Gabapentinoids: repeating mistakes of the past?

Gabapentinoid abuse and harms are increasing proportional to increased prescribing. Despite early indicators of problems and similar patterns with other drugs, regulatory controls over promotion and availability were introduced only after significant harms. Prescribers and consumers need new regulatory approaches to support quality use of high-risk medicines. The gabapentinoids, pregabalin and gabapentin, are blockbuster drugs. Since Food and Drug Administration (FDA) approval in 2004, sales of pregabalin rocketed to rank 10th of global pharmaceutical sales at just over 5 billion US dollars in 2018, and have continued to grow at approximately 3% per annum [1]. However, their commercial success is not paralleled by safe, judicious and cost-effective use of these medicines. They are registered in various countries for the treatment of epilepsy, neuropathic pain and fibromyalgia, and pregabalin for generalized anxiety disorder in Europe [1, 2]. Use far exceeds the prevalence of these conditions in the community [3]. Gabapentinoids are frequently prescribed off-label for various pain conditions where there is minimal evidence of effectiveness, and so harms outweigh benefits [3]. Harms from misuse are also increasingly recognized [2]. Exploring the epidemiology and evolution of this reveals some uncomfortable truths. Gabapentin and pregabalin misuse occurs commonly in combination with other sedating psychotrophics such as opioids or benzodiazepines, increasing the risk of harms [2]. Opioid use disorder is the greatest risk factor for misuse [2]. Other at-risk populations include people living with substance use disorder, chronic pain or mental health conditions and those in prison [2]. Morbidity and mortality associated with gabapentinoids are increasingly appreciated [2, 4]. Increasing deaths, particularly in combination with opioids, have been reported from Ireland, the United Kingdom, North America, Australia and Finland [2]. This increase is strongly correlated with gabapentinoid prescribing rates [4]. In Australia, ambulance attendances [5] and poisonings [6] are similarly linked to pregabalin availability. This begs the question of why early indicators of gabapentinoid-related harm were not recognized and acted upon more promptly, particularly with the increasing and timely availability of pharmacovigilance and post-marketing surveillance data. Prior experience of misuse of other prescription drugs such as barbiturates, benzodiazepines, opioids and, more recently, antipsychotics [7] has failed to mobilize early action to prevent recurrence of this pattern with gabapentinoids. It is particularly salutary to reflect upon the unfolding of the OxyContin (extended-release oxycodone) tragedy. OxyContin had demonstrated minimal benefit compared to other opioids in clinical trials. However, a combination of focused marketing, enhanced marketing budgets, provision of ‘starter packs’ and promotional material that overstated benefits and minimized potential harms, particularly in relation to addiction, resulted in a dramatic increase in prescribing [8]. The consequence was a dramatic increase in opioid use disorder and death [8]. What similar indicators were seen in the drug life-cycle of gabapentinoids that should have alerted regulators and clinicians earlier? Gabapentinoids act pre-synaptically to reduce neurotransmitter release and suppress neuronal excitability [9]. Gabapentinoids are psychoactive and also sedating, like many other misused prescription medicines including opioids [9]. Misuse potential was identified in early pre-clinical studies, with euphoria and benzodiazepine-like effects reported [10]. Clinical trials of gabapentinoids, as with other psychoactive analgesics, systematically excluded people with mental health disorders and those who use illicit drugs, and were of relatively short duration. These clinical trials are therefore not adequately designed to detect misuse, overdose and death as harms. Gabapentin was FDA-approved in 1993, during the misguided campaign to recognize pain as the fifth vital sign which contributed to the over-prescribing of opioids, and pregabalin in 2004 when the opioid epidemic was established and health professionals and patients were seeking non-opioid analgesics. As with Oxycontin, pharmaceutical companies marketing gabapentinoids have paid millions in fines for misrepresenting their safety and misuse potential and for promoting prescribing for off-label indications, inflating demand [11]. In the United States, gabapentinoids are now prescribed during one in four post-surgical admissions, often in combination with opioids or other analgesics, putatively to reduce opioid consumption [12], despite limited evidence for effectiveness peri-operatively [13] or of opioid-sparing effects [14]. Much of the longer-term off-label prescribing of gabapentinoids is to treat chronic low back pain, increasing availability among a population already vulnerable to misuse, with increased risk of harms through multiple co-prescribed sedative medications [15]. This has all occurred in the context of increasing ‘deaths of despair’ from suicide and drug poisoning since 2000, which are significant contributors to the falling life expectancy in the United States relative to other developed nations [16]. The socio-cultural phenomena that underpin this despair have similarities with the psychosocial factors that are major contributors to the genesis and maintenance of chronic primary pain, of which chronic low back pain is a subset [17]. Chronic primary pain is optimally managed with multi-faceted interventions [17], and yet treatments continue to focus upon biomedical rather than psychosocial interventions. Effective treatment of chronic pain needs to incorporate the psychosocial complexity and also acknowledge these social determinants. To provide solutions the policy response must sit outside the biomedical model. Individual practitioners need policy and regulatory support to provide multi-faceted interventions and desist from high-risk polypharmacy. Various interventions have been implemented in response to gabapentinoid-related harms such as re-scheduling and inclusion in prescription monitoring programmes [18]. The impact of these reactive policies is yet to be evaluated, and there are concerns about unintended consequences such as increased illicit use, as seen with opioids [18]. How can we make the best use of learnings from past mistakes? The FDA have started to address this by recently updating its guidance to industry on the assessment of abuse potential, but we believe further steps should be taken [19]. Absence of evidence is not evidence of absence, and failure to detect misuse potential in Phase III trials should not be sufficient for pharmaceutical companies to claim that a drug is not addictive. Claims about lack of addiction in promotional materials should be prohibited until sufficient post-marketing data are available and the risk to vulnerable populations is more clearly understood. If a medication is being considered for treatment of chronic pain, regulators and prescribers must approach psychoactive medicines with caution to mitigate the limitations of clinical trial data. Intermediate scheduling as a controlled substance is a potential strategy to prompt prescriber vigilance while these data are being collected. This scheduling can be reviewed once big data-based techniques have gathered sufficient data on real-world use and misuse potential. Alongside this, policy commitment is needed to refocus resources for chronic pain management away from biomedical and towards psychosocial interventions. J.B. and A.S are supported by a National Health and Medical Research Council (NHMRC) Centre of Research Excellence in Medicines Intelligence (ID: 1196900). J.B. is supported by an NHMRC Investigator Grant (ID: 1196560). R.C. is supported by an NHMRC Investigator Grant (ID: 1196516). A.S. is supported by a NHMRC Early Career Fellowship (ID: 1158763). None. Bridin Murnion: Conceptualization; project administration. Andrea Schaffer: Conceptualization. Rose Cairns: Conceptualization. Jonathan Brett: Conceptualization.