Prescriptions of opioid-containing drugs in patients with chronic cough.

BACKGROUND: Chronic cough (CC) affects about 10% of adults, but opioid use in CC is not well understood. OBJECTIVES: To determine the use of opioid-containing cough suppressant (OCCS) prescriptions in patients with CC using electronic health records. DESIGN: Retrospective cohort study. METHODS: Through retrospective analysis of Midwestern U.S. electronic health records, diagnoses, prescriptions, and natural language processing identified CC - at least three medical encounters with cough, with 56-120 days between first and last encounter - and a 'non-chronic cohort'. Student's t-test, Pearson's chi-square, and zero-inflated Poisson models were used. RESULTS: About 20% of 23,210 patients with CC were prescribed OCCS; odds of an OCCS prescription were twice as great in CC. In CC, OCCS drugs were ordered in 38% with Medicaid insurance and 15% with commercial insurance. CONCLUSION: Findings identify an important role for opioids in CC, and opportunity to learn more about the drugs' effectiveness.

Assessment and Management of Cough in Idiopathic Pulmonary Fibrosis: A Narrative Review.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal disease with an unknown cause. It is characterized by symptoms such as cough and breathlessness, which significantly impact patients' quality of life. Cough, in particular, has emerged as a burdensome symptom for individuals with IPF. The etiology of cough in IPF patients is believed to be complex, involving factors related to the disease itself, such as increased sensitivity of cough nerves, lung structural changes, inflammation, and genetic factors, as well as comorbidities and medication effects. Unfortunately, effective treatment options for cough in IPF remain limited, often relying on empirical approaches based on studies involving chronic cough patients in general and the personal experience of physicians. Medications such as opioids and neuromodulators are commonly prescribed but have shown suboptimal efficacy, imposing significant physical, psychological, and economic burdens on patients. However, there is hope on the horizon, as specific purinergic P2 receptor ligand-gated ion channel (P2X3) inhibitors have demonstrated promising antitussive effects in ongoing clinical trials. This review aims to provide a comprehensive overview of the evaluation and management of cough in IPF patients, as well as highlight emerging pharmacological and non-pharmacological approaches that target the cough reflex and are currently being investigated in clinical settings.

Diagnoses and management of adult cough: An Indian Environmental Medical Association (EMA) position paper.

BACKGROUND: Cough is a common yet distressing symptom that results in significant health care costs from outpatient visits and related consultations. OBJECTIVE: The understanding of the pathobiology of cough in recent times has undergone an evolution with Cough hypersensitivity syndrome (CHS) being suggested in most cases of dry cough. However, in the case of productive cough, ancillary mechanisms including impaired Mucociliary clearance, in addition to hypermucosecretory bronchospastic conditions of Smoker's cough, asthma-COPD overlap, bronchiectasis, and allergic bronchopulmonary aspergillosis, need to be critically addressed while optimizing patient care with symptomatic therapy in outpatient settings of India. METHODS: In this review, evidence-based graded recommendations on use of antitussives - & protussives as a Position Paper were developed based on the Level and Quality of Scientific evidence as per Agency for Health Care and Quality (AHRQ) criteria listing and Expert opinions offered by a multidisciplinary EMA panel in India. RESULTS: Management of acute or chronic cough involves addressing common issues of environmental exposures and patient concerns before instituting supportive therapy with antitussives or bronchodilatory cough formulations containing mucoactives, anti-inflammatory, or short-acting beta-2 agonist agents. CONCLUSION: The analyses provides a real world approach to the management of acute or chronic cough in various clinical conditions with pro- or antitussive agents while avoiding their misuse in empirical settings.

Upper Respiratory Tract Infection-Associated Acute Cough and the Urge to Cough: New Insights for Clinical Practice.

