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British Journal of Anaesthesia
BJA

Progress in pain medicine: where are we now?

Open ArchivePublished:June 04, 2019DOI:https://doi.org/10.1016/j.bja.2019.04.051
      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.
      • Colvin L.A.
      • Rowbotham D.J.I.
      Managing pain: recent advances and new challenges.
      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.
      GBD 2016 Disease and Injury Incidence and Prevalence Collaborators
      Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
      GBD 2015 Disease and Injury Incidence and Prevalence Collaborators
      Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.
      GBD 2017 Disease and Injury Incidence and Prevalence Collaborators
      Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017.
      • Rice A.S.
      • Smith B.H.
      • Blyth F.M.
      Pain and the global burden of disease.
      It is only in the latest update to the International Classification of Diseases that chronic pain is properly recognised and coded.
      • Treede R.D.
      • Rief W.
      • Barke A.
      • et al.
      A classification of chronic pain for ICD-11.
      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.
      • Blyth F.M.
      • Huckel Schneider C.
      Global burden of pain and global pain policy-creating a purposeful body of evidence.
      • Smith B.H.
      • Fors E.A.
      • Korwisi B.
      • et al.
      The IASP classification of chronic pain for ICD-11: applicability in primary care.
      Mills and Smith,
      • Mills S.N.
      • Nicolson K.P.
      • Smith B.H.
      Chronic pain: a review of its epidemiology and associated factors in population-based studies.
      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’.

      Taxonomy ITFo. Classification of chronic pain. Descriptions of chronic pain syndromes and definitions of pain terms. Available from: https://www.iasp-pain.org/PublicationsNews/Content.aspx?ItemNumber=1673&navItemNumber=677. [Accessed 22 April 2019]

