Analgesic strategies for ischaemic pain in chronic limb–threatening ischaemia: a systematic review and meta-analysis

To evaluate the effectiveness of pharmacological (eg, ketamine, lidocaine) and nonpharmacological (eg, spinal cord stimulation, mononuclear cell therapy) analgesic strategies-outside the WHO pain ladder-for patients with chronic limb-threatening ischaemia (CLTI). A systematic review and meta-analysis was conducted in accordance with PRISMA guidelines, searching 5 electronic databases for studies evaluating analgesia in CLTI. Both randomised and nonrandomised studies were included. Standardised mean differences (SMDs) in post-treatment pain scores were extracted or calculated, and random-effects meta-analyses performed for comparable studies. Twenty-one studies met inclusion criteria. Most investigated mononuclear cell therapy, hepatocyte growth factor, or prostaglandin infusions. Meta-analyses of mononuclear cell therapy vs standard treatment at 3 months showed significant benefit (3 studies; SMD = -2.12, 95% confidence interval [CI] -3.19 to -1.05, <i>P</i> = 0.001, I² = 86.95%). At 6 months, benefit persisted (3 studies; SMD = -2.54, 95% CI -3.95 to -1.14, <i>P</i> = 0.0004, I² = 92.0%). Across studies, mononuclear cell therapy showed the largest effect sizes but was associated with high heterogeneity and, due to restrictive exclusion criteria, had limited generalisability and poor practicality. Hepatocyte growth factor therapy showed a nonsignificant trend towards pain reduction, and prostaglandin infusion demonstrated no meaningful effect; both excluded large proportions of the CLTI cohort. Of the single-study interventions, subcutaneous lidocaine and ketamine provided short-term analgesic benefit with acceptable safety, whereas others did not produce statistically significant improvements. Pharmacological management of pain in CLTI remains challenging. No recommendations can be made for agents outside standard care. Several novel approaches, including ketamine and subcutaneous lidocaine, warrant further investigation. Further research into novel analgesics for CLTI is urgently needed.