Pharmacology Consult

Antihistamines for the common cold: Where’s the evidence?

Recommendations for the treatment of common viral upper respiratory tract infections (URTIs) in children have undergone significant changes over the past 10 years. In 2008, the FDA and the AAP recommended avoiding over-the-counter products for the treatment of URTI symptoms, including cough/cold (C/C), in young children. These products should be avoided in children aged younger than 4 years, and the AAP cautions about their use in children aged 4 to 6 years and only when the child is receiving care from a provider.

In 2017, the FDA labeled codeine as contraindicated for the treatment of cough in children aged younger than 12 years, and the agency added a labeled warning to avoid codeine use in children aged 12 to 18 years with certain high-risk conditions (eg, obesity, obstructive sleep apnea).

Edward A. Bell

Recently published data have evaluated trends in C/C product recommendations by providers over the past 14 years. Specifically, Horton and colleagues looked at the use of physician-prescribed C/C products in children aged younger than 18 years from 2002 to 2015, using data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey. These surveys provide nationally representative information from office-based and hospital-based ambulatory settings. The authors analyzed a sample representing 3.1 billion pediatric visits over the 14-year study period. During this period, more than 95 million C/C products were ordered. Recommendations for C/C products containing opioids and nonopioids decreased significantly, but recommendations for C/C products containing an antihistamine (single-agent antihistamine for URTI symptom treatment) increased significantly. Comparing the periods of 2002-2008 and 2009-2015, the researchers noted a statistically significant increase in antihistamine use among children aged younger than 2 years, 2 to 3 years and 6 to 11 years, with adjusted ORs exceeding 10 in these age groups (ie, greater than a 10-fold increase).

Evidence supporting the efficacy of commonly available orally administered C/C product ingredients (eg, cough suppressants, mucolytics, antihistamines, decongestants) in children does not exist. Sharfstein and colleagues discussed this in 2007 when they appealed to the FDA to justify the labeling of OTC C/C products for children aged younger than 6 years. Their commentary, published in The New England Journal of Medicine, resulted in changes to the labeling of pediatric C/C products. Authors of additional published studies, reviews and commentaries have similarly concluded that there are a lack of data to support C/C product efficacy in children. In 1991, Hutton and colleagues compared an antihistamine-decongestant product with placebo or no treatment in a randomized controlled trial, and in 1997, Clemens and colleagues compared an antihistamine-decongestant product with placebo in a randomized controlled, double-blind trial. Both studies evaluated children aged 6 months to 5 years with URTI symptoms, and each study demonstrated a lack of efficacy of the antihistamine-decongestant product. In a randomized, double-blind study of children aged 6 to 18 years with URTI symptoms, Paul and colleagues compared dextromethorphan and diphenhydramine with placebo for the treatment of nocturnal cough, and they found no significant differences between them. A 2015 Cochrane review assessed the effects of antihistamines on the common cold, evaluating data from 18 randomized controlled trials — including 4,342 participants, 212 (<5%), of whom were pediatric patients — and concluded that no evidence supports the efficacy of antihistamines for C/C. Authors of a 2018 review on the effectiveness of treatments for the common cold concluded that there is no evidence to support the effectiveness of decongestant or antihistamine formulations in children. In his testimony before the U.S. Congress on the FDA’s regulation of C/C products containing an antihistamine, Leslie Hendeles, PharmD, professor emeritus at the University of Florida College of Pharmacy, also concluded that scientific evidence does not support the effectiveness of antihistamines in the treatment of the common cold because histamine does not impart a clinically significant role in the symptoms of the common cold in nonatopic patients.

The lack of efficacy demonstrated in these studies and reviews compares unfavorably to the well-known adverse effect profile of antihistamines, including sedation, hallucinations and negative effects upon cognition.

The regulatory history of C/C product labeling for children is complicated but largely revolves around the concepts of dose extrapolation from adult data, an assumption of ingredient efficacy in children as compared with adults, a lack of specific pediatric efficacy data, limited product ingredient pediatric pharmacokinetic and pharmacodynamic data and competing pharmaceutical manufacturer-driven commercial interests to market and sell C/C products despite the lack of documented efficacy.

