A comprehensive literature search was conducted in February 2025 across PubMed, Cochrane Library, Embase, Scopus, and ClinicalTrials.gov to identify RCTs evaluating the effects of carbocysteine in chronic respiratory and otolaryngological diseases. The search had no restrictions on language or publication years to ensure the inclusion of all relevant studies.

The search strategy utilized a combination of MeSH terms and free-text keywords, adapted to each database. Boolean operators (AND, OR) were applied to optimize search sensitivity and specificity. The key terms used included: Intervention-related terms: “Carbocysteine”, “S-Carboxymethylcysteine”, “Mucoregulator”, “Mucoactive therapy”, “Mucolytic agent”. Chronic disease-related terms: “Chronic bronchitis”, “Chronic cough”, “Mucus hypersecretion”, “Chronic airway disease”, “pulmonary disease”, “Exacerbations”. Pathology-specific terms: “Chronic obstructive pulmonary disease”, “COPD”, “Cystic fibrosis”, “Otitis media with effusion”, “Recurrent otitis media”, “Middle ear effusion”. Clinical outcomes-related terms: “Lung function”, “FEV1”, “Airway clearance”, “Sputum viscosity”, “Expectoration”, “Hearing loss”, “Mucociliary clearance”. To maximize the coverage of relevant studies, reference lists from included articles and systematic reviews were also manually screened.

This systematic review included only RCTs investigating the effects of carbocysteine in chronic mucus-related respiratory and otorhinolaryngological diseases. Observational studies, case reports, editorials, and animal studies were excluded to ensure a high level of evidence. Studies were required to compare carbocysteine to placebo, standard treatment, or other mucolytics. The included studies evaluated the systemic or inhaled use of carbocysteine, regardless of the dosing regimen. Trials that used concomitant medication to treat the underlying pathological condition were included, provided that these treatments were administered equally in both the intervention and control groups.

Eligible studies included patients diagnosed with chronic bronchitis, COPD, cystic fibrosis, obstructive sleep apnea syndrome (OSAS) and recurrent or persistent otitis media with effusion (OME). Studies focusing on acute respiratory infections or short-term symptom relief without long-term follow-up were excluded, as this review specifically aimed to evaluate the role of carbocysteine in chronic disease management. All included studies were required to assess clinical variables, such as sputum viscosity, expectoration ease, mucociliary clearance, lung function parameters (FEV1, FVC), exacerbation rates, middle ear effusion volume, hearing improvement, or need for surgical intervention.

The study selection process followed PRISMA guidelines, using a two-step screening process. First, two independent reviewers screened all retrieved records by title and abstract, applying broad eligibility criteria to exclude studies unrelated to carbocysteine or chronic disease management. Articles that passed this stage underwent a full-text review, where predefined inclusion and exclusion criteria were applied. Any disagreements between reviewers were resolved through discussion, and if consensus was not reached, a third reviewer was consulted.

Since most of the included studies were conducted many years ago, the original authors were not contacted for additional information. To ensure comprehensive analysis, the reference lists of included studies and relevant systematic reviews were manually screened for additional trials that met the inclusion criteria.

A meta-analysis was conducted, incorporating both continuous and categorical data depending on the outcome analyzed. For continuous variables, means and standard deviations (SDs) were used to calculate standardized mean differences (SMDs) with 95% confidence intervals (CIs). For categorical variables, frequencies (n/N) were used to compute odds ratios (ORs) with 95% CIs.

To compare the incidence rates between the carbocysteine and placebo groups, a meta-analysis of rate ratios (RRs) was conducted. Incidence rates were calculated as the number of events per person-year in each study arm. The rate ratios and their corresponding standard errors (SEs) were computed using log-transformed values and pooled under a random-effects model to account for potential between-study heterogeneity. A continuity correction of 0.5 was applied when a study reported zero events in one of the treatment groups. Pooled estimates were presented as rate ratios with 95% confidence intervals (CIs).

For all meta-analyses, effect sizes were pooled using both fixed-effects and random-effects models, depending on the level of heterogeneity observed. The fixed-effects model (inverse variance method) assumes that all studies estimate a common underlying effect size, weighting each study proportionally to its precision. The random-effects model (DerSimonian-Laird method) accounts for potential between-study variability, if the true effect may differ across studies. Given the expected clinical and methodological heterogeneity, the random-effects model was prioritized for primary analyses, while the fixed-effects model was used for sensitivity analyses.

