Safety and Efficacy of Tramadol Adjuvant Therapy to Standard Care for COVID-19 Egyptian Patients: A Randomized Double Blind Controlled Clinical Trial

Background and Rationale: T cells play a critical role in antiviral immunity, their level was dramatically reduced in COVID-19 patients. There is a negative correlation between T cell numbers and cytokines serum level in COVID-19 patients. In those patients, there is up-regulation of inflammatory cytokines including interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, and interferon γ. This makes the use of tramadol reasonable in such patients because it has anti-inflammatory effect decreasing plasma level of TNF-α after treatment with a dose of 100 mg every 12 hours for 10 days, which may result in a subsequent increase in T cell numbers. Besides, COVID-19 patients with acute respiratory failure present with severe hypercoagulability due to hyperfibrinogenemia resulting in increased fibrin formation and polymerization that may predispose to thrombosis. It has been reported that tramadol has a hypocoagulable effect in the blood of women with gynecologic malignancies. Consequently, tramadol may be useful for patients who have a tendency toward a hypercoagulable status and thromboembolic complications. Moreover, tramadol could affect hemostatic parameters in favor of bleeding tendency in rats. On the other hand, the severity and mortality risk of COVID-19 have been associated with the age. This age-related mortality is attributed to the shortage of antioxidant mechanisms and increased oxidative damage. Tramadol increased the antioxidant enzymes superoxide dismutase and glutathione peroxidase while diminished the oxidative stress marker malondialdehyde in testicular ischemia-reperfusion injury in rats. Owing to its antioxidant properties, tramadol could reduce complications in COVID-19 patients. Moreover, tramadol was reported to significantly lower lactate dehydrogenase (LDH) level and to provide a cardio-protective effect. This property of tramadol seems beneficial since it was found that, about 60% of COVID-19 patients are presented with elevated LDH levels. Tramadol has also antitussive property. Tramadol is a unique analgesic offering moderate, dose-related pain relief through its action at multiple sites. In contrast to pure opioid agonists, it has a low risk of respiratory depression, tolerance, and dependence. Previous studies confirmed that tramadol dependence may occur when it is used daily for more than a few weeks/months. More interestingly, patients infected with COVID-19 may experience intense emotional and behavioral reactions, such as fear, loneliness, anxiety, insomnia, or anger. These conditions can be especially prevalent in quarantined patients. Tramadol is a centrally acting analgesic drug with a dual mechanism of action: binding to μ-opioid receptors and the inhibition of serotonin and norepinephrine reuptake. Through its ability to inhibit serotonin and norepinephrine reuptake, tramadol may exhibit antidepressant activity. In this context, the analgesic and antidepressant effects of tramadol may favor its use for COVID-19 patients. Tramadol also was found to have dose- and time-dependent bactericidal activity against Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, and Pseudomonas aeruginosa pathogens in vitro.