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Efficacy of levodropropizine in pediatric cough
Pulmonary Pharmacology & Therapeutics 25 (2012) 337e342
Contents lists available at SciVerse ScienceDirect
Pulmonary Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/ypupt
Review
Efficacy of levodropropizine in pediatric cough Francesco De Blasio a, Peter V. Dicpinigaitis b, Gianluca De Danieli c, *, Luigi Lanata c, Alessando Zanasi d a
Respiratory Medicine and Pulmonary Rehabilitation Section, Clinic Center, Private Hospital, Naples, Italy Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA c Medical Department, Dompé SPA, Via san Martino 12, Milan, Italy d Pneumology Unit, University of Bologna, S.Orsola Malpighi Hospital, Bologna, Italy b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 17 February 2012 Received in revised form 16 April 2012 Accepted 3 May 2012
Cough in children is among the most common problems managed by pediatricians, and occurs more frequently in preschool than in older children. Most acute episodes of cough are due to viral upper respiratory tract infections. The morbidity associated with acute cough in a child extends also to parents, teachers, and other family members and caregivers. Unfortunately, therapeutic options for acute cough in children are severely limited due to the absence of drugs shown to be effective antitussives with an acceptable safety profile. Agents used in the management of adult cough, such as narcotics (codeine, hydrocodone), the non-narcotic opioid dextromethorphan, first-generation, potentially sedating antihistamines, and decongestants such as pseudoephedrine, have all been deemed inadequate for treatment of acute pediatric cough on a risk/benefit basis. A growing body of evidence suggests that the peripherally acting antitussive, levodropropizine, may be an attractive alternative for the treatment of bothersome acute cough in children. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Levodropropizine Pediatric Children Antitussives
1. Introduction Cough in children is among the most common problems managed by pediatricians, and occurs more frequently in preschool than in older children [1] Two out of 3 children younger than age 4 visit their pediatricians at least once a year with acute respiratory infection, and up to three quarters of them will have a cough [2,3]. Most acute coughs are caused by viral upper respiratory tract infections (URIs); 7e12% of coughs are due to asthma, while other causes are uncommon [4]. Although most acute URIs are selflimited illnesses, cough as a bothersome symptom associated with URI results in more pediatric ambulatory health care visits than any other symptom in the United States [5,6]. The reported severity of a child’s cough may relate to how it affects parents and teachers as well as the child. Recent evidence has highlighted that parental reporting of the frequency and severity of a child’s cough is unreliable compared with objective measures, and this is especially true for nocturnal cough. Indeed, it has been suggested that cough as reported in surveys and as a clinical trial outcome should either not be used or, at least, be interpreted with caution [7e10]. Therapeutic intervention for cough may be directed at a specific underlying cause or, as in the case of viral URI-induced cough,
* Corresponding author. Tel.: þ39 3409491162. E-mail address: [email protected] (G. De Danieli). 1094-5539/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pupt.2012.05.010
suppression aimed at symptom relief. Potential benefits of early treatment of cough could include the prevention of a vicious cycle, wherein mechanical irritation of inflamed respiratory epithelial mucosa by persistent coughing perpetuates cough by ongoing trauma to the airways, and the superficially lying sensory afferent cough fibers contained therein. In recent years, much attention has been drawn to the fact that commonly-used antitussive agents for the pediatric population are not supported by adequate efficacy data to justify their use, especially in light of potential associated side effects [8,9]. In fact, pharmaceutical companies in the United States no longer market antitussives for children less than 4 years of age. Each of the antitussive classes of drugs used by adults is associated with an unacceptable side effect profile in children, including sedation with the narcotic opioids codeine and dihydrocodone, and the firstgeneration antihistamines. Decongestants containing pseudoephedrine, and oral sympathomimetic bronchodilators, may result in hyperstimulation of a child [9,10]. 2. Physiological mechanism of cough Cough is a vital defense mechanism that allows clearance of airway secretions and prevents aspiration of foreign material into the respiratory tract. However, in certain pathological states, excessive, maladaptive, dry cough serves no useful purpose, and results in significant morbidity to the individual, with symptoms
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F. De Blasio et al. / Pulmonary Pharmacology & Therapeutics 25 (2012) 337e342
including chest pain from persistent cough, insomnia, fatigue, nausea and headache that may adversely affect quality of life [9]. Cough results from the stimulation of the vagal afferent sensory fibers found in abundance in the mucosa of the upper and lower airway. Afferent neuronal subtypes can be identified based on their physicochemical sensitivity, adaptation to sustained lung inflation, neurochemistry, origin, myelination, conduction velocity, and sites of termination in the airways. These attributes can be used to identify at least three broad classes of airway afferent nerves which all three are involved on cough reflex: rapidly adapting receptors (RARs); slowly adapting stretch receptors (SARs); and C-fibers [11]. Currently available antitussives are generally classified according to their proposed site of action. Centrally acting agents such as narcotics penetrate the central nervous system (CNS), and thus are often associated with sedation and other undesirable side effects, whereas peripherally acting agents are excluded from the CNS, and typically demonstrate a more favorable side effect profile [12]. 3. Epidemiology of cough in children and effects on quality of life Pappas and colleagues [13] carried out an investigation among school-aged children in which diaries, containing pre-printed sheets listing common signs and symptoms, were kept for 10 days after onset of a cold. Nasopharyngeal aspirates were analyzed for respiratory viruses and potential bacterial pathogens. Of 81 cases studied, the most common signs were coughing and sneezing and the most common symptoms were congestion and a runny nose. These signs and symptoms persisted for the first week. Coughing was present in 46% at onset, peaking at 69% on day one and still present in 50% at day seven. Rhinoviruses were responsible for 37 (almost 50%) of cases. In an observational study of 433 children (mean age 6.1 years; SD 3.6 yr; median 5.2 yr) presenting to their pediatrician with acute cough due to URI, De Blasio et al. [14] evaluated the impact of cough on quality of life of the children and their parents using a pediatric cough questionnaire (PCQ) [14] containing four questions: To what extent did cough symptoms disturb children’s sleep? To what extent did children’s cough symptoms disturb their parent’s sleep? To what extent did children’s cough symptoms interfere in their scholastic activities?
