The Analgesic Efficacy of Therapies Used for Complex Regional Pain Syndrome: A Systematic Review.

Complex regional pain syndrome (CRPS) is a debilitating chronic pain condition that may develop after fractures, surgery, or soft tissue trauma. It is characterized by pain disproportionate to the initial injury, often accompanied by sensory, motor, autonomic, and trophic changes. Despite extensive research, pathophysiology remains unclear, and treatment approaches are varied, with inconsistent supporting evidence. Given its complexity and the potential for chronic disability, identifying effective therapies remains a clinical priority. This review systematically evaluated the analgesic efficacy of pharmacological and non-pharmacological therapies for CRPS, based on randomized controlled trials (RCTs) published between 2003 and 2025. The protocol was developed previously and registered in PROSPERO (CRD420251026503). A structured literature search using a PICO (Population, Intervention, Comparator, Outcome) framework was conducted across MEDLINE, PubMed, and the Cochrane Library. Search terms included "Complex Regional Pain Syndrome," its earlier term "Reflex Sympathetic Dystrophy," and intervention-specific keywords. Included were English-language RCTs in adults with clinically diagnosed CRPS (type I or II), assessing pain reduction as the primary outcome and function, quality of life, and pain medication use as secondary outcomes. Two reviewers independently screened and extracted studies. Risk of bias was assessed using the Cochrane Risk of Bias (ROB) 2. Publication bias was evaluated using funnel plots of standard errors and effect sizes. In total, 45 RCTs met the inclusion criteria and included 2,125 patients. Among pharmacological interventions, bisphosphonates showed consistent and significant pain reduction over six months. Intravenous ketamine demonstrated strong short-term analgesia, though findings were limited by small samples, variable protocols, and lack of long-term data. Combinations of local anesthetics and other medications (e.g., lidocaine with citalopram or parecoxib) were especially effective in acute CRPS. Steroid treatments (oral or regional) offered short-term pain relief and functional improvement, particularly in early or post-stroke CRPS. Non-pharmacological therapies also showed promise in reducing CRPS pain. Mirror therapy (MT) and graded motor imagery (GMI) consistently improved pain and motor function, especially when applied early. Pain exposure physical therapy (PEPT) improved range of motion but had a limited impact on overall functional outcomes. Neuromodulation methods, including spinal cord stimulation (SCS), dorsal root ganglion (DRG) stimulation, and transcutaneous electrical nerve stimulation (TENS), provided durable pain relief in select patients but were technically complex and associated with complications, particularly with SCS. In conclusion, CRPS remains a complex and difficult-to-treat condition, with substantial variability in treatment response. RCT evidence supports the use of bisphosphonates, ketamine, and early use of mirror or motor imagery therapies. Neuromodulation via electrical stimulation may benefit select cases but carries procedural risks. Physiotherapeutic strategies offer low-cost, low-risk benefits, especially when started early or combined with pharmacotherapy. However, many studies were limited by small size, short follow-up, or methodological flaws. There is an urgent need for large, high-quality, and mechanistically informed RCTs to guide long-term CRPS management.