To minimize heterogeneity, studies were grouped based on disease condition, comparison arm and outcome type. Chronic bronchitis simple (non-COPD) studies focused on outcomes related to sputum viscosity, mucociliary clearance, and expectoration. COPD studies assessed exacerbation rates, lung function parameters such as FEV1 and FVC, and symptom improvement. Cystic fibrosis studies evaluated mucus rheology and airway clearance. OME studies analyzed middle ear effusion resolution, hearing improvement, and the need for grommet placement. Studies on obstructive sleep apnea syndrome focused on outcomes related to airway patency, mucus clearance, and symptom improvement.

Statistical heterogeneity was assessed using Cochran’s Q test and the I² statistic, with I² values above 50% considered indicative of substantial heterogeneity. Sensitivity analyses were performed by excluding studies with a high risk of bias or those lacking a clearly defined control group. Publication bias was planned to be evaluated using funnel plots and Egger’s test for asymmetry if at least ten studies had been available per outcome. All statistical analyses were performed using STATA, with statistical significance set at p < 0.05.

The systematic search identified 236 studies, of which only 20 met the inclusion criteria after full-text review [9] - [27] . The included studies evaluated the effects of carbocysteine in chronic mucus-related respiratory and otorhinolaryngological diseases, with 8 studies focusing on COPD [9] - [16] , 3 on chronic bronchitis without airflow obstruction [17] - [19] , 1 on cystic fibrosis [20] , 1 on OSAS [21] , and 7 on OME [22] - [28] . The studies were published in English, French, Japanese, Polish, and Russian, reflecting a diverse body of international research on the therapeutic effects of carbocysteine ( Figure 1 ). For COPD, the trials varied in the number of recruited patients, ranging from 16 to 709 subjects. Most studies included patients with confirmed COPD diagnosis based on functional criteria, with FEV1/FVC values below 70% and different degrees of airflow obstruction. In terms of intervention, carbocysteine doses ranged from 750 mg to 1500 mg per day, usually administered in two or three doses. Some studies compared carbocysteine to placebo [14] [16] , while others evaluated it against another mucoregulator [10] or in combination with other therapies [11] .

The follow-up duration varied significantly among the trials. The longest study [16] had a 12-month follow-up, whereas other studies assessed shorter-term efficacy, ranging from 7 days to 3 months [12] [13] . All studies recorded clinical variables related to COPD, including exacerbation frequency, lung function, sputum viscosity, quality of life, and respiratory symptoms. ( Table 1 )

RCT: randomized controlled trial; N: number of patients; COPD: chronic obstructive pulmonary disease.

For chronic bronchitis, the three RCTs included in this review evaluated the efficacy of carbocysteine in this patient population. These studies included 24, 20, and 109 patients, respectively, all diagnosed with simple chronic bronchitis without significant airflow obstruction. The trials used a placebo-controlled design to assess the impact of carbocysteine on sputum viscosity, mucociliary clearance, lung function, and respiratory symptoms. The duration of treatment varied: one study [17] administered carbocysteine-lysine at a dose of 2.7 g/day for 4 days; another [18] used oral carbocysteine at 375 mg three times daily for 10 days; and the third [19] provided oral carbocysteine at 750 mg three times daily for six months. In the short-term studies, mucus samples were collected before and after treatment, and their rheological properties were analyzed. In the long-term trial, lung function was monitored monthly using PEFR, and data on acute exacerbations were also collected.

For cystic fibrosis, one randomized, single-blind, comparative study evaluated the effects of SCMC-Lys versus ambroxol hydrochloride (ABX) in 26 patients with confirmed cystic fibrosis and predominant respiratory involvement [20] . The study included both pediatric and adult patients, with dosing adjusted accordingly (SCMC-Lys: 900 mg TID for adults and 270 mg TID for children; ABX: 33 mg TID for adults and 10 mg QID for children). The treatment period lasted 80 days, during which clinical symptoms, sputum properties, arterial blood gases, and pulmonary function were assessed.

