Cough is a vital protective reflex whose primary function is to generate high-velocity airflow, thereby clearing the airways and maintaining respiratory function (Morice et al., 2020; Lee et al., 2021). When this response becomes excessive or uncontrolled, however, it may evolve into a chronic condition that markedly affects quality of life and increases the healthcare burden (Jakusova and Brozmanova, 2023; Weinberger and Hurvitz, 2020). Children are considered to have a chronic cough when symptoms persist for more than 4 weeks, whereas in adults the threshold is 8 weeks (Weinberger and Hurvitz, 2020). The leading causes of chronic cough include asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, eosinophilic bronchitis, chronic bacterial bronchitis (Weinberger et al., 2025), as well as upper airway cough syndrome and gastroesophageal reflux disease (GERD).

Increasing attention has been given to cough hypersensitivity syndrome (CHS), which is now recognized as a significant clinical entity accounting for a substantial proportion of patients with chronic cough in whom no clear underlying cause can be identified (Khan et al., 2024; Chung et al., 2016). This condition is characterized by an exaggerated cough response to otherwise innocuous stimuli (thermal, mechanical, or chemical), resulting from enhanced excitability and plasticity of airway sensory nerves, particularly involving vagal afferent pathways (Khan et al., 2024). Importantly, evidence suggests that, in addition to maladaptive neural plasticity, other pathophysiological mechanisms underlying cough hypersensitivity have not been sufficiently characterized (Song and Morice, 2017).

Other contributing factors comprise the use of antihypertensive agents such as angiotensin-converting enzyme (ACE) inhibitors, smoking, habit cough, and systemic disorders (Morice et al., 2020; Jakusova and Brozmanova, 2023). A so-called habit cough, more frequently observed in children and adolescents, is considered a functional disorder characterized by repetitive coughing without an identifiable organic cause, often influenced by behavioral or psychogenic factors (Weinberger et al., 2023). Identification of the etiologies of chronic cough is essential for effective management. In adults, the most common etiologies include cough-variant asthma (CVA), upper airway cough syndrome (UACS), and eosinophilic bronchitis (EB). In contrast, the etiologies of chronic cough in children differ, with protracted bronchitis (PB) predominating and asthma or CVA representing frequent etiologies in school-aged children. However, data on pediatric etiologies remain limited due to the restricted feasibility of diagnostic investigations (Yu et al., 2019).

Cough is one of the most common symptoms encountered in clinical practice, and despite significant progress in understanding its mechanisms, treating it remains a challenge for clinicians (Jakusova and Brozmanova, 2023; Rouadi et al., 2025).

For decades, the management of cough has relied on centrally acting agents, including codeine (Smith et al., 2006), dextromethorphan (Meeves et al., 2023), butamirate (Faruqi et al., 2014; Charpin and Weibel, 1990), and levodropropizine (Lee et al., 2022; Mannini et al., 2017), despite their limited and inconsistent clinical efficacy. Recent advances in the neurobiology of cough have led to the development of mechanism-based therapies, such as P2X3 receptor antagonists, that directly target peripheral cough pathways (Rouadi et al., 2025). This paradigm shift from symptom suppression to pathway-specific modulation marks a pivotal moment in antitussive research.

Alongside these agents, a wide range of natural or herbal remedies continues to be promoted for cough relief, reflecting patient preference for “natural” options (Murgia et al., 2021). It is estimated that nearly four billion people worldwide still rely primarily on herbal medicines for their healthcare needs (Wardani et al., 2023).

Natural cough medicines, often perceived as safer, offer an alternative to conventional over the counter (OTC) cough medications. It should also be emphasized that the market for so-called “natural” cough medicines is rapidly expanding, offering a wide range of preparations with diverse compositions and claimed mechanisms of action (Murgia et al., 2021). Moreover, because medicinal plants contain a variety of bioactive molecules that can simultaneously exert expectorant and antitussive effects, the classification of herbal cough remedies is difficult (Pourova et al., 2023).

An important aspect is the difficult-to-assess chemical composition of plant extracts, which can vary significantly depending on cultivation, harvesting, storage, and processing conditions. As a result, products sold under the same name may differ in composition and pharmacological activity (Murgia et al., 2021). Due to growing interest in natural cough remedies and the lack of consistent, high-quality scientific evidence, a critical assessment of the current state of knowledge is necessary.

Our study aimed to go beyond codeine and examine the current scientific evidence on the effectiveness and safety of conventional, natural, and novel antitussive therapies for the treatment of chronic cough. Therefore, we conducted a systematic review and meta-analysis to assess and compare the effectiveness and safety of antitussives. By integrating data from randomized clinical trials (RCTs), we aimed to provide an updated and comprehensive evidence synthesis to aid clinical decision-making in cough management.

