Investigation into Inappropriately Prescribed Analgesia and Patient Care: Focus on Gabapentinoids, Neuropathic Pain and the Role of Community Pharmacy

Abstract

The prescription of gabapentinoids has significantly increased over the past few years for managing neuropathic pain as a safe alternative to opioids. There have been growing concerns about the abuse potential of gabapentinoids, putting patients with neuropathic pain at risk. Therefore, in April 2019, gabapentinoids were reclassified as a controlled substance in the United Kingdom (UK) to tackle their misuse. The main focus of this thesis was to assess the safety of gabapentinoids in the management of neuropathic pain for adults, including their potential for misuse and abuse, as well as to clarify the role of community pharmacists (CPs) in tackling the misuse risk associated with gabapentinoids. Firstly, a systematic review and meta-analysis were conducted according to the PRISMA guidelines to investigate the published evidence for the safety of gabapentinoids (e.g., addictive potential and adverse events) (Chapter 2). A search of the MEDLINE (Ovid), EMBASE (Ovid), Web of Science, PsycoINFO, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) was performed. A total of 50 studies met the inclusion criteria. Most adverse events pertained to the nervous system (12 effects) or psychiatric (4 effects) disorders. Pregabalin was associated with more adverse events (36 effects) than gabapentin (22 effects). There was no evidence of addiction to gabapentinoids found. The euphoria was the only adverse event that may correlate with addiction potential, which was reported in six of 29 studies of pregabalin, but not for gabapentin. The literature suggests that gabapentinoids are significantly more frequently misused when taken in conjunction with an opioid analgesic, however the included studies' design did not consider gabapentinoids and opioid drug combinations, and therefore this was not investigated. To further investigate the abusive potential of gabapentinoids, the in-vivo study was carried out to investigate the reinforcing efficacy of pregabalin after exposure to morphine self administration (Chapter 3). The study was carried out on 12 naïve rats (adult male Sprague Dawley). After surgery, rats were trained in operant boxes. Each rat went through three phases: (1) acquisition phase (exposure to morphine), (2) extinction phase (exposure to saline), and (3) reinstatement phase (re-exposure to morphine followed by pregabalin). A significant difference was observed between the number of active lever responses maintained by pregabalin in the reinstatement phase compared to the extinction phase (P=0.0038). The in-vivo study concluded that pregabalin might have a reinforcing efficacy when substituted for self-administering morphine in naïve rats. To tackle gabapentinoid misuse and the evolving role of pharmacists in providing patients care, it is worthwhile to understand how CPs deal with this problem. Another systematic review (Chapter 4) was conducted to synthesise the existing literature on CPs-led interventions and the role of pharmacists in this area. A search of the EMBASE (Ovid), MEDLINE (Ovid), Web of Science and Scopus was undertaken. Six studies conducted in the USA and Ireland were included. The identified CP-led interventions were mapped to the Behaviour Change Wheel (BCW) to investigate the pharmacist and patient behaviours addressed by the interventions. Intervention functions addressing patient and pharmacist behaviours comprised education, training, enablement, and environmental restructuring. One study also identified restrictions as an intervention function targeting patient behaviour. There was limited evidence about CP-led interventions and a lack of clarity about the role of CPs in identifying analgesia misuse. A qualitative interview study (Chapter 5) was next conducted to explore the perspectives of CPs about addressing inappropriately prescribed analgesia (IPA). Semi-structured interviews informed by the BCW and the Theoretical Domains Framework (TDF) were conducted with 12 CPs. Nine TDF domains were identified as relevant to addressing IPA. Seventeen behaviour change techniques (BCTs) were identified that could be considered in the design of future interventions to facilitate the involvement of CPs in identifying IPA. In summary, the findings presented in this thesis provide a comprehensive safety profile of using gabapentinoids in patients with neuropathic pain. Despite gabapentinoids' adverse events on the nervous system, they did not appear to cause addiction in RCTs. However, since the self-administration study concluded that pregabalin might have reinforcing properties when substituted for morphine, further investigations are required to confirm this observation, particularly given the literature suggesting that gabapentinoids are significantly more frequently misused when taken in conjunction with an opioid analgesic. Finally, although there is limited evidence of CPs-led interventions to tackle IPA, this thesis provides an in-depth explanation and understanding of the barriers and facilitators to addressing this issue from the perspectives of CPs. Given the growing role of CPs in providing effective patient care, findings may help inform strategies to involve CPs in tackling this significant issue.