To what extent did children’s cough symptom interfere with sport activities? As displayed in Fig. 1, cough significantly disturbed the children’s quality of sleep, as well as scholastic and athletic activities. Furthermore, 72% of parents reported some degree of disturbance of their sleep due to the child’s illness; 32% reported significant sleep disturbance. Two studies that have examined parental beliefs and evaluations of their child’s coughing illness have described parental worries regarding disturbed sleep, discomfort, and fear that cough would cause permanent chest damage [15,16]. 4. Pharmacology of the peripherally acting antitussive levodropropizine Racemic dropropizine, or ()-3-(4-phenyl-1-piperazinyl)-1,2propanediol, has long been used as an antitussive drug. In the late 1980s, separation of the two isomers, levo (S) () and dextro (R) (þ), was achieved and their activity investigated as compared to the racemate. The (S) () enantiomer (hereinafter called levodropropizine) was shown to display the same antitussive activity of the racemate in a panel of different animal models of experimentally-induced cough, showing as well a better tolerability profile, i.e. less effects on the central nervous system [17,18]. Levodropropizine, is an orally-administered non-opioid agent whose peripheral antitussive action may result from its modulation of sensory neuropeptide levels within the respiratory tract [19]. In particular levodropropizine exerts its antitussive effect through an inhibitory action at the level of the C-fibers and it has been shown to be able to inhibit “in vitro” the release of sensor neuropeptides from C-fibers [20]. In addition, in anaesthetized cats, it markedly reduces the activation of C-fibers and abolishes the associated reflexes [21]. 5. Clinical studies of levodropropizine in adults Levodropropizine has been shown, in adults, to inhibit citricacid induced cough in healthy volunteers [22] as well as ultrasonically nebulized distilled water-induced cough in subjects with obstructive lung disease [23]. In adult patients with pathological cough, randomized, double-blind trials have demonstrated levodropropizine to be superior to placebo against bronchitis cough [24], comparable to dextromethorphan in non-productive cough
Fig. 1. Impact of cough on children’s and parent’s quality of life. Taken from Ref. [14].
F. De Blasio et al. / Pulmonary Pharmacology & Therapeutics 25 (2012) 337e342
339
Table 1 Clinical studies with levodropropizine in children. Study
Sample size
Study design
Condition
Results
Zanasi et al. [14]
(161)433; age 1e15
Observational
Cough due to URI
Kim et al. [27]
77; age 2e3
Double blind randomized Levodropropizine vs. Dextromethorphan
Bronchitis
Banderali et al. [28]
254; age 2e14
Double blind randomized Dropropizine vs. Levodropropizine
Non-productive Cough
Cough significantly disturbed children’s and parents’ sleep and daily activities. A significant advantage for levodropropizine was observed in terms of higher cough resolution and lower unsuccessful treatment, independently from cough intensity. P < 0.05 The results show the antitussive effectiveness of levodropropizine and point out a more favorable benefit/risk profile when compared vs. dextromethorphan. P < 0.05 Statistically significant decreases in the frequency of coughing spells and nocturnal awakenings after both levodropropizine and dropropizine treatments. Somnolence twice as frequent in dropropizine group (10.3% vs. 5.3%) though not statistically significant.
[25], and comparable to dihydrocodeine against cough associated with lung cancer [26].
6. Clinical studies of levodropropizine in the pediatric population Several clinical studies have been conducted with levodropropizine in the pediatric setting with a total population of 1511 children studied. Table 1 summarizes the most recent pediatric clinical studies performed with levodropropizine, including one large observational study [14] and two randomized clinical trials [27,28]. The observational study of De Blasio et al. [14] evaluated the use of antitussive drugs in the pediatric setting, using a questionnaire administered to parents. From February to April 2010, 433 children who required medical consultation for acute cough were enrolled. A subgroup of 161 children (i.e. those in whom the physician assessed cough severity, frequency and intensity score, and was treated at the discretion of their pediatrician) received levodropropizine or central antitussive treatment. Of the 433 children enrolled in this study, 52% were preschool (<6 years). The mean age of children was 6.2 years and URTI was the only reason for consulting. In 88% cough disturbed the children’s quality of sleep, and the scholastic and sport activities were affected in 76% and 61% of children, respectively while in 72% of parents decreased their quality of sleep. In the study population of 161 children, 80% were reported to have moderate or severe cough. More children were treated with levodropropizine (n ¼ 101) than with central cough suppressants
Fig. 2. Children treated with antitussive. Taken from Ref. [14].