Upper respiratory tract infection (URTI)-associated acute cough is the most common symptom both in children and adults worldwide and causes economic and social problems with significant implications for the patient, the patient's family, and the health care system. New pathogenic mechanisms in acute cough, including the urge to cough (UTC) mechanisms, have been recently identified. The brainstem neural network, pharyngeal sensory innervation, airway mechanical stimulation, inflammatory mediators, and postnasal drip actively participate in the onset and maintenance of acute cough and the urge to cough phenomenon. However, there is still no effective pharmacological treatment capable of interfering with the pathophysiologic mechanisms involved in URTI-associated acute cough. Moreover, severe adverse events frequently occur in administering such cough medications, mainly in children. New evidence has been provided concerning polysaccharides, resins, and honey as potential cough relievers with high antitussive efficiency, effect on the UTC, and minimal side effects.

Epidemiology and medical service use for spontaneous pneumothorax: a 12-year study using nationwide cohort data in Korea.

OBJECTIVE: This study aimed to promote an understanding of spontaneous pneumothorax by analysing the prevalence rate and medical service use by patients with spontaneous pneumothorax according to sociodemographic characteristics. DESIGN: A 12-year nationwide study. SETTING: Data obtained from the Korean National Health Insurance Service Sharing Service. PARTICIPANTS: A total of 4658 participants who used medical services due to spontaneous pneumothorax between 2002 and 2013 in Korea. OUTCOME MEASURES: For those diagnosed with spontaneous pneumothorax, use of medical services, hospitalisation data, sociodemographics, comorbidity, treatment administered and medication prescribed were recorded. RESULTS: The annual prevalence of spontaneous pneumothorax ranged from 39 to 66 per 100 000 individuals, while the prevalence of hospitalisation due to spontaneous pneumothorax ranged from 18 to 36 per 100 000 individuals. The prevalence rate of spontaneous pneumothorax in Korea has increased since 2002. The male to female ratio was approximately 4-10:1, with a higher prevalence rate in men. By age, the 15-34 years old group, and particularly those aged 15-19 years old, showed the highest prevalence rate; the rate then declined before increasing again for those aged 65 years or older. In total, 47%-57% of patients with spontaneous pneumothorax underwent hospitalisation. The average number of rehospitalisations due to pneumothorax was 1.56 per person, and more than 70% of recurrences occurred within 1 year. Chronic obstructive pulmonary disease was the most common comorbidity. The average treatment period was 11 days as an outpatient and 14 days in-hospital. The average medical costs were $94.50 for outpatients and $2523 for hospital admissions. The most common treatment for spontaneous pneumothorax was oxygen inhalation and thoracostomy, and the most commonly prescribed medications were analgesics, antitussives and antibiotics. CONCLUSIONS: We here detailed the epidemiology and treatments for spontaneous pneumothorax in Korea. This information can contribute to the understanding of spontaneous pneumothorax.

A comparative assessment of acute oral toxicity and traditional pharmacological activities between extracts of Fritillaria cirrhosae Bulbus and Fritillaria pallidiflora Bulbus.

