BJA
Editorials
27 Cook TM, Woodall N, Frerk C. Major complications of airway management in the UK: results of the Fourth National Audit Project of the Royal College of Anaesthetists and the Difficult Airway Society. Part 1: anaesthesia. Br J Anaesth 2011; 106: 617– 31 28 Grierson LE. Information processing, specificity of practice, and the transfer of learning: considerations for reconsidering fidelity. Adv Health Sci Educ Theory Pract 2014; 19: 281– 9 29 Aslani A, Ng SC, Hurley M, McCarthy KF, McNicholas M, McCaul CL. Accuracy of identification of the cricothyroid membrane in female subjects using palpation: an observational study. Anesth and Anal 2012; 114: 987–92 30 Friedman Z, You-Ten KE, Bould MD, Naik V. Teaching lifesaving procedures: the impact of model fidelity on acquisition and transfer of
31
32 33
34
cricothyrotomy skills to performance on cadavers. Anesth Analg 2008; 107: 1663– 9 Kolozsvari NO, Kaneva P, Brace C, et al. Mastery versus the standard proficiency target for basic laparoscopic skill training: effect on skill transfer and retention. Surg Endosc 2011; 25: 2063–70 Aggarwal R, Mytton OT, Derbrew M, et al. Training and simulation for patient safety. Qual Saf Health Care 2010; 19(Suppl 2): i34 –43 Hesselfeldt R, Kristensen MS, Rasmussen LS. Evaluation of the airway of the SimMan full-scale patient simulator. Acta Anaesthesiol Scand 2005; 49: 1339–45 Hubert V, Duwat A, Deransy R, Mahjoub Y, Dupont H. Effect of simulation training on compliance with difficult airway management algorithms, technical ability, and skills retention for emergency cricothyrotomy. Anesthesiology 2014; 120: 999– 1008
British Journal of Anaesthesia 114 (3): 361–3 (2015) Advance Access publication 24 September 2014 . doi:10.1093/bja/aeu323
Peripheral neuropathic pain: signs, symptoms, mechanisms, and causes: are they linked? L. A. Colvin 1* and P. M. Dougherty 2 1
Department of Anaesthesia, Critical Care and Pain Medicine, University of Edinburgh, Western General Hospital, Crewe Rd, Edinburgh EH4 2XU, UK 2 Department of Anesthesiology and Pain Management, The University of Texas M.D. Anderson Cancer Center, 1400 Holcombe Boulevard Unit 409, Houston, TX 77030, USA * Corresponding author. E-mail:
[email protected]
Neuropathic pain is a particularly distressing chronic pain syndrome, affecting between 2% and 8% of people with a major impact on quality of life.1 2 Peripheral neuropathic pain, defined as ‘Pain caused by a lesion or disease of the peripheral somatosensory nervous system’ (IASP, 2011), is a common and challenging chronic pain syndrome, with a range of diverse aetiologies. Broadly speaking, these can be divided into neural damage as a result of systemic processes such as disease, toxins, or drugs, often with a classical ‘glove and stocking’ distribution; or secondary to local damage such as trauma, surgery, or locally invasive malignancy. The diagnosis of neuropathic pain can be difficult, particularly for non-specialists, with new diagnostic criteria developed recently.3 – 5 It is well recognized that there are several symptoms typically associated with neuropathic pain, leading to the development of a number of screening tools.6 While many of the tools have similar components, there are some differences that are likely, at least in part, to be due to development in patient populations with different types of neuropathic pain.7 There are two important questions: first, how does the clinical presentation (signs and symptoms) correlate with the underlying neurobiology and secondly, what influence does the aetiology have on these neurobiological changes that may occur? The ongoing challenge for clinicians (and patients)
remains the frustration of not being able to determine which treatment is most likely to work for any one individual.
