BackgroundNon-specific acute low back pain (LBP) is a common health problem that may be accompanied by muscle spasm and decreased mobility. The combination of non-steroidal anti-inflammatory drugs and muscle relaxants represents an advantageous therapeutic option, however, available data on their combined use are conflicting.This prospective, randomized, single-blind, two-parallel-group trial assessed the efficacy of a single intramuscular (IM) injection of the fixed-dose combination (FDC) diclofenac (75 mg)-thiocolchicoside (4 mg/4 ml) product (test treatment) compared to diclofenac (75 mg/3 ml) alone (reference treatment) for the symptomatic relief of acute LBP. Tolerability and safety were also assessed as secondary variables.MethodsOne hundred thirty-four patients were enrolled (safety population) and randomly allocated to the combination or single-agent regimen. Pain intensity and muscle spasm, assessed respectively by the patient-reported visual analogue scale and investigator-performed finger-to-floor distance test, were determined prior to the injection as well as 1 and 3 h post-injection in 123 patients (per-protocol population). The patients were blinded to treatment. Safety was assessed up to 24 h post-injection.ResultsThe test treatment was superior in both alleviating the pain intensity and reducing the finger-to-floor distance at both 1 (p< 0.01 andp= 0.023 respectively) and 3 h post-injection (p< 0.01). A higher percentage of patients experienced > 30% reduction in pain intensity at 1 and 3 h with the test treatment (p= 0.037 andp< 0.01 respectively). The corresponding VAS (SD) scores for the test treatment group were at baseline, 1 and 3 h post-injection 72.03 (± 11.72), 45.37 (± 16.28) and 31.56 (± 15.08) respectively and for the reference treatment group 65.20 (± 12.16), 48.98 (± 18.76) and 44.52 (± 17.33) respectively. No adverse effects were reported with the combination treatment, whereas two patients treated with diclofenac reported dizziness.ConclusionsThe FDC treatment is an effective and well-tolerated option for the symptomatic treatment of LBP. Clinical and patient-reported assessments confirmed that a single IM injection of FDC diclofenac-thiocolchicoside was more effective than diclofenac alone in conferring rapid and sustained improvement in mobility and pain intensity.Trial registrationEudraCT No: 2017–004530-29 Available athttps://eudract.ema.europa.eu/Registered 04 Dec 2017.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12891-023-06599-0.