reported in 45% of cases. sion, tremor and craving for pregabalin.20 ventions both to support the patient in Other common symptoms included Two reports on withdrawals from pregaba­ managing the withdrawal from the gaba­ diaphoresis (36%), non-specified GI lin from the user website Erowid describe pentinoid and to support the patient in symptoms (23%), tremor, , the following: managing the presentation of the primary (each 18%) and • Insomnia, anxiety and depression indication. This may include, for example, (14%). Individual cases also presented • engagement with cognitive behavioural

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Pregabalin symptoms Gabapentin symptoms advice on the management of this ser­ vice user group. Insomnia Insomnia • Improve your knowledge as a prescriber Pains to ensure you can provide appropriate and Nausea advice and treatment when needed. This Anxiety, nervousness, depression Anxiety article and the associated references Diarrhoea Sweating should help to support your learning. Flu syndrome, pain and Convulsions Summary Pregabalin and gabapentin remain impor­ Table 2. Discontinuation symptoms for pregabalin and gabapentin withdrawal, as outlined tant evidence-based treatments for a in the summaries of product characteristics number of conditions. However, emerg­ therapy services for supporting patients • If a gabapentinoid is used for neuro­ ing evidence suggests that prescribers in the management of their GAD. pathic pain, review at eight weeks follow­ should adopt a cautious approach to ing initiation and discontinue (gradually) the assessment and management of Practical advice for prescribers if ineffective. patients who are prescribed gabapen­ To prevent the emergence of problems • Misuse of any psychoactive medication tinoids. Both misuse and dependence and to support patients in reducing harm is often linked to either a mental health have been reported with gabapentinoids, associated with the misuse of gaba­ co-morbidity and/or inadequate man­ and they have been widely implicated in a pentinoids, some practical steps can be agement of the primary physical health number of drug-related deaths. employed. These practical advice tips presentation. Ensure this is reviewed and Prescribers should make a balanced have been brought together from a vari­ managed appropriately especially if the judgement on prescribing gabapentinoids ety of sources. An excellent document gabapentinoid is removed from the phar­ based on a robust assessment process, supported by the Northern Ireland Public macotherapies available. especially when prescribing to patients Health Agency – Pregabalin: Guidance • advice for illicit users who may be at risk of misusing the medi­ for People Working with Pregabalin should include advice to take the medica­ cations. Patients should be provided with Users – is available,21 which provides tion orally and avoid injecting, and to fol­ information about the benefits and risks more comprehensive advice, especially low the adage of “start low and go slow”. of taking gabapentinoids and should be around harm reduction, for patients mis­ The dangers of polydrug use, including supported if they want to undertake a using pregabalin. the increased risk of drug-related death, detoxification programme. Harm reduc­ • Ensure a robust assessment process is should also be discussed. tion interventions remain an important undertaken and careful consideration is • Ensure naloxone (Prenoxad injection) approach to this complex phenomenon. given before prescribing gabapentinoids is issued to service users who also use to patients with a history of substance opioids (and provide advice on its use References misuse or those who have recently been as well as basic harm reduction advice). 1. Home Office. Pregabalin and gabapentin: released from prison. Use an alternative Many drug and alcohol specialist provid­ proposal to schedule under the Misuse of medication when clinically appropriate. ers now supply this routinely to service Drugs Regulations 2001. Closed consultation. • When gabapentinoids are prescribed, users who misuse opioids – contact your November 2017. Available from: https://www. warn patients about the benefits and local provider for more details. gov.uk/government/consultations/pregabalin- and-gabapentin-proposal-to-schedule-un­ risks (including dependence) of the med­ • When supporting service users with a der-the-misuse-of-drugs-regulations-2001. ications. planned reduction in gabapentinoid use, 2. Advisory Council on the Misuse of Drugs • Review treatment regularly to ensure use the schedules recommended by PHE (ACMD). Pregabalin and gabapentin advice. efficacious prescribing and monitor for to plan a collaborative process. January 2016. Available from: https:// potential misuse markers (see Table 1). • Be aware of services such as the Battle www.gov.uk/government/uploads/system/ • Ensure prescribed doses do not exceed Against Tranquilisers (BAT), who provide uploads/attachment_data/file/491854/ the therapeutic dose ranges (doses will support for service users with pregaba­ ACMD_Advice_-_Pregabalin_and_gabapentin. also need to be adjusted in patients with lin use disorders in the Bristol area,22 as pdf [accessed 3 February 2018]. reduced renal function). well as nationally through their website 3. eMC. Lyrica Capsules 25mg, 50mg, 75mg, • If there is a clinical need to prescribe and national support helpline. UK SMART 100mg, 150mg, 200mg, 225mg and 300mg. a gabapentinoid to a service user with a Recovery® also provides support for indi­ Available from: https://www.medicines. org.uk/emc/medicine/14651 [accessed 3 history of drug or alcohol misuse, ensure viduals who want to seek abstinence February 2018]. that it is prescribed as regular short from drug misuse through a network of 4. eMC. Neurontin 100mg Hard Capsules. 23 courses, eg every seven days, rather self-help and mutual aid meetings. If Available from: https://www.medicines.org. than the standard 28-day prescription to you need support, please speak to your uk/emc/product/158 [accessed 3 February improve monitoring for overuse and to local specialist drug and alcohol provider 2018]. minimise the risk of binge use. who can also give practical support and 5. National Institute for Health and Care prescriber.co.uk Prescriber April 2018 ❚ 29 ■ THERAPY FOCUS l Gabapentinoid misuse

