Neuropathic pain

Abstract

Neuropathic pain is caused by a lesion or disease of the somatosensory system, including peripheral fibres (Aβ, Aδ and C fibres) and central neurons, and affects 7-10% of the general population. Multiple causes of neuropathic pain have been described and its incidence is likely to increase owing to the ageing global population, increased incidence of diabetes mellitus and improved survival from cancer after chemotherapy. Indeed, imbalances between excitatory and inhibitory somatosensory signalling, alterations in ion channels and variability in the way that pain messages are modulated in the central nervous system all have been implicated in neuropathic pain. The burden of chronic neuropathic pain seems to be related to the complexity of neuropathic symptoms, poor outcomes and difficult treatment decisions. Importantly, quality of life is impaired in patients with neuropathic pain owing to increased drug prescriptions and visits to health care providers, as well as the morbidity from the pain itself and the inciting disease. Despite challenges, progress in the understanding of the pathophysiology of neuropathic pain is spurring the development of new diagnostic procedures and personalized interventions, which emphasize the need for a multidisciplinary approach to the management of neuropathic pain.

Conflict of interest statement

Competing interests

L.C. has received lecture honoraria (Georgetown University and Stanford University) and has acted as speaker or consultant for Grünenthal and Emmi Solution. R.B. is an industry member of AstraZeneca, Pfizer, Esteve, UCB Pharma, Sanofi Aventis, Grünenthal, Eli Lilly and Boehringer Ingelheim; has received lecture honoraria from Pfizer, Genzyme, Grünenthal, Mundipharma, Sanofi Pasteur, Medtronic Inc. Neuromodulation, Eisai, Lilly, Boehringer Ingelheim, Astellas, Desitin, Teva Pharma, Bayer-Schering, MSD and Seqirus; and has served as a consultant for Pfizer, Genzyme, Grünenthal, Mundipharma, Sanofi Pasteur, Medtronic Inc. Neuromodulation, Eisai, Lilly, Boehringer Ingelheim Pharma, Astellas, Desitin, Teva Pharma, BayerSchering, MSD, Novartis, Bristol-Myers Squibb, Biogen idec, AstraZeneca, Merck, AbbVie, Daiichi Sankyo, Glenmark Pharmaceuticals, Seqirus, Genentech, Galapagos NV and Kyowa Hakko Kirin. A.H.D. has acted as speaker or consultant forSeqirus, Grünenthal, Allergan and Mundipharma. D.B. has acted as a consultant for Grünenthal, Pfizer and Indivior. D.L.B. has acted as a consultant for Abide, Eli Lilly, Mundipharma, Pfizer and Teva. D.Y. received a lecture honorarium from Pfizer and holds equity in BrainsGate and Theranica. R.F. has acted as an advisory board member for Abide, Astellas, Biogen, Glenmark, Hydra, Novartis and Pfizer. A.T. has received research funding, lecture honoraria and acted as speaker or consultant for Mundipharma, Pfizer, Grünenthal and Angelini Pharma. N.A. has received honoraria for participation in advisory boards or speaker bureau by Astellas, Teva, Mundipharma, Johnson and Johnson, Novartis and Sanofi Pasteur MSD. N.B.F. has received honoraria for participation in advisory boards from Teva Pharmaceuticals, Novartis and Grünenthal, and research support from EUROPAIN Investigational Medicines Initiative (IMI). E.K. has served on the advisory boards of Orion Pharma and Grünenthal, and received lecture honoraria from Orion Pharma and AstraZeneca. R.H.D. has received research grants and contracts from the US FDA and the US NIH, and compensation for activities involving clinical trial research methods from Abide, Aptinyx, Astellas, Boston Scientific, Centrexion, Dong-A, Eli Lilly, Glenmark, Hope, Hydra, Immune, Novartis, NsGene, Olatec, Phosphagenics, Quark, Reckitt Benckiser, Relmada, Semnur, Syntrix, Teva, Trevena and Vertex. S.N.R. has received a research grant from Medtronic Inc. and honoraria for participation in advisory boards of Allergan, Daiichi Sankyo, Grünenthal USA Inc. and Lexicon Pharmaceuticals. C.E. and T.L. declare no competing interests.

