Managing the misuse potential and risk of psychological harm from gabapentinoids in primary care in New Zealand

Keywords: Pregabalin; gabapentin; general practice; prescribing.

Gabapentinoids are a class of drugs including pregabalin and gabapentin, originally indicated for the treatment of epilepsy. Pregabalin became fully subsidised without restriction in New Zealand in 2018. Prior to this, gabapentin was the only subsidised gabapentinoid. Gabapentinoid dispensing grew steadily before pregabalin became subsidised;¹ and has since accelerated (Figure 1).

Figure 1.  Trends in gabapentinoid dispensing in New Zealand from Q1 2016 to Q2 2021 show an increasing trend in dispensing following the subsidisation of pregabalin in 2018. Data sourced from the Ministry of Health National Pharmaceutical Data Warehouse (accessed November 2021).⁶²

Approved indications for gabapentinoids in New Zealand are partial seizures and neuropathic pain,^2,3 although findings of benefit for the latter are inconsistent and many patients will have no benefit and discontinue treatment.⁴ There are also several common ‘off label’ (unapproved) uses, including generalised anxiety disorder.^5,6 Evidence of efficacy is limited for some of these unapproved uses.⁷ Despite the limited evidence of benefit for non-neuropathic pain, gabapentinoid prescribing for this unapproved indication has increased.^8,9 The movement away from prescribing opioids in pain syndromes⁸ has left prescribers with a therapeutic gap, potentially contributing to this increase.

Internationally, in recent years, there have been significant increases in gabapentinoid prescribing, particularly of pregabalin, which has been associated with increasing harms, including misuse, dependence, overdose, and suicidal thoughts or behaviours.^10–12 Extra-medical use (use without a prescription or not as directed by a prescriber) has been observed, particularly in high-risk and vulnerable populations.^13,14 Dependence is a harm of concern in people using gabapentinoids medically and extra-medically, with evidence of euphoria during high-dose use and withdrawal symptoms.^15,16 Pregabalin may be more addictive than gabapentin, but appears to be less addictive than opioids and benzodiazepines.¹⁵ Concern has grown internationally over the increase in drug-induced deaths (both intentional and unintentional) involving gabapentinoids.^17,18 Although gabapentinoids alone are rarely detected post-mortem following overdose, concurrent use with other central nervous system depressants (particularly opioids, benzodiazepines, and alcohol) is frequently identified, and may additively increase overdose mortality risk.^19,20 New onset or worsening suicidal thoughts or behaviours and depression have also emerged as possible harms associated with gabapentinoid use.^21,22

With increasing awareness of the potential harms of gabapentinoids and limited effectiveness for some indications, prescribers need to be aware of how to identify patients who may be at greater risk of harm from gabapentinoids, how to monitor for increased harm, and when and how to discontinue these drugs. Discontinuing gabapentinoids may be associated with withdrawal symptoms,^15,23 and as discontinuation rates are high,^24,25 prescribers are likely to face this issue. A 2018 review outlined the misuse potential of pregabalin in New Zealand,²⁶ but currently there is limited clinical guidance for prescribers on managing harms broader than misuse; a gap this paper aims to fill.

There is no specific screening process to identify gabapentinoid-related harms; however, a systematic review undertaken in 2017 identified young age, current or past opioid misuse, previous substance use disorder, psychiatric co-morbidity, and low income as risk factors for misuse.²⁷ Since 2017, there has been a substantial increase in research examining gabapentinoid-related harms that are broader than misuse. International studies have been undertaken both at a population-level^{10,11,22,28–32} and in high-risk cohorts including people who use drugs,^33,34 people with bipolar disorder,³⁵ people with opioid use disorder,^14,36,37 and in people who experience non-fatal^17,38 and fatal^18,39–41 overdoses; however, we could not identify any studies specifically conducted in a primary care context.

From these studies, we identified three factors that prescribers can use to screen for patients who may be at greater risk of harm from gabapentinoids:

1. Psychiatric history or co-morbidity (including suicidal thoughts or behaviour). Multiple studies have identified this risk factor^{10,11,14,22,28,29,35} and because of the potential for gabapentinoids to increase suicide risk,^22,28 particular caution needs to be taken with patients who have a history of suicidal thoughts or behaviours.

2. Historical or concurrent substance use disorder. People with a historical or current substance use disorder (particularly opioid use disorder) are over-represented in gabapentinoid-related harms,^{10,22,29,30,32,33,36,37,41} and both gabapentin and pregabalin have been implicated in abuse-related adverse events.³²

3. Concurrent use of other sedative medications, particularly opioids and benzodiazepines. Use of other sedative medications increases the risk of harm, particularly overdose mortality.^{10,11,18,30,31,33,34,37–41} This is of particular concern for patients who may misuse gabapentinoids to enhance the effects of opioids.^33,34

Misuse of gabapentinoids appears to be more common in younger people,^10,22,29 whereas people in middle-age are at greater risk of overdose-related harms.^17,31 Sex does not appear to be a strong factor for predicting harm, with conflicting findings from different studies.^{17,22,23,40,42}

Gabapentinoid misuse typically involves supra-therapeutic doses, so monitoring for dose escalation and development of tolerance are important to identify gabapentinoid use for reinforcing or pleasurable effects.²⁷ Prescribers should also be alert to requests for other sedative medications. Gabapentinoid use is associated with suicide, although there is no current consensus on whether the link is causal.^22,28,43,44 This association is stronger with pregabalin than gabapentin,²² which in some cases is not explained by suicidal behaviour or predisposition to psychiatric disorder before treatment initiation.²⁸ Prescribers should therefore also monitor for mood changes or suicidal thoughts or behaviours emerging or worsening in patients using gabapentinoids, particularly pregabalin.

