RESEARCHED DRUG INFORMATION QUESTION - WHILE AT THE UNIVERSITY AT BUFFALO, 2014
by Timothy Zablocki
From Outpatient Care Rotation
Date of Question: 10/3/14 Date of Response: 10/4/14
Question Source: Precepting Pharmacist and Timothy Zablocki
Specific Question: Is there data to support a recommendation of diphenhydramine or another first generation antihistamine for acute cough?
Data Sources: PubMed search using the terms: “diphenhydramine” or “brompheniramine” and “cough”
Handbook of Nonprescription Drugs, 16th Edition
Response:
Background:
Cough is the most common symptom for which individuals seek over-the-counter medications.(1) Diseases associated with cough account for approximately one in five visits to a physician or health care facility. The common cold is considered the most frequent cause of acute cough, which is defined as cough lasting less than three weeks in duration.(2) Depending on whether the cough is a productive one or not, choice of over-the-counter medications is limited to a select few antitussives or expectorants that have been in existence for years.(1) The antitussive dextromethorphan and the protussive/expectorant guaifenesin are generally considered first-line in the treatment of acute cough, but little evidence of their effectiveness exists.
Diphenhydramine is a first-generation antihistamine that is typically used to treat allergic reactions. Its FDA-labeled indications include allergic rhinitis, anaphylaxis (adjunct), insomnia, motion sickness, parkinsonism and pruritus of the skin.(3) Although not specifically indicated for cough, it has also has been given an FDA indication for the treatment of the common cold. In their guideline for the treatment of cough associated with the common cold, the American College of Chest Physicians recommends a combination of a first-generation antihistamine with a decongestant.(2) Specifically, the guideline states that brompheniramine and sustained-release pseudoephedrine should be used in this setting and adds that naproxen can also be added to help decrease cough. This recommendation is stated as having a “fair” level of evidence, a “significant” benefit and a “Grade A” recommendation. Similarly to diphenhydramine, brompheniramine is a first-generation antihistamine with FDA-labeled indications for allergic rhinitis, anaphylaxis (adjunct), urticaria, urticarial transfusion reaction and vasomotor rhinitis. It is not indicated for the common cold or more specifically for cough. Given the existence of other first-line, FDA-indicated alternatives for cough, it may be worthwhile to look further into any existing studies that would help the community pharmacist rationalize such a recommendation.
Literature Review:
A couple of early studies demonstrated that diphenhydramine was effective as an antitussive. In a 1976 double-blind crossover study, diphenhydramine was compared at 25mg and 50mg doses to placebo every four hours for a total of four doses.(4) The study showed that the antihistamine was associated with both a statistically and a clinically significant reduction in cough, however, treatment duration was only 12 hours. Additionally, the patient population consisted only of individuals with chronic cough due to bronchitis. In a 1991 placebo-controlled crossover study, a 25mg dose of diphenhydramine was associated with a significant reduction in the number of cough counts over a four-hour test period.(5) Patients that took part were first dosed with either the test drug or placebo and were then challenged with a 5% citric acid aerosol to induce cough. Similarly to the 1976 study, although the results were favorable, the design was probably not close enough to approximating the specific scenario of cough due to the common cold.
A more recent study sought to compare the effects of diphenhydramine, dextromethorphan or placebo in children aged 2 to 18 years with nocturnal cough due to an upper respiratory tract infection.(6) About 100 patients were observed overnight prior to receiving any medication while parents utilized a numeric rating scale to judge criteria such as cough frequency, cough severity, cough “bother” and child/parent ability to sleep. Patients were then broken up into three approximately equal groups, with each group receiving one of the treatment options. The parents once again utilized the same questionnaire on the second night and rated their children’s coughs following medication administration. Ratings in each category and overall improved in each one of the three treatment groups, with neither dextromethorphan nor diphenhydramine having been shown to be more effective than placebo in improving scores.
In a follow-up article, the authors reported on a sub-group of 37 children (ages 6 through 18) that were part of the previous study, who also received a similar questionnaire at the same time as the parents over the two-night timespan.(7) Overall, the responses given by the children matched the parent responses and neither dextromethorphan nor diphenhydramine was shown to improve cough, sleep or total scores significantly. The authors did point out that diphenhydramine was noticeably associated with the largest score improvements in cough severity, cough bother, sleep impact and combined score total and that the small sample size may have been a factor in failing to detect statistical significance in the diphenhydramine score improvements.
The ACCP recommendation in their guideline is largely based on the strength of one study that compared patients treated with an antihistamine-decongestant combination to placebo-treated patients. In the double-blind study, 86 adult subjects who complained of symptoms associated with the common cold were randomized to receive 6mg dexbrompheniramine maleate plus 120mg pseudoephedrine sulfate or placebo for 7 days.(8) They were asked to rate 17 of their own symptoms, including 5 core symptoms of cough, nasal obstruction, nasal discharge, postnasal drip and throat clearing over a period of 14 days. Additionally, patients underwent pulmonary function testing every 4 to 6 days that included spirometry, flow-volume loops and methacholine inhalational challenge. Self-reported ratings for the 5 key symptoms were lower (better) in the antihistamine-decongestant group than in the placebo group over the course of all 14 days, with the exception of a few days in the postnasal drip category. The scores were significantly lower in the initial days of treatment when symptoms were much more bothersome. Antihistamine-decongestant therapy significantly improved symptoms associated with the common cold, including cough. The authors utilized pulmonary function test results to make further observations and concluded that postnasal drip was largely responsible for cough induction. The one drawback to the study was that the design did not make it possible to determine whether the antihistamine or the decongestant contributed more toward symptomatic improvement.
