Effect of Honey, Dextromethorphan, and
No Treatment on Nocturnal Cough and Sleep Quality
for Coughing Children and Their Parents

Ian M. Paul, MD, MSc; Jessica Beiler, MPH; Amyee McMonagle, RN;Michele L. Shaffer, PhD; Laura Duda, MD; Cheston M. Berlin Jr, MD Objectives: To compare the effects of a single noctur-
Main Outcome Measures: Cough frequency, cough
nal dose of buckwheat honey or honey-flavored dextro- severity, bothersome nature of cough, and child and par- methorphan (DM) with no treatment on nocturnal cough and sleep difficulty associated with childhood upper res-piratory tract infections.
Results: Significant differences in symptom improve-
ment were detected between treatment groups, with honey
consistently scoring the best and no treatment scoring
Design: A survey was administered to parents on 2 con-
the worst. In paired comparisons, honey was signifi- secutive days, first on the day of presentation when no cantly superior to no treatment for cough frequency and medication had been given the prior evening and then the combined score, but DM was not better than no treat- the next day when honey, honey-flavored DM, or no treat- ment for any outcome. Comparison of honey with DM ment had been given prior to bedtime according to a par- revealed no significant differences.
tially double-blinded randomization scheme.
Conclusions: In a comparison of honey, DM, and no treat-
Setting: A single, outpatient, general pediatric practice.
ment, parents rated honey most favorably for symptomaticrelief of their child’s nocturnal cough and sleep difficulty due Participants: One hundred five children aged 2 to 18
to upper respiratory tract infection. Honey may be a pref- years with upper respiratory tract infections, nocturnal erable treatment for the cough and sleep difficulty associ- symptoms, and illness duration of 7 days or less.
ated with childhood upper respiratory tract infection.
Trial Registration: Identifier:
Intervention: A single dose of buckwheat honey, honey-
flavored DM, or no treatment administered 30 minutesprior to bedtime.
Arch Pediatr Adolesc Med. 2007;161(12):1140-1146 COUGHISTHEREASONFOR Wehavepreviouslyshownthatnei-
jectively by parents.6 In that study, the occurs in conjunction with an upper respi- medications failed to produce an improve- ratory tract infection (URI).1 At night, it is ment in the frequency, severity, or both- particularly bothersome because it disrupts ersome nature of the cough to a greater de-gree than placebo. Importantly for parents,neither their child’s sleep nor their own See also page 1149
sleep was significantly better when theirchild received medication compared with URIs and cough, there are no accepted thera- pies for this annoying symptom. The use of edies such as honey are used to treat URI Author Affiliations:
over-the-counter(OTC)antitussive,fortreat- ment of cough in childhood is not supported lieved to be safe outside of the infant popu- the American College of Chest Physicians.2,3 benefits and has repeatedly been shown to (REPRINTED) ARCH PEDIATR ADOLESC MED/ VOL 161 (NO. 12), DEC 2007 2007 American Medical Association. All rights reserved.
1. How frequent was your child’s coughing last night? 2. How severe was your child’s cough last night? 3. How bothersome was last night’s cough to your child? 4. How much did last night’s cough affect your child’s ability to sleep? 5. How much did last night’s cough affect your (parent’s) ability to sleep? Figure 1. Survey questions to assess nocturnal cough and sleep difficulty.
honey is cited by the World Health Organization as a po- ease (eg, asthma, pneumonia, laryngotracheobronchitis, sinus- tential treatment.12 In the World Health Organization re- itis, allergic rhinitis). They were also ineligible when they had port on the treatment of URIs in young children, honey a history of reactive airways disease, asthma, or chronic lung is considered as a demulcent that is cheap, popular, and disease or were using a drug known to inhibit the metabolism safe. Although there is no scientific evidence to support of DM, such as selective serotonin reuptake inhibitors. Sub- the use of honey for symptoms associated with a URI, it jects were also excluded if on the prior evening they had takena medication that included an antihistamine or DM hydrobro- is suggested in the World Health Organization report that mide within 6 hours of bedtime or DM polistirex within 12 hours demulcents may soothe the throat and can be recom- of bedtime on the evening prior to or on the day of enroll- mended to provide some relief from cough in children.
