A comprehensive literature search was carried out on the PubMed databases to identify clinical studies and meta-analyses of levodropropizine for the treatment of cough in the adult or paediatric population. The search terms were ((cough) OR (chronic cough) OR (acute cough)) AND ((levodropropizine) OR (peripheral antitussives) OR (central antitussives) OR (codeine) OR (dihydrocodeine) OR (dextromethorphan) OR (dropropizine)) for articles published in peer-reviewed journals from their inception through November 2022. Additional searches were conducted in Google Scholar and from review article reference list through cross-referenced articles. There were no language restrictions. The search was restricted to studies conducted in human populations.

Following are the inclusion criteria used to select studies: Clinical studies (vs. both active-and placebo-controlled) and meta-analysis design, including paediatric and adult patients, and assessing efficacy endpoints related to cough outcomes, safety results, or quality of life data were selected. Patients of any age suffering from cough types such as chronic cough, lung cancer cough, moderate non-productive cough, bronchitis cough, acute cough caused by URTI, non-productive cough, or asthmatic cough were included in the narrative review. Studies using duplicate samples, case reports, editorial, letter were excluded. In determining eligibility, discrepancies were resolved through consensus among authors. Of the 748 studies identified, 13 were included. Out of 13 included studies, nine published clinical studies were conducted with levodropropizine in adults or children and met the eligibility criteria for efficacy and safety data, two studies were included for the impact on patients’ HRQoL, and one for the role of levodropropizine in the management of COVID-19-related cough and one meta-analysis that evaluated the pooled estimates of efficacy in adults and children were selected for summarizing the published evidence.

For all the included articles for comparative efficacy and safety parameters, we extracted and confirmed the data. The extracted outcomes included study design, sample size, participant age, comparator, indication or condition, dosing schedule, efficacy result and safety result.

Levodropropizine is a peripherally acting non-opioid antitussive agent that acts by inhibiting sensory neuropeptide release in the respiratory tract and suppresses the pulmonary afferent pathway. 18 Levodropropizine (S(-)3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol, DF 526) is the l-isomer of dropropizine, which is a racemic drug widely used in cough management. Compared with its racemate, levodropropizinehad weaker central sedative effects. It exerts cough suppressant effect through an inhibitory action of the airway sensory nerves with modulation of sensory neuropeptides within the respiratory tract. Levodropropizine also leads to in vitro inhibition of neuropeptides release from C-fibers. Levodropropizine exerts its cough suppressant effect by acting on H1-histaminic and alpha-adrenergic receptors. 111819 The peripheral mode of action of levodropropizine provides better efficacy outcome with a more favourable risk/benefit ratio when compared with centrally active drugs such as dextromethorphan. 1118

Levodropropizine has linear pharmacokinetic (PK) characteristics at doses ranging from 30 to 90 mg. After oral administration, levodropropizine is rapidly absorbed into the intestine and goes into first pass metabolism, with reaching its maximum drug plasma concentration (Cmax) within 0.25 to 0.75 hours (Tmax). 19,20 Levodropropizine faster onset of action is due to high bioavailability (75%) and rapid distribution in the body compartment. The mean terminal half- life (t1/2) of levodropropizine is 2.73 h, which resulted into rapid elimination after systemic absorption. 14,20,21 The faster onset of action and high bioavailability of levodropropizine ensure rapid relief from cough in comparison with centrally acting anti-tussive. 1421

Levodropropizine is an effective antitussive drug in patients of all ages that has shown statistically significant better outcomes compared with central antitussive agents in terms of efficacy, tolerability, reducing cough intensity, frequency, and night awakenings. 11 Levodropropizine has also been shown to be significantly better in overall efficacy outcomes in cough suppressant caused by various underlying diseases, including dry cough in patients with lung cancer, tuberculosis and URTI.3

Zanasi et al. reported a meta-analysis that evaluated the pooled estimates of efficacy in adults and children. This meta-analysis comprising three double-blind RCTs with 389 adult patients compared the antitussive activity of levodropropizine compared to central antitussive drugs. The results showed significant difference in overall efficacy in favour of levodropropizine as compared to centrally active antitussive agent.11 The overall antitussive efficacy of levodropropizine vs. controls reported as standardized mean delta with 95% between confidence interval between treatment groups (−0.176, (−0.282 −0.069) p=0.0015).11

