2026-08-07 | Intravenous ketamine for complex regional pain syndrome: Pain outcomes and predictors of response. A systematic review and meta‑analysis.
Intravenous ketamine is used for complex regional pain syndrome (CRPS), but variable response and uncertain durability limit patient selection. This systematic review evaluated reported predictors of response to intravenous ketamine in CRPS and quantified the extent and duration of pain relief. The protocol is registered in PROSPERO (CRD420250655066). Databases were searched from inception through March 26, 2026. Randomized trials and observational studies reporting intravenous ketamine in CRPS were included. Pain scores were rescaled to a 0-10 scale, and the mean difference in change from baseline was pooled for the earliest post-infusion assessment within 14 days using inverse-variance random-effects meta-analysis. Random-effects meta-regression modeled outcomes at 14 days or later. Predictors of response were synthesized narratively. Twenty-one studies (3 randomized trials) included 605 ketamine-treated patients, with most studies having a moderate to high risk of bias. The pooled mean baseline pain score was 7.4. At the earliest post-infusion assessment within 14 days, the mean change in pain was -3.6 (95%CI -4.7 to -2.5). Limited longer-term data up to 90 days suggested attenuation of effect, with a gradual return toward baseline. Responder definitions varied widely, with a median responder rate of 65% (range 0-100%). Only 3 studies formally evaluated predictors, and quantitative synthesis was not feasible. Reported associations included sympathetically maintained pain (aOR 6.54, 95%CI 1.83-23.44) and obesity (aOR 8.75, 95%CI 1.45-52.73). Other exploratory predictors included bone scintigraphy phase ratios and baseline microRNAs. Intravenous ketamine may reduce pain, but limited predictor evidence precludes firm conclusions for individualized treatment selection. PERSPECTIVE: This systematic review supports intravenous ketamine as a potential interventional option for complex regional pain syndrome, while emphasizing that standardized outcome reporting and validated predictors are needed before treatment can be reliably individualized.
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2026-08-05 | Why do bisphosphonates work in the treatment of CRPS? A translational pharmacological perspective to solve a conundrum.
Bisphosphonates (BPs) have consistently yielded positive results in the treatment of Complex Regional Pain Syndrome (CRPS). However, biochemical and histopathological evidence suggests that osteoclasts, the primary pharmacological target of BPs, is not a key driver in the early pathogenetic steps of CRPS. To critically review and integrate current evidence on pharmacological mechanisms of action of BPs in CRPS and to propose unifying hypotheses explaining their clinical efficacy beyond antiosteoclastic activity. Literature from in vitro studies, animal models, and randomized clinical trials was integrated. Approximately 80 primary and review articles were critically reviewed. BPs efficacy in CRPS is best explained by a bone-driven pharmacological model by which local drug accumulation is achieved in the site of disease. This enables modulation of inflammatory and nociceptive processes on adjacent non-bone cells, including macrophages, neutrophils, keratinocytes, and nociceptive fibers. Inhibition of the mevalonate pathway in these cells may reduce inflammatory cytokines, nerve growth factor (NGF), and reactive oxygen species (ROS), while modulating nociceptive signaling pathways. Additional mechanisms, including modulation of vascular tone and neuropeptide signaling, may further contribute to therapeutic effects. This hypothesis may inform optimal treatment strategies and together improve understanding of CRPS pathophysiology.
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2026-07-17 | Transradial Amputation With Nerve Management: Case Presentation and Surgical Technique.
Transradial amputation of appropriate length preserves forearm rotation and facilitates prosthetic use; however, high rates of phantom limb pain and neuropathic medication use persist. This case describes a multidisciplinary approach to transradial amputation that integrates targeted muscle reinnervation, regenerative peripheral nerve interfaces, and bone and soft tissue management to optimize pain control and prosthetic success. A 29-year-old man with a severe ballistic injury and complex regional pain syndrome underwent transradial amputation with targeted muscle reinnervation and regenerative peripheral nerve interface. Limb length was preserved in accordance with prosthetic guidelines, and myodesis was performed to improve residual limb stability and myoelectric signal quality. This case highlights how nerve management and prosthetic-informed surgical planning optimizes functional outcomes and quality of life after traumatic transradial amputation.
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2026-07-14 | Advances in evidence-based management of complex regional pain syndrome
Use of the best available evidence is fundamental to management of complex regional pain syndrome (CRPS), a rare and debilitating chronic pain disorder. While understanding of CRPS has evolved in recent decades, important clinical and research challenges remain. This thesis aimed to provided new evidence to advance CRPS management. Chapter Two showed that while the evidence supporting most CRPS interventions is of poor methodological quality, bisphosphonates, N-methyl D-aspartate receptor antagonists, and sensorimotor rehabilitation are promising treatments. Chapter Three found moderate certainty evidence that bisphosphonates may be effective for CRPS and identified important treatment effect modifiers that warrant further investigation before clinical implementation. Chapter Four found no clear evidence for the efficacy of ketamine and other N-methyl D-aspartate receptor antagonists for chronic pain. Chapter Five developed a guideline-informed, evidence-based treatment algorithm to inform international management of CRPS. Chapter Six outlined the design and analysis plan of MEMOIR, a 2x2 factorial randomised trial of memantine and graded motor imagery for CRPS. Chapter Seven provided data on the progress, participant characteristics, treatment adherence and safety of MEMOIR, showing rapid participant accrual and high follow-up rates. This program of work provides new evidence to improve the evidence-based management of CRPS by addressing important evidence gaps and proposing potential solutions to advance treatment identification and evaluation.
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2026-07-14 | Inhibition of Janus kinase/signal transducer and activator of transcription reduces nociceptive sensitization in a murine model of complex regional pain syndrome.
Complex regional pain syndrome (CRPS) is a disabling condition relying in part on the production of pain-supporting autoantibodies. The Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling system regulates the adaptive system of immunity and is targeted to control autoimmune diseases. To evaluate the hypothesis that JAK-STAT inhibition could reduce the behavioral, cellular, and biochemical correlates of CRPS in a well-characterized murine tibia fracture model. Tofacitinib was used to inhibit JAK-STAT activity. Mechanical sensitization and hindlimb unweighting were used to follow nociceptive changes. Assays of regional lymph node hypertrophy, germinal center formation, and autoantibody production probed activation of adaptive immunity while single cell mass cytometry (CyTOF) identified specific cell sets sensitive to tofacitinib in this model. Tofacitinib reduced hindlimb allodynia and unweighting in male and female mice after tibial fracture. Subsequent experiments focused on male mice showed reduced autoantibody binding to keratin 16, histone 3.2, GFAP, and NMDAR2B in fracture animals treated with tofacitinib. The enhanced deposition of IgM in the skin of fracture limb hind paws was also eliminated by tofacitinib. Correspondingly, tofacitinib reduced lymph node hypertrophy and germinal center formation. Mass cytometry demonstrated that CD4+ and CD8+ T lymphocytes in regional lymph nodes show tofacitinib-sensitive changes in the activation of key immune signaling systems after fracture including BCL6, IkB, pCREB, and pS6. Conversely, enhanced production of the innate immune mediators IL-1β and IL-6 were not suppressed by tofacitinib. We conclude that tofacitinib reduces the regional nociceptive changes found in a murine model of CRPS possibly through inhibition of autoantibody production.
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