This systematic review and meta-analysis included centrally, and peripherally acting medications commonly used to treat cough. The analysis aimed to assess their efficacy and safety based on the results of available RCTs. It should be emphasized that this study did not present quantitative data for codeine, butamirate, dextromethorphan, and levodropropizine. Only qualitative analysis was possible for these antitussives (Table 2). The inability to conduct a meta-analysis of the data from the included studies confirms previous observations that the available studies are characterized by significant heterogeneity. Furthermore, their conclusions are inconsistent. Consequently, it is impossible to draw clear conclusions about the efficacy of these medications in treating cough.

As shown in Table 2, the observed heterogeneity results from significant differences across studies, including drug doses used, therapy duration, methods of efficacy assessment, and heterogeneity in the patient population (age, cough etiology, and comorbidities). These factors contributed to the discrepancy in results and limited the comparability of data in this meta-analysis.

Eccles et al. (1992) in a study using a 30 mg codeine syrup, no significant differences in cough frequency or subjective cough severity were observed between the codeine and placebo groups, either in the laboratory or during home monitoring. These results suggest that cough mechanisms during viral infections may be poorly responsive to opioid antitussives, underscoring the need to explore alternative agents with distinct mechanisms of action.

Moreover, a study (Smith et al., 2006) in patients with stable COPD demonstrated that codeine, although considered a standard antitussive, did not significantly affect cough frequency or subjective cough severity compared with placebo. Despite a slight decrease in cough time after codeine administration compared to baseline, this difference was not statistically significant compared to the control group. These results suggest that cough mechanisms in COPD may be resistant to the effects of opioid antitussives, questioning the validity of using codeine as a reference point in studies of new antitussive agents.

Similarly, a clinical trial in children (Bhattacharya et al., 2013) with upper respiratory tract infection (URTI) found that neither dextromethorphan nor promethazine was more effective than placebo at reducing nocturnal cough or improving sleep quality. Analogously, a study of adults with URTI (Lee et al., 2000) showed no significant advantage over placebo in relieving cough.

These results emphasize that the routine use of antitussives in children and adults with acute upper respiratory tract infection is unjustified, and the effectiveness of both opioid and non-opioid antitussives remains limited. The antitussive effect of dextromethorphan in acute URTI is marginal at best, casting doubt on its routine use in treating viral cough.

Contrary results were obtained in a recent clinical trial in children aged 6–11 years with cough associated with colds (Meeves et al., 2023) Multiple doses of dextromethorphan hydrobromide resulted in statistically significant, although modest, reductions in cough frequency and severity compared with placebo. This effect was most pronounced during the day, but there were no differences between groups in nocturnal cough frequency or sleep quality. These results suggest that dextromethorphan may have some antitussive efficacy in children, particularly for daytime cough, although its effect remains limited. Furthermore, the study highlights the importance of using objective, validated cough assessment tools in the pediatric population to increase the sensitivity of analyses of antitussive efficacy.

Other observations were reported in a study evaluating the efficacy of codeine and levodropropizine in patients with chronic cough (Lee et al., 2022). Codeine was significantly more effective than levodropropizine in reducing cough severity, as confirmed by changes in the VAS, Cough Severity Scale (CSS), and LCQ. Adverse events such as drowsiness, constipation, and headache were more frequently observed in the codeine-treated group, although these did not lead to a higher number of treatment discontinuations. These results indicate that codeine may be more effective in relieving chronic cough, but its use is associated with the risk of side effects typical of opioid medications. In contrast, levodropropizine, despite being slightly less effective, has a more favorable safety profile, making it a potentially better choice for long-term therapy.

The present review also identified several studies evaluating natural antitussive agents that could not be included in the quantitative synthesis due to substantial heterogeneity in study design, methodology, outcome measures, endpoints, and study populations.

Similarly, studies assessing natural or plant-based preparations demonstrated encouraging yet inconsistent results. Barth et al. showed that a combination of aqueous ethanolic extracts of Justicia adhatoda L. leaf, Echinacea purpurea (L.) Moench root and Eleutherococcus senticosus Harms root have an antitussive effect in patients aged 18–65 years with non-complicated URTI (Barth et al., 2015). What is more, another study (Canciani et al., 2014) confirmed that the use of Grintuss® syrup containing resins, polysaccharides, saponins, flavonoids and sugars derived from Grindelia robusta, Plantago lanceolata, Helichrysum italicum and honey leads to an improvement in cough symptoms in children, especially nocturnal cough, after just 4 days of use. Carnevall et al. also demonstrated that KalobaTUSS® syrup (acacia honey in combination with Malva sylvestris, Inula helenium, Plantago major, and Helichrysum stoechas extracts) reduced the severity and duration of daytime and nighttime cough in children with acute cough. However, it should be noted that these two studies focused on entirely different ingredients, so there is considerable risk in interpreting the results comprehensively (Carnevali et al., 2021). Another new substance was investigated in a study conducted in Iran (Ghaemi et al., 2020), which showed that lozenges containing licorice root extract (Glycyrrhiza glabra L.) effectively relieved symptoms of chronic cough of unknown etiology. After 2 weeks of treatment and at a four-week follow-up, a significant reduction in cough severity was observed compared to placebo, while quality of life, as assessed by the LCQ, improved.