Figures

Figure 1. The peripheral and central changes induced by nerve injury or peripheral neuropathy

Preclinical animal studies have shown that damage to all sensory peripheral fibres (namely, Aβ, Aδ and C fibres; BOX 1) alters transduction and transmission due to altered ion channel function. These alterations affect spinal cord activity, leading to an excess of excitation coupled with a loss of inhibition. In the ascending afferent pathways, the sensory components of pain are via the spinothalamic pathway to the ventrobasal medial and lateral areas (1), which then project to the somatosensory cortex allowing for the location and intensity of pain to be perceived (2). The spinal cord also has spinoreticular projections and the dorsal column pathway to the cuneate nucleus and nucleus gracilis (3). Other limbic projections relay in the parabrachial nucleus (4) before contacting the hypothalamus and amygdala, where central autonomic function, fear and «anxiety are altered (5). Descending efferent pathways from the amygdala and hypothalamus (6) drive the periaqueductal grey, the locus coeruleus, A5 and A7 nuclei and the rostroventral medial medulla. These brainstem areas then project to the spinal cord through descending noradrenaline (inhibition via α2 adrenoceptors), and, in neuropathy, there is a loss of this control and increased serotonin descending excitation via 5-HT3 receptors (7). The changes induced by peripheral neuropathy on peripheral and central functions are shown. Adapted with permission from REF. , Mechanisms and management of diabetic painful distal symmetrical polyneuropathy, American Diabetes Association, 2013. Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association.

Figure 2. Neuroanatomical distribution of pain symptoms and sensory signs in neuropathic pain conditions

Distribution of pain and sensory signs in common peripheral and central neuropathic pain conditions. *Can sometimes be associated with central neuropathic pain. ‡Can sometimes be associated with peripheral neuropathic pain.

Figure 3. Schematic representation of the conditioned pain modulation

The conditioned pain modulation (CPM) paradigm is used in the research setting to assess the change of perceived pain by a test stimulus under the influence of a conditioning stimulus. A test stimulus can be a thermal contact stimulation (1), mechanical pressure (2), an electrical stimulus (3) — for each, either pain threshold or suprathreshold magnitude estimation can be used — or nociceptive withdrawal reflex (4). A typical conditioning stimulus consists of thermal contact stimulation (5), or immersion in a cold (6) or hot (7) water bath. Other modalities can be used as well. During a CPM assessment, a test stimulus is given first, then the conditioning stimulus is given, and the test is repeated during or immediately after the conditioning.