(codeine and cloperastine, n ¼ 60). All antitussive drugs reduced cough intensity and frequency. However, cough resolution was significantly greater with levodropropizine than with central antitussives (47% vs. 28% respectively, p ¼ 0.0012) as shown in Fig. 2. The superiority of the peripheral antitussive levodropropizine in terms of cough resolution was evident also in the subgroups of patients with higher cough intensity (moderate and severe), with statistically significant difference vs. central cough suppressants (see Figs. 3 and 4). The conclusions of this study were that both peripheral and central antitussives were effective in reducing the frequency and intensity of cough. A significant advantage with levodropropizine was observed in terms of higher cough resolution and lower incidence of unsuccessful treatment, independent of cough intensity (Figs. 5e7). Kim and colleagues [27] evaluated in a double blind randomized study the efficacy and tolerability of levodropropizine compared to
Fig. 3. Treatment results e moderate cough. Taken from Ref. [14].
Fig. 4. Treatment results e severe cough. Taken from Ref. [14].
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F. De Blasio et al. / Pulmonary Pharmacology & Therapeutics 25 (2012) 337e342
Fig. 7. The final efficacy coughing score after administration of levodropropizine or Dextromethorphan. P < 0.01 between levodropropizine and dextromethorphan treated Groups. Taken from Ref. [27].
Fig. 5. The severity change of coughing after administration of levodropropizine or Dextromethorphan. P < 0.01 between levodropropizine and dextromethorphan treated groups. Taken from Ref. [27].
the central antitussive dextromethorphan in children with bronchitis [27]. The severity of cough was more significantly reduced after 2e3 days of administration in the levodropropizine group than in the dextromethorphan group (P ¼ 0.003). The frequency of cough was also reduced after 2 days (P ¼ 0.009) and 3 days (P ¼ 0.003) in the levodropropizine group. The final efficacy score was higher in levodropropizine group (3.2 0.9) than in the dextromethorphan group (2.6 1.0) (P ¼ 0.003). The results of this study demonstrated the antitussive effectiveness of levodropropizine and suggested a more favorable benefit profile when compared to dextromethorphan. In a double blind, randomized study, Banderali and colleagues [28] evaluated the efficacy and tolerability of levodropropizine, in comparison with dropropizine, in the management of nonproductive cough in pediatric patients [28]. The results demonstrated statistically significant decreases in the frequency of coughing spells and nocturnal awakenings after both levodropropizine and dropropizine therapy, with no significant difference between groups. Baseline cough counts were similar
in the two groups. Though somnolence was twice as frequent in the dropropizine group (10.3% vs. 5.3%) this difference did not achieve statistical significance. A marked reduction in the number of coughing spells was detectable after the first dose of each treatment, and became more prominent by the third day. In both groups the maximum decrease in cough frequency was observed at 3 h after dosing, and the frequency remained substantially unchanged during the last 2 h of assessment .The improvement in cough compared with baseline and with the first hour of observation on each treatment day was statistically significant in both groups (P < 0.0001), whereas no significant differences between groups were observed. The number of cough-related nocturnal awakenings decreased progressively following institution of treatment in each group (see Table 2). In the levodropropizine group, the percentage of patients with nocturnal awakenings due to cough decreased from 39% at baseline to 26% and 14% after 1 and 3 days of treatment, respectively. Among dropropizine-treated patients, 38% reported nocturnal awakenings at baseline compared with 26% and 18% after 1 and 3 days of treatment, respectively. The decrease in the number of awakenings did not differ significantly between the two groups (see Table 2). Other published studies evaluating the antitussive effect and tolerability of levodropropizine in children with URI include several open-label trials representing a total of 422 children [29e31]. These uncontrolled studies demonstrated reduction in frequency and intensity of cough with levodropropizine, and further supported the tolerability of the drug. In order to provide an overview of major evidences of Levodropropizine in terms of efficacy in pediatric setting, a table including a summary of published studies evaluating the antitussive efficacy of levodropropizine vs. control was performed. Table 3.
Table 2 Number of cough-related nocturnal awakenings before treatment and on days 1 and 3 of treatment in patient with non-productive cough treated with 3 mg/kg dropropizine or 6 mg/kg levodropropizine daily for 3 days. Taken from Ref. [28]. Assessment
Fig. 6. The frequency change of coughing after administration of levodropropizine or Dextromethorphan. P < 0.01 between levodropropizine and dextromethorphan treated Groups. Taken from Ref. [27].
Baseline Day 1 Day 3 F value/P value
Number of nocturnal awakenings Levodropropizine
Dropropizine
1.3 0.2 (n ¼ 130) 0.7 0.1* (n ¼ 130) 0.3 0.1* (n ¼ 130) 25/<0.001
1.4 0.2 (n ¼ 125) 0.9 0.2* (n ¼ 125) 0.4 0.1* (n ¼ 125) 21.3/<0.001
Values are means SEM * P < 0.025 vs previous test-time.
F. De Blasio et al. / Pulmonary Pharmacology & Therapeutics 25 (2012) 337e342
341
Table 3 Summary of clinical studies comparing levodropropizine vs. control in children.