An antihistamine-decongestant combination was also studied in pediatric patients.(9) Fifty-nine children aged 6 months to 5 years that had been recently diagnosed with an upper respiratory infection were divided approximately evenly to receive brompheniramine maleate (2mg/5mL) and phenylpropanolamine HCl (12.5mg/mL) in elixir form or placebo that was essentially identical in taste and texture. Parents administered the treatments over the next 48 hours and rated three main symptoms of runny nose, nasal congestion and cough using a 7-point Likert scale. There were no significant differences between the two treatment groups in the proportion of children showing improvement. However, the proportion of children that were asleep two hours after administration was significantly higher in the antihistamine-decongestant group.
The results of one other study that compared brompheniramine to placebo in patients with induced rhinovirus colds mirrored those from the one done by Curley, et al.(10) Over 200 adult subjects that received an experimental virus and developed cold symptoms were treated starting on the day following virus challenge with 12mg brompheniramine in extended release tablets or placebo of identical taste and appearance. Treatments were given once in the morning and once in the evening and patients were monitored over a 5-day period. Study nurses recorded the subjects’ scoring of their own symptoms each day based on a numerical rating scale. Nasal secretion weights were also recorded. Sneeze counts and scores for sneeze and rhinorrhea severity were improved in the brompheniramine population and significantly so for most of the days that the patients were observed. Nasal secretion weights were significantly lower on days 2, 3 and 4. Cough count and scores for cough severity were also lower (better) each day in the brompheniramine group and were reduced by approximately 30% to 40% more than placebo each day. The difference between the two groups was statistically significant on day 2 for the cough count and day 3 for the cough severity score. Although this study did not look at a population with natural colds it did address the issue by pointing to previous studies that utilized the same study technique and were found to be in line with what was later observed in individuals with natural colds. The strong point of this study was that it tested the efficacy of brompheniramine alone without the aid of a decongestant.
Summary:
In conclusion, there are a few first-line options available to patients when it comes to treating cough associated with the common cold, but many individuals may still not feel any relief after trying them. Although some studies show that there is little benefit to treatment with first-generation antihistamines in such a situation, other studies appear quite convincing to the contrary. The two studies by Curley et al., and Gwaltney and Druce, which demonstrated the efficacy of brompheniramine plus decongestant and brompheniramine alone, are particularly strong. A recommendation of brompheniramine for the treatment of cough associated with the common cold based on these two studies and the ACCP guideline especially after other first-line options have been exhausted might be very appropriate. Given that brompheniramine may not be readily available in community pharmacies, a recommendation of the more popular first-generation antihistamine diphenhydramine could also be of benefit to the patient. The pharmacist should keep in mind, however, that neither medication carries a specific FDA-labeled indication for cough and that the anticholinergic adverse effects of both drugs should be weighed against any possible benefits. Still, first-generation antihistamines may be a good option for reducing post-nasal drip and consequently cough associated with the common cold and the data in support of their efficacy may be no less convincing than what has been shown for the more popular over-the-counter options.
References:
1. Berardi RR, et al. Handbook of Nonprescription Drugs: an Interactive Approach to Self-Care, 16th Ed. Washington: APhA, 2009.
2. Pratter MR. “Cough and the common cold: ACCP evidence-based clinical practice guidelines.” Chest. 2006 Jan; 129 (1 Suppl): 72S-74S.
3. Micromedex 2.0. Truven Health Analytics Inc. Available at: http://www.micromedexsolutions.com/. Accessed October 3, 2014.
4. Lilienfield LS, Rose JC, Princiotto JV. “Antitussive activity of diphenhydramine in chronic cough.” Clinical Pharmacology and Therapeutics. 1976 Apr; 19 (4): 421-425.
5. Packman EW, Ciccone PE, Wilson J, Masurat T. “Antitussive effects of diphenhydramine on the citric acid aerosol-induced cough response in humans.” International Journal of Clinical Pharmacology, Therapy and Toxicology. 1991 Jun; 29 (6): 218-222.
6. Paul IM, Yoder KE, Crowell KR, Shaffer ML, McMillan HS, Carlson LC, Dilworth DA, Berlin CM Jr. “Effect of dextromethorphan, diphenhydramine, and placebo on nocturnal cough and sleep quality for coughing children and their parents.” Pediatrics. 2004 Jul; 114 (1): e85-e90.
7. Yoder KE, Shaffer ML, La Tournous SJ, Paul IM. “Child assessment of dextromethorphan, diphenhydramine, and placebo for nocturnal cough due to upper respiratory infection.” Clinical Pediatrics. 2006 Sep; 45 (7): 633-640.
8. Curley FJ, Irwin RS, Pratter MR, Stivers DH, Doern GV, Vernaglia PA, Larkin AB, Baker SP. “Cough and the common cold.” The American Review of Respiratory Disease. 1988 Aug; 138 (2): 305-311.
9. Clemens CJ, Taylor JA, Almquist JR, Quinn HC, Mehta A, Naylor GS. “Is an antihistamine-decongestant combination effective in temporarily relieving symptoms of the common cold in preschool children?” The Journal of Pediatrics. 1997 Mar; 130 (3): 463-466.
10. Gwaltney JM Jr, Druce HM. “Efficacy of brompheniramine maleate for the treatment of rhinovirus colds.” Clinical Infectious Diseases. 1997 Nov; 25 (5): 1188-1194.