Currently, tapering is the only intervention that can be identified from the literature for gabapentinoids. Three randomised controlled trials (RCTs) of pregabalin for generalised anxiety disorder describe a tapering protocol and the tolerability and effects of that protocol;^45–47 however, these studies assessed tapering for people taking therapeutic doses of pregabalin (ranging from 150–600 mg/day) for relatively short time periods, and were not designed to investigate tapering for someone dependent on gabapentinoids or using supra-therapeutic doses. All three studies found that a week-long taper of pregabalin was well tolerated for doses up to 600 mg/day.^45–47 Two of these studies reported withdrawal symptoms including anxiety or nervousness, headache, insomnia and irritability,^45,46 which occurred in approximately one-third of patients following a 12-week treatment period.⁴⁶ No RCTs of tapering versus abrupt cessation, or of different tapering protocols, were identified.

Although this evidence suggests that a 1-week taper is tolerated,^45–47 this is based on a small number of studies, none of which were designed to assess an optimal approach to tapering. This timing has been reflected in clinical guidance,^2,48 although other sources provide an alternate tapering protocol of a maximum reduction rate of 50–100 mg a week for pregabalin and 300 mg every 4 days for gabapentin.^49,50 During discontinuation, patients should be monitored for withdrawal symptoms including anxiety, irritability, insomnia, depression and pain (including headache),^45,46,51 which may develop even with tapering.^45,46,52,53 A case of a patient with no seizure history who had a generalised seizure on gabapentinoid withdrawal has been reported,⁵⁴ but this appears to be a rare outcome. There is no evidence to suggest that adjunctive treatment with benzodiazepines will attenuate gabapentinoid withdrawal,⁵¹ and concurrent use may increase risk of harm.¹⁰ There is currently no evidence for adjunctive treatment to support patients through gabapentinoid withdrawal.⁴⁹

Any changes to gabapentinoid prescribing practices must consider the health equity implications, particularly in respect to Te Tiriti o Waitangi. The prevalence of chronic pain is not evenly distributed across the New Zealand population, and is more common in people experiencing more socioeconomic deprivation.⁵⁵ Additionally, the most commonly reported physical disorder in Māori is chronic pain, and among Māori with any 12-month mental health disorder, almost 50% report co-morbid chronic pain.⁵⁶ A recent study of kaiāwhina (Māori community health workers) perspectives found that Māori have significant unmet need for pain management approaches that are culturally responsive and that treatment of chronic pain in primary care relies heavily on medication-based approaches.⁵⁷ This is reflected in prescribing data, with older Māori more likely to be prescribed strong opioids than non-Māori of the same age.⁵⁸ These findings present both a challenge and an opportunity. A challenge, in that if Māori are more likely to meet the screening factors discussed above, there may be a widening of the therapeutic gap in relation to treatment of chronic pain. However, there is an opportunity to develop and improve non-pharmaceutical pain management approaches by and for Māori that are culturally responsive.

To date, there has been no research into gabapentinoid prescribing and harms specifically in New Zealand. This gap could be addressed by studies at a population level, and in high-risk cohorts. Research should focus on primary care contexts, and could seek to validate the screening factors described, as well as improving understanding of prescribing practices and clinical decision-making in relation to gabapentinoid prescribing. Data linkage studies may be particularly useful to better understand gabapentinoid prescribing patterns in New Zealand.

More evidence is required to validate tapering protocols in different populations and with varied doses of gabapentinoids, including management of withdrawal symptoms. Beyond tapering, there is currently no evidence for interventions to address gabapentinoid-related harms, or on when referral for further treatment should occur. Research should focus on brief interventions utilised for other substance use disorders, particularly pharmaceutical opioids and benzodiazepines, for potential efficacy with gabapentinoids. These could include psychological interventions, motivational interviewing, or cognitive behavioural therapy,⁵⁹ which could be employed alongside tapering. Filling these knowledge gaps may enable the development of a screening, brief intervention, referral to treatment (SBIRT)^60,61 framework for gabapentinoids. We suggest there is sufficient evidence to populate the screening component of this model, but there is limited evidence for relevant brief interventions or referral to treatment.

In New Zealand, gabapentinoid dispensing continues to increase, primarily driven by pregabalin,⁶² and with it, the risk of harms including misuse, overdose, and suicidal thoughts or behaviours.^10–12 Although gabapentinoids will be of benefit to some patients, others will experience harms or need to discontinue their use. Therefore, we have sought to provide prescribers with clear guidance on managing the risks associated with gabapentinoid prescribing. Through screening, potential harm from gabapentinoid prescribing can be reduced for high-risk patients in primary care, but further research is needed for effective interventions, improved guidance on tapering, and when referral for further treatment may be warranted.

The authors declare no competing interests for this study. Author RC has previously received funding as an untied educational grant from Seqirus for a project unrelated to this work.

This article did not receive any specific funding and was conducted as a Trainee Intern student project at the University of Otago.

The primary data source for this paper was published academic literature. The data used to create Figure 1 are available from the National Pharmaceutical Data Warehouse (https://www.health.govt.nz/nz-health-statistics/national-collections-and-surveys/collections/pharmaceutical-collection).