7. Safety and tolerability of levodropropizine Several clinical trials (both in adults and paediatrics patients) have demonstrated its efficacy but above all its tolerability. In adults [25,26] two clinical studies of comparison between levodropropizine and central antitussives (dextromethorphan and dihydrocodeine respectively) showed that levodropropizine has less incidence of somnolence than patients who received central antitussives. Regarding pediatric patients, levodropropizine showed a very high safety profile, not only in open-label studies [29e31], but also when compared with central antitussive drugs [14,27,28]. In a large observational study from De Blasio et al. [14] levodropropizine showed to be a very well tolerated drug. In one study in children with bronchitis levodropropizine provided antitussive efficacy with a more favorable risk/benefit ratio when compared with dextromethorphan [27]. In another study the tolerability of levodropropizine was compared with dropropizine in the management of non-productive cough in pediatric patients. In this study the antitussive effects of levodropropizine were similar to dropropizine, but it caused less daytime somnolence [28]. In three open-label studies in pediatric setting [29e31] the safety profile of levodropropizine was judged by the physicians involved in these studies; in all studies they defined levodropropizine as a cough suppressant very well tolerated. Thus, the safety profile of levodropropizine appears favorable compared to other available cough and cold products, especially in light of recently-published concerns regarding opiates, dextromethorphan, antihistamines, and decongestants in medicines targeted for use in children [8,9]. 8. Conclusion Therapeutic options for the management of acute cough in children are severely limited because of the lack of data to support the efficacy of currently available antitussives, as well as safety concerns associated with these agents. All cough suppressants currently marketed to adults present an unacceptable risk/benefit
profile for pediatric use, because of potential for excessive sedation (narcotics, dextromethorphan, and first-generation antihistamines) or hyperstimulation (pseudoephedrine, phenylephrine). Indeed, recent national guidelines by the American College of Chest Physicians [8], and more recent systematic reviews [8,32] do not recommend pharmacological treatment of acute cough in children. Rather, supportive care with analgesics, hot beverages, lozenges, and honey is the preferred strategy of many pediatricians. Unfortunately, for persistent and/or severe cough in children, these non-pharmacological, supportive strategies are often ineffective, and thus, a safe and effective antitussive remains a significant area of unmet need. Given its demonstrated antitussive efficacy and safety in adults [22e26], and the encouraging data supporting its efficacy and safety in children [27e31], levodropropizine appears to be an appropriate candidate for further evaluation as a potential antitussive for the pediatric population.
Acknowledgments This review was supported by Dompé SPA through an unrestricted grant. F. De Blasio, P.V. Dicpinigaitis, and A. Zanasi are members of an International Advisory Board supported by an unrestricted educational grant from Dompé SPA. G. De Danieli and L. Lanata are employees of Dompé SPA, Medical Department.
References [1] Morrell DC. Symptom interpretation in general practice. J R Coll Gen Pract 1972;22(118):297e309. [2] McCormick A, Fleming D, Charlton J. Morbidity statistics from general practice fourth national morbidity survey. London, UK: HMSO, Office for National Statistics; 1991-92. [3] Ayres JG, Noah ND, Fleming DM. Incidence of episodes of acute asthma and acute bronchitis in general practice 1976-87. Br J Gen Pract 1993;43(374): 361e4. [4] Cherry DK, Woodwell DA. National ambulatory medical care survey: 2000 summary. Adv Data 2002;328:1e32.
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[5] Hay AD, Heron J, Ness A. The prevalence of symptoms and consultations in preschool children in the avon longitudinal study of parents and children (ALSPAC): a prospective cohort study. Fam Pract 2005;22:367e74. [6] Archer LNJ, Simpson H. Night cough counts and diary cough scores in asthma. Arch Dis Child 1985;60:473e4. [7] Chang AB, Newman RG, Carlin JB, Phelan PD, Robertson CF. Subjective scoring of cough in children: parental-completed vs child completed diary cards vs an objective method. Eur Respir J 1998;11:462e6. [8] Irwin RS, Baumann MH, Bolser DC, Boulet LP, Braman SS, Brightling CE, et al. Diagnosis and management of cough executive summary: ACCP evidencebased clinical practice guidelines. Chest 2006;129:1Se23S. [9] Paul IM. Therapeutic options for acute cough due to upper respiratory tract infections in children. Lung 2011. http://dx.doi.org/10.1007/s00408-0119319-y. published on line 4 September 2011. [10] Irwin RS, Rosen MJ, Braman SS. Cough: a comprehensive review. Arch Intern Med 1977;137:1186e9. [11] Canning BJ. Afferent nerves regulating the cough reflex: mechanisms and mediators of cough in disease. Otolaryngol Clin North Am 2010;43:15e25. [12] De Blasio F, Virchow JC, Polverino M, Zanasi A, Behrakis PK, Kilinç G, et al. Cough management: a practical approach 7:7, http://www.coughjournal.com/ content/7/1/7; 2011. [13] Pappas DE, Hendley JO, Hayden FG, Winther B. Symptom profile of common colds in school-aged children. Pediatr Infect Dis J 2008;27:8e11. [14] De Blasio F, Dicpinigaitis PV, Rubin BK, De Danieli G, Lanata L, Zanasi A. An observational study on cough in children: epidemiology, impact on quality of sleep and treatment outcome. Cough 2012;23(8):1. [15] Ford PA, Barnes PJ, Usmani OS. Chronic cough and Holmes-Adie syndrome. Lancet 2007;369:342. [16] Cornford CS, Morgan M, Ridsdale L. Why do mothers consult when their children cough? Fam Pract 1993;10:193e6. [17] Malandrino S, Melillo G, Bestetti A, Borsa M, Giuliani P, Tonon GC. Antitussive properties of levodropropizine. Arzneim Forsch/Drug Rev 1988;38:1141e3. [18] Melillo G, Rossoni G, Caselli G, Bestetti A, Borsa M, Tonon GC, et al. General pharmacology of the new antitussive levodropropizine. Arzneim Forsch/Drug Res 1988;38:1144e50. [19] Dicpinigaitis PV. Current and future peripherally-acting antitussives. Resp Physiol Neurobiol 2006;152:356e62.