ETHNOPHARMACOLOGICAL RELEVANCE: Fritillariae Bulbus ("Beimu" in Chinese) is a famous traditional Chinese medicine used to treat cough, expectoration and asthma for more than 2000 years, which belongs to the Fritillaria genus in Liliaceae family. Bulbs of Fritillaria cirrhosa D.Don (BFC) and bulbs of Fritillaria pallidiflora Schrenk (BFP) are two important drugs of Beimu. Due to the significant similarities in their outward appearance characters and chemical profiles, BFC has often been adulterated with BFP in Chinese Traditional Medicine markets. AIM OF THE STUDY: This study aims to compare the oral acute toxicity and the traditional pharmacological activities including antitussive, expectorant and anti-inflammatory effects between the extract of BFC and BFP, to clear and definite if the BFP can be used as a substitute of the BFC in the application of traditional medicine. MATERIALS AND METHODS: The extracts were prepared through refluxing with 80% ethanol solvent. For the acute toxicity tests, graded doses of BFP extracts and the maximum dose of BFC extracts were administered orally to mice. The animals were observed for toxic symptoms and mortality daily for 14 days. For the pharmacological activities tests, graded doses of BFP and BFC extracts were administered orally to mice. To observe the effects relieving cough, expelling phlegm and lessening the ear swelling of BFC extracts and BFP extracts through ammonia liquor inducing cough, phenol red apophlegmating in mice and the xylene-induced auricular swelling of mouse, respectively. RESULTS: In the acute toxicity study, the LD50 value of BFP in mice was calculated to be 213.57 g/kg body weight, and the maximum feasible dose (MFD) value of BFC in mice was 452.14 g/kg. Histopathological analysis has shown inflammatory cells infiltration and cells edema in liver, multinucleated giant cell proliferation in spleen, perivascular exudate and hemorrhage in lung, glomerulus atrophy in kidney of mice after oral administrations of BFP extracts. But only liver cells edema was observed in BFC group. Both BFC extract and BFP extract significantly increased latent period of cough and inhibited cough frequency in mice induced by ammonia. Besides, the two extracts also obviously enhanced mice's tracheal phenol red output in expectorant assessment and inhibited the development of ear edema in anti-inflammatory evaluation assay. CONCLUSION: To summarize, the BFP has the significant similarities in morphological characteristics, chemical profiles and traditional pharmacological activities compared with the BFC. The result of this study provide some valid scientific support for using BFP as a plant substitute of the BFC, but considering the toxicity of BFP is much higher than BFC, we don't recommend long-term oral administration of BFP or exceeding recommended dosage of Chinese Pharmacopoeia 2015.

Genotoxicity assessment of the novel antitussive agent Benzonatate and its major metabolite.

Benzonatate (TESSALON®) is a peripherally acting oral antitussive. It undergoes rapid ester hydrolysis producing 4-(butylamino) benzoic acid (BBA) and methylated polyethylene glycol (MPG) metabolites, which are eliminated in urine and feces. The nonclinical and clinical efficacy of Benzonatate has been demonstrated over the last 60 years, but its safety was not fully assessed. In this study, we tested the genotoxicity of Benzonatate and its major metabolite BBA in an in vitro bacterial reverse mutation and in vivo micronucleus assays. A chromosomal aberration assay was also performed on Benzonatate and BBA. In the reverse mutation assay, Benzonatate and BBA doses 1.5-5000 µg/plate ±â€¯S9 metabolic activation were used and the numbers of revertants/plate were compared to various controls. Chromosomal aberration assays with human peripheral blood lymphocytes used Benzonatate and BBA concentrations 25-2000 and 62.5-1930 µg/mL, respectively. A CByB6F1 mouse bone marrow micronucleus assay was performed as part of a 28-day oral toxicology study at up to 250 mg/kg/day. The frequencies of micronuclei in polychromatic erythrocytes in treated groups were compared with the control group. Neither Benzonatate nor BBA induced significant mutagenicity in any of the bacterial strains, with or without metabolic activation. They also did not produce any biologically relevant structural or numerical aberrations in human chromosomes. Benzonatate and its BBA and MPG metabolites rapidly produced from esterase activity did not produce any significant increase in the incidence of micronucleated polychromatic erythrocytes. In conclusion, Benzonatate and its major metabolite BBA were not mutagenic and did not cause numerical or structural chromosome alterations. While the MPG metabolite was not tested, studies on structural analogues indicated it was also unlikely to be genotoxic. This was supported by oral rodent carcinogenicity assays showing no increase in malignancies.

Effects of over-the-counter sales restriction of antibiotics on substitution with medicines for symptoms relief of cold in Mexico and Brazil: time series analysis.