For OSAS, one RTC trial assessed the effects of carbocysteine compared to continuous positive airway pressure (CPAP) in 40 patients with moderate to severe OSAS [21] . Patients were randomly assigned to receive either 1500 mg of oral carbocysteine daily or CPAP therapy for six weeks. The study evaluated changes in polysomnographic parameters, oxidative stress markers, and endothelial function.

The studies evaluating the effects of carbocysteine in OME varied in design, sample size, and follow-up duration [22] - [28] . The number of participants ranged from 38 to 250 children, with most studies including pediatric patients aged between 3 and 14 years. Some trials focused specifically on children with chronic otitis media with effusion and adenoid hypertrophy, while others included broader populations with middle ear effusion. The treatment regimens differed among studies, with carbocysteine administered either as a monotherapy or as part of a combined approach with other therapies such as decongestants or antihistamines. Dosing strategies varied, with most studies using S-carboxymethylcysteine (SCMC) syrup at a dosage of 125 mg/5 mL, given three times daily for periods ranging from 4 to 12 weeks.

The control groups consisted of either placebo [24] [25] [27] or alternative treatments such as antihistamine-decongestant combinations [26] . The primary outcomes assessed included the resolution of middle ear effusion, improvement in audiometric parameters, and reduction in the need for surgical intervention, such as tympanostomy tube insertion.

To enable meta-analytic pooling, only outcomes consistently reported across two or more trials were included in the quantitative synthesis, while study-specific results were excluded from this section.

Incidence rate of exacerbations

A meta-analysis of incidence rates comparing carbocysteine to placebo showed a pooled RR of 0.48 (95% CI: 0.32 - 0.72; p < 0.001), indicating a significant 52% reduction in exacerbations in the carbocysteine group. Despite substantial heterogeneity among the included studies (I² = 88.2%), all individual trials consistently favored carbocysteine, reinforcing the robustness of its therapeutic benefit across different populations and clinical settings. ( Figure 2A )

To assess the robustness of the findings, a sensitivity analysis was performed excluding the earliest study, which differed from the others in having a shorter follow-up period (6 months versus 12 months) and being conducted more than a decade prior to the remaining trials. After excluding this study, the pooled RR remained directionally consistent and statistically significant (RR = 0.44; 95% CI: 0.23 - 0.83; p < 0.001), confirming that the observed benefit was not driven by this single data point ( Figure 2B ). However, the level of heterogeneity increased rather than decreased (I² = 91.9%), suggesting that variability among the more recent studies remained substantial despite the exclusion. This further underscores the importance of considering clinical and methodological differences across trials when interpreting the pooled effect.

Mean number of exacerbations

A meta-analysis of four RCTs evaluated the effect of carbocysteine on the mean number of exacerbations. A random-effects model was applied due to high heterogeneity (I² = 99.6%, p < 0.0001). The pooled SMD was −3.39 (95% CI: −6.36 to −0.42; p < 0.001), indicating a significant reduction in the mean number of exacerbations among patients receiving carbocysteine. ( Figure 3 )

Quality of life

The effect of carbocysteine on quality of life was assessed in a meta-analysis of two RCTs. Due to substantial heterogeneity (I² = 95.1%, p < 0.0001), a random-effects model was used. The pooled analysis demonstrated a significant benefit in favor of carbocysteine (SMD −1.45; 95% CI: −2.43 to −0.48; p < 0.001), suggesting a clinically meaningful improvement despite notable variability between studies. ( Figure 4 )

Adverse events

The safety profile of carbocysteine was assessed through a meta-analysis of four RCTs. A fixed-effects model was used given the absence of significant heterogeneity (I² = 0.0%, p = 0.620). The pooled OR was 0.93 (95% CI: 0.64 - 1.35; p > 0.05), indicating no significant difference in adverse event rates between carbocysteine and placebo. These findings suggest that carbocysteine is well tolerated and does not increase the risk of adverse events. ( Figure 5 )

Common colds

Two RCTs evaluating the incidence of common colds were included in a meta-analysis. A random-effects model was applied, with moderate heterogeneity detected (I² = 68.2%, p = 0.076). The combined rate ratio was 0.47 (95% CI: 0.35 - 0.63; p < 0.001), indicating a significant 53% reduction in the risk of common colds with carbocysteine compared to placebo. ( Figure 6 )

Although a small number of COPD trials included active comparators, such as N-acetylcysteine or combination therapies (e.g., carbocysteine plus sobrerol), no more than one study was available per comparator with sufficiently similar design and outcomes to allow meta-analysis. These studies are not discussed individually, to avoid overinterpretation and preserve consistency in the level of evidence presented for this specific condition.

