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

Comorbid pain and depression commonly coexist and worsen outcomes for both conditions, increasing disability and economic burden. Recent research has focused on glutamatergic dysfunction in depression and on ketamine, an NMDA receptor antagonist, which has produced rapid but often short-lived antidepressant effects when given intravenously. Practical barriers to repeated IV administration and concerns about durability have stimulated interest in alternative routes of administration such as intranasal, sublingual and oral ketamine. Jafarinia and colleagues set out to evaluate whether a fixed daily oral dose of ketamine could safely and effectively reduce symptoms of mild-to-moderate depression in patients with chronic headache-related pain. The trial compared oral ketamine with oral diclofenac over six weeks in a randomised, double-blind, parallel-group design, aiming to assess depressive symptom change, response and remission rates, pain intensity, and adverse events in this population.

This was a 6-week, randomised, double-blind, controlled, parallel-group outpatient trial conducted at Imam Hospital (Tehran University of Medical Sciences) from January to December 2015. The protocol received institutional ethics approval and participants provided written informed consent. Trial registration is reported (IRCT201508201556N80). Eligible participants were men and women aged 20–55 years with chronic, persistent headache lasting at least six months who required analgesia and met DSM-IV-TR criteria for major depression with mild-to-moderate severity (HDRS score <19 on the 17-item HDRS). Key exclusions included recent antidepressant use, recent ECT, other DSM-IV Axis I disorders, substance dependence (except nicotine), severe depression or suicidality, relevant medical contraindications (cardiovascular disease, intracranial pathology, glaucoma, pregnancy/lactation), and concomitant medications with major interactions with ketamine. Intervention arms received either oral ketamine 50 mg capsules three times daily (total 150 mg/day) or oral diclofenac 50 mg capsules three times daily for six weeks. Capsules were manufactured to be indistinguishable and participants were not permitted other psychotropic treatments or behavioural therapy during the trial. Adherence was monitored by weekly capsule counts. Primary and secondary outcomes were measured at baseline, week 3 and week 6. The primary outcome was change in depressive symptoms measured by the HDRS, analysed using repeated-measures models. Secondary outcomes included HADS depression subscale scores, response (≥50% HDRS reduction), remission (HDRS ≤7), pain intensity by visual analogue scale (VAS 0–100), time to response/remission, and adverse events collected via checklist with an open-ended prompt. A sample size of 46 (allowing for 10% attrition) was calculated to detect a projected difference (57% response for ketamine vs 18% for diclofenac) with 80% power and α = 0.05. Randomisation used a computer-generated sequence with 1:1 allocation in blocks of four, administered by an independent party and concealed in sequentially numbered, sealed, opaque envelopes. Participants, investigators and raters were blinded. Analyses followed an intention-to-treat approach using SPSS. Continuous variables were compared with t-tests; repeated-measures ANOVA and GLM assessed Time × Treatment interactions; Cohen's d effect sizes are reported for between-group differences. Kaplan–Meier and log-rank tests compared time-to-event outcomes. P values <0.05 were considered statistically significant.

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.