      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.
      • Charier D.V.
      • Vogler M.C.
      • Zantour D.
      • et al.
      Assessing pain in the postoperative period: analgesia Nociception Index™ (ANI) versus pupillometry.
      • Ledowski T.
      Objective monitoring of nociception—mission completed? A review of current commercial solutions.
      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.
      • Fallon M.
      • Walker J.
      • Colvin L.
      • et al.
      Pain management in cancer center inpatients: a cluster randomized trial to evaluate a systematic integrated approach—the Edinburgh Pain Assessment and Management Tool.
      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.
      • Corradi-Dell’Acqua C.F.
      • Foerster M.
      • Sharvit G.
      • et al.
      Pain management decisions in emergency hospitals are predicted by brain activity during empathy and error monitoring.
      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.
      • Colvin L.A.
      • Bull F.
      • Hales T.G.
      Perioperative opioid analgesia—when is enough too much? A review of opioid-induced tolerance and hyperalgesia.
      • Neuman M.D.
      • Bateman B.T.
      • Wunsch H.
      Inappropriate opioid prescription after surgery.
      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.
      • Berterame S.
      • Erthal J.
      • Thomas J.
      • et al.
      Use of and barriers to access to opioid analgesics: a worldwide, regional, and national study.
      International Association for the Study of Pain
      IASP statement on opioids.
      The increasing number of patients presenting for surgery who are already on a strong opioid creates challenges for acute pain management.
      • Hollmann M.W.
      • Rathmell J.P.
      • Lirk P.
      Optimal postoperative pain management: redefining the role for opioids.
      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.
      • Coluzzi F.
      • Bifulco F.
      • Cuomo A.
      • et al.
      The challenge of perioperative pain management in opioid-tolerant patients.
      • Wenzel J.T.
      • Schwenk E.S.
      • Baratta J.L.
      • Viscusi E.R.
      Managing opioid-tolerant patients in the perioperative surgical home.
      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.
      • Goel A.A.S.
      • Weissman J.
      • Shanthanna H.
      • et al.
      Perioperative Pain and Addiction Interdisciplinary Network (PAIN) clinical practice advisory for perioperative management of buprenorphine—results of a modified Delphi process.
      The importance of continued review and assessment of all patients on strong opioids after surgery may be one way to reduce longer-term problems.
      • Neuman M.D.
      • Bateman B.T.
      • Wunsch H.
      Inappropriate opioid prescription after surgery.
      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.
      • Macrae W.A.
      Chronic post-surgical pain: 10 years on.
      • Macrae W.A.
      • Davies H.T.O.
      Chronic postsurgical pain.
      • Glare P.
      • Aubrey K.R.
      • Myles P.S.
      Transition from acute to chronic pain after surgery.
      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.
      • Kemp H.L.
      • Costello A.
      • Brett S.J.
      Chronic pain in critical care survivors.
      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.
      • Moore R.A.
      • Derry S.
      • Wiffen P.J.
      Challenges in design and interpretation of chronic pain trials. [Review].
      • Moore R.A.
      • Straube S.
      • Eccleston C.
      • et al.
      Estimate at your peril: imputation methods for patient withdrawal can bias efficacy outcomes in chronic pain trials using responder analyses.
      • Moore R.A.
      • Derry S.
      • McQuay H.J.
      • et al.
      Clinical effectiveness: an approach to clinical trial design more relevant to clinical practice, acknowledging the importance of individual differences.
      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.
      • Forstenpointner J.
      • Otto J.
      • Baron R.
      Individualized neuropathic pain therapy based on phenotyping: are we there yet?.
      • Smith S.M.
      • Dworkin R.H.
      • Turk D.C.
      • et al.
      The potential role of sensory testing, skin biopsy, and functional brain imaging as biomarkers in chronic pain clinical trials: IMMPACT considerations.
      • Lotsch J.
      • Ultsch A.
      • Kalso E.
      Prediction of persistent post-surgery pain by preoperative cold pain sensitivity: biomarker development with machine-learning-derived analysis.
      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.
      • Davis K.D.
      • Flor H.
      • Greely H.T.
      • et al.
      Brain imaging tests for chronic pain: medical, legal and ethical issues and recommendations.
      • Tracey I.
      • Woolf C.J.
      • Andrews N.A.
      Composite pain biomarker signatures for objective assessment and effective treatment.
      • Wanigasekera V.
      • Wartolowska K.
      • Huggins J.P.
      • et al.
      Disambiguating pharmacological mechanisms from placebo in neuropathic pain using functional neuroimaging.
      • Wanigasekera V.
      • Mezue M.
      • Andersson J.
      • Kong Y.
      • Tracey I.
      Disambiguating pharmacodynamic efficacy from behavior with neuroimaging: implications for analgesic drug development.
      • Vase L.W.
      • Wartolowska K.
      Pain, placebo, and test of treatment efficacy: a narrative review.
      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.
      • Themistocleous A.C.
      • Crombez G.
      • Baskozos G.
      • Bennett D.L.
      Using stratified medicine to understand, diagnose, and treat neuropathic pain.
      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.
      • Themistocleous A.C.
      • Crombez G.
      • Baskozos G.
      • Bennett D.L.
      Using stratified medicine to understand, diagnose, and treat neuropathic pain.
      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.
      • Gabriel L.Y.
      • Young J.
      • Hoesli I.
      • Girard T.
      • Dell-Kuster S.
      Generalizability of randomized trials of the programmed intermittent epidural bolus technique used for maintenance of labour analgesia: a prospective cohort study.
      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.
      • Sikandar S.
      • Dickenson A.H.
      II. No need for translation when the same language is spoken.
      • Rice A.S.C.
      • Finnerup N.B.
      • Kemp H.I.
      • Currie G.L.
      • Baron R.
      Sensory profiling in animal models of neuropathic pain: a call for back-translation.
      • Percie du Sert N.
      • Rice A.S.
      Improving the translation of analgesic drugs to the clinic: animal models of neuropathic pain.
      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.
      • Yamamoto G.K.
      • Kamiya Y.
      • Sasaki M.
      • Ikoma M.
      • Baba H.
      • Kohno T.
      Neurosteroid dehydroepiandrosterone sulphate enhances pain transmission in rat spinal dorsal horn.
      • van Amerongen G.S.
      • Siebenga P.S.
      • Gurrell R.
      Analgesic potential of PF-06372865, an α2/α3/α5 subtype selective GABAA partial agonist, demonstrated using a battery of evoked pain tasks in humans.
      • Zhou XLZ C.J.
      • Peng Y.N.
      • Wang Y.
      • Xu H.J.
      • Liu C.M.
      ROR2 modulates neuropathic pain via phosphorylation of NMDA receptor GluN2B subunit.
      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.
      • Habib A.M.
      • Okorokov A.L.
      • Hill M.N.
      Microdeletion in a FAAH pseudogene identified in a patient with high anandamide levels and pain insensitivity.
      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.
      • Huggins J.P.
      • Smart T.S.
      • Langman S.
      • Taylor L.
      • Young T.
      An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee.
      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.
      • Benson N.
      • Metelkin E.
      • Demin O.
      • Li G.L.
      • Nichols D.
      • van der Graaf P.H.
      A systems pharmacology perspective on the clinical development of Fatty Acid amide hydrolase inhibitors for pain.
      • Fowler C.J.
      The potential of inhibitors of endocannabinoid metabolism for drug development: a critical review.
      • Edwards R.R.
      • Dworkin R.H.
      • Turk D.C.
      • et al.
      Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations.
      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 ).

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