Neuropathic pain: a practical guide for the clinician

Abstract

Neuropathic pain, caused by various central and peripheral nerve disorders, is especially problematic because of its severity, chronicity and resistance to simple analgesics. The condition affects 2%-3% of the population, is costly to the health care system and is personally devastating to the people who experience it. The diagnosis of neuropathic pain is based primarily on history (e.g., underlying disorder and distinct pain qualities) and the findings on physical examination (e.g., pattern of sensory disturbance); however, several tests may sometimes be helpful. Important pathophysiologic mechanisms include sodium-and calcium-channel upregulation, spinal hyperexcitability, descending facilitation and aberrant sympathetic-somatic nervous system interactions. Treatments are generally palliative and include conservative nonpharmacologic therapies, drugs and more invasive interventions (e.g., spinal cord stimulation). Individualizing treatment requires consideration of the functional impact of the neuropathic pain (e.g., depression, disability) as well as ongoing evaluation, patient education, reassurance and specialty referral. We propose a primary care algorithm for treatments with the most favourable risk-benefit profile, including topical lidocaine, gabapentin, pregabalin, tricyclic antidepressants, mixed serotonin-norepinephrine reuptake inhibitors, tramadol and opioids. The field of neuropathic pain research and treatment is in the early stages of development, with many unmet goals. In coming years, several advances are expected in the basic and clinical sciences of neuropathic pain, which will provide new and improved therapies for patients who continue to experience this disabling condition.

Fig. 1: Man with postherpetic neuralgia in the left fifth and sixth thoracic dermatomes. Red lines delineate area of sensory loss, and black dashed lines delineate area of allodynia (touch-evoked pain). Extension of allodynia above and below the originally affected dermatomes is a feature of central sensitization.

Box 1

Fig. 2: Neuropathic pain arises following nerve injury or dysfunction. A: After nerve damage, transcription and axonal trafficking of sodium channels to the site of injury is increased, with concomitant attenuation of potassium channels. The altered expression of ion channels results in neurons becoming hyperexcitable and generating ectopic activity, which is thought to lead to the genesis of spontaneous and paroxysmal pain. B: At the cell body of primary afferent neurons within the dorsal root ganglia (DRG), sympathetic neuronal sprouting occurs and may account for sympathetically maintained pain. C: Peripheral nerve injury causes a multitude of changes in gene transcription and activation of various kinases and proteins, including enhanced N-methyl-D-aspartate (NMDA) receptor activity. However, nerve injury also elicits hypertrophy and activation of glial cells, including microglia within the grey matter of the spinal cord. Microglia express P2X4 purinergic receptors, allowing them to be activated by adenosine triphosphate (ATP). Following activation, microglia release various pronociceptive cytokines, such as interleukin-1 (IL-1), tumour necrosis factor alpha (TNF-α) and neurotrophins, including brain-derived neurotrophic factor, which in turn exacerbates nociceptive transmission and contributes to the sensitization and maintenance of neuropathic pain. Note: Aβ = A beta neuron, Aδ = A delta neuron, C = C nociceptor, 5HT = serotonin, KCC2 = chloride transporter, NA = noradrenaline, Na_v = sodium channel, NO = nitric oxide, K_v = potassium channel, PGs = prostaglandins, PKs = protein kinases, P2X4 = purinergic receptor.

Fig. 3: Algorithm for the management of neuropathic pain in primary care.