Accepted

The National Institutes of Health's Patient-Reported Outcomes Measurement Information System (PROMIS)® includes an item bank for measuring misuse of prescription pain medication (PROMIS-Rx Misuse). The bank was developed and its validity evaluated in samples of community-dwelling adults and patients in addiction treatment programs. The goal of the current study was to investigate the validity of the item bank among patients with mixed-etiology chronic pain conditions.

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.

Background and Purpose- Central poststroke pain (CPSP) is a disabling condition in stroke patients, and evidence suggests that altered corticospinal and motor intracortical excitability occurs in neuropathic pain. The objective of this study was to investigate changes in motor cortex excitability and sensorimotor interaction and their correlates with clinical manifestations and alterations in somatosensory systems in CPSP patients. Methods- Fourteen patients with CPSP but no motor weakness were compared with age- and sex-matched healthy controls for motor cortex excitability and sensorimotor interaction assessed by transcranial magnetic stimulation to measure resting motor thresholds, short-interval intracortical inhibition, intracortical facilitation, and afferent inhibitions. The sensory pathway was evaluated by quantitative sensory testing, contact heat evoked potential, and somatosensory evoked potentials. Clinical pain and quality of life were assessed with validated tools. Results- The duration of CPSP was 3.3±3.0 years (ranging 0.5-10 years), and pain significantly impaired quality of life. Compared with the unaffected hemisphere, the stroke hemisphere had higher thermal thresholds, lower contact heat evoked potential amplitudes, and prolonged cortical somatosensory evoked potential latencies. There was no difference in resting motor thresholds between the stroke and unaffected hemisphere or between patients and controls. CPSP patients had a reduction in short-interval intracortical inhibition in the stroke hemisphere compared with that in the unaffected hemispheres of patients and controls. No changes were noted in afferent inhibitions between the stroke and unaffected hemispheres. The short-interval intracortical inhibition of the stroke hemisphere was negatively correlated with self-rated health on a visual analog scale and positively correlated with cortical somatosensory evoked potential latencies. Conclusions- CPSP patients with intact corticospinal tracts showed reduced motor intracortical inhibition in the stroke hemisphere, suggesting defective gamma-aminobutyric acid-ergic inhibition. This disinhibition was associated with impaired quality of life and was related to dorsal column-medial lemniscus pathway dysfunction.