Phenotyping peripheral neuropathies with and without pruritus: a cross-sectional multicenter study.

ABSTRACT: Pruritus often escapes physicians' attention in patients with peripheral neuropathy (PNP). Here we aimed to characterize neuropathic pruritus in a cohort of 191 patients with PNP (large, mixed, or small fiber) and 57 control subjects with deep phenotyping in a multicenter cross-sectional observational study at 3 German sites. All participants underwent thorough neurological examination, nerve conduction studies, quantitative sensory testing, and skin biopsies to assess intraepidermal nerve fiber density. Patients filled in a set of questionnaires assessing the characteristics of pruritus and pain, the presence of depression and anxiety, and quality of life. Based on the severity of pruritus and pain, patients were grouped into 4 groups: "pruritus," "pain," "pruritus and pain," and "no pruritus/no pain." Although 11% (21/191) of patients reported pruritus as their only symptom, further 34.6% (66/191) reported pruritus and pain. Patients with pain (with or without pruritus) were more affected by anxiety, depression, and reduced quality of life than control subjects. Patients with pruritus (with and without pain) had increases in cold detection threshold, showing Aδ-fiber dysfunction. The pruritus group had lower intraepidermal nerve fiber density at the thigh, concomitant with a more proximal distribution of symptoms compared with the other PNP groups. Stratification of patients with PNP by using cross-sectional datasets and multinominal logistic regression analysis revealed distinct patterns for the patient groups. Together, our study sheds light on the presence of neuropathic pruritus in patients with PNP and its relationship with neuropathic pain, outlines the sensory and structural abnormalities associated with neuropathic pruritus, and highlights its impact on anxiety levels.

Perioperative pain management for appendicectomy: A systematic review and Procedure-specific Postoperative Pain Management recommendations.

BACKGROUND: Despite being a commonly performed surgical procedure, pain management for appendicectomy is often neglected because of insufficient evidence on the most effective treatment options. OBJECTIVE: To provide evidence-based recommendations by assessing the available literature for optimal pain management after appendicectomy. DESIGN AND DATA SOURCES: This systematic review-based guideline was conducted according to the PROSPECT methodology. Relevant randomised controlled trials, systematic reviews and meta-analyses in the English language from January 1999 to October 2022 were retrieved from MEDLINE, Embase and Cochrane Databases using PRISMA search protocols. ELIGIBILITY CRITERIA: We included studies on adults and children. If articles reported combined data from different surgeries, they had to include specific information about appendicectomies. Studies needed to measure pain intensity using a visual analogue scale (VAS) or a numerical rating scale (NRS). Studies that did not report the precise appendicectomy technique were excluded. RESULTS: Out of 1388 studies, 94 met the inclusion criteria. Based on evidence and consensus, the PROSPECT members agreed that basic analgesics [paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs)] should be administered perioperatively for open and laparoscopic appendicectomies. A laparoscopic approach is preferred because of lower pain scores. Additional recommendations for laparoscopic appendicectomies include a three-port laparoscopic approach and the instillation of intraperitoneal local anaesthetic. For open appendicectomy, a preoperative unilateral transverse abdominis plane (TAP) block is recommended. If not possible, preincisional infiltration with local anaesthetics is an alternative. Opioids should only be used as rescue analgesia. Limited evidence exists for TAP block in laparoscopic appendicectomy, analgesic adjuvants for TAP block, continuous wound infiltration after open appendicectomy and preoperative ketamine and dexamethasone. Recommendations apply to children and adults. CONCLUSION: This review identified an optimal analgesic regimen for open and laparoscopic appendicectomy. Further randomised controlled trials should evaluate the use of regional analgesia and wound infiltrations with adequate baseline analgesia, especially during the recommended conventional three-port approach. REGISTRATION: The protocol for this study was registered with the PROSPERO database (Registration No. CRD42023387994).

Phenotype- and species-specific skin proteomic signatures for incision-induced pain in humans and mice.

BACKGROUND: Acute pain after surgery is common and often leads to chronic post-surgical pain, but neither treatment nor prevention is currently sufficient. We hypothesised that specific protein networks (protein-protein interactions) are relevant for pain after surgery in humans and mice. METHODS: Standardised surgical incisions were performed in male human volunteers and male mice. Quantitative and qualitative sensory phenotyping were combined with unbiased quantitative mass spectrometry-based proteomics and protein network theory. The primary outcomes were skin protein signature changes in humans and phenotype-specific protein-protein interaction analysis 24 h after incision. Secondary outcomes were interspecies comparison of protein regulation as well as protein-protein interactions after incision and validation of selected proteins in human skin by immunofluorescence. RESULTS: Skin biopsies in 21 human volunteers revealed 119/1569 regulated proteins 24 h after incision. Protein-protein interaction analysis delineated remarkable differences between subjects with small (low responders, n=12) and large incision-related hyperalgesic areas (high responders, n=7), a phenotype most predictive of developing chronic post-surgical pain. Whereas low responders predominantly showed an anti-inflammatory protein signature, high responders exhibited signatures associated with a distinct proteolytic environment and persistent inflammation. Compared to humans, skin biopsies in mice habored even more regulated proteins (435/1871) 24 h after incision with limited overlap between species as assessed by proteome dynamics and PPI. Immunohistochemistry confirmed the expression of high priority candidates in human skin biopsies. CONCLUSIONS: Proteome profiling of human skin after incision revealed protein-protein interactions correlated with pain and hyperalgesia, which may be of potential significance for preventing chronic post-surgical pain. Importantly, protein-protein interactions were differentially modulated in mice compared to humans opening new avenues for successful translational research.

Assessing outcome in postoperative pain trials: are we missing the point? A systematic review of pain-related outcome domains reported in studies early after total knee arthroplasty.

ABSTRACT: The management of acute postoperative pain remains suboptimal. Systematic reviews and Cochrane analysis can assist with collating evidence about treatment efficacy, but the results are limited in part by heterogeneity of endpoints in clinical trials. In addition, the chosen endpoints may not be entirely clinically relevant. To investigate the endpoints assessed in perioperative pain trials, we performed a systematic literature review on outcome domains assessing effectiveness of acute pain interventions in trials after total knee arthroplasty. We followed the Cochrane recommendations for systematic reviews, searching PubMed, Cochrane, and Embase, resulting in the screening of 1590 potentially eligible studies. After final inclusion of 295 studies, we identified 11 outcome domains and 45 subdomains/descriptors with the domain "pain"/"pain intensity" most commonly assessed (98.3%), followed by "analgesic consumption" (88.8%) and "side effects" (75.3%). By contrast, "physical function" (53.5%), "satisfaction" (28.8%), and "psychological function" (11.9%) were given much less consideration. The combinations of outcome domains were inhomogeneous throughout the studies, regardless of the type of pain management investigated. In conclusion, we found that there was high variability in outcome domains and inhomogeneous combinations, as well as inconsistent subdomain descriptions and utilization in trials comparing for effectiveness of pain interventions after total knee arthroplasty. This points towards the need for harmonizing outcome domains, eg, by consenting on a core outcome set of domains which are relevant for both stakeholders and patients. Such a core outcome set should include at least 3 domains from 3 different health core areas such as pain intensity, physical function, and one psychological domain.