We evaluated changes in the use of non-steroidal anti-inflammatory drugs (NSAIDs), non-opioid analgesics and cough and cold medicines and its relation with the use of antibiotics after the over-the-counter (OTC) antibiotic sales restrictions in Mexico and Brazil. IMS Health provided retail quarterly data from the private sectors in Mexico and Brazil from the first quarter of 2007 to the first quarter of 2013. Data of each active substance of antibiotics, easily accessible medicines perceived as antibiotics substitutes (cough and cold medicines, analgesics and NSAIDs-the latter two being combined in the analyses), and medicines to control for external factors that can affect the medicines usage trend (antihypertensives) were converted from kilograms to defined daily doses per 1000 inhabitants days (DDD/TID). Interrupted time series were used to estimate changes in level of medicines use at the intervention point and slope after the regulation. The Gregory-Hansen cointegration test was used to explore the relation between the use of antibiotics and perceived substitutes. After the regulation in Mexico NSAIDs-analgesics usage level increased by 1.1 DDD/TID with a slope increase of 0.2 DDD/TID per quarter and the cough and cold medicines usage level increased by 0.4 DDD/TID. In Brazil NSAIDs-analgesics usage level increased by 1.9 DDD/TID, and cough and cold medicines did not change. In the two countries, NSAIDs-analgesics usage changes were related with antibiotic usage changes; in Mexico cough and cold medicines usage changes had a relation with the antibiotics usage changes. These results showed a substitution effect on the use of other medicines, especially NSAIDs and analgesics, after reinforcement of OTC antibiotics sales restrictions. These regulations aimed to improve the antibiotics use and as a consequence reduce antimicrobial resistance; however, this type of policies should be comprehensive and take into account the potential substitution effects on the use of other medicines.

Establishment of a standard reference material (SRM) herbal DNA barcode library of Vitex negundo L. (lagundi) for quality control measures.

The majority of the population in the Philippines relies on herbal products as their primary source for their healthcare needs. After the recognition of Vitex negundo L. (lagundi) as an important and effective alternative medicine for cough, sore throat, asthma and fever by the Philippine Department of Health (DOH), there was an increase in the production of lagundi-based herbal products in the form of teas, capsules and syrups. The efficiency of these products is greatly reliant on the use of authentic plant material, and to this day no standard protocol has been established to authenticate plant materials. DNA barcoding offers a quick and reliable species authentication tool, but its application to plant material has been less successful due to (1) lack of a standard DNA barcoding loci in plants and (2) poor DNA yield from powderised plant products. This study reports the successful application of DNA barcoding in the authentication of five V. negundo herbal products sold in the Philippines. Also, the first standard reference material (SRM) herbal library for the recognition of authentic V. negundo samples was established using 42 gene accessions of ITS, psbA-trnH and matK barcoding loci. Authentication of the herbal products utilised the SRM following the BLASTn and maximum-likelihood (ML) tree construction criterion. Barcode sequences were retrieved for ITS and psbA-trnH of all products tested and the results of the study revealed that only one out of five herbal products satisfied both BLASTn and ML criterion and was considered to contain authentic V. negundo. The results prompt the urgent need to utilise DNA barcoding in authenticating herbal products available in the Philippine market. Authentication of these products will secure consumer health by preventing the negative effects of adulteration, substitution and contamination.

Burden of influenza in Germany: a retrospective claims database analysis for the influenza season 2012/2013.

OBJECTIVE: Seasonal influenza occurs in annual epidemics. The virus can cause severe illness and concomitant diseases with the highest risk for children, the elderly, and individuals with disease dispositions. The study objective is to assess the influenza burden in Germany. METHODS: This retrospective claims data analysis used the Health Risk Institute research database containing anonymized data of 4 million individuals. The study period comprised the influenza season 2012/2013 in which patients with documented influenza were identified. Disease frequency rates were calculated for a population with disease dispositions and a population not at high risk. Disease burden was assessed based on health-services utilization during the influenza season. Vaccine rates were calculated by identifying vaccinations. RESULTS: We observed 65,826 patients with influenza, resulting in 1,160,646 documented influenza cases after extrapolation. Overall, otitis media and pneumonia was higher in the influenza-infected population compared to the non-influenza-infected population and especially high in children. Hospitalization cost amounted to €87,202,485 with a mean stay of 7 days, and total outpatient costs were €14,947,976. Vaccination rates were <4 % for children and 37 % for patients aged >60. CONCLUSIONS: Seasonal influenza can cause severe outcomes with hospitalizations and excess costs. Especially influenza-infected children are affected by concomitant diseases with higher disease burden. Furthermore, documented vaccination rates are quite low.

