II. No need for translation when the same language is spoken

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25 Aasvang EK, Gmaehle E, Hansen JB, et al. Predictive risk factors for persistent postherniotomy pain. Anesthesiology 2010; 112: 957–69 26 Lee MC, Zambreanu L, Menon DK, Tracey I. Identifying brain activity specifically related to the maintenance and perceptual consequence of central sensitization in humans. J Neurosci 2008; 28: 11642– 9 27 Bingel U, Wanigasekera V, Wiech K, et al. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci Transl Med 2011; 3: 70ra14 28 Tracey I. Getting the pain you expect: mechanisms of placebo, nocebo and reappraisal effects in humans. Nat Med 2010; 16: 1277– 83 29 Maier C, Baron R, Tolle TR, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain 2010; 150: 439–50 30 Attal N, Bouhassira D, Baron R, et al. Assessing symptom profiles in neuropathic pain clinical trials: can it improve outcome? Eur J Pain 2011; 15: 441–3 31 Tracey I. Can neuroimaging studies identify pain endophenotypes in humans? Nat Rev Neurol 2011; 7: 173– 81 32 Mogil JS. Pain genetics: past, present and future. Trends Genet 2012; 28: 258– 66 33 Kalso E. Persistent post-surgery pain: research agenda for mechanisms, prevention, and treatment. Br J Anaesth 2013; 111: 9–12 34 Smith BH, Lee J, Price C, Baranowski AP. Neuropathic pain: a pathway for care developed by the British Pain Society. Br J Anaesth 2013; 111: 73 –9

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EDITORIAL II

No need for translation when the same language is spoken S. Sikandar and A. H. Dickenson* Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK * E-mail: [email protected]

Advancing our understanding of pain mechanisms and the need for improved analgesic treatments faces challenges in both clinical and laboratory domains. The preclinical approaches provide advances in our fundamental understanding of the neurobiology of pain, but the gaps between molecules and pathways to the patients need to be addressed. Viewpoints differ on the notion that animal models are the culprits of the failure to produce new pain drugs.1 But perhaps, it is not a fault of the models, but the interpretation of the information provided by them? Pain measured in humans often relies on an analogue scale (i.e. a standard rating scale of 0–10). By definition, the threshold would lie around 2 and this is what is measured by reflex responses in animals. Consequently, a drug that is effective on threshold measures is likely

to fail when confronted by the pain levels of 6–7 that patients in trials report. Here, a different approach to preclinical investigation of drug efficacy is needed. We confess to being besotted by neuronal responses obtained by in vivo electrophysiology, but these do provide an unbiased, objective measure of low and suprathreshold multi-modal responses in pain models. Indeed, these electrophysiological measures of neuronal activity likely equate better to clinical pains.2 But then again, we might be geeks . . .. We would argue that done well, preclinical studies can be strong predictors of drug efficacy in the clinic; identification of cyclooxygenase-2 (COX-2) blockers, triptans, anti-nerve growth factor (NGF), and anti– tumour necrosis factor a (TNFa) therapies are all examples of successful translation

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16 Al-Hashimi M, Scott SWM, Thompson JP, Lambert DG. Opioids and immune modulation: more questions than answers. Br J Anaesth 2013; 111: 80–8 17 Gach K, Wyrebska A, Fichna J, Janecka A. The role of morphine in regulation of cancer cell growth. [Review] Naunyn Schmiedebergs Arch Pharmacol 2011; 384: 221–30 18 Cleeland CS, Bennett GJ, Dantzer R, et al. Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? A cytokine-immunologic model of cancer symptoms. Cancer 2003; 97: 2919– 25 19 Colvin LA, Fallon MT, Buggy DJ. Cancer biology, analgesics, and anaesthetics: is there a link? Br J Anaesth 2012; 109: 140– 3 20 Sikandar S, Dickenson AH. No need for translation when the same language is spoken. Br J Anaesth 2013; 111: 3–6 21 Currie G, Delaney A, Bennett MI, et al. Animal models of bone cancer pain: systematic review and meta-analyses. Pain 2013; 154: 917– 26 22 Macleod M, van der Worp HB. Animal models of neurological disease: are there any babies in the bathwater? Pract Neurol 2010; 10: 312–4 23 Roberts K, Shenoy R, Anand P. A novel human volunteer pain model using contact heat evoked potentials (CHEP) following topical skin application of transient receptor potential agonists capsaicin, menthol and cinnamaldehyde. J Clin Neurosci 2011; 18: 926– 32 24 Yarnitsky D, Crispel Y, Eisenberg E, et al. Prediction of chronic postoperative pain: pre-operative DNIC testing identifies patients at risk. Pain 2008; 138: 22– 8

