Dr. Prasanna K Thomas, Dr. Pramod Jog, Dr. Nitin R Vohra, have no competing interests. Dr. Krishna C Veligandla and Dr. Anup U Petare are Dr. Reddy's Laboratories Ltd employees.
Safe and effective antitussive therapy remains a significant area of unmet need for cough management. Antitussive drugs are commonly used cough suppressants and include centrally acting (opioids and non-opioids) cough suppressants and peripherally acting antitussives. Authors searched PubMed, Google Scholar and additional studies from reference lists via cross-referencing to identify studies assessing levodropropizine for the treatment of cough. Of the 748 studies identified, 13 were included. Recent clinical evidence, guideline recommendations and findings from this review suggest that levodropropizine is a peripheral antitussive which reduces cough intensity, frequency, and nocturnal awakenings in children and adults and provides better efficacy outcomes with a more favourable risk/benefit ratio compared to centrally acting antitussive agents which pose greater safety concerns and present an unacceptable risk–benefit profile. This review is aimed at Indian primary care physicians for making effective cough management decisions where the clinical evidence needs to be translated to clinical practice.
The usage of currently available centrally acting antitussive agent is greatly limited by their central depressing action and frequent side effect. The findings of this review indicate that levodropropizine is an effective antitussive agent and well tolerated in the management of cough in patients of all ages.
Coughing is a vital defensive reflex that allows clearance of excessive airway secretions and prevents the entry of foreign bodies into the respiratory tract.
The American College of Chest Physicians (ACCP) defines subacute cough as cough that resolves spontaneously on its own, with negative chest radiography ruling out pneumonia
There is a need to find an effective antitussive medication with a high tolerability profile because the usage of the currently available centrally acting antitussive for the treatment of cough is severely restricted by the central depressive action and abusive side effects.
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.
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).
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.
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Open-label, RCT | 88 | 50.83 | Codeine | Chronic cough | Orally administered codeine (60 mg/day) and LDP (180 mg/day) for two weeks | Codeine & LDP are effective antitussive for chronic cough | Frequency of TEAEs was substantially higher in the codeine group than in the LDP group (44.4% vs. 14.0%, P = 0.002) |
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RCT (double-blind) | 140 | > 18 | Dihydrocodeine (DHC) | Lung cancer cough | Oral administration t.i.d. for seven days | LDP antitussive impact was comparable to the standard DHC treatment | LDP and DHC both had a similar number of patients (n=6) and patients (n=4) reporting side events. However, compared to DHC group (22%), the percentage of patients who reported somnolence in the LDP group (8%) was much lower. |
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RCT (double-blind) | 209 | 18–75 | Dextromethorphan (DXM) | Moderate non-productive cough | Oral administration t.i.d. for five days | Significant reduction in cough frequency with both treatments; LDP significantly more effective in reducing nocturnal awakenings | The number of patients reporting AEs was significantly higher (P<0.05) in the DXM (12.1%) than in the LDP (3.6%) group |
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RCT (double-blind) | 174 | >13 | Placebo (two studies) Morclofone 1% (2 studies) Cloperastine drops 2% (two studies) | Bronchitis cough | Oral administration t.i.d. for three days | LDP was shown to be effective in approximately 80% of patients. The cough frequency was reduced by 33-51% in responder. LDP antitussive activity was shown to be greater than placebo, morclofone, and comparable to cloperastin. | LDP was generally well tolerated and mild side-effects were reported for only 3% of patients. |
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Prospective observational study | 330 | 0.4-14 | Antibiotic regimen | Acute cough caused by URTI | Treatment given for six days | The resolution of cough was significantly higher with LDP than with antibiotics | No relevant AEs reported |
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Observational study | 433 | 6.1 | cloperastine/ codeine | Acute cough associated with a URTI | Given for six days | Cough severity reduced by all antitussives | Codeine induced sedation reported |
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RCT double-blind, two parallel groups | 77 | 3 | DXM | Acute or chronic bronchitis with non-recurrent or slightly recurrent cough | Oral administration t.i.d. for three days | Improvement in cough frequency and severity significantly higher with LDP | Sedation reported in DXM group |
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RCT double-blind, double- dummy,two parallel groups, | 267 | 2-14 | Dropropizine | Non-productive cough | Oral administration t.i.d. for three days | Significant decrease in cough frequency and night awakenings with both treatment | Somnolence was reported twice in dropropizine group |
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RCT double-blind trial | 12 | 2- 8 | None | Asthmatic cough | Oral administration of LDP single dose for four weeks | Significant improvement in nocturnal awakening reduction observed with LDP | Not stated |
AE- Adverse event, DHC- Dihydrocodeine, DXM- Dextromethorphan, LDP- levodropropizine, RCT- Randomized controlled trial, TEAE- Treatment emergent adverse events, T.i.d.- three times a day, URTI- Upper respiratory tract infections
In a clinical investigation conducted by Mannini et al., it was demonstrated that levodropropizine does not have a central depressive impact and had no effect on the hyper ventilatory response to hypercapnia. The study findings supported the peripheral action and good safety profile of levodropropizine, especially in children.
Levodropropizine and dextromethorphan were compared for effectiveness in a double-blind, two-parallel groups, randomized controlled trial by Kim et al. in 77 children with bronchitis and non-recurrent or mildly recurrent cough. Levodropropizine significantly reduced cough frequency and severity more than dextromethorphan after two to three days of dosing.
Furthermore, the overall efficacy score with levodropropizine compared to dextromethorphan was significantly greater, indicating a much more beneficial anti-tussive effectiveness of levodropropizine than dextromethorphan.
In a double blind, double dummy two parallel groups, randomized study carried out by Banderali et al. to evaluate the efficacy of levodropropizine vs central antitussive dropropizine in 258 children for non-productive cough treatment. The study findings showed that both levodropropizine and dropropizine reduced the frequency of coughing fits and nighttime awakenings.
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.
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
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.
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
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 (
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.
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.
The comparative analysis reported in the efficacy section above for peripherally acting antitussive levodropropizine was found to be safer and more effective to manage the cough. These findings are also consistent with current international recommendations, which recommend the use of peripherally acting antitussive such as levodropropizine for management of cough.
Cough is frequently treated using symptomatic drugs. The use of peripheral antitussive agents over centrally acting antitussive agents has increased significantly in recent years, but despite the available evidence, these findings have yet to be translated into clinical practice in India. The usage of currently available cough medications is greatly limited by their central depressing action and frequent side effect. Among the current available drugs, levodropropizine appears to be unique in acting on the sensory fibers and has proven efficacy in cough control with an evident lack of central depressant action. Studies undertaken as part of this review for levodropropizine show that this antitussive agent is effective and well tolerated in the management of cough in patients of all ages, thus further reinforcing the favourable benefit-risk profile of levodropropizine in patients of all ages.
The review article manuscript writing charges and article processing charges are funded by Dr Reddy’s laboratories.
The review article manuscript writing charges and article processing charges are funded by Dr Reddy’s laboratories.