Reduction of sputum viscosity

A meta-analysis of two RCTs assessed the impact of carbocysteine on sputum viscosity in patients with chronic bronchitis without airflow obstruction. A random-effects model was used due to substantial heterogeneity (I² = 87.8%, p = 0.004). The pooled SMD was −2.67 (95% CI: −5.28 to −0.05; p < 0.05), confirming a significant reduction in sputum viscosity with carbocysteine treatment. ( Figure 7 )

Resolution OME

A meta-analysis of two RCTs evaluated the effect of carbocysteine on OME resolution. A fixed-effects model was applied due to a lack of heterogeneity (I² = 0.0%, p = 0.574). The pooled OR was 1.45 (95% CI: 1.00 - 2.11; p = 0.050), indicating a borderline statistically significant benefit in favor of carbocysteine. ( Figure 8 )

Audiometric improvement

The effect of carbocysteine on audiometric outcomes in patients with OME was assessed in two RCTs. Using a fixed-effects model (I² = 0.0%, p = 0.573), the pooled OR was 1.52 (95% CI: 1.02 - 2.27; p = 0.038), demonstrating a significant improvement in hearing thresholds with carbocysteine compared to placebo. ( Figure 9 )

Only one study was identified evaluating carbocysteine lysine salt monohydrate (SCMC-Lys) in cystic fibrosis, so a meta-analysis could not be performed. The trial compared SCMC-Lys and ambroxol hydrochloride (ABX) in 26 patients over 80 days, showing similar efficacy in reducing sputum viscosity and elasticity and improving oxygenation.

In the SCMC-Lys group, sputum viscosity significantly decreased from 5002 ± 736 to 3493 ± 411 mPas (p < 0.01), while sputum elasticity was reduced from 401 ± 59 to 311 ± 40 G (p < 0.05). Oxygenation improved, with PaO₂ increasing from 36.1 ± 2.1 to 40.7 ± 2.0 mmHg (p < 0.01) and HbO₂ saturation rising from 64.1 ± 3.6 to 69.5 ± 3.5% (p < 0.02). Lung function showed significant gains, with tidal volume increasing from 74.5 ± 5.0 to 78.8 ± 4.8% (p < 0.005), FEV₁ from 65.3 ± 8.2 to 68.2 ± 8.1% (p < 0.02), and PEF from 63.9 ± 5.8 to 68.2 ± 2.2% (p = 0.05).

Notably, SCMC-Lys significantly improved cough symptoms (p < 0.05), a benefit not observed with ABX, suggesting a potential advantage in enhancing expectoration. No adverse events were reported in either group.

Only one study was identified evaluating carbocysteine in OSAS, so a meta-analysis could not be performed. The Wu et al. (2016) trial randomized 40 patients with moderate to severe OSAS to receive carbocysteine (1500 mg/day) or continuous positive airway pressure (CPAP) for six weeks, assessing polysomnographic parameters, oxidative stress biomarkers, and endothelial function.

In the carbocysteine group, the Apnea-Hypopnea Index (AHI) significantly decreased from 43.3 ± 7.2 to 29.8 ± 6.5 events/hour (p < 0.01), indicating an improvement in sleep-disordered breathing. Daytime sleepiness, measured by the Epworth Sleepiness Scale (ESS), improved from 10.18 ± 4.28 to 6.82 ± 3.66 (p < 0.01). Additionally, endothelial function, assessed via flow-mediated dilation (FMD), significantly improved from 6.12 ± 1.45% to 8.35 ± 1.57% (p < 0.01), suggesting a beneficial effect on vascular health.

These results indicate that carbocysteine may reduce apnea severity and improve sleep-related symptoms in OSAS patients, potentially due to its mucoregulatory and anti-inflammatory properties. However, as CPAP remains the gold standard treatment, further studies are needed to clarify the clinical relevance of carbocysteine in OSAS management.