In this meta-analysis for paediatric patients, four studies with 789 children were included in which levodropropizine was compared with central antitussive in three studies 272829 and one study against a placebo.32 The results showed that levodropropizine statistically significantly improved the cough severity and nocturnal awakenings results compared to central antitussive drugs in children. These findings support levodropropizine favourable benefit/risk profile in treating cough in paediatric patients.30

A safe and effective antitussive therapy remains a significant area of unmet need for cough management. The safety profile of centrally acting antitussive drugs raises greater safety concerns and present an unacceptable risk–benefit profile for use because of the potential for excessive sedation, a higher risk of developing toxic effects such as life-threatening respiratory depression.1233 The lack of a central depressant action by levodropropizine support the favourable safety profile of levodropropizine especially in children.18 The safety profile of levodropropizine compared with codeine was evaluated by Lee et al. in 88 adult patients with chronic Cough. The study reported the frequency of treatment-emergent adverse events was substantially higher in the codeine group than in the levodropropizine group (44.4% vs. 14.0%, P = 0.002). Four of the 20 patients who experienced adverse effects from the drug codeine discontinued their treatments as a result. (Figure 1).30

The Tolerability evaluation of levodropropizine compared with dextromethorphan by Catena et al. in 209 adult patients showed that patients reporting adverse events were significantly greater in the dextromethorphan (12.1%) group compared to the levodropropizine (3.6%) group (P<0.05). The overall tolerability assessments indicate a more favourable benefit/risk profile of levodropropizine as compared to dextromethorphan.23 A summary of published clinical study evaluating safety outcome of levodropropizine are summarized in Table 1.

Cough is one of the most frequent symptoms that can affect the patients' HRQoL by inducing nausea and sleep disturbance. In an observational study conducted by Blasio et al., the impact of cough on quality of sleep and children’s activities was evaluated using paediatric cough questionnaire (PCQ), developed by the Italian Society of Cough Study. This study included 433 children with a mean age of 6.1 years who had acute cough caused by a URTI. The study result reported the significantly higher cough resolution proportion in the levodropropizine group compared to the central antitussives group (47% vs. 28%, respectively, p = 0.0012), and there was also a notable reduction in irritability and an improvement in their general health (Figure 2).27,34 A total of 60 adult patients with acute cough enrolled in a randomized controlled trial conducted by Alifer et al. to compare the HRQoL of the patients after receiving levodropropizine to a control. The study findings showed that the physical component of HRQoL significantly improved in the levodropropizine group compared to the control group. (Figure 3).35

Cough is one of the most common symptoms of COVID-19 which can persist for weeks or months after SARS-CoV-2 infection. The management of cough-related symptoms in COVID-19 patients requires an evidence-based therapeutic approach.36 Zaitsev et al. carried out an open observational multi-center trial to compare the efficacy and tolerability of levodropropizine to conventional medications (mucolytic agent e.g., ambroxol) for the treatment of cough in COVID-19 patients. A total of 250 patient COVID 19 participants who complained of a non-productive cough were enrolled in the study. Significant differences were found in the levodropropizine group between baseline and day four in terms of a significant reduction in the severity of daytime cough (p = 0.002). Although the comparison group also showed positive outcomes, but significant differences were seen only between the baseline and day 8 at night (р = 0.001). The study reported that levodropropizine has demonstrated good efficacy and safety in the treatment of dry, non-productive cough in comparison to standard symptomatic therapy starting on the fourth day.37

Wu et al. used computational methods to investigate the levodropropizine as therapeutic targets for SARS-CoV-2. The screening results suggested that levodropropizine may have a high binding affinity to papain-like protease (PLpro) and may be useful in the treatment of SARS-CoV-2. However, in vivo evaluations of both potency and toxicities of such inhibitors are required before using them against SARS-CoV-2.38 The clinical parameters during the observation period at baseline, day 4 and 8 in patients included in the study shows in Figure 4.