document: over - the - counter ( otc ) cough and cold medications have long been criticized for lack of evidence supporting their efficacy . 
   this study demonstrates that diphenhydramine indeed inhibits cough reflex sensitivity.diphenhydramine , a commonly - used first - generation antihistamine in the us , is rightfully also classified as an antitussive ( cough suppressant ) in the united states food and drug administration ( fda ) otc monograph . over - the - counter 
   ( otc ) cough and cold medications have long been criticized for lack of evidence supporting their efficacy . 
   diphenhydramine , a commonly - used first - generation antihistamine in the us , is rightfully also classified as an antitussive ( cough suppressant ) in the united states food and drug administration ( fda ) otc monograph . 
   cough is the most common complaint for which patients in the united states seek medical attention . 
   although billions of dollars are spent annually on non - prescription , otc cough preparations , scant evidence exists supporting the efficacy of these drugs as antitussives . 
   three non - narcotic oral agents are listed as antitussives in the united states food and drug administration ( fda ) final monograph for otc antitussive drug products : chlophedianol , dextromethorphan , and the first - generation h1-antihistamine , diphenhydramine . 
   chlophedianol was first introduced as an antitussive in germany in the 1950s , but very little published literature supports its efficacy . 
   dextromethorphan , also available since the 1950s , is the most commonly used otc antitussive in the united states and many other areas of the world . although published studies exist demonstrating the ability of dextromethorphan to inhibit experimentally induced cough in healthy volunteers and to diminish pathological cough , most of these investigations are decades old and lack the more robust objective and subjective end points employed in current antitussive trials . 
   diphenhydramine has been shown to inhibit citric acid - induced cough in healthy volunteers , as well as to diminish pathological chronic cough relative to placebo . 
   furthermore , the guidelines of the american college of chest physicians ( accp ) recommend the combination of a first - generation h1-antihistamine and a decongestant as the treatment of choice for chronic cough due to upper airway cough syndrome ( formerly known as postnasal drip syndrome ) and acute cough due to the common cold , though this recommendation is based largely on a vast body of clinical experience and expert opinion , in the absence of adequately powered , prospective , randomized , controlled clinical trials . 
   acute cough due to viral upper respiratory tract infection ( uri ; common cold ) accounts for the majority of the approximately 27 million cough - related health care provider office visits annually in the united states , as well as the significant cost of otc products purchased to suppress troublesome cough . yet , to the authors knowledge , none of the three fda - approved otc antitussive products ( chlophedianol , dextromethorphan , and diphenhydramine ) has ever been shown to inhibit experimentally induced cough in subjects with acute cough due to uri . 
   capsaicin , the pungent extract of red peppers , has been shown in over three decades of clinical experience , to induce cough in a safe , dose - dependent and reproducible manner . 
   thus , capsaicin cough challenge testing has become an important tool in clinical research , allowing for the accurate measurement of the effect of a pharmacological intervention on the sensitivity of the cough reflex [ 9 , 10 ] . the standard end point measured in capsaicin cough challenge testing 
   is the concentration of capsaicin inducing 5 or more coughs ( c5 ) . in healthy volunteers , 
   this end point has been demonstrated to be highly reproducible , in the short - term ( 20  min to 14  days ) and long term ( months to years ) . 
   recently , it has been demonstrated that cough reflex sensitivity , though transiently enhanced during acute uri , remains stable in the first week of illness . 
   thus , in a clinical trial , any changes in cough reflex sensitivity observed during this period may be attributed to the pharmacological intervention being studied , rather than to spontaneous variation in cough reflex sensitivity . 
   to evaluate the effect of a diphenhydramine - containing , multicomponent syrup , compared with a dextromethorphan - containing syrup and placebo , on cough reflex sensitivity in otherwise healthy subjects with acute uri . 
   the study protocol was approved by the institutional review board of montefiore medical center , bronx , ny . 
   otherwise healthy adult nonsmokers with the onset of symptoms consistent with acute viral upper respiratory tract infection ( uri ) within the previous 72  h were recruited and enrolled after providing informed consent . 
   the study protocol was approved by the institutional review board of montefiore medical center , bronx , ny . subjects did not have a history of asthma or other pulmonary disease , nor history or symptoms suggestive of gastroesophageal reflux disease . 
