Chronic morphine therapy has been associated with paradoxically increased pain. Codeine is a widely used opioid, which is metabolized to morphine to elicit analgesia. Prolonged morphine exposure exacerbates pain by activating the innate immune toll-like receptor-4 (TLR4) in the central nervous system. In silico docking simulations indicate codeine also docks to MD2, an accessory protein for TLR4, suggesting potential to induce TLR4-dependent pain facilitation. We hypothesized codeine would cause TLR4-dependent hyperalgesia/allodynia that is disparate from its opioid receptor-dependent analgesic rank potency. Hyperalgesia and allodynia were assessed using hotplate and von Frey tests at days 0, 3 and 5 in mice receiving intraperitoneal equimolar codeine (21 mg kg⁻¹), morphine (20 mg kg⁻¹) or saline, twice daily. This experiment was repeated in animals with prior partial nerve injury and in TLR4 null mutant mice. Interventions with interleukin-1 receptor antagonist (IL-1RA) and glial-attenuating drug ibudilast were assessed. Analyses of glial activation markers (glial fibrillary acid protein and CD11b) in neuronal tissue were conducted at the completion of behavioural testing. Despite providing less acute analgesia (P=0.006), codeine induced similar hotplate hyperalgesia to equimolar morphine vs saline (−9.5 s, P<0.01 and −7.3 s, P<0.01, respectively), suggesting codeine does not rely upon conversion to morphine to increase pain sensitivity. This highlights the potential non-opioid receptor-dependent nature of codeine-enhanced pain sensitivity—although the involvement of other codeine metabolites cannot be ruled out. IL-1RA reversed codeine-induced hyperalgesia (P<0.001) and allodynia (P<0.001), and TLR4 knock-out protected against codeine-induced changes in pain sensitivity. Glial attenuation with ibudilast reversed codeine-induced allodynia (P<0.001), and thus could be investigated further as potential treatment for codeine-induced pain enhancement.

Introduction Patients with chronic headache who consume large amounts of analgesics are often encountered in clinical practice. Excessive intake of analgesics is now considered to be a cause, rather than simply a consequence, of frequent headaches, and as such the diagnosis “medication-overuse headache” (MOH) has been formulated. Despite the prevalence and clinical impact of MOH, the pathophysiology behind this disorder remains unclear and specific mechanism-based treatment options are lacking. Discussion Although most acute headache treatments have been alleged to cause MOH, here we conclude from the literature that opioids are a particularly problematic drug class consistently associated with worsening headache. MOH may not be a single entity, as each class of drug implicated may cause MOH via a different mechanism. Recent evidence indicates that chronic opioid administration may exacerbate pain in the long term by activating toll-like receptor-4 on glial cells, resulting in a pro-inflammatory state that manifests clinically as increased pain. Thus, from the available evidence it seems opioid-overuse headache is a phenomenon similar to opioid-induced hyperalgesia, which derives from a cumulative interaction between central sensitisation, due to repeated activation of nociceptive pathways by recurrent headaches, and pain facilitation due to glial activation. Conclusion Treatment strategies directed at inhibiting glial activation may be of benefit alongside medication withdrawal in the management of MOH.

Introduction: Practice‐based research is essential in enhancing medication knowledge, quality use of medicines, the scope of the pharmacy profession and improving patient outcomes. This systematic review aims to uncover the attitudes of hospital pharmacists towards practice‐based research and their perceptions of the barriers and facilitators to undertaking practice‐based research.Methods: A systematic search of MEDLINE, Embase, International Pharmaceutical Abstracts and Cumulative Index to Nursing and Allied Health Literature databases from 1 January 2000 to 11 March 2021 was conducted. Peer‐reviewed empirical studies exploring hospital pharmacists’ perceptions of – as well as barriers and facilitators to – practice‐based research were included and a descriptive synthesis used to identify common themes.Results: Nine studies were included in this review. Barriers and facilitators across four broad themes were related to pharmacist capacity and capability, workplace environment, research resources, and research culture. Hospital pharmacists had a high interest in conducting research, but limited research experience. Common barriers identified were lack of time, workplace support, funding, research culture, and competing priorities. Having a post‐graduate qualification and a positive attitude towards research facilitated research participation. Departmental support, designated research time and creation of research networks and forums were seen as facilitators for practice‐based research.Conclusion: Hospital pharmacists recognise the importance of practice‐based research in improving knowledge, patient care and advancing pharmacy practice. However, large variation has been reported for their confidence and experience in practice‐based research. Building research capacity and capability by supporting post‐graduate research qualification, providing designated time and creating research networks may strengthen the research culture amongst hospital pharmacists.