Cough, codeine and confusion.

Codeine is widely prescribed in clinical practice with over the counter (OTC) preparations of codeine freely available for consumption typically as a component of remedies for the common cold/cough. We describe the first reported case of acute confusional state in a previously healthy 14-year-old girl ultimately attributed to inappropriate codeine use. The usage of codeine in the paediatric setting has been highlighted in recent years with many reported deaths--mostly due to respiratory depression. The risks associated with codeine usage may be particularly unnecessary with OTC cough suppressants as evidence of efficacy is absent. Finally, codeine dependence is a common problem among adults and has been reported locally and internationally among adolescents. The combination of lack of efficacy, risk of acute intoxication and dependence, suggests that the use of OTC codeine preparations may be unwarranted.

Clinical perspective - cough: an unmet need.

Cough is among the most common complaints for which individuals worldwide seek medical attention. The vast majority of cases of acute cough (<3 weeks duration) are due to acute viral upper respiratory tract infection (URI) (common cold). Fortunately, acute cough is typically transient and self-limited. However, should severe and/or persistent acute cough require pharmacological treatment, satisfactory therapeutic options are scarce. Narcotic antitussives are limited by unacceptable side effects at therapeutic doses, and most over-the-counter (OTC) remedies are not supported by adequate clinical trials. The goal in chronic cough (>8 weeks duration) is to meticulously evaluate and treat all potential underlying etiologies. Despite thorough investigation, a significant minority of patients will suffer refractory, unexplained cough. For this challenging population, safe, effective, non-narcotic antitussive therapies are desperately needed.

The impact of chronic cough: a cross-sectional European survey.

PURPOSE: Studies that investigate the impact of chronic cough have largely focused on patients attending secondary care. Our aim was to investigate the opinions of the wider general population across Europe. METHODS: An internet survey was made available in 12 languages on the European Lung Foundation website, between January 2012 and April 2013. RESULTS: Of 1120 respondents from 29 different European countries, 67 % were female, mean age 51 years (SD 15), median cough duration 2-5 years. The majority of respondents reported cough impacted their quality of life, mood and ability to undertake activities. Despite 72 % of respondents having visited their doctor ≥3 times, only 53 % had received a diagnosis. Asthma was the most common diagnosis (23 %). Most respondents reported limited or no effectiveness of medications. 88 % of respondents reported that they would like more information to be available on chronic cough. CONCLUSIONS: Chronic cough has a negative impact on quality of life. Further work is needed to raise awareness, promote management strategies, develop effective treatments and consider the educational and support needs of patients with chronic cough.

A comprehensive evaluation of rationality of cough and cold medicines available in Indian market.

To analyse various cough and cold formulations available in the Indian market and to study their pharmacological rationale and cost effectiveness, a cross-sectional, observational study was carried out for evaluation of the drugs listed in Current Index of Medical Specialities (CIMS) India, September 2010.The formulations were assessed for their total number, type of dosage form, number of constituents in each formulation, their pharmacological group and rationality. The total daily cost and its association with type of dosage form was analysed. Out of a total 1297 preparations evaluated, 94% were fixed dose combination. The mean number of constituents was 3.20 +/- 1.03. Liquid oral formulations were largest in number (64.4%). The formulations contained various antitussives (30.30%), expectorants (33.92%), antihistamines (71.09%), mucolytics (35.62%), decongestants (56.28%), bronchodilators (16.81%) and analgesics/antipyretics (31.30%). None of the preparation was listed in the Model list of Essential Medicines, WHO (March 2011) under section 25 of "Medicines acting on the respiratory tract". Only 2% of the preparations had pharmacological rationale for their use in cough and common cold; 9.6% were containing more than one ingredient of the same pharmacological group and 6.85% were containing both antitussive and expectorant having opposing action. Highest number of preparations (36.85%) was having cost of therapy of Rs 6-10 per day. Liquid oral dosage forms had significantly higher cost than solid dosage form (p < 0.0001) and topical nasal dosage forms had significantly higher cost than liquid (p < 0.03) and solid (p < 0.001) dosage forms. It is conducted that various cough and cold medicines available in Indian market lacked therapeutic rationale for their use, leading to wasteful expenditure.