ment. Patients were not excluded when analgesic medications In addition to the demulcent effect, honey has antioxi- such as acetaminophen or ibuprofen were administered on either dant properties and increases cytokine release, which may night of the study. While many more patients with URIs pre- sented to the practice during the recruitment period, the ex- The objective of this trial was to compare the effects of clusions, particularly the exclusion of taking medication on the a single nocturnal dose of honey or honey-flavored DM previous evening, disqualified many subjects.
with no treatment on nocturnal cough and the sleep dif- Subjective parental assessments of their child’s cough and ficulty associated with URIs. A no-treatment arm was in- sleep difficulty on the previous night were assessed after in- cluded instead of one with a placebo group for 2 reasons: formed consent was obtained through previously validated ques- (1) our previous study found no difference between DM tions using a 7-point Likert scale (Figure 1).19 Trained study
and placebo for any outcome,6 so including both a DM arm coordinators were responsible for survey administration, andsurvey responses ranged from extremely (6 points) to not at and a placebo arm would be unnecessary, and (2) a cri- all (0 points). In an effort to study a population that was likely tique suggested that the study cohort was already improv- to receive a therapeutic intervention by parents, minimum symp- ing at the time when DM or placebo was given, which lim- tom severity criteria for enrollment were established. Only par- ited our ability to detect a treatment effect.18 Given the pre- ents who answered at least somewhat (3 points) for a mini- vious demonstration of DM’s nonsuperiority to placebo, mum of 2 of the 3 questions related to nocturnal cough this study design allowed us to address previous critiques frequency, effect on the child’s sleep, and effect on parental sleep and answer a clinically important question by hypothesiz- based on the previous night’s symptoms were eligible.
ing that both honey and DM will be superior to no treat- After stratification for age (ages 2-5, 6-11, and 12-18 years), ment for control of nocturnal cough due to URI as well each child was randomly assigned in a partially double- blinded fashion to receive artificially honey-flavored DM (17mg/5 mL prepared using DM hydrobromide powder [100% pureUnited States Pharmacopeia grade], artificial honey flavoring, coloring, stevia liquid extract, methocel, and simple syrup [Pro-fessional Compounding Centers of America, Houston, Texas]), From September 2005 through March 2006, patients were re- buckwheat honey, or nothing in a 10-mL syringe. A compound- cruited from a single university-affiliated pediatric practice in ing pharmacy prepared the DM to approximate the consis- Hershey, Pennsylvania, on presentation for an acute care visit.
tency, texture, flavor, smell, and sweetness of honey. The ran- Eligible patients were aged 2 through 18 years with cough at- domization sequence was constructed by a statistician not tributed to URIs. The URIs were characterized by the presence affiliated with the study (Susan Boehmer, MS) and was then of rhinorrhea and cough for 7 or fewer days’ duration. Other used by the study coordinators to assign treatment groups.
symptoms may have included but were not limited to conges- The syringes used for all of the 3 treatment groups were tion, fever, sore throat, myalgias, and headache. Patients were opaque and were placed in brown paper bags to avoid inves- excluded if they had signs or symptoms of a more treatable dis- tigator unblinding. Although the no-treatment group was not (REPRINTED) ARCH PEDIATR ADOLESC MED/ VOL 161 (NO. 12), DEC 2007 2007 American Medical Association. All rights reserved.
