Human Studies

Complex regional pain syndrome (CRPS) typically develops after fracture or trauma. Many of the studies so far have analyzed clinical and molecular markers of CRPS in comparison to healthy or pain controls. This approach, however, neglects mechanisms occurring during physiological trauma recovery. Therefore, we compared the clinical phenotype, sensory profiles, patients reported outcomes (PRO) and exosomal immunobarrier microRNAs (miRs) regulating barrier function and immune response between CRPS and fracture controls (FC) not fulfilling the CRPS diagnostic criteria. We included upper extremity FCs, acute CRPS I patients within one year after trauma, a second disease control group (painful diabetic polyneuropathy, pDN) and healthy controls. FCs were not symptoms-free, but reported some pain, disability, anxiety and cold pain hyperalgesia in quantitative sensory testing (QST). CRPS patients had higher scores for pain, disability and all PROs. In QST, ipsi- and contralateral side differed significantly. However, on the affected side CRPS patients were more sensitive in only three parameters (pinprick pain and blunt pressure) when compared to FCs. Two principal components were identified in the cohort: pain and psychological parameters distinguishing FC and CPRS. Furthermore, the immunobarrier-protective hsa-miR-223-5p was increased in plasma exosomes in FCs with normal healing, but not in CRPS and healthy controls. Low hsa-miR-223-5p was particularly observed in subjects with edema pointing towards barrier breakdown. In summary, normal trauma healing includes some CRPS signs and symptoms. It is the combination of different factors which distinguish CRPS and FC. FC as a control group can assist to discover resolution factors after trauma.

Cutaneous mechanical hyperalgesia can be induced in healthy volunteers in early-phase analgesic studies to model central sensitization, a key mechanism of persistent pain. However, such hyperalgesia is short-lived (a matter of hours), and is used only for assessing only single drug doses. In contrast, post-surgical peri-incisional hyperalgesia may be more persistent, and hence be a more useful model for the assessment of the efficacy of new analgesics. We undertook quantitative sensory testing in 18 patients at peri-incisional and non-operated sites before open inguinal hernia repair and up to the 24 post-surgical week. The spatial extent of punctate hyperalgesia and brush allodynia at the peri-incisional site were greatest at weeks 2 and 4, but had resolved by week 24. Heat allodynia, suggestive of local inflammation or peripheral sensitization, were not observed; instead, there were deficits in cold and heat sensory detection that persisted until week 24. The findings suggest that central sensitization contributes significantly to mechanical hyperalgesia at the peri-incisional site. The prolonged duration of hyperalgesia would be advantageous as a pain model, but there was considerable variability of mechanical hyperalgesia in the cohort; the challenges of recruitment may limit its use to small, early phase analgesic studies. Perspective: Peri-incisional mechanical hyperalgesia persists for at least 4 weeks after open inguinal hernia repair and reflects central sensitization; this may have utility as a model of chronic pain to assess the potential of anti-neuropathic analgesics.

Topical application of lidocaine and prilocaine (LP) cream attenuates the functionality of small cutaneous nerve fibers. The aim of this human study was to measure the underlying excitability modulation of small cutaneous nerve fibers using a novel and fast perception threshold tracking (PTT) technique.

The clinical use of noninvasive cortical stimulation procedures is hampered by the limited duration of the analgesic effects and the need to perform stimulation in hospital settings. Here, we tested the feasibility and pilot efficacy of an internet-based system for at-home, long-duration, medically controlled transcranial motor cortex stimulation (H-tDCS), via a double-blinded, sham-controlled trial in patients with neuropathic pain refractory to standard-of-care drug therapy. Each patient was first trained at hospital, received a stimulation kit, allotted a password-protected Web space, and completed daily tDCS sessions during 5 weeks, via a Bluetooth connection between stimulator and a minilaptop. Each session was validated and internet-controlled by hospital personnel. Daily pain ratings were obtained during 11 consecutive weeks, and afterwards via iterative visits/phone contacts. Twenty full procedures were completed in 12 consecutive patients (500 daily tDCS sessions, including 20% sham). No serious adverse effects were recorded. Superficial burning at electrode position occurred in 2 patients, and nausea/headache in two others, all of whom wished to pursue stimulation. Six out of the 12 patients achieved satisfactory relief on a scale combining pain scores, drug intake, and quality of life. Daily pain reports correlated with such combined assessment, and differentiated responders from nonresponders without overlap. Clinical improvement in responders could last up to 6 months. Five patients asked to repeat the whole procedure when pain resumed again, with comparable results. At-home, long-duration tDCS proved safe and technically feasible, and provided long-lasting relief in 50% of a small sample of patients with drug-resistant neuropathic pain.