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Feedback from the higher centres of the brain project back to the spinal cord where further modulation of nociceptive information occurs. Balance between inhibition and excitation in descending pathways holds the key to the level of pain processing.17 In humans, imaging reveals similar anatomical systems recruited in placebo analgesia where inhibitions are produced, and in chronic pain states with abnormal facilitations.21 22 Diffuse noxious inhibitory controls are reduced in many human pain states and have been shown to be a risk factor in the transition from acute to chronic pain.23 Study of descending facilitatory and inhibitory pathways has not only improved our understanding of the mechanisms of drugs used to treat pain, such as the antidepressants, but also our knowledge of events underlying the persistence of pain states. More recent studies have explored the eminent question as to why some people develop chronic pain and others do not. Fear and anxiety, and also pain intensity, impact on the provision of rescue medication after hysterectomy in the acute setting.24 Anxiety and the level of pain in the perioperative period have also been highlighted as risk factors for chronic pain after certain surgical procedures.25 Given the close association of pain and affect, it is likely that central sensitization can drive spinal, supraspinal plastic changes, or both that maintain high pain levels and impact fear and anxiety. These in turn shift the balance of descending controls towards facilitation. This balance between excitation and inhibition through descending pathways is critical in the development and maintenance of chronic pain—indeed, ablation of brainstem neurones at the origins of descending facilitations leads to a short-lasting mechanical hypersensitivity after nerve injury in animals that fails to become persistent.26 The role of the brainstem in maintaining pain states is further explored by a study by De Felice and colleagues27 investigating the incidence of the neuropathic pain phenotype, where in contrast to the majority of rat studies, only the minority of patients with neuropathy develop pain. Indeed, this has been put forward as a major criticism of the animal studies, but the argument in defence has always been that the strain of animal chosen exhibits the required behavioural endpoint after nerve injury. De Felice and colleagues have studied this in detail and shown that different strains of rats have different probabilities of developing pain behaviour after neuropathy. Clearly, the genetic background explains the difference and indeed the heterogeneity at the genetic level in humans likely underlies the reason why not all patients with neuropathy have pain. Particular genetic profiles are likely to protect or enhance pain, nerve damage and immune responses.13 16 Remarkably, De Felice and colleagues also demonstrated a recruitment of descending inhibition (partly noradrenergic) in the group of rats where 50% of animals had nerve damage with no pain. Crucially, this is in parallel with enhanced descending facilitations evoked by neuropathy. Although the degree and extent of peripheral damage was identical in all animals, in some cases chronic pain was shown to arise from continued peripheral input but in others, brainstem modulation could suppress the pain phenotype. Clearly in cases such as the De Felice study, CS must engage brain circuits. However, from a defined spinal mechanism the