Table. Baseline Characteristicsa
Patients Receiving Honey
Patients Receiving DM
Patients Receiving No Treatment
Cough effect on child sleep score, mean ± SD Cough effect on parent sleep score, mean ± SD a No significant difference between treatment groups exists for any baseline characteristic.
blinded to their treatment arm, the honey and DM groups re- cough outcome. These analyses were extended to include age mained blinded. Dosage for DM approximated typical OTC la- (in continuous form) and sex separately in analysis of covari- bel recommendations, with children aged 2 to 5 years receiv- ance models. As adjustment for these covariates did not change ing 8.5 mg/dose (1/2 teaspoon), children aged 6 to 11 years the findings, the results of the unadjusted analyses are re- receiving 17 mg/dose (1 teaspoon), and children aged 12 to 18 ported. Fisher exact tests were used to compare adverse event years receiving 34 mg/dose (2 teaspoons). Of note, these con- centrations slightly exceed typical OTC products, which con- The study was approved by the Pennsylvania State Univer- tain 15 mg/5 mL, and were the result of the compounding pro- sity College of Medicine’s Human Subjects Protection Office, cess but may be more likely to achieve a beneficial effect based and the trial was registered at prior on our previous analyses.20 For the honey group, the volume to the first subject’s enrollment. Informed consent was ob- of honey dispensed was equivalent to the age-driven volume tained from all of the participating parents and verbal assent dispensed for DM. The bags and syringes were refrigerated prior was obtained from all of the children aged 7 years or older.
to being dispensed. Parents were instructed that their child’streatment could be given with a noncaffeinated beverage andshould be administered within 30 minutes of the child going to sleep. A second survey asking the same questions as thoseanswered at enrollment was then administered via telephone One hundred thirty children with URIs were enrolled and interview the following day to the same parent by trained study 105 (81%) completed the single-night study. The me- coordinators ( J.B., A.M., Sarah Sturgis, CRNP, Jennifer Stokes, dian age of the patients completing the study was 5.22 years RN, Susan LaTournous, RN, and Diane Kitch, RN), who wereblinded to the treatment group, to assess symptom severity for (range, 2.22-16.92 years), with no significant difference the night when DM, honey, or no treatment was given. No phy- between treatment groups (Table). Thirty-five patients
sician examination was performed on the second study day un- received honey, 33 received DM, and 37 received no treat- less dictated by illness progression.
ment. Fifty-three percent of the children were female and The prospectively estimated sample size necessary to de- the participants were ill a mean±SD of 4.64±1.68 days be- tect a 1-point difference between any 2 treatment groups with fore participation, without significant differences in either 80% power was 35 subjects per treatment group for a total sample variable between treatment groups (P=.60). In addition, size of 105 subjects with ␣=.05. This calculation was based on there were no significant differences between measures of a 2-sided, 2-sample t test inflated to reflect the loss of effi- ciency that would result if it was necessary to use Wilcoxon- Symptom scores were obtained to describe the night Mann-Whitney tests for pairwise comparisons of the treat-ments. The 1-point difference for the primary outcome has been before enrollment when no participants received treat- used previously,6 and it resulted in a sample size that is greater ment, and they were compared with scores from the sub- than several other well-known and similar clinical trials.21,22 The sequent night when honey, honey-flavored DM, or no principal outcome measure of interest was the change in the treatment was given before bed. When separated by treat- frequency of cough between the 2 nights, and secondary out- ment group, significant differences were detected in the come measures of importance were changes in the cough se- amount of improvement reported for all of the study out- verity, the bothersome nature of the cough, the effect of the comes in the planned 3-way comparison (Figure 2). All
cough on sleep for both the child and parents, and the com- of the outcomes found honey to yield the greatest im- provement, followed by DM, while no treatment consis- Baseline characteristics were compared between treatment tently showed the least amount of improvement. For groups using a ␹2 test for sex, a Kruskal-Wallis test for age, and1-way analysis of variance for the remaining variables. The cough cough frequency, those who received honey had a mean outcomes showed no significant departures from normality; 1.89-point improvement as rated by their parents com- therefore, treatment group comparisons were conducted using pared with a 1.39-point change for those receiving DM 1-way analysis of variance. The Tukey method was used to ad- and a 0.92-point change for those who had no treat- just P values for the pairwise treatment comparisons for each ment on the second night (P Ͻ.001). Parents also noted (REPRINTED) ARCH PEDIATR ADOLESC MED/ VOL 161 (NO. 12), DEC 2007 2007 American Medical Association. All rights reserved.