[20] Lavezzo A, Melillo G, Clavenna G, Omini C. Periipheral site of action of levodropropizine in experimental-induced cough: role of sensory neuropeptides. Pulm Pharmacol 1992;5:143e7. [21] Melillo G, Malandrino S, Rossoni G, Caselli G, Bestetti A, Borsa M, et al. General pharmacology of the new antitussive levodropropizine. Arzneim Forsch/Drug Res 1998;38:1144e50. [22] Fumagalli G, Cordaro CI, Vanasia M. A comparative study of the antitussive activity of levodropropizine and dropropizine in the citric acid-induced cough model in normal subjects. Drugs Exp Clin Res 1992;18:303e9. [23] Bariffi F, Tranfa C, Vatrella A, Ponticiello A. Protective effect of levodropropizine against cough induced by inhalation of nebulized distilled water in patients with obstructive lung disease. Drugs Exp Clin Res 1992;18:113e8. [24] Allegra L, Bossi R. Clinical trials with the new antitussive levodropropizine in adult bronchitic patients. Arzneimittelforschung 1988;38:1163e6. [25] Catena E, Daffonchio L. Efficacy and tolerability of levodropropizine in adult patients with non-productive cough. Comparison with dextromethorphan. Pulm Pharmacol Ther 1997;10:89e96. [26] Luporini G, Barni S, Marchi E, Daffonchio L. Efficacy and safety of levodropropizine and dihydrocodeine on nonproductive cough in primary and metastatic lung cancer. Eur Respir J 1998;12:97e101. [27] Kim DS, Sohn MH, Jang GC. Levodropropizine in children with bronchitis. Diagn Treatment 2002;22(9):1029e34 [Korean]. [28] Banderali G, Riva E, Fiocchi A, Cordaro CI, Giovannini M. Efficacy and tolerability of levodropropizine and dropropizine in children with nonproductive cough. J Int Med Res 1995;23:175e83. [29] Fiocchi A, Zuccotti GV, Vignati B, Pogliani L, Sala M, Riva E. Evaluation of the treatment with levodropropizine of respiratory diseases in children. Pediatr Med Chir 1989;11:519e22 [Italian]. [30] Tamburrano D, Romandini S. Multicentric study on tolerability and efficacy of levodropropizine, a new antitussive drug, in a wide pediatric study group. Terapie Essenziali in Clinica 1989;4e89:3e7 [Italian]. [31] Cogo R, Tamburrano D, Romandini S, Rugarli PL. Multincentric study on efficacy and tolerability of levodropropizine: a new antitussive drug. Farmaci 1989;3:8e13 [Italian]. [32] Smith SM, Schroeder K, Fahey T. Over-the-counter medications for acute cough in children and adults in ambulatory settings. Cochrane Database Syst Rev Jan 23 2008;(1):CD001831.
Contents lists available at SciVerse ScienceDirect
Pulmonary Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/ypupt
Review
Efficacy of levodropropizine in pediatric cough Francesco De Blasio a, Peter V. Dicpinigaitis b, Gianluca De Danieli c, *, Luigi Lanata c, Alessando Zanasi d a
Respiratory Medicine and Pulmonary Rehabilitation Section, Clinic Center, Private Hospital, Naples, Italy Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA c Medical Department, Dompé SPA, Via san Martino 12, Milan, Italy d Pneumology Unit, University of Bologna, S.Orsola Malpighi Hospital, Bologna, Italy b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 17 February 2012 Received in revised form 16 April 2012 Accepted 3 May 2012
Cough in children is among the most common problems managed by pediatricians, and occurs more frequently in preschool than in older children. Most acute episodes of cough are due to viral upper respiratory tract infections. The morbidity associated with acute cough in a child extends also to parents, teachers, and other family members and caregivers. Unfortunately, therapeutic options for acute cough in children are severely limited due to the absence of drugs shown to be effective antitussives with an acceptable safety profile. Agents used in the management of adult cough, such as narcotics (codeine, hydrocodone), the non-narcotic opioid dextromethorphan, first-generation, potentially sedating antihistamines, and decongestants such as pseudoephedrine, have all been deemed inadequate for treatment of acute pediatric cough on a risk/benefit basis. A growing body of evidence suggests that the peripherally acting antitussive, levodropropizine, may be an attractive alternative for the treatment of bothersome acute cough in children. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Levodropropizine Pediatric Children Antitussives
1. Introduction Cough in children is among the most common problems managed by pediatricians, and occurs more frequently in preschool than in older children [1] Two out of 3 children younger than age 4 visit their pediatricians at least once a year with acute respiratory infection, and up to three quarters of them will have a cough [2,3]. Most acute coughs are caused by viral upper respiratory tract infections (URIs); 7e12% of coughs are due to asthma, while other causes are uncommon [4]. Although most acute URIs are selflimited illnesses, cough as a bothersome symptom associated with URI results in more pediatric ambulatory health care visits than any other symptom in the United States [5,6]. The reported severity of a child’s cough may relate to how it affects parents and teachers as well as the child. Recent evidence has highlighted that parental reporting of the frequency and severity of a child’s cough is unreliable compared with objective measures, and this is especially true for nocturnal cough. Indeed, it has been suggested that cough as reported in surveys and as a clinical trial outcome should either not be used or, at least, be interpreted with caution [7e10]. Therapeutic intervention for cough may be directed at a specific underlying cause or, as in the case of viral URI-induced cough,
* Corresponding author. Tel.: þ39 3409491162. E-mail address: [email protected] (G. De Danieli). 1094-5539/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pupt.2012.05.010