Neurobiology and translation to clinical presentation Much of our understanding of the neurobiological changes in neuropathic pain has come from the study of animal models, although there has been significant recent debate over the utility of these.8 This has centred on a perceived failure of translation of basic science data into effective new medications, which may have several possible reasons.9 One concern is the reliance of preclinical studies on reflexive measures, while human pain includes higher order processes that may not be captured in these types of assays. Another is that animal models of disease may not adequately recapitulate the clinical condition the experimenter is trying to model. Yet, animal models have clearly advanced our understanding of the physiological basis of nociception, led to the identification of neurotransmitters, receptors, intracellular messengers, and genes involved in pain signalling; and in understanding the basic mechanisms of many effective pain treatments.10 11 The majority of clinical trials have previously relied solely on subjective pain intensity rating measures. Given the wide-ranging spectrum of factors that this type of rating might encompass
361
BJA the main driving factor when a potential new analgesic fails to advance is not always clear. The solution to this issue on the preclinical side has been the groundswell in the use of operant measures of spontaneous pain. Future clinical trials should consider a more comprehensive assessment of the different dimensions of pain, including evoked pain measures as used in preclinical studies.12 13 For example, using a non-pharmacological treatment [Transcutaneous Electrical Nerve Stimulation (TENS)], Sluka and colleagues14 have repeatedly shown a measured reduction in hyperalgesia (increased sensitivity to evoked pain measures) in animal models of disease. Although TENS had no effect on spontaneous pain in postoperative pain, osteoarthritis, or fibromyalgia, it significantly reduced walking pain and hyperalgesia in these populations.15 16 While there have been some notable failures of translation, there are successes based on animal models in producing new treatments for neuropathic pain, such as the use of tumour necrosis factor-a antibodies for rheumatoid arthritis and N-type calcium channel antagonists (ziconotide) and potentially nerve growth factor antibodies (tanezumab) for chronic neuropathic pain.17 – 20 Animal models of the clinically challenging systemic peripheral neuropathies, chemotherapy-induced and HIV-related neuropathic pain, are providing some potential translatable routes for novel therapies. Studies from various laboratories have shown that innate immunity, oxidative stress, loss of distal innervation, the generation of hyperexcitability in peripheral and spinal neurones, and maladaptive plasticity in spinal glia each contribute to the pain state.21 – 29 These studies have already resulted in the initiation of several clinical studies to investigate the potential of these new therapeutic targets (e.g. www.clincaltrials.gov NCT01906008). The paper from Rice’s group in this issue of the BJA explores the mechanisms of neural injury in HIV-associated neuropathy, focusing on the HIV-1 envelope glycoprotein gp120, with evidence that the toxic effects of gp120 are indirectly mediated through macrophages. While preliminary, this adds to previous evidence and may offer an alternative novel therapeutic approach via modulation of macrophage activity through the C–C chemokine receptor type 5 (CCR5 receptor). So, does the clinical presentation reflect the neurobiology? There is considerable interest in how signs and symptoms may be linked to mechanisms.30 By carefully assessing sensory phenotypes in individual patients, it may be possible to group patients and then stratify into defined subgroups when assessing treatment responses. There is some emerging evidence for this approach, with clustering of neuropathic signs and symptoms in larger scale studies using detailed phenotyping, some including psychophysical testing.31 32 It could be argued that this clinical approach can be combined with relevant laboratory measures to reduce the potential disconnect between preclinical and clinical studies, where disparate measures of analgesic effects are used.