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from animals to patients.3 – 6 The new molecule tapentadol is a clever example signifying the value of preclinical studies that explore mechanisms of potential pain drugs. This opioid agonist with synergistic actions for blocking noradrenergic reuptake was translated from animal models of neuropathy and inflammation to prove effective in both major types of pain, leading to further positive studies in lower back pain.7 We find it difficult to argue against the importance of preclinical investigations of drug targets, and after all, the mode of action of gabapentinoids, antidepressants in pain, ketamine analgesia, and ziconotide all came from preclinical studies and relate to important pain therapies in patients.8 – 11 Of course, animals cannot be expected to reveal the entire array of complex human side-effects, so our claims are based on efficacy rather than tolerability. The latter will only be revealed when the molecules enter humans, and here patients may have co-existing problems that impact upon side-effects. We owe a great deal of our understanding of pain mechanisms to animal studies. Central sensitization (CS) comprises a series of key physiological events that contribute to the chronification of pain states. Studies conducted in animals have described the associated mechanisms of wind-up whereby a repeated noxious stimulus permits spinal NMDA receptor activation to drive enhanced neuronal responsivity and enlarge their receptive fields. This is the most plausible mechanism behind mechanical allodynias, and indeed, CS and abnormal wind-up have been reported in many patient groups, so the concept has translated well.12 Genetic engineering has pioneered the identification of numerous ion channels ranging from sodium channels through to transient receptor potential (TRP) channels. Their roles were revealed primarily by knock-out studies in mice, but there are now several known human channelopathies, including loss and gain of function of Nav1.7 in humans, gain-of-function of TRPA1, and polymorphisms in TRPV1, all that allow forward- and back-translation of transgenic animal models.13 – 15 Other targets such as the P2X7 receptor join the list with further implications for understanding individual variations in pain.16 And it is more than just the molecules that translate. Our knowledge about the midbrain and brainstem circuitry that underlie descending controls and mediate spinal-supraspinal cross talk stems from animal studies.17 18 Spinal neurones that are activated by noxious input project to thalamocortical sites and generate the sensory discriminative aspects of pain relating to location and intensity, while other spinal neurones project in parallel to limbic areas. These latter ancient midbrain areas are involved in fear, anxiety, mood, and stress responses and thereby underlie affective and emotional aspects of a noxious stimulus. Anxiety, sleep disorders, and depression are all common co-morbidities in chronic pain patients that have a major impact on the suffering experienced.19 We have recently shown that neurones in the amygdala, a key centre for emotional memories and implicated in the central drive of descending controls, are altered after nerve injury.20 Asymmetric and time-related changes ensue, spanning the postoperative to the persistent neuropathic state. The association of pain with sleep disturbances, depression, and anxiety are explicable in terms of these networks.

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on Neuropathic Pain (DFNS). Sensory profiling in patients will identify the most relevant components of the pain phenotype that robustly reflects the underlying mechanism/combination of mechanisms operating in the patients. Pharmacological studies could follow to inform on responses based on sensory profiles; in this case, certain pain descriptors could lead to a targeted treatment if particular sensory profiles can predict responses to drugs. Of the many issues that arise, one is that five sub-groups can be separated out in patients with neuropathic pain, and these are independent of aetiology.33 If two of the five groups respond to a treatment, it is highly likely that a clinical trial would fail, despite the drug being effective in patient sub-groups. It is essential to improve analgesic treatments by directing pain research towards individualized medicine. One way to progress would be to validate questionnaires for repeated testing in order to link symptoms and signs to treatments over a time course. In this regard, ongoing and different modalities of evoked pains could be gauged in the patients along with drug effects, bringing the human studies into alignment with the animal models. Effective translation of pain research is easy when we speak the same language. The key issues to overcome are effective clinical profiling of pain phenotypes, followed by the appropriate use and interpretation of animal research. Linking ties between clinical and preclinical data is crucial for a successful translation of pain research into improved analgesic treatments.

Acknowledgements There are no conflicts of interest to report. S.S. and A.H.D. are supported by IMI Europain and the Wellcome Trust London Pain Consortium.

Declaration of interest None declared.

References 1 van der Worp HB, Howells DW, Sena ES, et al. Can animal models of disease reliably inform human studies? PLoS Med 2010; 7: e1000245 2 Sikandar S, Ronga I, Iannetti GD, Dickenson A. Neural coding of nociceptive stimuli—from rat spinal neurones to human perception. Pain 2013 (in press) 3 Hefti FF, Rosenthal A, Walicke PA, et al. Novel class of pain drugs based on antagonism of NGF. Trends Pharmacol Sci 2006; 27: 85– 91 4 Horiuchi T, Mitoma H, Harashima S, Tsukamoto H, Shimoda T. Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents. Rheumatology (Oxford) 2010; 49: 1215–28 5 Nappi G, Sandrini G, Sances G. Tolerability of the triptans: clinical implications. Drug Saf 2003; 26: 93–107 6 Warner TD, Mitchell JA. Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J 2004; 18: 790–804 7 Hartrick CT, Rozek RJ. Tapentadol in pain management: a mu-opioid receptor agonist and noradrenaline reuptake inhibitor. CNS Drugs 2011; 25: 359– 70 8 Kukkar A, Bali A, Singh N, Jaggi AS. Implications and mechanism of action of gabapentin in neuropathic pain. Arch Pharm Res 2013; 36: 237– 51

