Hydroxychloroquine in a COVID-19 patient on chronic Pregabalin therapy- Is it safe?

Dear Editor,

A 58-year-old male patient, weighing 90 kg presented with fever, shortness of breath, and cough for one week. The RT-PCR was tested positive for COVID-19. Patient had hypertension for past 15 years and controlled on amlodipine 5-mg OD and pregabalin 75-mg and clonazepam 0.5-mg OD for cervical spondylosis for the last 4 years. Pulse rate was 106/min, blood pressure 118/74 mm Hg, and respiratory rate was 28 breaths/min. His condition deteriorated and was shifted to ICU where his oxygen saturation improved to 98% on partial rebreathing face mask from 83% on room air. On auscultation, crepitations were present in bilateral lower lung fields. All routine investigations were within normal limit except for high WBC count (15000/µL) and electrocardiogram (ECG) demonstrating a heart rate of 150/min and QTc interval of 480ms(Bazett’sformula). Chest X-ray revealed bilateral lower zone infiltrates. He received tazobactam-piperacllin, teicoplanin, ivermectin, enoxaparin, dexamethasone, salmeterol MDI, vitamin C, zinc and had already received azithromycin. Considering the ECG changes, hydroxychloroquine (HCQ) was not administered. It was revealed that he was on both pregabalin and clonazepam till a day before and was immediately stopped. The ECG changes resolved on next day i.e. within 36 h. Following which, HCQ was administered in a dose of 400-mg OD for 5 days; ECG on all days was normal. Patient improved clinically and discharged thereafter.

Cardiac events with pregabalin are rarely reported and is related to its binding to a2d2 subunits of voltage-gated calcium channel causing potassium-evoked accentuation of calcium influx. Recently, a population-based database concluded the relation between new exposure to pregabalin and initiating AF treatment with the incidence of 8.6 per 1000 and RR 2.79 (95% CI 1.05–7.40) when compared to the patients started on opiates.[1] Also, in an animal model, increase in HR and QTc prolongation was observed with pregabalin.[2]

The role of HCQ has been controversial in the therapeutic management of COVID19. However, it is shown to significantly reduce the viral load in COVID-19 patients further reinforced by coadministration of azithromycin.[3] This particular evidence led to the exponential increase in its use for therapeutic management in the initial few months of this pandemic and was the time the present case was managed. Recently, a cohort study observed significant QTc prolongation in patients on HCQ and azithromycin combination therapy; however, did not report any arrhythmogenic deaths.[4]

In this case, we attribute QTc prolongation to chronic pregabalin and/or clonazepam therapy. The oral bioavailability of pregabalin is approximately 90% and is not plasma protein bound with elimination half-life of 6.3 h. The steady-state plasma concentration is achieved within 24–48 h.[2] This explains the normalization of ECG approximately within 36 h of the last pregabalin dose. Similarly, literature search reveals only a single case report implicating clonazepam, a long-acting benzodiazepine to be a potential cause of QTc prolongation in a paediatric patient.[5]

To conclude, the judicious and cautious use of proarrhythmic drugs like hydroxychloroquine and/or azithromycin in patients with COVID-19 on chronic pregabalin and/or clonazepam therapy as it may potentiate the risk of arrhythmia.

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