An inexpensive system for evaluating the tussive and anti-tussive properties of chemicals in conscious, unrestrained guinea pigs.

INTRODUCTION: Commercial whole-body plethysmography systems used to evaluate the anti-tussive potential of drugs employ sophisticated technology, but these systems may be cost prohibitive for some laboratories. The present study describes an alternative, inexpensive system for evaluating the tussive and anti-tussive potential of drugs in conscious, unrestrained guinea pigs. METHODS: The system is composed of a transparent small animal anesthesia induction box fitted with a microphone, a camera and a pneumotachometer to simultaneously capture audio, video, air flow and air pressure in real time. Data acquisition and analysis was performed using free software for audio and video, and a research pneumotach system for flow and pressure. System suitability testing was performed by exposing conscious, unrestrained guinea pigs to nebulized aqueous solutions of a selective agonist for TRPV1 (citric acid) or a selective agonist for TRPA1 (AITC), with or without pre-treatment with a selective antagonist for TRPV1 (BCTC) or a selective antagonist for TRPA1 (HC-030031). RESULTS: The system easily discerned coughs from other respiratory events like sneezes. System suitability test results are as follows: AITC caused 10.7 (SEM=1.4592) coughs vs. 5.8 (SEM=1.6553) when pre-treated with HC-030031 (P<0.05). Citric acid caused 12.4 (SEM=1.4697) coughs vs. 3.2 (SEM=1.3928) when pre-treated with BCTC (P<0.002). DISCUSSION: We have described in detail an inexpensive system for evaluating the tussive and anti-tussive potential of chemicals in conscious, unrestrained guinea pigs. Suitability testing indicates that the system is comparable to a commercial whole-body plethysmography system for detecting and differentiating between coughs and sneezes. This system may provide some investigators a cost-conscious alternative to more expensive commercial whole-body plethysmography systems.

Determination of the active metabolite of moguisteine in human plasma and urine by LC-ESI-MS method and its application in pharmacokinetic study.

In this study, a sensitive and reproducible electro-spray ionization liquid chromatography-mass spectrometry (LC-ESI-MS) method was established to determine the concentration of M1, the main active metabolite of moguisteine in human plasma and urine. The analysis was performed on a Diamonsil® C18(2) column (150 mm × 4.6 mm, 5 µm) with the mobile phase consisting of 0.1% formic acid-acetonitrile (57:43, v/v, pH=3.0) at a flow rate of 0.8 mL min⁻¹. The pseudo-molecular ions [M+H]+ (m/z 312.2 for M1 and 446.3 for glipizide) were selected as the target ions for quantification in the selected ion monitoring (SIM) mode. Plasma samples were analyzed after being processed by acidification with formic acid and protein precipitation with acetonitrile. Urine samples were appropriately diluted with blank urine for analysis. Calibration curve was ranged from 0.02 to 8 µg mL⁻¹. The extraction recovery in plasma was over 90%. Both the inter- and intra-day precision values were less than 7.5%, and the accuracy was in the range from -6.0% to 6.0%. This is the first reported LC-ESI-MS method for analyzing M1 in human plasma and urine. The method was successfully applied to the pharmacokinetic study after oral administration of single-dose and multiple-dose of moguisteine tablets in healthy Chinese subjects.

Intentional Coricidin product exposures among Illinois adolescents.