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term ‘central sensitization’ is nowadays frequently used to cover any complex and often diffuse pain states. Wind-up and other manifestations of CS are seen in spinal circuits—the events do not need the brain. It is also hard to envisage a spread of excitability beyond a few segments through spinal mechanisms and most animal models of pain with peripheral pathology reveal changes confined to the damaged nerve territories or tissue. Clearly, CS can drive neuroadaptive changes in the brain. Many limbic brain areas have whole body receptive fields and the descending controls appear to be bilateral and diffuse in character. Thus, we should differentiate between spinal, localized CS and diffuse pains, likely consequent to altered excitability and neuronal activity of supraspinal centres.28 Another criticism of animal models is that measured endpoints usually relate to evoked pain whereas patients have major problems with spontaneous pain. However, ongoing activities in the absence of stimuli have been long recorded in neurones in animal preparations and of course; there are now several behavioural approaches to measuring ongoing pain. Yet, the clinical data on ongoing and evoked activity is still sparse. The use of conditioned place preference (CPP) is convincing but the effective agents against ongoing pain generally overlap with those effective on evoked pains.29 30 Clinical research has barely touched on this issue, so future human studies comparing drugs on evoked and ongoing pain are a key to effective back-translation. Here, study design is crucial to extract the most information from patients; the large majority of clinical trials on drugs simply asks the patient to report their level of pain, but how does the patient go about reporting this if one of these components (evoked or ongoing) was changed by a drug and not the other? One interesting mismatch has surfaced in this regard. TRPA1 is an irritant sensor and in pharmacological studies comparing CPP and evoked pain in animals with diabetic or surgical neuropathy, TRPA1 was reported to be involved in evoked mechanical responsivity but not ongoing pain.31 This may appear to be a bit too molecular if you are searching for the patient link, but bear in mind the inherited TRPA1 gain-of-function mutation leaves affected individuals with normal acute pain and no ongoing pain, but a pain syndrome that is triggered by external and internal factors, namely cold, fatigue, and hunger.15 Yet, we are still not convinced that the issue of measuring ongoing pain is simple. In a thought provoking review, Bennett32 has raised the issue that pain that may seem to be ongoing may in fact be evoked or triggered by normal daily events, such as the touch of clothes, the local environment or changes in temperature if mechanical and thermal allodynia is present in the subjects. Of course, a further complication is that pain may wax and wane and fluctuate over the course of the day. This begs the question—have we really fully understood and reported the clinical incidents of spontaneous and ongoing pain? Only then would we be able to effectively model these in animals through back-translation. Given that genotyping large numbers of patients is unlikely the most practical approach, sensory profiles might come to the rescue. Indeed, a promising success in phenotyping large patient cohorts is being led by the German Research Network

