Stem Cell Therapies for Pain Management: Trends and Insights From Clinical Trials (2007–2025)

METHODS

We conducted a landscape analysis of clinical trials evaluating stem cell therapies for pain management using the Trialtrove database. Interventional trials involving stem cell–based interventions were included, while non-stem cell and observational studies were excluded. Data extracted included trial phase, status, outcomes, primary endpoints, stem cell type, pain indication, sponsor, and geographic distribution. All data were independently verified by two investigators.

RESULTS

Between 2007 and 2025, the number of clinical trials evaluating stem cell therapies for pain management fluctuated, with peaks observed in 2015 and 2019 (Figure 1A; Supplemental Digital Content S1, Table 1, https://links.lww.com/AA/F764). Most trials were early-phase studies, with 34 of 108 (31.5%) phase II and 33 of 108 (30.6%) phase I/II trials predominating, while only 11 of 108 (10.2%) had progressed to phase III or IV, indicating an overall early stage of clinical development. Among all trials, 70 of 108 (64.8%) were completed. Among the completed trials, 38 of 70 (54.3%) reported positive outcomes, 2 of 70 (2.9%) reported negative outcomes, and 30 of 70 (42.9%) did not disclose results. Ongoing trials accounted for 24 of 108 (22.2%), and 12 of 108 (11.1%) were terminated.

MSCs overwhelmingly dominated the clinical landscape, accounting for 101 of 108 (93.5%) of all trials. This predominance may reflect their accessibility and regulatory feasibility relative to other stem cell types. MSC sources included bone marrow, adipose tissue, umbilical cord, cord blood, placenta, and synovium. Autologous and allogeneic approaches were nearly equally represented, at 55 of 108 (50.9%) and 53 of 108 (49.1%), respectively (Figure 1C; Supplemental Digital Content S2, Table 2, https://links.lww.com/AA/F764). Primary endpoints most frequently included Visual Analog Scale (VAS) pain scores (51/108 [47.2%]), adverse events (39/108 [36.1%]), and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (28/108 [25.9%]) (Figure 1D; Supplemental Digital Content S3, Table 3, https://links.lww.com/AA/F764).

Target indications were primarily knee osteoarthritis (50/108 [46.3%]), discogenic low back pain (17/108 [15.7%]), and neuropathic pain associated with spinal cord injury (7/108 [6.5%]). In knee osteoarthritis, adipose-derived MSCs (19/50 [38%]) and bone marrow–derived MSCs (14/50 [28%]) were most frequently studied. Discogenic low back pain trials predominantly employed bone marrow–derived MSCs (6/17 [35.3%]) and adipose-derived MSCs (5/17 [29.4%]), while spinal cord injury–associated neuropathic pain trials most commonly used bone marrow–derived MSCs (4/7 [57.1%]) and umbilical cord–derived MSCs (2/7 [28.6%]) (Figure 2; Supplemental Digital Content S4, Table 4, https://links.lww.com/AA/F764). Trials were predominantly conducted in the United States (23/108 [21.3%]) and China (19/108 [17.6%]) (Supplemental Digital Content S5, Table 5, https://links.lww.com/AA/F764), with academic institutions serving as the primary sponsors (80/108 [74.1%]) (Supplemental Digital Content S6, Table 6, https://links.lww.com/AA/F764).

DISCUSSION

Stem cell–based therapies represent a conceptually transformative approach to pain management, particularly for patients with limited or transient responses to conventional pharmacological and surgical treatments. Our analysis reveals that the current clinical trial landscape is dominated by early-phase studies focused primarily on knee osteoarthritis, discogenic low back pain, and neuropathic pain following spinal cord injury. Collectively, these trials indicate analgesic benefit associated with regenerative approaches, underscoring their therapeutic potential in pain management (Supplemental Digital Content S7, Table 7, https://links.lww.com/AA/F764).

Across completed trials with available safety data, no serious treatment-related adverse events have been reported within the limited follow-up periods assessed, supporting short-term procedural safety rather than long-term risk assessment (Supplemental Digital Contents S7 and S8, Tables 7 and 8, https://links.lww.com/AA/F764). Mechanistically, the analgesic effects of MSC-based therapies are thought to be mediated predominantly through paracrine mechanisms rather than direct tissue replacement. MSCs secrete a diverse array of cytokines, growth factors, and matrix-regulating proteins that modulate inflammatory tone, promote tissue repair, and influence the neuroimmune microenvironment central to chronic pain persistence.⁴

Nevertheless, several randomized trials have failed to demonstrate clear superiority of stem cell therapies over control interventions, highlighting the substantial placebo response intrinsic to pain research.^5,6 Pain trials are uniquely vulnerable to expectancy-driven effects, necessitating rigorous methodological safeguards. Improved patient selection that accounts for disease stage and psychosocial factors, comprehensive blinding of investigators and outcome assessors with formal assessment of blinding integrity,^7,8 and the use of well-matched or active placebo controls⁹ may help mitigate placebo-related confounding and enhance interpretability.

Regulatory considerations further shape the translational trajectory of regenerative pain therapies.¹⁰ In the United States, placental- and amniotic-derived stem cell products remain restricted to investigational use, while international regulatory frameworks vary substantially, contributing to heterogeneous trial standards. Although emerging guidelines cautiously support the selective use of biologic therapies—such as autologous MSCs, PRP, and amniotic-derived products—for specific musculoskeletal pain conditions, widespread clinical adoption will require regulatory harmonization, standardized manufacturing practices, and rigorously designed late-phase trials. Together, these efforts will be essential to determine whether regenerative therapies can achieve durable, clinically meaningful pain relief beyond placebo effects.

DISCLOSURES

Conflicts of Interest: None. Funding: This research received funding from the Natural Science Foundation of Liaoning Province under Grant No: 2025-BS-0674. This manuscript was handled by: Carole Torsney, PhD, FHEA.