As of December 2022, seroprevalence studies suggest that up to 80%–90% of the global population has already had an infection with SARS-CoV-2 (Huang et al., 2020). The key strategies to battle the infection are crucial to reducing disease spread—including physical distancing, wearing masks, and avoiding crowds (Dhand and Li, 2020). The cough is a key symptom of COVID-19 comparable to the more common but less severe respiratory infections, including common cold or flu in the acute and post-infective phases of the infection. Moreover, cough increases the risk of community transmission by respiratory droplets, distressing patients and leading to social isolation (Song et al., 2021). Many mechanisms have been suggested for COVID-19- induced cough including neuroinflammation or neuroimmunomodulation via the sensory nerves (Song et al., 2021). Another potential mechanism of cough in COVID-19 is bradykinin syndrome which is defined as the reduced degradation of bradykinin in the body that may further lead to dry cough not responding to regular treatments (Alkotaji and Al-Zidan, 2021). Identifying ways to relieve COVID-19-associated cough could help to prevent community transmission and disease spread, along with removing the stigma of this symptom (Dhand and Li, 2020). As well, the exact mechanisms of COVID-19-associated cough are unclear. Accordingly, evidence-based treatment options for COVID-19 cough are needed (Song et al., 2021). The current antitussive medication used for the treatment of cough includes diphenhydramine which has much anticholinergic activity leading to blurred vision, constipation, urinary retention and xerostomia. Most elderly patients will not tolerate these adverse events. Moreover, opioid antitussives including dextromethorphan may induce central nervous system (CNS) depression and they also may be associated with respiratory issues (Enna and Bylund 2008).

Different measures have existed in viral respiratory infections to treat cough. Among them, natural and herbal products are common (Shergis et al., 2015). Products containing noscapine or licorice are used widely to relieve cough (Shergis et al., 2015; Kuang et al., 2018). Noscapine is a naturally occurring opium-isoquinoline alkaloid that is related to papaverine. It acts centrally as a cough suppressant and has actions and uses similar to dextromethorphan (Enna and Bylund 2008). Unlike opioid antitussives, respiratory and CNS depression, as well as addiction, have not been reported with noscapine (Enna and Bylund 2008). Moreover, noscapine can help decrease bradykinin-mediated cytokine release due to Angiotensin converting 2 enzyme inhibition by SARS-CoV-2. In turn, it can reduce tissue damage, especially in the lungs (Ebrahimi, 2020). As the previous studies have shown that the accumulation of bradykinin along with cytokine storms may be the culprit for the pathogenesis of SARS-CoV-2 (Wilczynski et al., 2021). A cytokine storm is a hyperinflammatory state that can lead to excessive production of cytokines by a deregulated immune system (Zanza et al., 2022).

The licorice is a popular traditional Chinese medicine (TCM) used to treat respiratory diseases, including cough, sore throat, asthma, and bronchitis (Kuang et al., 2018).

Noscough^® is a natural syrup (containing noscapine and licorice extract) used as an antitussive medication. Based on these reasons, the use of Noscough^® may be a safe and effective option for the treatment of COVID-19 cough. Hence, this study aimed to investigate the effects of Noscough^® syrup in relieving cough in the outpatients with COVID-19.

The results of our trial confirmed that Noscough^® syrup which consists of noscapine and licorice has similar effects with diphenhydramine in terms of response to treatment. However, Noscough^® syrup was superior to diphenhydramine in terms of quality of life, dyspnea relief, and cough severity.

Notably, the effect size of the response to treatment as the primary outcome of the study was 0.06 in favor of Noscough^® syrup, which is considered a small effect size (Rahlfs and Zimmermann, 2019). Hence, it can be concluded that noscapine may be slightly superior to diphenhydramine in terms of response to treatment, and the study was underpowered to detect this small difference. Moreover, the mean scores of CSS, VAS, and CQLQ, were all in favor of the Noscough^® group with significant results with adjustment of their baseline values. The presence of dyspnea was also significantly lower in the Noscough^® group by the end of day five. The number needed to treat (NNT) was calculated to be 17, which is also considered a small effect.

Noscough^® syrup consists of noscapine and licorice. Noscapine is an opioid antitussive that has been shown to reduce bradykinin-induced cough in humans (Ebrahimi, 2020). Moreover, studies have shown many symptoms related to COVID-19 can be justified with the development of bradykinin (Garvin et al., 2020). Hence, bradykinin and cytokine storms might be associated with worse outcomes in COVID-19. Therefore, mediating these pathways may lead to better symptom-relieving (Rex et al., 2022). Noscapine is considered a safe candidate with the potential benefits of modulating both pathways (Luo et al., 2020; Kumar et al., 2022). The advantages of this medication to diphenhydramine are lack of sedative effects and unlike diphenhydramine it has no anticholinergic effects which is an important advantage in the elderly. In Addition, unlike other opioids, no addiction or respiratory issues have been reported with this medication. Noscugh^® side effects only include potential sedative effects in non-pharmacologic doses based on the manufacturer label.

Licorice also has been shown to have antiviral effects against various families, including SARS coronaviruses (Diomede et al., 2021). Moreover, a study using bioinformatics analysis and molecular dynamic stimulation has shown that phaseol in licorice may have beneficial effects in reducing the inflammatory response to COVID-19 by inhibiting the activation of CXCL8 and IL2RA (Cao et al., 2022). An in silico analysis performed by Neeraj kumar et al., showed that the combination of noscapine and hydroxychloroquine conjugates has much binding affinity for main protease of SARS-CoV-2 which has critical role in pathogenesis of COVID-19 (Kumar et al., 2022). Other potential effects against COVID-19 symptoms have also been shown for other ingredients of licorice, including Glycerol and Glyasperin F (Cao et al., 2022). Another in vitro study has revealed that licorice may block SARS-CoV-2 replication by inhibiting the viral main protease (van de Sand et al., 2021).

The main limitation of the study was that the patients were not blinded to the study interventions. Due to the differences in dosing and interval of administrations blinding was not feasible. Hence, their own believes of the antitussive medication might have influenced the study results. Another limitation is that the investigators had considered a significant effect for Noscough^® syrup based on the potential literature-based mechanisms while powering the study. Due to this fact, the study did not meet its primary endpoint as the sample size was not large enough to detect smaller effects. It is suggested to perform the study with larger sample size and also with different reference products as control group including the other opioids.

Noscough^® syrup was slightly superior to diphenhydramine in relieving the symptoms of cough and dyspnea in COVID-19 outpatients. The severity of cough and cough-related quality of life were also in favor of Noscough^® syrup significantly. Considering the favorable safety profile of this syrup, Noscough^® may be a valuable treatment in relieving cough in COVID-19 outpatients.