similar improvements in the severity of their child’s cough:1.80 points with honey, 1.30 points with DM, and 1.11 points with no treatment (P Ͻ.001). While parents feltthe cough also was less bothersome on the second night, again honey provided the greatest relief with a 2.23- point change compared with a 1.94-point change and a1.30-point change for those children who received DM and no treatment, respectively (P Ͻ.001). Parents rated their children’s sleep better after receiving honey, with a 2.49-point improvement for the honey group com- pared with a 1.79-point change for the DM group and a 1.57-point change for those not receiving treatment on the second night (P Ͻ.001). As might be expected, pa- rental sleep improved in a fashion similar to that of theirchildren, with the honey treatment arm improving the most by a mean of 2.31 points, followed by 1.97 points for DM and 1.51 points for no treatment (PϽ.001). When the results for these outcomes were combined by add- ing the scores from the individual categories, honey again proved to be the most effective treatment. The children in this group improved by an average of 10.71 points com- pared with 8.39 points for DM-treated children and 6.41points for those who were not treated (P Ͻ.001).
In pairwise comparisons, honey was significantly su- perior to no treatment for our a priori primary outcome of cough frequency (P=.01) as well as the combined symp- tom score (P=.04), with marginally significant superior- ity for child sleep (P=.09) and the bothersome nature ofthe cough (P = .08). Nonsignificant outcomes included cough severity (P=.18) and parent sleep (P=.17). In con- trast, DM was not significantly better than no treatment for any study outcome. Similarly, pairwise comparison of honey with DM revealed no statistically significant differences.
Even though the mean illness duration was not signifi- cantly different between treatment groups (P=.15), be-cause of the possibility that the treatment effect was modi- Figure 2. Comparison of the effect of honey, dextromethorphan (DM), and
fied by the duration of illness, the analysis of variance models no treatment on cough frequency (A), cough severity (B), the cough being were extended to include the duration of illness and an in- bothersome to the child (C), the child’s sleep (D), the parent’s sleep (E), and teraction term between treatment and the duration of ill- ness. This interaction term only reached statistical signifi-cance for cough frequency (P = .05) and child’s sleep effective treatment for all of the outcomes related to cough, (P=.04); however, all of the outcome measures showed a child sleep, and parent sleep. Further, honey but not DM similar pattern of treatment effect modification. Improve- was superior to no treatment for nocturnal symptoms as- ment with the use of honey or no treatment increased as sociated with childhood URI. Notably, however, direct the duration of illness increased, whereas improvement with comparison between honey and DM yielded no statisti- DM decreased as the duration of illness increased.
cally significant differences. These findings comple- Few adverse events occurred in this investigation. The ment the results of our previous study6 that found no combination of mild reactions that include hyperactivity, difference between DM, diphenhydramine, or placebo nervousness, and insomnia occurred in 5 patients treated for children with URIs, and they now provide a gener- with honey, 2 patients in the DM group, and no patients ally safe and well-tolerated alternative for practitioners in the no-treatment arm (P=.04). In the honey group, the parent of 1 patient reported drowsiness and the parents of Honey has well-established antioxidant and antimi- 2 patients reported stomachache, nausea, or vomiting, but crobial effects,13,15,23-30 which have been suggested as the these adverse events were not significant when examined mechanism for its efficacy in wound healing and may help separately from a statistical perspective (drowsiness, P=.65; to explain its superiority in this study. Buckwheat honey stomachache, nausea, vomiting, P=.21).
is a dark variety of honey, and darker honeys tend to havea higher content of phenolic compounds. These com-pounds have been associated with the antioxidant prop- erties of honey that may have contributed to its effect inthis study.15,16,31 Further, its topical demulcent effect may The results of this study demonstrate that in the overall contribute to its benefits for cough as postulated by the comparison of the 3 treatment groups, honey was the most (REPRINTED) ARCH PEDIATR ADOLESC MED/ VOL 161 (NO. 12), DEC 2007 2007 American Medical Association. All rights reserved.