Excellence. Generalised anxiety disor- Dependence Update 2017 Independent January 2015. Available from: http:// der and in adults: manage- Expert Working Group. Drug misuse and www.sfad.org.uk/userfiles/files/ ment. CG113. January 2011. Available dependence: UK guidelines on clinical man- DownAStonyRoadDrugTrendsSurvey2014.pdf from: https://www.nice.org.uk/guidance/ agement. London: Department of Health, [accessed 3 February 2018]. cg113/resources/generalised-anxiety- July 2017. Available from: https://www.gov. 17. Evoy KE, et al. Abuse and misuse of disorder-and-panic-disorder-in-adults-manage­ uk/government/uploads/system/uploads/ pregabalin and gabapentin. Drugs 2017; ment-pdf-35109387756997 [accessed 13 attachment_data/file/673978/clinical_ 77(4):403–26. February 2018]. guidelines_2017.pdf 18. Smith RV, et al. Gabapentin misuse, abuse 6. National Institute for Health and Care 12. Erowid. Documenting the complex rela­ and diversion: a systematic review. Addiction Excellence. in adults: phar- tionship between humans and psychoac­ 2016;111(7):1160–74. macological management in non-specialist tives. Available at: https://www.erowid.org/ 19. Mersfelder TL, Nichols WH. Gabapentin: settings. CG173. November 2013. Available [accessed 13 February 2018]. abuse, dependence and withdrawal. Annals of from: https://www.nice.org.uk/guidance/ 13. Medicines and Healthcare products Pharmacotherapy 2016;50(3):229–33. cg173/resources/neuropathic-pain-in-adults- Regulatory agency (MHRA). Interactive drug 20. Grosshans M, et al. Pregabalin abuse, pharmacological-management-in- analysis profile. Pregabalin. Available from: dependence, and withdrawal: a case report. nonspecialist-settings-pdf-35109750554053 https://info.mhra.gov.uk/drug-analysis- Am J Psychiatry 2010;167(7):869. [accessed 13 February 2018]. profiles/dap.html?drug=./UK_EXTERNAL/ 21. Extern. Pregabalin: Guidance for people 7. Lyndon A, et al. Risk to heroin users of NONCOMBINED/UK_NON_000416710145. working with pregabalin users. Available from: polydrug use of pregabalin or gabapentin. zip&agency=MHRA [accessed 3 February http://www.extern.org/sites/default/files/ Addiction 2017;112(9):1580–9. 2018]. news_docs/pregabalin_guidance_booklet_ 8. Schifano F, et al. Is there a recreational 14. Public Health England, NHS England. a4_final_web.pdf potential for pregabalin? Analysis of anecdo­ Advice for prescribers on the risk of the mis­ 22. Battle Against Tranquillisers (BAT). tal online reports in comparison with related use of pregabalin and gabapentin. December Available at: http://bataid.org/ gabapentin and data. 2011. 2014. Available from: https://www.gov.uk/ 23. UK SMART Recovery®. Self-management Available from: https://uhra.herts.ac.uk/ government/uploads/system/uploads/ and recovery training. Available at: https:// bitstream/handle/2299/9328/905139. attachment_data/file/385791/PHE-NHS_ www.smartrecovery.org.uk/ pdf?sequence=1 [accessed 13 February England_pregabalin_and_gabapentin_advice_ 2018]. Dec_2014.pdf [accessed 3 February 2018]. Declaration of interests 9. Reeves RR, Burke RS. Abuse of combi­ 15. NHS England. Pain management formu- Graham Parsons has received funding nations of gabapentin and quetiapine. Prim lary for prisons: The formulary for acute, per- from Martindale Pharma to provide edu­ Care Companion CNS Disord 2014;16(5), doi: sistent and neuropathic pain, 2nd edn. October cational talks at conferences and from 10.4088/PCC.14I01660. 2017. Available from: https://www.england. Indivior to attend a conference. 10. Baird CRW, et al. Gabapentinoid abuse in nhs.uk/wp-content/uploads/2017/11/ order to potentiate the effect of methadone: a prison-pain-management-formulary.pdf survey among substance misusers. Eur Addict [accessed 3 February 2018]. Graham Parsons is chielf pharmacist and Res 2014;20:115–8. 16. DrugScope. Down a stony road: The pharmacist independent prescriber at 11. Clinical Guidelines on Drug Misuse and 2014 Drug Scope Street Drug Survey. Turning Point, London

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