Antihistamine pharmacology and adverse effects

Antihistamines are generally classified as first or second generation (see Table). First-generation antihistamines include chlorpheniramine, brompheniramine, diphenhydramine, doxylamine, dimenhydrinate, meclizine, promethazine and hydroxyzine. Chlorpheniramine, brompheniramine and diphenhydramine are the antihistamines most commonly found in pediatric OTC C/C products. Diphenhydramine is significantly more sedating and is often included in “nighttime” C/C products or OTC sleep-aid products. Sedation results from the ability of first-generation antihistamines to cross the blood-brain barrier and to block central histamine1 receptors. In contrast, second-generation antihistamines are commonly described as nonsedating. These include cetirizine, levocetirizine, loratadine, desloratadine and fexofenadine. Cetirizine (eg, Zyrtec), a commonly used second-generation antihistamine, has been associated with mild sedative effects in some studies. Loratadine (eg, Claritin) is unlikely to be sedating. Another difference between first-generation and second-generation antihistamines is their effect on nonhistamine receptors. First-generation antihistamines block cholinergic and serotonergic receptors in addition to histamine receptors, resulting in the potential for dry mouth, urinary retention, cardiac effects (eg, increased heart rate) and increased appetite.

Although sedation may be regarded as a beneficial pharmacologic effect of the first-generation antihistamines, it may not be appreciably recognized for its deleterious potential in children. Published data have demonstrated that first-generation antihistamines may also produce cognitive, learning or memory impairments without a noticeable drowsiness effect. Psychomotor responses, such as reaction times, may also be impaired, and this may be a more important consideration for adolescent patients (ie, when driving). Although the second-generation antihistamines are described as nonsedating, some published evidence indicates that their use, when compared with nonatopic individuals, may still result in some negative effects upon cognitive or psychomotor performance.

Conclusions

Despite changes in the labeling and recommendations for the use of pediatric C/C products over recent years, new data indicate that recommendations for antihistamines may be increasing as a pharmacotherapeutic treatment response. Yet, published studies on the use of antihistamines for the treatment of URTI symptoms in nonatopic children have failed to demonstrate efficacy. Researchers have documented adverse effects from antihistamines, which can range from mildly bothersome to clinically and pragmatically significant.

Disclosure: Bell reports no relevant financial disclosures.

Recommendations for the treatment of common viral upper respiratory tract infections (URTIs) in children have undergone significant changes over the past 10 years. In 2008, the FDA and the AAP recommended avoiding over-the-counter products for the treatment of URTI symptoms, including cough/cold (C/C), in young children. These products should be avoided in children aged younger than 4 years, and the AAP cautions about their use in children aged 4 to 6 years and only when the child is receiving care from a provider.

In 2017, the FDA labeled codeine as contraindicated for the treatment of cough in children aged younger than 12 years, and the agency added a labeled warning to avoid codeine use in children aged 12 to 18 years with certain high-risk conditions (eg, obesity, obstructive sleep apnea).

Edward A. Bell

Recently published data have evaluated trends in C/C product recommendations by providers over the past 14 years. Specifically, Horton and colleagues looked at the use of physician-prescribed C/C products in children aged younger than 18 years from 2002 to 2015, using data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey. These surveys provide nationally representative information from office-based and hospital-based ambulatory settings. The authors analyzed a sample representing 3.1 billion pediatric visits over the 14-year study period. During this period, more than 95 million C/C products were ordered. Recommendations for C/C products containing opioids and nonopioids decreased significantly, but recommendations for C/C products containing an antihistamine (single-agent antihistamine for URTI symptom treatment) increased significantly. Comparing the periods of 2002-2008 and 2009-2015, the researchers noted a statistically significant increase in antihistamine use among children aged younger than 2 years, 2 to 3 years and 6 to 11 years, with adjusted ORs exceeding 10 in these age groups (ie, greater than a 10-fold increase).