Another explanation for some of the beneficial that a larger sample size may have had enough statisti- effects of honey was recently described in a provocative cal power to detect a difference between DM and no treat- review by Eccles.32 This article argues that the sweet- ment, for the individual outcome measures, the ob- ness of liquid preparations used to treat cough accounts served differences were all smaller than the 1-point for a significant portion of the treatment effect and difference believed to be clinically meaningful prior to also explains why studies have shown that antitussive study initiation. In any case, the fact that there was preparations containing DM are not significantly supe- sufficient power to find that honey was superior to no rior to sweet, liquid placebos. This hypothesis is based treatment adds to the validity of our previous findings on the suggestion that sweet substances naturally suggesting that DM was no better than a placebo treat- cause reflex salivation and may also cause the secre- ment of simple syrup without a pharmacologically ac- tion of airway mucus and lead to a demulcent effect on the pharynx and larynx, thereby reducing cough (par- This study is somewhat limited by the fact that each ticularly dry, unproductive cough). For productive child had a physician visit between the 2 nights of the cough, Eccles suggests that these secretions could study, which may provide some of the explanation for improve mucociliary clearance in the airway via an the improvement in all of the groups, including the no- expectorant mechanism. Additionally, the review treatment group. Alternatively, much of the improve- mentions the evidence related to endogenous opioids ment can also be attributed to the natural history of URIs, that are produced following consumption of sweet which generally improve with time and supportive care.
substances, a phenomenon that has been repeatedly The subjective survey used for this study may also be studied for its analgesic properties. Because of the considered by some to be a limitation, but clinicians and close anatomical relationship between the sensory parents often make decisions based on subjective assess- nerve fibers that initiate cough and the gustatory nerve ment of symptom severity as has been argued pre- fibers that taste sweetness, Eccles suggests that an viously.22,70 Additionally, investigators at the Massachu- interaction between the opioid-responsive sensory setts General Hospital recently validated this survey fibers and the gustatory nerves may help to produce with 120 caregivers of children aged 1 to 18 years and the antitussive effects of sweet substances via a central found it to be reliable for assessing changes in cough fre- quency and severity over time.19 Further, compliance with Dextromethorphan continues to be used very fre- medication administration could not be guaranteed even quently in the United States despite numerous studies, though every parent did report that the treatment was evidence-based reviews, and policy statements describ- taken by their child without difficulty regardless of ran- ing its lack of efficacy.2,3,6,21,22,33-38 Although it was gen- domization arm, but the lack of treatment in 1 of the study erally well tolerated in the cohort of children who took arms could be viewed as causing biased results in that the medication in this study, its OTC availability is es- pecially concerning given the numerous reports of seri- As we have stated previously, the desire to ease the ous adverse events described in the medical literature, symptoms associated with URIs, particularly cough and such as dystonia,39 anaphylaxis,40 and bullous mastocy- its associated sleep difficulty, is great.6 Both physicians tosis41 with standard doses, and dependence,42,43 psycho- and parents want symptomatic relief for children sis,44,45 mania,46,47 hallucinations,48 ataxia,49,50 somno- afflicted with these common and annoying illnesses.
lence,50 insulin-dependent diabetes mellitus,51 peripheral While our findings and the absence of contemporary neuropathy,52 cerebellar degeneration,53 megaloblastic ane- studies supporting the use of DM continue to question mia,52,53 and death54 with higher doses. Further, DM is its effectiveness for the treatment of cough associated increasingly being used as a recreational drug of abuse, with URIs, we have now provided evidence supporting particularly by adolescents,55-64 and one recent report63 honey, which is generally regarded as safe for children indicated that nearly 5% of 12th graders in Dayton, Ohio, older than 1 year, as an alternative. While additional have tried this drug for this purpose.
studies to confirm our findings should be encouraged, In contrast with DM, honey is generally recognized each clinician should consider the findings for honey, as safe with the exceptions of the risk of infantile botu- the absence of such published findings for DM, and the lism for children younger than 1 year65-68 and the rare risk potential for adverse effects and cumulative costs asso- of grayanotoxin-mediated syndrome characterized by sali- ciated with the use of DM when recommending treat- vation, emesis, circumoral and extremity paresthesias, hy- potension, bradycardia, and, occasionally, cardiac rhythmdisturbances.69 Our study did find that the mild adverse Accepted for Publication: May 29, 2007.
effect grouping of hyperactivity, nervousness, and in- Correspondence: Ian M. Paul, MD, MSc, Department of
somnia was significantly more common in those treated Pediatrics, H085, Milton S. Hershey Medical Center, with honey, a finding that could affect clinician recom- Pennsylvania State University, 500 University Dr, PO Box 850, Hershey, PA 17033-0850 ([email protected]).