How does aetiology affect neurobiology? The majority of new treatments for neuropathic pain are trialled in patients with a single defined aetiology such as
362
Editorials
post-herpetic neuralgia or diabetic neuropathy. The underlying assumption therefore is that the cause of the peripheral neuropathic pain is the major determinant in the pathophysiological changes that occur. If that is the case, then this approach to trial design is reasonable and should effectively identify new analgesics likely to be successful in treating the clinical condition. However, if the aetiology is only one of many factors that contribute to the pathophysiology, with interactions between genetic factors, immune system activity, age, gender, etc., then we need to reconsider clinical trial design; this has been recognized by many researchers in the field, including the Initiative on Methods, Measurement and Pain Assessment for Clinical Trials (www. immpact.org).33 34 This limited correlation between aetiology and mechanisms was clearly illustrated in early imaging work on upper limb amputees with phantom limb pain (PLP). Cortical remapping in the primary somatosensory cortex was shown to correlate strongly with the severity of PLP. In those patients who demonstrated remapping, an effective brachial plexus block reversed the cortical remapping in only half of the patients, with an associated reduction in PLP. The other half had no change in remapping and no reduction in PLP. Thus, in this study of patients with the same causative factor for their PLP—upper limb amputation—in one group, the pain is maintained by mechanisms distal to the brachial plexus, while in the other group, more proximal changes must be important.35 36 Similar differences have been found in other neuropathic pain conditions such as post-herpetic neuralgia. The problem this poses for clinical trials is that if, for example, a peripherally directed agent is being assessed, it is unlikely to have any chance of working in centrally maintained pain—and if the patient population being studied is selected on the basis of aetiology rather than mechanisms, then there is (and probably has been) the potential to miss new treatments that may be very effective in subgroups of patients.37 Despite the variability in mechanisms, the causative disease process, toxin, or injury clearly has some impact on the pathophysiological changes that occur. Thus, animal models do differ depending on the type of model used. Similarly, in the clinical setting, while other factors contributed to the variability in signs and symptoms, identified symptom clusters were thought to be affected at least in part by aetiological factors.38 Further study is needed to determine the complex interaction between factors unique to the individual, the cause of neural damage, and the subsequent development of neuropathic pain.8 39 By further advancing our understanding of mechanisms from laboratory studies and how these are translated clinically, we can move a step closer to improving our evaluation of new treatments.40 From this, we can progress to developing individualized treatment: there will never be one therapy that is effective for everyone, but for most people, there will be at least one drug that will have some efficacy.41 The challenge is to develop our clinical assessment of neuropathic pain in tandem with ongoing laboratory work to identify effective treatments for individual patients.
Editorials
Declaration of interest None declared.
References 1 Torrance N, Smith BH, Bennett MI, et al. The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain 2006; 7: 281–9 2 Smith BH, Torrance N. Epidemiology of neuropathic pain and its impact on quality of life. Curr Pain Headache Rep 2012; 16: 191–8 3 Baron R, Binder A, Wasner G. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol 2010; 9: 807– 19 4 Haanpaa M, Attal N, Backonja M, et al. NeuPSIG guidelines on neuropathic pain assessment. Pain 2011; 152: 14– 27 5 Cruccu G, Sommer C, Anand P, et al. EFNS guidelines on neuropathic pain assessment: revised 2009. Eur J Neurol 2010; 17: 1010– 8 6 Bennett MI, Attal N, Backonja MM, et al. Using screening tools to identify neuropathic pain. Pain 2007; 127: 199–203 7 Jones RC III, Backonja MM. Review of neuropathic pain screening and assessment tools. Curr Pain Headache Rep 2013; 17: 363 8 Sikandar S, Dickenson AH. II. No need for translation when the same language is spoken. Br J Anaesth 2013; 111: 3– 6 9 Mogil JS. Animal models of pain: progress and challenges. Nat Rev Neurosci 2009; 10: 283–94 10 Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011; 152: S2– 15 11 Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell 2009; 139: 2667– 84 12 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 13 Dworkin RH, Turk DC, Peirce-Sandner S, et al. Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations. Pain 2010; 149: 177– 93 14 Sluka KA, Marchand S, Bjordal JM, Rakel BA. What makes transcutaneous electrical nerve stimulation work? Making sense of the mixed results in the clinical literature. Phys Ther 2013; 93: 1397 – 402 15 Vance CG, Rakel BA, Blodgett NP, et al. Effects of transcutaneous electrical nerve stimulation on pain, pain sensitivity and function in people with knee osteoarthritis: a randomized controlled trial. Phys Ther 2012; 167: 45 –9 16 Rakel B, Frantz R. Effectiveness of transcutaneous electrical nerve stimulation on postoperative pain with movement. J Pain 2003; 4: 455– 64 17 Alonso-Ruiz A, Pijoan JI, Ansuategui E, Urkaregi A, Calabozo M, Quintana A. Tumor necrosis factor alpha drugs in rheumatoid arthritis: systematic review and metaanalysis of efficacy and safety. BMC Musculoskelet Disord 2008; 9: 52 18 Backonja MM. Neuropathic pain therapy: from bench to bedside. Semin Neurol 2012; 32: 264– 8 19 Katz N, Borenstein DG, Birbara C, et al. Efficacy and safety of tanezumab in the treatment of chronic low back pain. Pain 2011; 152: 2248– 58 20 Schroeder CI, Craik DJ. Therapeutic potential of conopeptides. Future Med Chem 2012; 4: 1243–55 21 Boyette-Davis J, Xin W, Zhang H, Dougherty PM. Intraepidermal nerve fiber loss corresponds to the development of taxol-induced hyperalgesia and can be prevented by treatment with minocycline. Pain 2011; 152: 308–13
BJA 22 Li Y, Zhang H, Zhang H, Kosturakis AK, Jawad AB, Dougherty PM. Tolllike receptor 4 signaling in primary sensory neurons and spinal astrocytes contribute to paclitaxel-induced peripheral neuropathy. J Pain 2014; 15: 712– 25 23 Zhang H, Boyette-Davis JA, Kosturakis AK, et al. Induction of monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR2 in primary sensory neurons contributes to paclitaxel-induced peripheral neuropathy. J Pain 2013; 14: 1031–44 24 Ellis A, Bennett DL. Neuroinflammation and the generation of neuropathic pain. Br J Anaesth 2013; 111: 26–37 25 Zheng FY, Xiao WH, Bennett GJ. The response of spinal microglia to chemotherapy-evoked painful peripheral neuropathies is distinct from that evoked by traumatic nerve injuries. Neuroscience 2011; 176: 447– 54 26 Zheng H, Xiao WH, Bennett GJ. Functional deficits in peripheral nerve mitochondria in rats with paclitaxel- and oxaliplatin-evoked painful peripheral neuropathy. Exp Neurol 2011; 232: 154–61 27 Joseph EK, Levine JD. Comparison of oxaliplatin- and cisplatininduced painful peripheral neuropathy in the rat. J Pain 2009; 10: 534– 41 28 Chen X, Levine JD, Chen X, Levine JD. Mechanically-evoked C-fiber activity in painful alcohol and AIDS therapy neuropathy in the rat. Mol Pain 2007; 3: 5 29 Milligan ED, O’Connor KA, Nguyen KT, et al. Intrathecal HIV-1 envelope glycoprotein gp120 induces enhanced pain states mediated by spinal cord proinflammatory cytokines. J Neurosci 2001; 21: 2808– 19 30 Jensen TS, Baron R. Translation of symptoms and signs into mechanisms in neuropathic pain. Pain 2003; 102: 1– 8 31 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 32 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 33 Hoeijmakers JG, Faber CG, Lauria G, Merkies IS, Waxman SG. Smallfibre neuropathies—advances in diagnosis, pathophysiology and management. Nat Rev Neurol 2012; 8: 369–79 34 Grace PM, Hutchinson MR, Maier SF, Watkins LR. Pathological pain and the neuroimmune interface. Nat Rev Immunol 2014; 14: 217– 31 35 Flor H, Elbert T, Knecht S, et al. Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature 1995; 375: 482–4 36 Birbaumer N, Lutzenberger W, Montoya P, et al. Effects of regional anesthesia on phantom limb pain are mirrored in changes in cortical reorganization. J Neurosci 1997; 17: 5503–8 37 Rowbotham MC. Mechanisms of neuropathic pain and their implications for the design of clinical trials. Neurology 2005; 65: S66– 73 38 von Hehn CA, Baron R, Woolf CJ. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron 2012; 73: 638– 52. Neuron 2012; 73: 638– 52 39 Sikandar S, Patel R, Patel S, Sikander S, Bennett DL, Dickenson AH. Genes, molecules and patients—emerging topics to guide clinical pain research. Eur J Pharmacol 2013; 716: 188–202 40 Dworkin RH, Turk DC, Katz NP, et al. Evidence-based clinical trial design for chronic pain pharmacotherapy: a blueprint for ACTION. Pain 2011; 152: S107 –15 41 Moore RA, Derry S, Wiffen PJ. Challenges in design and interpretation of chronic pain trials. Br J Anaesth 2013; 111: 38– 45
363
