The nationwide multicenter trials of the German Research Network on Neuropathic Pain (DFNS) aim to characterize the somatosensory phenotype of patients with neuropathic pain. For this purpose, we have implemented a standardized quantitative sensory testing (QST) protocol giving a complete profile for one region within 30 min. To judge plus or minus signs in patients we have now established age- and gender-matched absolute and relative QST reference values from 180 healthy subjects, assessed bilaterally over face, hand and foot. We determined thermal detection and pain thresholds including a test for paradoxical heat sensations, mechanical detection thresholds to von Frey filaments and a 64 Hz tuning fork, mechanical pain thresholds to pinprick stimuli and blunt pressure, stimulus/response-functions for pinprick and dynamic mechanical allodynia, and pain summation (wind-up ratio). QST parameters were region specific and age dependent. Pain thresholds were significantly lower in women than men. Detection thresholds were generally independent of gender. Reference data were normalized to the specific group means and variances (region, age, gender) by calculating z-scores. Due to confidence limits close to the respective limits of the possible data range, heat hypoalgesia, cold hypoalgesia, and mechanical hyperesthesia can hardly be diagnosed. Nevertheless, these parameters can be used for group comparisons. Sensitivity is enhanced by side-to-side comparisons by a factor ranging from 1.1 to 2.5. Relative comparisons across body regions do not offer advantages over absolute reference values. Application of this standardized QST protocol in patients and human surrogate models will allow to infer underlying mechanisms from somatosensory phenotypes.

Current IASP diagnostic criteria for CRPS have low specificity, potentially leading to overdiagnosis. This validation study compared current IASP diagnostic criteria for CRPS to proposed new diagnostic criteria (the “Budapest Criteria”) regarding diagnostic accuracy. Structured evaluations of CRPS-related signs and symptoms were conducted in 113 CRPS-I and 47 non-CRPS neuropathic pain patients. Discriminating between diagnostic groups based on presence of signs or symptoms meeting IASP criteria showed high diagnostic sensitivity (1.00), but poor specificity (0.41), replicating prior work. In comparison, the Budapest clinical criteria retained the exceptional sensitivity of the IASP criteria (0.99), but greatly improved upon the specificity (0.68). As designed, the Budapest research criteria resulted in the highest specificity (0.79), again replicating prior work. Analyses indicated that inclusion of four distinct CRPS components in the Budapest Criteria contributed to enhanced specificity. Overall, results corroborate the validity of the Budapest Criteria and suggest they improve upon existing IASP diagnostic criteria for CRPS.

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.

That a minor injury can trigger a complex regional pain syndrome (CRPS) - multiple system dysfunction, severe and often chronic pain and disability - has fascinated scientists and perplexed clinicians for decades. However, substantial advances across several medical disciplines have recently increased our understanding of CRPS. Compelling evidence implicates biological pathways that underlie aberrant inflammation, vasomotor dysfunction, and maladaptive neuroplasticity in the clinical features of CRPS. Collectively, the evidence points to CRPS being a multifactorial disorder that is associated with an aberrant host response to tissue injury. Varying susceptibility to perturbed regulation of any of the underlying biological pathways probably accounts for the clinical heterogeneity of CRPS.

This study showed reorganization of the S1 cortex contralateral to the CRPS affected side. The reorganization appeared to be linked to complaints of neuropathic pain.

Changes of the somatotopic map within the S1 cortex may depend on CRPS pain and its recovery.

The aim of this study was to evaluate the psychophysical effects of both TRPA1 and TRPM8 activation in humans by application of either cinnamaldehyde or menthol. We applied 10% cinnamaldehyde or 40% menthol solutions on the forearm in 10 study participants. Quantitative sensory testing and laser Doppler imaging was performed before and after exposure to the compounds. Cinnamaldehyde evoked significant spontaneous pain and induced heat and mechanical hyperalgesia, cold hypoalgesia and a neurogenic axon reflex erythema. In contrast, TRPM8 activation by menthol produced no axon reflex reaction and resulted in cold hyperalgesia. We conclude that agonists of TRPA1 and TRPM8 channels produce strikingly different psychophysical patterns.

The complex regional pain syndrome (CRPS) is a disabling neuropathic pain condition that may develop following injuries of the extremities. In the present study we sought to characterize motor dysfunction in CRPS patients using kinematic analysis and functional imaging investigations on the cerebral representation of finger movements. Firstly, 10 patients and 12 healthy control subjects were investigated in a kinematic analysis assessing possible changes of movement patterns during target reaching and grasping. Compared to controls, CRPS patients particularly showed a significant prolongation of the target phase in this paradigm. The pattern of motor impairment was consistent with a disturbed integration of visual and proprioceptive inputs in the posterior parietal cortex. Secondly, we used functional MRI (fMRI) and investigated cortical activations during tapping movements of the CRPS-affected hand in 12 patients compared to healthy controls (n = 12). During finger tapping of the affected extremity, CRPS patients showed a significant reorganization of central motor circuits, with an increased activation of primary motor and supplementary motor cortices (SMA). Furthermore, the ipsilateral motor cortex showed a markedly increased activation. When the individual amount of motor impairment was introduced as regressor in the fMRI analysis, we were able to demonstrate that activations of the posterior parietal cortices (i.e. areas within the intraparietal sulcus), SMA and primary motor cortex were correlated with the extent of motor dysfunction. In summary, the results of this study suggest that substantial adaptive changes within the central nervous system may contribute to motor symptoms in CRPS.