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Evidence supporting the efficacy of commonly available orally administered C/C product ingredients (eg, cough suppressants, mucolytics, antihistamines, decongestants) in children does not exist. Sharfstein and colleagues discussed this in 2007 when they appealed to the FDA to justify the labeling of OTC C/C products for children aged younger than 6 years. Their commentary, published in The New England Journal of Medicine, resulted in changes to the labeling of pediatric C/C products. Authors of additional published studies, reviews and commentaries have similarly concluded that there are a lack of data to support C/C product efficacy in children. In 1991, Hutton and colleagues compared an antihistamine-decongestant product with placebo or no treatment in a randomized controlled trial, and in 1997, Clemens and colleagues compared an antihistamine-decongestant product with placebo in a randomized controlled, double-blind trial. Both studies evaluated children aged 6 months to 5 years with URTI symptoms, and each study demonstrated a lack of efficacy of the antihistamine-decongestant product. In a randomized, double-blind study of children aged 6 to 18 years with URTI symptoms, Paul and colleagues compared dextromethorphan and diphenhydramine with placebo for the treatment of nocturnal cough, and they found no significant differences between them. A 2015 Cochrane review assessed the effects of antihistamines on the common cold, evaluating data from 18 randomized controlled trials — including 4,342 participants, 212 (<5%), of whom were pediatric patients — and concluded that no evidence supports the efficacy of antihistamines for C/C. Authors of a 2018 review on the effectiveness of treatments for the common cold concluded that there is no evidence to support the effectiveness of decongestant or antihistamine formulations in children. In his testimony before the U.S. Congress on the FDA’s regulation of C/C products containing an antihistamine, Leslie Hendeles, PharmD, professor emeritus at the University of Florida College of Pharmacy, also concluded that scientific evidence does not support the effectiveness of antihistamines in the treatment of the common cold because histamine does not impart a clinically significant role in the symptoms of the common cold in nonatopic patients.

The lack of efficacy demonstrated in these studies and reviews compares unfavorably to the well-known adverse effect profile of antihistamines, including sedation, hallucinations and negative effects upon cognition.

The regulatory history of C/C product labeling for children is complicated but largely revolves around the concepts of dose extrapolation from adult data, an assumption of ingredient efficacy in children as compared with adults, a lack of specific pediatric efficacy data, limited product ingredient pediatric pharmacokinetic and pharmacodynamic data and competing pharmaceutical manufacturer-driven commercial interests to market and sell C/C products despite the lack of documented efficacy.

PAGE BREAK

Antihistamine pharmacology and adverse effects

Antihistamines are generally classified as first or second generation (see Table). First-generation antihistamines include chlorpheniramine, brompheniramine, diphenhydramine, doxylamine, dimenhydrinate, meclizine, promethazine and hydroxyzine. Chlorpheniramine, brompheniramine and diphenhydramine are the antihistamines most commonly found in pediatric OTC C/C products. Diphenhydramine is significantly more sedating and is often included in “nighttime” C/C products or OTC sleep-aid products. Sedation results from the ability of first-generation antihistamines to cross the blood-brain barrier and to block central histamine1 receptors. In contrast, second-generation antihistamines are commonly described as nonsedating. These include cetirizine, levocetirizine, loratadine, desloratadine and fexofenadine. Cetirizine (eg, Zyrtec), a commonly used second-generation antihistamine, has been associated with mild sedative effects in some studies. Loratadine (eg, Claritin) is unlikely to be sedating. Another difference between first-generation and second-generation antihistamines is their effect on nonhistamine receptors. First-generation antihistamines block cholinergic and serotonergic receptors in addition to histamine receptors, resulting in the potential for dry mouth, urinary retention, cardiac effects (eg, increased heart rate) and increased appetite.

Although sedation may be regarded as a beneficial pharmacologic effect of the first-generation antihistamines, it may not be appreciably recognized for its deleterious potential in children. Published data have demonstrated that first-generation antihistamines may also produce cognitive, learning or memory impairments without a noticeable drowsiness effect. Psychomotor responses, such as reaction times, may also be impaired, and this may be a more important consideration for adolescent patients (ie, when driving). Although the second-generation antihistamines are described as nonsedating, some published evidence indicates that their use, when compared with nonatopic individuals, may still result in some negative effects upon cognitive or psychomotor performance.

Conclusions

Despite changes in the labeling and recommendations for the use of pediatric C/C products over recent years, new data indicate that recommendations for antihistamines may be increasing as a pharmacotherapeutic treatment response. Yet, published studies on the use of antihistamines for the treatment of URTI symptoms in nonatopic children have failed to demonstrate efficacy. Researchers have documented adverse effects from antihistamines, which can range from mildly bothersome to clinically and pragmatically significant.

Disclosure: Bell reports no relevant financial disclosures.