Efficacy and safety of oral ketamine versus diclofenac to alleviate mild to moderate depression in chronic pain patients: A double-blind, randomized, controlled trial

Seventy-nine patients were screened and 46 were randomised (23 to ketamine, 23 to diclofenac). Forty participants (20 per arm) completed the trial and had the two post-baseline assessments; all dropouts occurred before week 3, so the analysis was performed on these 40 completers. Baseline demographic and clinical characteristics did not differ significantly between groups. HDRS scores showed no baseline difference between groups. A repeated-measures ANOVA identified a significant Time × Intervention interaction on HDRS over the study (F(2,76) = 3.406; P = 0.038). At week 3, HDRS reduction was greater in the ketamine arm (mean reduction 5.55 ± 3.86) than in the diclofenac arm (3.70 ± 3.42), but this difference did not reach statistical significance (mean difference 1.85, 95% CI −0.48 to 4.18; Cohen's d = 0.51; P = 0.117). By week 6 the ketamine group showed significantly larger HDRS improvement (6.95 ± 3.86 vs 4.10 ± 3.34), with a mean difference of 2.85 (95% CI 0.54–5.16), Cohen's d = 0.79, P = 0.017. The HADS depression subscale also showed a significant Time × Treatment interaction (GLM repeated measures F(2,76) = 7.77; P = 0.001), indicating greater reductions in depressive symptoms in the ketamine arm across follow-up. (The extracted text reports statistically lower HADS depression scores in the ketamine group at both week 3 and week 6 in the abstract.) Pain intensity measured by VAS decreased over time in both arms but did not differ between groups at baseline, week 3 or week 6. GLM repeated-measures analysis found no significant Time × Treatment effect for VAS (F = 0.289; P = 0.715), and between-group differences at week 3 and week 6 were non-significant. Treatment response (≥50% HDRS reduction) and remission rates favoured ketamine. At week 3 the difference in response rates was not significant, whereas at week 6 participants receiving ketamine were significantly more likely to respond (reported P = 0.008, odds ratio for response 8.50) and to remit (HDRS ≤7; P = 0.031). Time-to-event analyses showed faster benefit with ketamine: mean time to response 4.80 ± 0.34 weeks versus 5.55 ± 0.28 weeks (Log-Rank P = 0.002), and mean time to remission 5.25 ± 0.30 weeks versus 5.70 ± 0.23 weeks (Log-Rank P = 0.013). Adverse events were generally mild and similar in frequency between groups. No serious adverse events or deaths occurred, and no cardiovascular adverse events were detected on examination and ECG. Individual reports included blurred vision, tremor and abdominal pain (each affecting one participant in both arms) and a transient loss of appetite in one ketamine-treated participant. No participant discontinued treatment because of adverse events.

Jafarinia and colleagues interpret the findings as evidence that oral ketamine 50 mg three times daily produced superior antidepressant effects compared with oral diclofenac in patients with chronic headache and mild-to-moderate depression over a six-week period. The advantage was apparent on both HDRS and HADS depression measures, with higher response and remission rates and shorter times to response and remission in the ketamine arm. Analgesic effects measured by VAS were comparable between ketamine and diclofenac, and both treatments were generally well tolerated without serious adverse events. The authors note that HADS emphasises affective features such as anhedonia and omits somatic items, whereas HDRS includes somatic symptoms; the complementary pattern of findings across these scales is used to argue for broad-spectrum antidepressant activity of oral ketamine in this comorbid pain population. They situate the trial as the first controlled comparison of daily oral ketamine against an active comparator for depression secondary to chronic pain and compare their longer-duration results favourably with prior IV and shorter oral/sublingual studies, suggesting that oral administration may yield clinically meaningful and sustained benefit. Several limitations are acknowledged. The sample size was small, limiting subgroup analyses and generalisability. Follow-up was short, so long-term efficacy, relapse risk and late-emerging adverse effects were not assessed. The study did not investigate molecular mechanisms underlying the antidepressant effects, and oral ketamine's relatively low bioavailability (reported in the text as roughly 17% due to first-pass metabolism to norketamine) could produce variable individual responses. The trial also did not measure abuse potential, which the authors flag as important given preclinical and clinical concerns about repeated ketamine use. Finally, the authors note preclinical signals that S-ketamine may have different neurobiological effects than R-ketamine and suggest that enantiomer-specific safety merits further study. Overall, the investigators recommend larger, longer, and mechanistically oriented trials—including placebo-controlled designs where appropriate—to confirm efficacy, clarify durability, examine safety in the longer term, and explore mechanisms of action for oral ketamine in depressive disorders comorbid with chronic pain.

Oral ketamine given as 50 mg capsules three times daily over six weeks appeared safe and produced greater reductions in depressive symptoms than diclofenac in this small sample of chronic pain patients with mild-to-moderate depression. The authors conclude that oral ketamine may be a viable, non-invasive alternative to IV administration, but they call for larger studies with longer follow-up to confirm these preliminary findings and to assess long-term safety and abuse potential.