The use of a no-treatment arm somewhat negates the Author Contributions: Dr Paul takes responsibility for
criticism of our prior study that argued that the effect of the integrity of the data. Dr Shaffer had full access to all DM could not be determined because of the large pla- of the data in the study and takes responsibility for the cebo effect seen. The current results surprisingly indi- accuracy of the data analysis. Study concept and design: cate that DM was not significantly better than no treat- Paul, Beiler, and Berlin. Acquisition of data: Beiler, ment at all. While the trend seen in the results suggests McMonagle, and Duda. Analysis and interpretation of data: (REPRINTED) ARCH PEDIATR ADOLESC MED/ VOL 161 (NO. 12), DEC 2007 2007 American Medical Association. All rights reserved.
Paul, Beiler, Shaffer, Duda, and Berlin. Drafting of the 20. Paul IM, Shaffer ML, Yoder KE, Sturgis SA, Baker MS, Berlin CM Jr. Dose- manuscript: Paul. Critical revision of the manuscript for im- response relationship with increasing doses of dextromethorphan for childrenwith cough. Clin Ther. 2004;26(9):1508-1514.
portant intellectual content: Beiler, McMonagle, Shaffer, 21. Korppi M, Laurikainen K, Pietikainen M, Silvasti M. Antitussives in the treatment Duda, and Berlin. Statistical analysis: Shaffer. Obtained of acute transient cough in children. Acta Paediatr Scand. 1991;80(10): funding: Paul. Administrative, technical, and material sup- port: Paul, Beiler, McMonagle, and Duda. Study supervi- 22. Taylor JA, Novack AH, Almquist JR, Rogers JE. Efficacy of cough suppressants sion: Paul, Beiler, Duda, and Berlin.
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23. Gheldof N, Engeseth NJ. Antioxidant capacity of honeys from various floral sources Financial Disclosure: Dr Paul has been a consultant to
based on the determination of oxygen radical absorbance capacity and inhibi- the Consumer Healthcare Products Association and tion of in vitro lipoprotein oxidation in human serum samples. J Agric Food Chem.
Funding/Support: This work was supported by an un-
24. Henriques A, Jackson S, Cooper R, Burton N. Free radical production and quench- restricted research grant from the National Honey Board, ing in honeys with wound healing potential. J Antimicrob Chemother. 2006;58(4):773-777.
an industry-funded agency of the US Department of Ag- 25. Lusby PE, Coombes AL, Wilkinson JM. Bactericidal activity of different honeys against pathogenic bacteria. Arch Med Res. 2005;36(5):464-467.
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Responsiveness of gill na+/k+-atpase to cortisol

The Journal of Experimental Biology 202, 987–995 (1999)Printed in Great Britain © The Company of Biologists Limited 1999JEB1918 RESPONSIVENESS OF GILL Na+/K+-ATPase TO CORTISOL IS RELATED TO GILL CORTICOSTEROID RECEPTOR CONCENTRATION IN JUVENILE RAINBOW TROUT J. MARK SHRIMPTON* AND STEPHEN D. MCCORMICK Conte Anadromous Fish Research Center, Biological Resources Division, USGS, Turners F

«Giuseppe nome dell’avo paterno, Alessandro del padre di mia madre, Giosuè di un amico di mio padre. Ho da ringraziare Iddio che la matta vanità di farsi romanzeschi fin ne’ nomi non mettesse ne’ parenti miei il bel pensiero di appiccicarmi un qualche nome settentrionale; per esempio, Enrico, Alfredo, Arminio, o che so io. E in vero che questa Italia non contenta di non avere di suo né

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