Pharmacotherapy of phantom pain in modern condition: clinical approaches, toxicological risks and pharmaceutical provision

Abstract

Phantom pain (PP) is a complex multifactorial neuropathic syndrome that develops as a result of combined peripheral and central mechanisms of damage – ectopic activity of peripheral afferents, central sensitization, neuroplastic reorganization of the somatosensory cortex, and imbalance in the pain modulation system. Under the conditions of the full-scale war in Ukraine the number of patients with mine-blast, gunshot, and polystructural injuries has sharply increased, many of which are accompanied by limb amputations and long-term pain syndromes. According to data from Ukrainian military medical hospitals, amputations account for up to 18% of all combat injuries, and more than 70% of these patients suffer from PP or postamputation neuropathic syndromes. This highlights not only the medical but also the social significance of the problem in the context of rehabilitation of injured soldiers and civilians. The aim of the study – to summarize current scientific evidence on the pathophysiological mechanisms of PP formation and to systematize the evidence base for the effectiveness of pharmacological, neuromodulatory, and psychophysiological treatment methods in patients with combat-related injuries. An analytical review of current literature (PubMed, Scopus, Cochrane Library, 2002–2025) was conducted, including systematic reviews, meta-analyses, and randomized controlled trials evaluating therapeutic strategies for PP and other neuropathic syndromes. The pathogenesis of PP involves both peripheral and central mechanisms, which justify the need for a multimodal approach to therapy. First-line pharmacological agents include gabapentinoids (gabapentin, pregabalin) and antidepressants from the SNRI/TCA classes (duloxetine, amitriptyline). Their combination provides an additive analgesic effect with a lower risk of dose-dependent adverse reactions. The updated Cochrane review confirmed short-term efficacy of morphine, gabapentin, and ketamine, whereas no convincing evidence was found for amitriptyline and memantine. In resistant cases, second-line agents such as dual-action opioids (tapentadol), NMDA receptor antagonists (ketamine, dextromethorphan), and topical agents (5% lidocaine or 8% capsaicin patches) may be considered. Neuromodulation techniques – tDCS, rTMS, SCS, and PNS – have proven effect in reducing pain intensity, particularly when combined with pharmacotherapy and rehabilitation programs. Additionally, psychophysiological methods such as mirror therapy and virtual reality facilitate normalization of somatosensory representation and reduction of central sensitization, demonstrating moderate but clinically meaningful efficacy. Toxicological monitoring remains a critical component of therapy: balanced dosing, individualized treatment, and continuous monitoring of adverse effects help minimize cumulative toxicity during long term analgesic use. Modern management of PP relies on a stepwise multimodal strategy that integrates pharmacological therapy, neuromodulatory techniques, and psychophysiological interventions within a unified rehabilitation framework. However the implementation of such strategies remains limited by systemic issues in pharmaceutical accessibility. Several evidence-based drugs (pregabalin, duloxetine, tapentadol, ketamine) are not reimbursed under the National Health Service of Ukraine Medical Guarantee Program. Incorporating these agents based on formal Health Technology Assessment (HTA) into the National List of Essential Medicines would enhance treatment effectiveness, shorten rehabilitation periods, and promote social reintegration of affected patients.