The rationale of the use of tramadol for COVID-19 patients is attributed to its anti-inflammatory, hypocagulatory, antioxidant, cardio-protective, analgesic, antitussive, bactericidal and antidepressant effect.
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.
Drug: Tramadol
tramadol 100 mg twice daily for 10 days
Other Name: tramal
Other: Standard care delivered in the isolation hospitals.
Oxygen ventilation.
Other Name: nasal oxygen
Inclusion Criteria:
- Newly diagnosed symptomatic COVID-19 patients with mild to moderate respiratory
manifestations, adults (18-65 Years old), and both sexes.
Exclusion Criteria:
- Patients with abnormal liver function (ALT, AST), chronic kidney disease or dialysis
(CrCl< 30 ml/min)
- Pregnant women or women who are breastfeeding
- Immunocompromised patients taking medication upon screening
- Subjects with comorbid condition like hypertension, cardiovascular disease, diabetes
mellites, asthma, COPD, malignancy
- Patients having allergy to Hydroxychloroquine and/or Nitazoxanide
- Patients with contraindication towards the study medication including retinopathy,
G6PD deficiency and QT prolongation.
Nahla Elashmawy, PhD
201116721982
nahla.elashmawi@pharm.tanta.edu.eg
Nahla Elashmawy, PhD, Principal Investigator
Tanta University