suppression aimed at symptom relief. Potential benefits of early treatment of cough could include the prevention of a vicious cycle, wherein mechanical irritation of inflamed respiratory epithelial mucosa by persistent coughing perpetuates cough by ongoing trauma to the airways, and the superficially lying sensory afferent cough fibers contained therein. In recent years, much attention has been drawn to the fact that commonly-used antitussive agents for the pediatric population are not supported by adequate efficacy data to justify their use, especially in light of potential associated side effects [8,9]. In fact, pharmaceutical companies in the United States no longer market antitussives for children less than 4 years of age. Each of the antitussive classes of drugs used by adults is associated with an unacceptable side effect profile in children, including sedation with the narcotic opioids codeine and dihydrocodone, and the firstgeneration antihistamines. Decongestants containing pseudoephedrine, and oral sympathomimetic bronchodilators, may result in hyperstimulation of a child [9,10]. 2. Physiological mechanism of cough Cough is a vital defense mechanism that allows clearance of airway secretions and prevents aspiration of foreign material into the respiratory tract. However, in certain pathological states, excessive, maladaptive, dry cough serves no useful purpose, and results in significant morbidity to the individual, with symptoms
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including chest pain from persistent cough, insomnia, fatigue, nausea and headache that may adversely affect quality of life [9]. Cough results from the stimulation of the vagal afferent sensory fibers found in abundance in the mucosa of the upper and lower airway. Afferent neuronal subtypes can be identified based on their physicochemical sensitivity, adaptation to sustained lung inflation, neurochemistry, origin, myelination, conduction velocity, and sites of termination in the airways. These attributes can be used to identify at least three broad classes of airway afferent nerves which all three are involved on cough reflex: rapidly adapting receptors (RARs); slowly adapting stretch receptors (SARs); and C-fibers [11]. Currently available antitussives are generally classified according to their proposed site of action. Centrally acting agents such as narcotics penetrate the central nervous system (CNS), and thus are often associated with sedation and other undesirable side effects, whereas peripherally acting agents are excluded from the CNS, and typically demonstrate a more favorable side effect profile [12]. 3. Epidemiology of cough in children and effects on quality of life Pappas and colleagues [13] carried out an investigation among school-aged children in which diaries, containing pre-printed sheets listing common signs and symptoms, were kept for 10 days after onset of a cold. Nasopharyngeal aspirates were analyzed for respiratory viruses and potential bacterial pathogens. Of 81 cases studied, the most common signs were coughing and sneezing and the most common symptoms were congestion and a runny nose. These signs and symptoms persisted for the first week. Coughing was present in 46% at onset, peaking at 69% on day one and still present in 50% at day seven. Rhinoviruses were responsible for 37 (almost 50%) of cases. In an observational study of 433 children (mean age 6.1 years; SD 3.6 yr; median 5.2 yr) presenting to their pediatrician with acute cough due to URI, De Blasio et al. [14] evaluated the impact of cough on quality of life of the children and their parents using a pediatric cough questionnaire (PCQ) [14] containing four questions: To what extent did cough symptoms disturb children’s sleep? To what extent did children’s cough symptoms disturb their parent’s sleep? To what extent did children’s cough symptoms interfere in their scholastic activities?
To what extent did children’s cough symptom interfere with sport activities? As displayed in Fig. 1, cough significantly disturbed the children’s quality of sleep, as well as scholastic and athletic activities. Furthermore, 72% of parents reported some degree of disturbance of their sleep due to the child’s illness; 32% reported significant sleep disturbance. Two studies that have examined parental beliefs and evaluations of their child’s coughing illness have described parental worries regarding disturbed sleep, discomfort, and fear that cough would cause permanent chest damage [15,16]. 4. Pharmacology of the peripherally acting antitussive levodropropizine Racemic dropropizine, or ()-3-(4-phenyl-1-piperazinyl)-1,2propanediol, has long been used as an antitussive drug. In the late 1980s, separation of the two isomers, levo (S) () and dextro (R) (þ), was achieved and their activity investigated as compared to the racemate. The (S) () enantiomer (hereinafter called levodropropizine) was shown to display the same antitussive activity of the racemate in a panel of different animal models of experimentally-induced cough, showing as well a better tolerability profile, i.e. less effects on the central nervous system [17,18]. Levodropropizine, is an orally-administered non-opioid agent whose peripheral antitussive action may result from its modulation of sensory neuropeptide levels within the respiratory tract [19]. In particular levodropropizine exerts its antitussive effect through an inhibitory action at the level of the C-fibers and it has been shown to be able to inhibit “in vitro” the release of sensor neuropeptides from C-fibers [20]. In addition, in anaesthetized cats, it markedly reduces the activation of C-fibers and abolishes the associated reflexes [21]. 5. Clinical studies of levodropropizine in adults Levodropropizine has been shown, in adults, to inhibit citricacid induced cough in healthy volunteers [22] as well as ultrasonically nebulized distilled water-induced cough in subjects with obstructive lung disease [23]. In adult patients with pathological cough, randomized, double-blind trials have demonstrated levodropropizine to be superior to placebo against bronchitis cough [24], comparable to dextromethorphan in non-productive cough
Fig. 1. Impact of cough on children’s and parent’s quality of life. Taken from Ref. [14].
