THERAPY FOCUS ■ Guide to the management of gabapentinoid misuse GRAHAM PARSONS In light of the SPL government’s proposals to reclassify pregabalin and gabapentin as Class C controlled drugs 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 seizure 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 gabapentinoids 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 epilepsy.3,4 Pregabalin also has concern led to the government launch­ a licence for the treatment of generalised ing a consultation on the reclassification anxiety disorder (GAD).3 Pregabalin is of pregabalin and gabapentin as Class recommended by NICE as a second­line 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, duloxetine, 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 neuralgia).6 Off­ potential than gabapentin. It explores the label uses for gabapentinoids include prescriber.co.uk Prescriber April 2018 ❚ 25 ■ THERAPY FOCUS l Gabapentinoid misuse the treatment of migraine, alcohol use • Presenting intoxicated, impaired or dishevelled (especially if this is a change to disorders, mania and bipolar disorder.7 the normal presentation) NICE recommends early and regu­ • Loss of interest in alternative pleasures or activities (the medication 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 out­of­hours 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 gamma­aminobutyric acid (GABA) and rapidly cross the blood­brain Table 1. Markers for potential misuse of gabapentinoids barrier. The gabapentinoids bind to the alpha­2­delta subunit of the voltage­de­ 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 excretion with drugs can also be a problem – as demon­ neurotransmitters glutamate, noradrena­ an elimination half­life of between five to strated in a case report describing the line, substance P and calcitonin gene­re­ 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 non­pre­ inhibitory neurotransmitter GABA, ie they Gabapentinoids have been reported to scribed drugs including methadone.7,8,10 exhibit GABA­mimetic properties. produce alcohol/gamma hydroxybutyrate Animal models also support the hypoth­ Pregabalin is rapidly absorbed on (GHB)/benzodiazepine­type effects esis that the effects of morphine and an empty stomach with peak plasma mixed with euphoria. 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 bioavailability (≥90%) 12% but this has been for therapeutic The onset of action of the gabapenti­ and a mean elimination half­life of 6.3 doses.8 Other reported actions include noids ranges from between 10 minutes, hours and undergoes almost no metab­ dissociative effects, improved sociability, ie quick acting, and two hours depend­ olism with the parent drug being largely relaxation and sense of calm, and psy­ ing on the route of administration and excreted unchanged in the urine. The chedelic effects. both dependent and recreational use linear pharmacokinetics of pregabalin Schifano et al. reported that signifi­ has been reported. Rapid development (compared with the non­linear 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 potency (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 drug­related 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 Addiction suggests that pregabalin gabapentinoids both in the UK and inter­ ing oral administration is less rapid than is used to enhance the effects of heroin 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 Medicines and Healthcare products increasing dose. Absolute bioavaila­ be used to reduce the amount of heroin Regulatory Agency (MHRA) received its 26 ❚ Prescriber April 2018 prescriber.co.uk Gabapentinoid misuse l THERAPY FOCUS ■ 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 depressant effects of the gaba­ alterations/hallucinations, double and blurred vision, uninhibited behaviours, pentinoids and opioids (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 drug­related 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 dextromethorphan/DXM­like drug­related 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,