Uncertainties in Stem Cell Therapy for Neuropathic Pain in Spinal Cord Injury: Letter to Editor

Dear Editor, With interest, I read the systematic review by Mittal et al.1 in Neurology India, which assesses the role of stem cell therapy in managing neuropathic pain in patients with spinal cord injury (SCI). The authors conclude that stem cell transplantation, particularly using autologous mesenchymal stromal cells (MSCs), shows promise for pain relief, potentially mediated by transforming growth factor β (TGF-β) secretion. However, several methodological and interpretative concerns challenge the robustness of these findings and require clarification to guide clinical practice. Firstly, the review reports variable outcomes regarding neuropathic pain, with some studies noting a reduction in pain intensity,2,3 while others observe an increased incidence post-transplantation.4-6 This inconsistency, evident in 55.8% of patients developing neuropathic pain in one study,4 raises questions about whether stem cell therapy mitigates or exacerbates pain. The authors attribute pain to aberrant axonal regeneration and cytokine upregulation (e.g., IL-1, TNF-α, IL-6), but the lack of standardized pain assessment tools, such as the visual analog scale (VAS) across all studies, limits comparability. I recommend that future trials adopt uniform outcome measures, such as VAS or the neuropathic pain symptom inventory, to enhance consistency. Secondly, the absence of control groups in most included studies (9/15) undermines the ability to attribute outcomes solely to stem cell therapy.1 For instance, studies like those by Vaquero et al.2,3 report improvements in motor, sensory, and bladder functions, but without controls, natural recovery or placebo effects cannot be excluded. The review’s reliance on non-randomized and quasi-experimental designs further introduces selection bias, as noted in 42.8% of studies with attribution bias. Larger, randomized controlled trials (RCTs) with well- defined control groups are essential to establish causality. Thirdly, the review highlights the safety of intrathecal MSC administration, with no serious adverse events reported.1 However, the optimal dosage, frequency, and timing of transplantation remain unclear. Studies like Levi et al.7 and Shin et al.8 were prematurely terminated or limited by short follow-up periods, precluding long-term safety and efficacy data. I suggest that future research focus on dose-escalation studies and extended follow-up to assess the durability of effects and potential late-onset complications, such as neuropathic pain exacerbation. Finally, the review’s inclusion criteria, while adhering to PRISMA guidelines,9 encompass heterogeneous SCI populations (acute, subacute, chronic) and varying injury levels (cervical, thoracic). This heterogeneity complicates the interpretation of neuropathic pain outcomes, as pain mechanisms differ across SCI phases and anatomical levels.10 Stratifying patients by injury phase and level in future studies could clarify the contexts in which stem cell therapy is most effective. Overall, Mittal et al.’s review provides a valuable synthesis of stem cell therapy’s potential in SCI-related neuropathic pain but is limited by inconsistent outcomes, methodological flaws, and small sample sizes. To advance this field, I urge researchers to prioritize RCTs with standardized pain metrics, robust control groups, and long-term follow-up. These steps are critical to establishing stem cell therapy as a reliable treatment for neuropathic pain in SCI. Abbreviations SCI, spinal cord injury; MSC, mesenchymal stromal cells; AIS, American Spinal Injury Association Impairment Scale; TGF-β, transforming growth factor β; PRISMA, preferred reporting items for systematic reviews and meta-analyses; VAS, visual analog scale. Compliance with ethics guidelines This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. Author contribution M. D. drafted, wrote, designed, read, reviewed, and submitted the manuscript. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.