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Table 1 Clinical studies with levodropropizine in children. Study
Sample size
Study design
Condition
Results
Zanasi et al. [14]
(161)433; age 1e15
Observational
Cough due to URI
Kim et al. [27]
77; age 2e3
Double blind randomized Levodropropizine vs. Dextromethorphan
Bronchitis
Banderali et al. [28]
254; age 2e14
Double blind randomized Dropropizine vs. Levodropropizine
Non-productive Cough
Cough significantly disturbed children’s and parents’ sleep and daily activities. A significant advantage for levodropropizine was observed in terms of higher cough resolution and lower unsuccessful treatment, independently from cough intensity. P < 0.05 The results show the antitussive effectiveness of levodropropizine and point out a more favorable benefit/risk profile when compared vs. dextromethorphan. P < 0.05 Statistically significant decreases in the frequency of coughing spells and nocturnal awakenings after both levodropropizine and dropropizine treatments. Somnolence twice as frequent in dropropizine group (10.3% vs. 5.3%) though not statistically significant.
[25], and comparable to dihydrocodeine against cough associated with lung cancer [26].
6. Clinical studies of levodropropizine in the pediatric population Several clinical studies have been conducted with levodropropizine in the pediatric setting with a total population of 1511 children studied. Table 1 summarizes the most recent pediatric clinical studies performed with levodropropizine, including one large observational study [14] and two randomized clinical trials [27,28]. The observational study of De Blasio et al. [14] evaluated the use of antitussive drugs in the pediatric setting, using a questionnaire administered to parents. From February to April 2010, 433 children who required medical consultation for acute cough were enrolled. A subgroup of 161 children (i.e. those in whom the physician assessed cough severity, frequency and intensity score, and was treated at the discretion of their pediatrician) received levodropropizine or central antitussive treatment. Of the 433 children enrolled in this study, 52% were preschool (<6 years). The mean age of children was 6.2 years and URTI was the only reason for consulting. In 88% cough disturbed the children’s quality of sleep, and the scholastic and sport activities were affected in 76% and 61% of children, respectively while in 72% of parents decreased their quality of sleep. In the study population of 161 children, 80% were reported to have moderate or severe cough. More children were treated with levodropropizine (n ¼ 101) than with central cough suppressants
Fig. 2. Children treated with antitussive. Taken from Ref. [14].
(codeine and cloperastine, n ¼ 60). All antitussive drugs reduced cough intensity and frequency. However, cough resolution was significantly greater with levodropropizine than with central antitussives (47% vs. 28% respectively, p ¼ 0.0012) as shown in Fig. 2. The superiority of the peripheral antitussive levodropropizine in terms of cough resolution was evident also in the subgroups of patients with higher cough intensity (moderate and severe), with statistically significant difference vs. central cough suppressants (see Figs. 3 and 4). The conclusions of this study were that both peripheral and central antitussives were effective in reducing the frequency and intensity of cough. A significant advantage with levodropropizine was observed in terms of higher cough resolution and lower incidence of unsuccessful treatment, independent of cough intensity (Figs. 5e7). Kim and colleagues [27] evaluated in a double blind randomized study the efficacy and tolerability of levodropropizine compared to
Fig. 3. Treatment results e moderate cough. Taken from Ref. [14].
Fig. 4. Treatment results e severe cough. Taken from Ref. [14].
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Fig. 7. The final efficacy coughing score after administration of levodropropizine or Dextromethorphan. P < 0.01 between levodropropizine and dextromethorphan treated Groups. Taken from Ref. [27].
Fig. 5. The severity change of coughing after administration of levodropropizine or Dextromethorphan. P < 0.01 between levodropropizine and dextromethorphan treated groups. Taken from Ref. [27].