OBJECTIVES: We sought to describe the demographics and trends of Coricidin product abuse in children in Illinois and to calculate an approximate total charge to the health-care system. METHODS: In this retrospective database review, we identified 652 cases of intentional exposure to Coricidin products among children < 18 years old in the Illinois Poison Center database from 2001 to 2006. Demographic, historical, clinical, and outcome data were recorded. RESULTS: The mean (standard deviation) age was 15.7 (1.58) years. A significant increase in exposures occurred during the study period which showed a cyclic nature with peaks in the fall months. Of the patients with disposition data available, 28.6% were admitted to a critical care unit, 15.2% to a noncritical care hospital unit, 6.3% were admitted for inpatient psychiatric care, and 46.4% were evaluated in the emergency department and discharged home. Moderate or major outcomes were reported in 42.7% of cases in which data were available. No deaths were reported. The total approximate hospital charge was $2,119,881.90 or $353,313.65/year. CONCLUSIONS: Intentional abuse of Coricidin products reported to the poison center occurred primarily among adolescents and was often associated with significant short-term clinical effects and a clear financial burden to the health-care system. SCIENTIFIC SIGNIFICANCE: This investigation demonstrates that Coricidin product abuse continues to be a problem particularly among adolescents. Parents and clinicians need to continue to be aware of these substances as drugs of abuse and curbing sales to adolescents should be considered.

Analysis of the impact of removing mucolytics and expectorants from the list of reimbursable drugs on prescription rates: a time-series analysis for France 1998-2010.

OBJECTIVES: After a comprehensive review of the therapeutic advantage of all drugs reimbursed by the French Public Health Insurance, a large number of drugs were removed from the list of reimbursable drugs, among them mucolytics and expectorants (ATC Class R05C) in March 2006. The aim of this study is to evaluate the impact of this measure on the mucolytic and expectorant class, on the prescription of possible substitute drugs (other bronchodilators, antitussives and antibacterials) and on the costs for Public Health Insurance. METHODS: Prescription data were taken from a 850 French physicians sample surveyed by the IMS-Health Permanent Survey on Medical Prescription from 1998 to 2010. We performed linear segmented regression to determine changes in the level and slope of the prescription rates and to estimate the budget impact. RESULTS: Following their removal from the list of reimbursable drugs, the prescription rate for mucolytics declined significantly and we recorded an increase in the prescription rates for antitussives and bronchodilators. The medically unexpected increase in antitussives can be viewed as a negative side-effect of the policy. Four years after the reform, total savings for Public Health Insurance were estimated at EUR 32.1 million. CONCLUSIONS: Further removals from the list of reimbursable drugs should take into account the possibility of negative impact on public health and potential savings.

Cough: an unmet clinical need.

Cough is among the most common complaints for which patients worldwide seek medical attention. Thus, the evaluation and treatment of cough result in tremendous financial expenditure and consumption of health care resources. Yet, despite the clinical significance of cough, research efforts aimed at improving diagnostic capabilities and developing more effective therapeutic agents have been, to date, disappointing in their limited scope and outcomes. Acute cough due to the common cold represents the most common type of cough. Currently, available medications for the symptomatic management of acute cough are inadequate due to lack of proven efficacy and/or their association with undesirable or intolerable side effects at anti-tussive doses. Subacute cough, often representing a prolonged post-viral response, is typically refractory to standard anti-tussive therapy. Few clinical trials have evaluated therapeutic options for subacute cough. Diagnostic challenges facing the clinician in the management of chronic cough include the determination of whether symptoms of upper airway cough syndrome (formerly, postnasal drip syndrome) or gastro-oesophageal reflux disease are indeed the underlying cause of cough. Chronic, refractory unexplained (formerly, idiopathic) cough must be distinguished from cough that has not been fully evaluated and treated according to current guideline recommendations. Eagerly awaited are new safe and effective anti-tussive agents for use when cough suppression is desired, regardless of underlying aetiology of cough, as well as practical, validated ambulatory cough counters to aid clinical assessment and future research in the field of cough.