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sensitization in a cohort of osteoarthritis patients. Arthritis Rheum 2009; 61: 1226– 34 Yarnitsky D. Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): its relevance for acute and chronic pain states. Curr Opin Anaesthesiol 2010; 23: 611–5 Pinto PR, McIntyre T, Fonseca C, Almeida A, Araujo-Soares V. Pre- and post-surgical factors that predict the provision of rescue analgesia following hysterectomy. Eur J Pain 2013; 17: 423 – 33 Theunissen M, Peters ML, Bruce J, Gramke HF, Marcus MA. Preoperative anxiety and catastrophizing: a systematic review and meta-analysis of the association with chronic postsurgical pain. Clin J Pain 2012; 28: 819– 41 Porreca F, Burgess SE, Gardell LR, et al. Inhibition of neuropathic pain by selective ablation of brainstem medullary cells expressing the mu-opioid receptor. J Neurosci 2001; 21: 5281–8 De Felice M, Sanoja R, Wang R, et al. Engagement of descending inhibition from the rostral ventromedial medulla protects against chronic neuropathic pain. Pain 2011; 152: 2701–9 Meeus M, Nijs J. Central sensitization: a biopsychosocial explanation for chronic widespread pain in patients with fibromyalgia and chronic fatigue syndrome. Clin Rheumatol 2007; 26: 465– 73 King T, Vera-Portocarrero L, Gutierrez T, et al. Unmasking the tonicaversive state in neuropathic pain. Nat Neurosci 2009; 12: 1364–6 Park HJ, Stokes JA, Pirie E, Skahen J, Shtaerman Y, Yaksh TL. Persistent hyperalgesia in the cisplatin-treated mouse as defined by threshold measures, the conditioned place preference paradigm, and changes in dorsal root ganglia activated transcription factor 3: the effects of gabapentin, ketorolac, and etanercept. Anesth Analg 2013; 116: 224–31 Wei H, Viisanen H, Amorim D, Koivisto A, Pertovaara A. Dissociated modulation of conditioned place-preference and mechanical hypersensitivity by a TRPA1 channel antagonist in peripheral neuropathy. Pharmacol Biochem Behav 2013; 104: 90– 6 Bennett GJ. What is spontaneous pain and who has it? J Pain 2012; 13: 921– 9 Baron R, Forster M, Binder A. Subgrouping of patients with neuropathic pain according to pain-related sensory abnormalities: a first step to a stratified treatment approach. Lancet Neurol 2012; 11: 999– 1005

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EDITORIAL III

Pain research: what have we learned and where are we going F. Cervero Faculty of Medicine, Anesthesia Research Unit, Faculty of Dentistry and The Alan Edwards Centre for Research on Pain, McGill University, McIntyre Medical Bldg. Room 1207, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada E-mail: [email protected]

We have always wondered why do we feel pain, how is it caused, what it means to us and, more importantly, how can

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we prevent or reduce it. We can trace the origin of pain research back to the beginning of our time on earth. From spiritual

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9 Dharmshaktu P, Tayal V, Kalra BS. Efficacy of antidepressants as analgesics: a review. J Clin Pharmacol 2012; 52: 6– 17 10 D’Mello R, Dickenson AH. Spinal cord mechanisms of pain. Br J Anaesth 2008; 101: 8 –16 11 Matthews EA, Dickenson AH. Effects of spinally delivered N- and P-type voltage-dependent calcium channel antagonists on dorsal horn neuronal responses in a rat model of neuropathy. Pain 2001; 92: 235– 46 12 Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 2009; 10: 895– 926 13 Binder A, May D, Baron R, et al. Transient receptor potential channel polymorphisms are associated with the somatosensory function in neuropathic pain patients. PLoS One 2011; 6: e17387 14 Dib-Hajj SD, Yang Y, Black JA, Waxman SG. The Na(V)1.7 sodium channel: from molecule to man. Nat Rev Neurosci 2013; 14: 49– 62 15 Kremeyer B, Lopera F, Cox JJ, et al. A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome. Neuron 2010; 66: 671– 80 16 Sorge RE, Trang T, Dorfman R, et al. Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nat Med 2012; 18: 595– 9 17 Bannister K, Bee LA, Dickenson AH. Preclinical and early clinical investigations related to monoaminergic pain modulation. Neurotherapeutics 2009; 6: 703– 12 18 Porreca F, Ossipov MH, Gebhart GF. Chronic pain and medullary descending facilitation. Trends Neurosci 2002; 25: 319– 25 19 Gormsen L, Rosenberg R, Bach FW, Jensen TS. Depression, anxiety, health-related quality of life and pain in patients with chronic fibromyalgia and neuropathic pain. Eur J Pain 2010; 14: 127 e1 –8 20 Goncalves L, Dickenson AH. Asymmetric time-dependent activation of right central amygdala neurones in rats with peripheral neuropathy and pregabalin modulation. Eur J Neurosci 2012; 36: 3204– 13 21 Eippert F, Bingel U, Schoell ED, et al. Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron 2009; 63: 533–43 22 Gwilym SE, Keltner JR, Warnaby CE, et al. Psychophysical and functional imaging evidence supporting the presence of central

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