the central antitussive dextromethorphan in children with bronchitis [27]. The severity of cough was more significantly reduced after 2e3 days of administration in the levodropropizine group than in the dextromethorphan group (P ¼ 0.003). The frequency of cough was also reduced after 2 days (P ¼ 0.009) and 3 days (P ¼ 0.003) in the levodropropizine group. The final efficacy score was higher in levodropropizine group (3.2 0.9) than in the dextromethorphan group (2.6 1.0) (P ¼ 0.003). The results of this study demonstrated the antitussive effectiveness of levodropropizine and suggested a more favorable benefit profile when compared to dextromethorphan. In a double blind, randomized study, Banderali and colleagues [28] evaluated the efficacy and tolerability of levodropropizine, in comparison with dropropizine, in the management of nonproductive cough in pediatric patients [28]. The results demonstrated statistically significant decreases in the frequency of coughing spells and nocturnal awakenings after both levodropropizine and dropropizine therapy, with no significant difference between groups. Baseline cough counts were similar
in the two groups. Though somnolence was twice as frequent in the dropropizine group (10.3% vs. 5.3%) this difference did not achieve statistical significance. A marked reduction in the number of coughing spells was detectable after the first dose of each treatment, and became more prominent by the third day. In both groups the maximum decrease in cough frequency was observed at 3 h after dosing, and the frequency remained substantially unchanged during the last 2 h of assessment .The improvement in cough compared with baseline and with the first hour of observation on each treatment day was statistically significant in both groups (P < 0.0001), whereas no significant differences between groups were observed. The number of cough-related nocturnal awakenings decreased progressively following institution of treatment in each group (see Table 2). In the levodropropizine group, the percentage of patients with nocturnal awakenings due to cough decreased from 39% at baseline to 26% and 14% after 1 and 3 days of treatment, respectively. Among dropropizine-treated patients, 38% reported nocturnal awakenings at baseline compared with 26% and 18% after 1 and 3 days of treatment, respectively. The decrease in the number of awakenings did not differ significantly between the two groups (see Table 2). Other published studies evaluating the antitussive effect and tolerability of levodropropizine in children with URI include several open-label trials representing a total of 422 children [29e31]. These uncontrolled studies demonstrated reduction in frequency and intensity of cough with levodropropizine, and further supported the tolerability of the drug. In order to provide an overview of major evidences of Levodropropizine in terms of efficacy in pediatric setting, a table including a summary of published studies evaluating the antitussive efficacy of levodropropizine vs. control was performed. Table 3.
Table 2 Number of cough-related nocturnal awakenings before treatment and on days 1 and 3 of treatment in patient with non-productive cough treated with 3 mg/kg dropropizine or 6 mg/kg levodropropizine daily for 3 days. Taken from Ref. [28]. Assessment
Fig. 6. The frequency change of coughing after administration of levodropropizine or Dextromethorphan. P < 0.01 between levodropropizine and dextromethorphan treated Groups. Taken from Ref. [27].
Baseline Day 1 Day 3 F value/P value
Number of nocturnal awakenings Levodropropizine
Dropropizine
1.3 0.2 (n ¼ 130) 0.7 0.1* (n ¼ 130) 0.3 0.1* (n ¼ 130) 25/<0.001
1.4 0.2 (n ¼ 125) 0.9 0.2* (n ¼ 125) 0.4 0.1* (n ¼ 125) 21.3/<0.001
Values are means SEM * P < 0.025 vs previous test-time.
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Table 3 Summary of clinical studies comparing levodropropizine vs. control in children.
7. Safety and tolerability of levodropropizine Several clinical trials (both in adults and paediatrics patients) have demonstrated its efficacy but above all its tolerability. In adults [25,26] two clinical studies of comparison between levodropropizine and central antitussives (dextromethorphan and dihydrocodeine respectively) showed that levodropropizine has less incidence of somnolence than patients who received central antitussives. Regarding pediatric patients, levodropropizine showed a very high safety profile, not only in open-label studies [29e31], but also when compared with central antitussive drugs [14,27,28]. In a large observational study from De Blasio et al. [14] levodropropizine showed to be a very well tolerated drug. In one study in children with bronchitis levodropropizine provided antitussive efficacy with a more favorable risk/benefit ratio when compared with dextromethorphan [27]. In another study the tolerability of levodropropizine was compared with dropropizine in the management of non-productive cough in pediatric patients. In this study the antitussive effects of levodropropizine were similar to dropropizine, but it caused less daytime somnolence [28]. In three open-label studies in pediatric setting [29e31] the safety profile of levodropropizine was judged by the physicians involved in these studies; in all studies they defined levodropropizine as a cough suppressant very well tolerated. Thus, the safety profile of levodropropizine appears favorable compared to other available cough and cold products, especially in light of recently-published concerns regarding opiates, dextromethorphan, antihistamines, and decongestants in medicines targeted for use in children [8,9]. 8. Conclusion Therapeutic options for the management of acute cough in children are severely limited because of the lack of data to support the efficacy of currently available antitussives, as well as safety concerns associated with these agents. All cough suppressants currently marketed to adults present an unacceptable risk/benefit
profile for pediatric use, because of potential for excessive sedation (narcotics, dextromethorphan, and first-generation antihistamines) or hyperstimulation (pseudoephedrine, phenylephrine). Indeed, recent national guidelines by the American College of Chest Physicians [8], and more recent systematic reviews [8,32] do not recommend pharmacological treatment of acute cough in children. Rather, supportive care with analgesics, hot beverages, lozenges, and honey is the preferred strategy of many pediatricians. Unfortunately, for persistent and/or severe cough in children, these non-pharmacological, supportive strategies are often ineffective, and thus, a safe and effective antitussive remains a significant area of unmet need. Given its demonstrated antitussive efficacy and safety in adults [22e26], and the encouraging data supporting its efficacy and safety in children [27e31], levodropropizine appears to be an appropriate candidate for further evaluation as a potential antitussive for the pediatric population.
Acknowledgments This review was supported by Dompé SPA through an unrestricted grant. F. De Blasio, P.V. Dicpinigaitis, and A. Zanasi are members of an International Advisory Board supported by an unrestricted educational grant from Dompé SPA. G. De Danieli and L. Lanata are employees of Dompé SPA, Medical Department.
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