It is also worth mentioning a study combining conventional asthma therapy with a traditional Chinese medicine preparation (Pan et al., 2025). This study demonstrated that Suhuang Zhike capsules can be an effective and safe adjunct to therapy in patients with mild to moderate asthma whose symptoms were inadequately controlled despite inhaled corticosteroids (ICS) and long-acting beta₂-agonists (LABA) therapy. Although no significant improvement in Asthma Control Test (ACT) scores was observed in the overall population, a subgroup analysis of patients on stable treatment prior to enrollment demonstrated significant clinical improvement and reduced cough severity.

Another study (Núñez et al., 2024) showed that Sediflù syrup, containing active plant ingredients, effectively relieved cough during both the day and the night in children with upper respiratory tract infections. Significant improvement in cough severity was observed after just 2 days of treatment, and this effect persisted and intensified in subsequent days.

It should be emphasized, however, that the studies discussed in this paper differed significantly in terms of design, population, intervention type, and endpoints, which prevented their direct comparison in a meta-analysis. Some studies included preparations with mechanical or protective effects (Grintuss®, KalobaTUSS®, Sediflù), while others involved herbal products with potential anti-inflammatory or immunomodulatory effects (licorice, Suhuang Zhike, Xiehuangjiejing). The patient populations also varied, from children with acute infectious cough to patients with chronic cough or asthma, as did the intervention duration and methods for assessing efficacy (symptom scales, LCQ, VAS). Despite favorable clinical outcomes and a good safety profile, these results should be interpreted with caution because they come from studies of varying methodological quality and often a limited number of participants.

While several trials reported modest symptomatic relief, particularly in cough frequency and sleep quality, methodological weaknesses and lack of standardized outcomes considerably limit the strength and generalizability of these findings. Together, these observations underscore the urgent need for more rigorous, harmonized clinical trials with standardized outcome measures, adequate sample sizes, and improved study designs to assess better the comparative efficacy of both pharmacological and natural antitussive therapies.

The meta-analysis revealed that among the available RTCs on antitussive medications, those on P2X3 receptor antagonists demonstrated the greatest methodological consistency, particularly in the outcome measures used. Therefore, statistical analyses could be performed primarily for this group of medications, yielding reliable, comparable results on their efficacy and safety. Other interventions, due to the heterogeneity of cough assessment methods and the limited number of studies, could not be included in the quantitative analysis. This represents a significant limitation but also highlights the methodological advances in research on P2X3 antagonists.

The subgroup analysis revealed no statistically significant differences between P2X3 antagonists, indicating a consistent treatment effect across compounds. All subgroups demonstrated a reduction in cough frequency, suggesting that the observed effect is a class-related response rather than compound-specific.

After gefapixant administration, we also observed a statistically significant lower VAS score and a higher LCQ score, with a moderate, potentially clinically relevant effect and high certainty of evidence compared to placebo. In addition, after gefapixant administration, we observed that the intervention increased the risk of AEs by 41% compared with the placebo group, with low certainty of evidence. Also, sivopixant increased the risk of AEs by approximately 76% compared to the placebo group with moderate certainty of evidence. In contrast, eliapixant and camlipixant administration resulted in reductions of AEs of 2% and 15%, respectively, with low certainty of evidence. Furthermore, we noted that the type of P2X3 receptor has a significant impact on AEs frequency.

The GRADE assessment showed varying levels of evidence certainty across outcomes. Low heterogeneity, consistent effects, and narrow confidence intervals characterized high-certainty results. Moderate and low certainty were mainly due to heterogeneity, wide intervals, or a limited number of studies. Despite these differences, the overall results consistently indicated a beneficial effect of the intervention, supporting its clinical relevance.

The obtained results are consistent with previous meta-analyses and systematic reviews (Ramadan et al., 2023; Yamamoto et al., 2024), which also indicated the high efficacy of P2X3 receptor antagonists in reducing cough frequency in patients with refractory chronic cough.

From a clinical perspective, recent findings, together with our results, support the potential role of P2X3 antagonists as a targeted therapeutic option primarily for patients with refractory or unexplained chronic cough. By directly modulating cough hypersensitivity at the level of peripheral sensory pathways, these agents offer a mechanism-based, symptom-oriented approach rather than a replacement for etiological treatment, which remains the cornerstone of chronic cough management. Based on available clinical evidence, P2X3 antagonists may be best positioned as add-on or later-line therapies for patients whose symptoms persist despite optimized standard care. This treatment strategy aligns with emerging views that modulation of sensory neural pathways represents a promising adjunct approach in the management of chronic cough.