Figure 4. Diagnosing neuropathic pain, a

The flowchart summarizes the clinical steps in diagnosing neuropathic pain, which involves taking the patient history, examining the patient and following up with confirmatory tests. If the answer is ‘no’ after examination, the patient might still have probable neuropathic pain. In such cases, confirmation tests could be performed if sensory abnormalities are not found; for example, in some hereditary conditions, sensory abnormalities are not found at the moment of examination. *History of a neurological lesion or disease relevant to the occurrence of neuropathic pain. ‡The patient's pain distribution reflects the suspected lesion or disease. §Signs of sensory loss are generally required. However, touch-evoked or thermal allodynia might be the only finding at bedside examination. ||‘Definite’ neuropathic pain refers to a pain that is compatible with the features of neuropathic pain and confirmatory tests are consistent with the location and nature of the lesion or disease, although this may not imply any causality. b | The confirmatory tests for neuropathic pain include quantitative sensory testing (in which the patient provides a subjective report on a precise and reproducible stimulus), blink reflex testing (whereby the trigeminal afferent system is investigated by recording the R1 and R2 reflex responses recorded from the orbicularis oculi muscle) and nerve conduction study (which assesses non-nociceptive fibre function of the peripheral nerves). Somatosensory-evoked potentials (N9 is generated by the brachial plexus and N20 by the somatosensory cortex) and laser-evoked potentials (LEPs), both recorded from the scalp, are neurophysiological tools that investigate large and small afferent fibre function. The N1 LEP wave is a lateralized component and generated by the secondary somatosensory cortex, and the negative-positive complex of LEP (N2-P2) is a vertex recorded potential, which is generated by the insular cortex bilaterally and the cingulate cortex. A skin biopsy enables the quantification of the intraepidermal nerve fibres, which provides a measure of small-fibre loss. Finally, corneal confocal microscopy assesses corneal innervation, which consists of small nerve fibres. In most patients with neuropathic pain, standard neurophysiological testing, such as blink reflex, nerve conduction study and somatosensory-evoked potentials, is sufficient for showing the damage of the somatosensory system. However, in patients with selective damage of the nociceptive system, a nociceptive-specific tool, such as LEPs, skin biopsy or corneal confocal microscopy, is needed. Typically, tests are performed in the sequence of increasing invasiveness; that is, quantitative sensory testing, blink reflex, nerve conduction study, somatosensory-evoked potentials, LEPs, skin biopsy and corneal confocal microscopy. SNAP, sensory nerve action potential. Adapted with permission from REF , Macmillan Publishers Limited. The corneal innervation image in part b (left panel) is reproduced with permission from REF , Elsevier.

Figure 5. Subgrouping patients with peripheral neuropathic pain based on sensory signs

On the basis of two well-established testing (n = 902) (part a) and control (n=233) (part b) data sets, three categories of patient phenotypes for neuropathic pain have been proposed: sensory loss, thermal hyperalgesia and mechanical hyperalgesia. Positive scores indicate positive sensory signs (hyperalgesia), and negative scores indicate negative sensory signs (hypoaesthesia or hypoalgesia). Values observed in those with neuropathic pain are significantly different from those of healthy participants when the 95% CI does not cross the zero line, which defines the average of data from normal subjects. Insets (right) show the numerical rating scale (NRS; 0–10) values for dynamic mechanical allodynia (DMA) on a logarithmic scale and the frequency of paradoxical heat sensation (PHS) on a scale of 0–3. These findings indicate that patients with neuropathic pain have different expression patterns of sensory signs. These subgroup results suggest that different mechanisms of pain generation are involved in the pain condition. Furthermore, the first clinical trial to show phenotype stratification based on these sensory profiles has predictive power for treatment response. Error bars are the graphical representation of the variability of the data present in the database. CDT, cold detection threshold; CPT, cold pain threshold; HPT, heat pain threshold; MDT, mechanical detection threshold; MPS, mechanical pain sensitivity; MPT, mechanical pain threshold; PPT, pressure pain threshold; QST, quantitative sensory test; TSL, thermal sensory limen; VDT, vibration detection threshold; WDT, warm detection threshold; WUR, wind-up ratio. Reproduced with permission from REF , Baron, R. et al., Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles, Pain, 158, 2, 261–272, http://journals.lww.com/pain/Fulltext/2017/02000/Peripheral_neuropathic_pain___a_mechanism_related.10.aspx

Figure 6. Example interventional treatments for neuropathic pain. a

Spinal cord stimulation traditionally applies a monophasic square-wave pulse (at a frequency in the 30–100 Hz range) that results in paraesthesia in the painful region. b | Cortical stimulation involves the stimulation of the pre-central motor cortex below the motor threshold using either invasive epidural or transcranial non-invasive techniques (such as repetitive transcranial magnetic stimulation (TMS) and transcranial direct current stimulation). c | Deep brain stimulation uses high-frequency chronic intracranial stimulation of the internal capsule, various nuclei in the sensory thalamus, periaqueductal and periventricular grey, motor cortex, septum, nucleus accumbens, posterior hypothalamus and anterior cingulate cortex as potential brain targets for pain control. d | Intrathecal treatments provide a targeted drug delivery option in patients with severe and otherwise refractory chronic pain. The pumps can be refilled through an opening at the skin surface.