Progress in pain medicine: where are we now?

The current issue of the British Journal of Anaesthesia includes a special focus on pain medicine that presents a mixture of invited reviews and original research across a broad range of pain-related topics. Looking back to the previous BJA pain special issue in July 2013, there has been progress in our understanding of the problems and how to address them.¹ The challenge remains of translating these to clinical benefit, although there are steps in the right direction. In this editorial, we highlight some of the themes presented in this issue within the context of current pain research.

The Global Burden of Disease (http://www.healthdata.org/gbd) is a unique initiative to improve our understanding of the epidemiology of a disease, which is essential in order to develop effective, cohesive policies to improve healthcare and reduce inequities. The most recent analysis shows that chronic pain and mental health impose a major burden at a global level, with low back pain being the leading cause globally of the number of years lived with disability, followed by headache (above diabetes mellitus and chronic obstructive pulmonary disease). This also does not fully take account of the hidden burden of pain within other chronic diseases, such as diabetes and rheumatoid arthritis.2, 3, 4, 5 It is only in the latest update to the International Classification of Diseases that chronic pain is properly recognised and coded.⁶ If used properly, this may be used to better inform future developments, although we do need to consider how to best use this information to influence and implement effective pain management policies.7, 8 Mills and Smith,⁹ in this issue, give a useful update of risk factors and demographic associations in chronic pain. Risk factors may require a number of approaches to modify them, both at an individual and, perhaps more importantly, at a population-based level through public health policy, in order to impact on long-term outcomes.

The International Association for the Study of Pain (IASP) defines pain as ‘an unpleasant sensory and emotional experience, associated with actual or potential tissue damage, or described in terms of such damage’, and nociception as ‘the neural process of encoding noxious stimuli’.¹⁰ One area where measurement of nociception as a surrogate for pain may be useful is in situations where communication is impaired (e.g. under anaesthesia and critical care). For clinical utility, an objective measure of nociception would need to be reliable, consistently sensitive to analgesic interventions, and easy to use in different clinical situations. The effect of nociception on autonomic function (e.g. heart rate, blood pressure, and pupil diameter) has been utilised in a number of monitors to provide a way to guide analgesia in areas where self-report and pain assessment are difficult. Several papers in this issue emphasise the need for rigorous evaluation of such devices in relevant clinical settings before widespread use.11, 12

Whilst an objective approach to nociception may be possible, the assessment and subsequent management of pain remain subjective, and often suboptimal, even with the use of defined protocols and guidelines.¹³ Education of healthcare staff and improved understanding of what factors affect clinical decision-making around analgesia are explored using neuroimaging. Empathy and risk taking were shown to be some of the factors impacting on how patients with pain were managed in the emergency department.¹⁴

Management of patients with chronic non-malignant pain using long-term potent opioids has been the subject of much discussion, with concerns about increasing addiction and dependence rates, and the contribution that surgery may make to this problem.15, 16 The IASP has produced a position statement around the use of opioids for chronic pain, which reflects these concerns, although ensuring that continued, appropriate use of opioids in acute and cancer pain management is important, especially in lower- and middle-income countries.17, 18 The increasing number of patients presenting for surgery who are already on a strong opioid creates challenges for acute pain management.¹⁹ Buprenorphine, used for chronic pain and increasingly for opioid replacement therapy, is a partial agonist with concerns about ceiling analgesic effects. There is a limited evidence base for how to manage acute pain in this patient group when they present for surgery and for post-discharge analgesia.20, 21 Using a Delphi approach, clinical recommendations have been developed, with key recommendations to continue buprenorphine throughout the perioperative period, with careful consideration of discharge planning.²² The importance of continued review and assessment of all patients on strong opioids after surgery may be one way to reduce longer-term problems.¹⁶

There has been a considerable amount of research on the progression of acute to chronic pain after surgery, with much greater understanding of this problem since it was first systematically studied several decades ago.23, 24, 25 Interestingly, research in this area for patients after critical care admission is identified as being much less advanced in the review by Kemp and colleagues.²⁶ The majority of studies in this area have not used pain-specific questionnaires, but more general quality-of-life measures, where there has not been a focus on persistent pain as a primary outcome despite the fact that it may affect up to 77% of survivors. Future studies should utilise pain-specific outcome measures, with extended follow-up periods.

