EFFECT OF TRAMADOL AS AN ADJUNCTIVE PHARMACOLOGICAL TREATMENT FOR MAJOR DEPRESSIVE DISORDER: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL
Authors: Boin *Andre Campiolo , Scarabelot Luis Felipe , Loureiro Camila Marcelino , Roza Daiane Leite , Graeff Frederico Guilherme , Del-Ben Cristina Marta 
Published: February 2025

Abstract

Background
Usual pharmacological treatment of Major Depressive Disorder (MDD) with serotonin/noradrenaline reuptake inhibitors is effective but clinical response may take several weeks to emerge [1], and around 30% of the patients will not achieve complete remission [2,3]. Adjunctive drugs may be an alternative to accelerate clinical improvement. Opioid agents have been effective in reversing depressed mood in preclinical and clinical studies. The opioid analgesic tramadol combines a weak stimulating action on the μ-opioid with serotonin and noradrenaline reuptake inhibition.

Aims & Objectives
To compare tramadol augmentation to treatment as usual for a limited period (14 days) in patients with moderate/severe major depressive episode (MDE) without psychotic features over a 4-week follow-up.

Method
In a randomized, double-blind, placebo-controlled study, we included depressed patients of both sexes aged between 18 and 65 years old. Treatment-naive patients or non-responders to previous treatment were included. Volunteers were randomized into two groups of intervention (tramadol 50 mg vs placebo) taken every 8 hours for 14 days. Both groups took antidepressants (SSRIs, NSRI or others) as usual during the follow-up period. Patients were assessed weekly by the Hamilton Depression Rating Scale (HAM-D). Baseline data between groups were compared using the Student’ s t test and Fisher’ s exact test. Data means were compared across treatment using linear mixed-effects models, including group and time interaction terms, fitted using the “proc mixed” package of SAS software. The validity of the regression models was verified by residual analysis and in some variables we used logarithmic transformation in the response variable. The significance level used was 5%.Results:The final sample consisted of 42 volunteers (tramadol=22, placebo=20), with a mean age of 35.9±12.9, mainly composed of women (82.0%), with self-reported skin colour as white (57.1%) and more than 9 years of education (69.1%). The MDE was categorized as moderate (57.1%) or severe (42.9%), with HAM-D total score 24.50± (5,51) and 26.0±30.4 weeks duration. The majority of the patients were under SSRIs (61.9%); the remaining were under NSRI (16.7%), tricyclics 911.9%) or atypical (9.5%), without significant differences between adjunctive treatment groups. Regarding demographics, there were no significant differences between the treatment groups. At the baseline, groups did not differ in the severity of depressive symptoms (HAM-D total score: placebo=24.50±5.40; tramadol=23.59±4.19; p=0.294). On the 7th day of treatment, the severity of depressive symptoms of patients under tramadol (HAM- D=11.95±6.31) were significantly lower than patients under placebo (13.96±8.22; p=0.021). The trend of lower HAM-D scores in the tramadol group than in placebo group remained on the 14th day (13.72± 5.72 &15.26±6.60; p=0.075) and on the 21th day (13.99±6.39 &15.66±6.78, p=0.054). On the 28th day, no significant differences between treatment groups were observed (tramadol = 14.19±6.31; placebo = 14.32±5.83, p=0.882).

Discussion &Conclusion
Our preliminary results suggest that tramadol as an adjunctive to the usual pharmacological treatment of MDE may faster the clinical response in the first weeks of treatment. Larger clinical trials with different doses for testing the efficacy of tramadol as adjunctive treatment in major depression are warranted.

References
Baldwin DS, Stein DJ, Dolberg OT, Bandelow B. How long should a trial of escitalopram treatment be in patients with major depressive disorder, generalised anxiety disorder or social anxiety disorder? An exploration of the randomised controlled trial database. Hum Psychopharmacol. 2009 Jun;24(4):269-75. doi: 10.1002/hup.1019. PMID: 19334042.
Warden D, Rush AJ, Trivedi MH, Fava M, Wisniewski SR. The STAR*D Project results: a comprehensive review of findings. Curr Psychiatry Rep. 2007 Dec;9(6):449-59. doi: 10.1007/s11920-007-0061-3. PMID: 18221624.
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006 Nov;163(11):1905-17. doi: 10.1176/ajp.2006.163.11.1905. PMID: 17074942.