Safety and tolerability are central to the clinical implementation of P2X3 antagonists, particularly given their intended use in long-term treatment of chronic cough. In clinical studies with gefapixant, a high incidence of taste-related adverse effects has been reported, attributed to inhibition of the heteromeric P2X2/3 receptor (Yamamoto et al., 2024; Francke et al., 2025). Consequently, the development of more selective P2X3 antagonists has been pursued to improve tolerability while maintaining efficacy (Francke et al., 2025). Morice et al. (2021) showed that taste-related adverse events following eliapixant administration were less frequent at therapeutic doses than with the less selective P2X3 antagonist gefapixant. Although generally reversible upon discontinuation of treatment, taste-related adverse effects may negatively affect treatment adherence, especially during prolonged therapy. Significantly, the development of next-generation P2X3 antagonists with increased receptor selectivity has been associated with a lower incidence and severity of taste disturbances, suggesting a more favorable tolerability profile and supporting the feasibility of chronic administration. On the other hand, Morice et al. (2021) hypothesized that filapixant would be associated with a lower incidence of taste-related adverse effects compared with the non-selective P2X3/P2X2/3 antagonist gefapixant and the less selective P2X3 antagonist eliapixant. However, the results of their study were unexpected. Although filapixant was generally well tolerated, the frequency of taste-related adverse events was higher than anticipated. Therefore, further studies are required to evaluate sustained tolerability, optimal dosing strategies that balance efficacy and adverse effects, and to identify patient subgroups most likely to benefit from therapy with minimal impact on quality of life. Such data will be essential for defining the role of P2X3 antagonists within future chronic cough management algorithms and for informing clinical decision-making in routine practice.

This meta-analysis included only pharmacological agents classified as antitussive drugs, acting directly on the cough reflex through central or peripheral mechanisms. Medications that may indirectly reduce cough by treating underlying airway inflammation or hyperresponsiveness, such as inhaled corticosteroids, leukotriene receptor antagonists, or bronchodilators, were not included. Therefore, the results primarily reflect the efficacy of classical antitussive therapy rather than broader pharmacological strategies targeting disease-specific mechanisms. This may limit the generalizability of the findings to patients whose cough is secondary to inflammatory or allergic airway disorders, such as asthma or eosinophilic bronchitis.

The available evidence may be influenced by publication bias, as studies with positive outcomes are more likely to be published, potentially overestimating the therapeutic efficacy of novel antitussive agents. Second, substantial heterogeneity exists across studies in terms of outcome measures, including differences in cough frequency assessment, patient-reported endpoints, and study duration, which limits direct comparability and quantitative synthesis of results. Finally, while P2X3 receptor antagonists are supported by the most robust clinical data to date, the number of high-quality, randomized trials evaluating alternative mechanistic targets remains limited. This imbalance limits broader conclusions about the relative efficacy of non-P2X3 therapies and underscores the need for well-designed trials across diverse antitussive strategies.

Although the literature search included both acute and chronic cough, only studies focusing on chronic cough met the inclusion criteria for quantitative synthesis. As a result, the meta-analysis and forest plots reflect evidence exclusively related to chronic cough. The absence of eligible studies on acute cough highlights a gap in the current literature and limits the generalizability of the findings to chronic cough populations only. Consequently, conclusions regarding the efficacy of P2X3 antagonists should not be extrapolated to acute cough.

Another limitation of this work is the inclusion of only English-language publications, which may have introduced a language-related selection bias. As a result, relevant studies published in other languages, particularly those originating from regions with extensive research on traditional medicine, such as China, may not have been captured. Numerous studies have investigated traditional herbal remedies with potential antitussive effects, however, many were excluded due to language restrictions and classification difficulties. Consequently, the exclusion of non-English studies and traditional herbal formulations may limit the completeness of the evidence base and should be considered when interpreting the findings of this review.

Our study confirms that despite the long history of use of codeine and other antitussives, both centrally (butamirate, dextromethorphan) and peripherally (levodropropizine), evidence for their effectiveness remains limited, and the available data are scattered and inconsistent. In recent years, there has been growing interest in natural preparations as alternatives to traditional antitussives. However, their efficacy and safety remain inconsistent, highlighting the need for further, high-quality clinical trials. P2X3 receptor antagonists deserve particular attention, as they have shown potential to reduce cough frequency and severity in available studies. In addition, all P2X3 antagonists reduced cough frequency, with no significant differences between compounds. Accordingly, P2X3 represents a promising direction for the development of new therapies. In this context, the concept of “beyond codeine” takes on particular significance–it encompasses not only the search for more effective and safer synthetic drugs but also the development of therapies targeting new, peripheral molecular targets, such as P2X3 receptors.