Efficacy of prolotherapy in comparison to other therapies for chronic soft tissue injuries: A systematic review and network meta-analysis

Abstract

Introduction: Prolotherapy and other injections, primarily acting on pathways associated with maladaptive tissue repair, are recommended for recalcitrant chronic soft tissue injuries (CSTI). However, selection of injection is challenging due to mixed results. This network meta-analysis (NMA) aimed to compare prolotherapy with other therapies, particularly injections, for CSTI and establish robustness of the results.

Methodology: Pubmed, Medline, SPORTDiscus and Google scholar were searched from inception to 4th January 2021 for randomised controlled trials (RCTs) involving injection therapies (e.g. blood derivatives, corticosteroid, hyaluronic acid, botulinum toxin) for CSTI. The primary and secondary outcomes were pain and function, respectively, at (or nearest to) 6 months. Effect size (ES) was presented as standardised mean difference with 95% confidence interval (CI). Frequentist random effect NMA was used to generate the overall estimates, subgroup estimates (by region and measurement time point) and sensitivity analyses.

Results: A total of 91 articles (87 RCTs; 5859 participants) involving upper limb (74%), lower limb (23%) and truncal/hip (3%) injuries were included. At all time points, prolotherapy had no statistically significant pain benefits over other therapies. This observation remained unchanged when tested under various assumptions and with exclusion of studies with high risk of bias. Although prolotherapy did not offer statistically significant functional improvement compared to most therapies, its ES was consistently better than non-injections and corticosteroid injection for both outcomes. At selected time points and for selected injuries, prolotherapy demonstrated potentially better pain improvement over placebo (<4 months: shoulder [ES 0.65; 95% CI 0.00 to 1.30]; 4-8 months: elbow [ES 0.91; 95% CI 0.12 to 1.70]; >8 months: shoulder [ES 2.08; 95% CI 1.49, to 2.68]). Injections generally produced greater ES when combined with non-injection therapy.

Conclusion: While clinical outcomes were generally comparable across types of injection therapy, prolotherapy may be used preferentially for selected conditions at selected times.

Fig 1. PRISMA flow chart.

Fig 2. Network geometry.

Note: BP = blood product; BPcombo = blood product combination therapy; Botox = botulinum toxin; CS = corticosteroid; CScombo = corticosteroid combination therapy; HA = hyaluronic acid; Noninj = non-injections; Pcb = placebo; Prolo = prolotherapy; Prolocombo = prolotherapy combination therapy. The size of the node corresponds to the number of participants assigned to the intervention while thickness of the connecting line corresponds to the number of the studies included.

Fig 3. Interval plot of treatment efficacy relative to placebo.

Note: BP = blood product; BPcombo = blood product combination therapy; Botox = botulinum toxin; CS = corticosteroid; CScombo = corticosteroid combination therapy; HA = hyaluronic acid; Noninj = non-injections; Pcb = placebo; Prolo = prolotherapy.

Fig 4. Risk of bias of individual study.

Fig 5. Functional outcome.

Note: BP = blood product; BPcombo = blood product combination therapy; Botox = botulinum toxin; CS = corticosteroid; CScombo = corticosteroid combination therapy; HA = hyaluronic acid; Noninj = non-injections; Pcb = placebo; Prolo = prolotherapy.