Insula Deep Brain Stimulation for Neuropathic Pain: A Cross-Over, Randomized, Sham-Controlled Trial

Despite neuropathic pain affecting a significant portion of the population, many people still experience refractory conditions. Here, we evaluated the efficacy and safety of posterior-superior insula deep brain stimulation for pharmaco-resistant neuropathic pain. This was a phase 2 randomized, double-blind, sham-controlled, cross-over trial. Subjects with chronic pharmaco-resistant neuropathic pain, whose pain had previously responded to deep repetitive transcranial magnetic stimulation of the posterior-superior insula, underwent stereotactically guided implantation of electrodes targeting this same region. The study comprised three phases: double-blind (2 × three months), single-blind (three months), and open-label (six months). The primary outcome was the proportion of participants achieving ≥30% reduction in average pain intensity compared with baseline. Secondary outcomes included pain interference, quality of life, and neuropsychiatric assessments. Ten participants (80% men; age range: 31-67 years) were enrolled. There was an 82.3% posterior probability that active posterior-superior insula-deep brain stimulation yields a higher responder rate than does sham stimulation after three months, with a 95% credible interval for the difference ranging from 10% to 130%. Probabilities of pain interference score reduction exceeded 95% during follow-up, particularly concerning sleep and mood. Quality-of-life scores also showed significant improvements under active, compared with sham, stimulation treatments. No major adverse events were reported, and the stimulation was well tolerated. This study showed that posterior-superior insula deep brain stimulation is a feasible and potentially useful treatment for people with refractory neuropathic pain, with reasonable safety profiles. Phase 3 trials are warranted to confirm these findings and to explore the applicability of this intervention. The Clinicaltrials.gov registration number for the study is NCT04279548.