BACKGROUND: This systematic review and meta-analysis seeks to investigate the effectiveness and safety of manual therapy (MT) interventions compared to oral pain medication in the management of neck pain. METHODS: We searched from inception to March 2023, in Cochrane Central Register of Controller Trials (CENTRAL), MEDLINE, EMBASE, Allied and Complementary Medicine (AMED) and Cumulative Index to Nursing and Allied Health Literature (CINAHL; EBSCO) for randomized controlled trials that examined the effect of manual therapy interventions for neck pain when compared to medication in adults with self-reported neck pain, irrespective of radicular findings, specific cause, and associated cervicogenic headaches. We used the Cochrane Risk of Bias 2 tool to assess the potential risk of bias in the included studies, and the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach to grade the quality of the evidence. RESULTS: Nine trials (779 participants) were included in the meta-analysis. We found low certainty of evidence that MT interventions may be more effective than oral pain medication in pain reduction in the short-term (Standardized Mean Difference -0.39; 95% CI -0.66 to -0.11; 8 trials, 676 participants), and moderate certainty of evidence that MT interventions may be more effective than oral pain medication in pain reduction in the long-term (Standardized Mean Difference -0.36; 95% CI -0.55 to -0.17; 6 trials, 567 participants). We found low certainty evidence that the risk of adverse events may be lower for patients that received MT compared to the ones that received oral pain medication (Risk Ratio 0.59; 95% CI 0.43 to 0.79; 5 trials, 426 participants). CONCLUSIONS: MT may be more effective for people with neck pain in both short and long-term with a better safety profile regarding adverse events when compared to patients receiving oral pain medications. However, we advise caution when interpreting our safety results due to the different level of reporting strategies in place for MT and medication-induced adverse events. Future MT trials should create and adhere to strict reporting strategies with regards to adverse events to help gain a better understanding on the nature of potential MT-induced adverse events and to ensure patient safety. TRIAL REGISTRATION: PROSPERO registration number: CRD42023421147.

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