As we move forward, we need to consider novel approaches to the development and evaluation of interventions for chronic pain. There are acknowledged deficiencies in the standard RCT approach to assessing chronic pain, with a potential to either overestimate treatment effects or to miss signals of efficacy and abandon potentially promising new therapies as a result.27, 28, 29 Different approaches to assessing novel analgesics, utilising biomarkers, may reduce required sample sizes, with increased sensitivity to detect signals of efficacy. The use of detailed sensory phenotyping is showing promise in predicting treatment efficacy or identifying individuals at increased risk of persistent pain, moving towards the Holy Grail of a personalised approach to pain medicine.30, 31, 32 Neuroimaging and other physiological measures may contribute to this, improving our understanding of pain perception, how it is modulated by expectation, and the impact of the placebo effect, although further work needs to be done before translation to clinical use.33, 34, 35, 36, 37 Understanding the molecular profile, aided by the use of large data sets, such as the UK Biobank (www.ukbiobank.ac.uk/), is an additional important piece of the puzzle that could improve clinical trial design by accurate stratification of patients leading to individualisation of therapy.³⁸

Whilst accurate stratification of patients is an important approach in assessing the efficacy of novel analgesics, wider applicability needs to be assessed in a different way.³⁸ Pragmatic clinical trials can be used to ensure broad applicability to the wider patient population that is managed in routine clinical practice, rather than the carefully selected ones in RCTs. For example, many obstetric studies are limited to nulliparous women. A more pragmatic trial found that, whilst programmed intermittent epidural bolus techniques are useful in obstetric analgesia, shorter but more intense labour in multiparous women may require a modification of the approach evidenced in RCTs.³⁹

Our understanding of pain neurobiology advances, with novel pathways and targets identified for future improvements in analgesia. However, especially in chronic pain, despite major investment, these, by and large, have not been translated into clinically useful treatments. Whilst not being unique to chronic pain, the problem is largely one of limitations in the internal and external validity of the preclinical science approaches currently used.40, 41, 42 A number of potential novel targets are reported in this issue, with targets related to the inhibitory (e.g. gamma-aminobutyric acid)/excitatory (N-methyl-D-aspartate) balance well recognised as contributing to chronic pain states.43, 44, 45 In addition to laboratory and experimental pain models being used to identify novel targets, the case report of an individual with a congenital insensitivity to pain illustrates how astute clinical observation can be used to help understand pain mechanisms. In this case, the observation that minimal analgesia was required for a surgical procedure combined with a careful history resulted in further investigation of this individual and her family. Genotyping revealed the causative mutation in the fatty acid amide hydrolase (FAAH) pathway, reflected in corresponding abnormalities in the endogenous cannabinoid system with high circulating levels of anandamide.⁴⁶ It is refreshing that this serendipitous finding may be used to develop novel analgesics, emphasising the importance of a strong link between clinicians and academics. Not only is this essential in ensuring that research is relevant and important in the clinical setting, but it is a good illustration of how observations from the clinic can be used to drive and direct pain research. It is, however, important to emphasise that careful evaluation of any new agent is needed, with early clinical studies of FAAH not showing any benefit in osteoarthritis pain.⁴⁷ There is an ongoing interest in FAAH inhibitors as analgesics, but a precision medicine approach may be more suited to assessing these and other novel interventions.48, 49, 50

In conclusion, has there been progress in the field of pain research over the past 6 yr? Whilst the steps may seem slow, there is no doubt that there is incremental progress in a number of areas. Advances in information technology allow us to interrogate large clinical data sets effectively to improve understanding at a population level, whilst improvements in our understanding of individual mechanisms may take us a step closer to personalised medicine in the field of chronic pain. Collaborations need to be supported to bring together the diverse expertise that will be needed to take full advantage of these approaches. The traditional view of ‘translational pain medicine’ as basic science to the clinic needs to be re-evaluated to reflect this. A further area that we must consider is how we can address the problem at a global level, developing simple and effective solutions that can be used in resource-poor areas. New strategic funding opportunities, such as those through the Medical Research Council UK, and the Versus Arthritis Research Roadmap for Pain (https://www.arthritisresearchuk.org/research/news-and-updates-for-researchers/research-newsletter/april-2018/research-roadmap-for-pain.aspx) are to be welcomed, and perhaps, at last, reflect a recognition of the public health challenge that is posed by chronic pain. It is with a feeling of optimism that we look forward to the future research developments that will be reported in the next pain special issue of the BJA.

Authors' contributions

Concept, design, writing, and approval of final draft: both authors.

Declarations of interest

LAC is an editor for the British Journal of Anaesthesia. ASCR reports personal fees from Imperial College London consultants and Spinifex/Novartis outside the submitted work. In addition, ASCR has patents pending (WO 2005/079771 and EP13702262.0/WO2013 110945).