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Neuropathic pain is accompanied by both positive and negative sensory signs. To explore the spectrum of sensory abnormalities, 1236 patients with a clinical diagnosis of neuropathic pain were assessed by quantitative sensory testing (QST) following the protocol of DFNS (German Research Network on Neuropathic Pain), using both thermal and mechanical nociceptive as well as non-nociceptive stimuli. Data distributions showed a systematic shift to hyperalgesia for nociceptive, and to hypoesthesia for non-nociceptive parameters. Across all parameters, 92% of the patients presented at least one abnormality. Thermosensory or mechanical hypoesthesia (up to 41%) was more frequent than hypoalgesia (up to 18% for mechanical stimuli). Mechanical hyperalgesias occurred more often (blunt pressure: 36%, pinprick: 29%) than thermal hyperalgesias (cold: 19%, heat: 24%), dynamic mechanical allodynia (20%), paradoxical heat sensations (18%) or enhanced wind-up (13%). Hyperesthesia was less than 5%. Every single sensory abnormality occurred in each neurological syndrome, but with different frequencies: thermal and mechanical hyperalgesias were most frequent in complex regional pain syndrome and peripheral nerve injury, allodynia in postherpetic neuralgia. In postherpetic neuralgia and in central pain, subgroups showed either mechanical hyperalgesia or mechanical hypoalgesia. The most frequent combinations of gain and loss were mixed thermal/mechanical loss without hyperalgesia (central pain and polyneuropathy), mixed loss with mechanical hyperalgesia in peripheral neuropathies, mechanical hyperalgesia without any loss in trigeminal neuralgia. Thus, somatosensory profiles with different combinations of loss and gain are shared across the major neuropathic pain syndromes. The characterization of underlying mechanisms will be needed to make a mechanism-based classification feasible.

Although cold hyperalgesia is a frequent symptom in patients with neuropathic pain, it is poorly understood. We investigated the mechanisms of cold pain by studying the effect of menthol on pain, temperature perception, touch sensation and skin perfusion. In 10 subjects, 40% l-menthol, and ethanol, serving as control, were topically applied to the forearm in a double-blinded two-way crossover study. Menthol induced significant pain and cold sensations, punctate and cold hyperalgesia and an increase in cutaneous perfusion. Other mechano-sensory and thermal tests were unchanged (touch, cold and warm detection thresholds, heat pain threshold; no dynamic and static hyperalgesia, no wind-up). To investigate the underlying mechanisms, the effects of menthol versus ethanol on the dorsum of the hand were tested during A fibre conduction blockade of the superficial radial nerve in another 10 subjects. The block itself led to hypoaesthesia for mechanical stimuli and anaesthesia for cold perception, but induced an increase in cold-mediated pain. This was due to lack of inhibition of C nociceptors normally exerted by concomitant activation of A fibres. Under these conditions, menthol-induced cold sensation and punctate hyperalgesia were abolished. However, menthol induced spontaneous pain with a trend to higher values than without block. Furthermore, the hyperalgesia to cold stimuli, that was already present during A fibre block, was further increased significantly by menthol. We suggested that menthol acts to sensitize cold-sensitive peripheral vasoactive C nociceptors and activates cold-specific A delta fibres. Punctate hyperalgesia is due to central sensitization based on the ongoing activity in the sensitized cold-sensitive peripheral C nociceptors. In conclusion, topical menthol is a human model for cold pain by exposing for the first time the mechanism of sensitized peripheral cold C nociceptors that may also be involved in neuropathic pain.

Pain is a nonmotor symptom that substantially affects the quality of life of at least one-third of patients with Parkinson disease (PD). Interestingly, patients with PD frequently report different types of pain, and a successful approach to distinguish between these pains is required so that effective treatment strategies can be established. Differences between these pains are attributable to varying peripheral pain mechanisms, the role of motor symptoms in causing or amplifying pain, and the role of PD pathophysiology in pain processing. In this Review, we propose a four-tier taxonomy to improve classification of pain in PD. This taxonomy assigns nociceptive, neuropathic and miscellaneous pains to distinct categories, as well as further characterization into subcategories. Currently, treatment of pain in PD is based on empirical data only, owing to a lack of controlled studies. The facultative symptom of 'dopaminergically maintained pain' refers to pain that benefits from antiparkinson medication. Here, we also present additional pharmacological and nonpharmacological treatment approaches, which can be targeted to a specific pain following classification using our taxonomy.