   subjects presenting with symptoms suggestive of influenza , such as high fever , myalgias , or severe illness , were excluded . 
   individuals with uri who had taken any cough / cold medicines for their illness were excluded , as were those currently receiving any medication known to affect cough reflex sensitivity , or who had received any such medication within a time frame that would leave the possibility of a lingering effect of a previously - ingested medication on the sensitivity of the cough reflex . upon enrollment 
   , subjects were randomized to receive each of the three study formulations within a 35  days period , in random order , 2  h prior to capsaicin challenge testing , in a double - blind fashion . 
   the study drugs consisted of : diphenhydramine ( 25  mg ) and phenylephrine ( 10  mg ) in a natural cocoa formulation ( dr . cocoa , infirst healthcare , london , uk ) ; dextromethorphan ( 30  mg ) syrup with licorice and sugar water among inactive ingredients ( father john s medicine , oakhurst co. , levittown , ny , usa ) ; and , a solution of dextrose in water . a post - ingestion period of 2  h 
   was chosen to coincide with near - peak blood concentrations of diphenhydramine   and dextromethorphan [ 2 , 13 ] . 
   study drugs were prepared as 20  ml liquid doses in opaque bottles that each subject was instructed to drink , without commenting on the taste or smell of the liquid . 
   the investigators therefore were unaware of the appearance , smell , and other characteristics of the study drugs administered . 
   briefly , subjects inhaled single , vital - capacity breaths of ascending , doubling concentrations ( range 0.491000  m ) of aerosolized capsaicin solution , administered via a compressed air - driven nebulizer controlled by a dosimeter , with 1-min intervals between inhalations , until 5 or more coughs resulted in the 15  s following an inhalation 
   the end point of capsaicin challenge testing is the concentration of capsaicin inducing 5 or more coughs ( c5 ) . to evaluate the effect of each of the three study formulations , differences in log c5 responses 
   were analyzed by 1-way anova for dependent samples combined with tukey s hsd test for pairwise comparisons . 
   twenty - two subjects [ 16 females ; mean age 39.2    13.3(sd ) year ] were recruited and completed the study . 
   sd ) log c5 values observed after administration of each of the study drugs were : 0.57    0.75 after placebo ; 0.80    0.83 after dextromethorphan ; and , 0.97    0.74 after the diphenhydramine - containing formulation ( fig .  1 ) . 
   differences in log c5 responses were analyzed by 1-way anova for dependent samples combined with tukey s hsd test for pairwise comparisons . a significant difference ( p  =  0.0024 ) 
   was established among the groups , with pairwise analysis revealing a significant increase in mean log c5 [ 0.4    0.55(sd ) ; p  <  0.01 ] for the diphenhydramine - containing medication versus placebo , but not for dextromethorphan versus placebo.fig . 
   1values for cough reflex sensitivity to capsaicin ( log c5 ) determined 2  h after ingestion of diphenhydramine ( dph ) , dextromethorphan ( dx ) , and placebo in adult nonsmokers with acute viral upper respiratory tract infection . 
   cough reflex sensitivity was significantly inhibited ( log c5 increased ) after diphenhydramine ( p  <  0.01 ) . 
   error bars represent sem values for cough reflex sensitivity to capsaicin ( log c5 ) determined 2  h after ingestion of diphenhydramine ( dph ) , dextromethorphan ( dx ) , and placebo in adult nonsmokers with acute viral upper respiratory tract infection . 
   cough reflex sensitivity was significantly inhibited ( log c5 increased ) after diphenhydramine ( p  <  0.01 ) . 
   error bars represent sem in terms of side effects , five subjects reported slight drowsiness after ingesting the diphenhydramine - containing formulation , as did one subject after placebo . 
   five subjects reported side effects after ingesting the dextromethorphan syrup : slight drowsiness in two subjects , slight nausea in two subjects , and dry mouth in one subject . 
   in the united states , the majority of otc cough preparations contain dextromethorphan or diphenhydramine as the pharmacologically active component . 
   significant criticism has been directed at the otc cough and cold market because of the lack of adequately performed clinical trials demonstrating these agents to be effective antitussives [ 2.7 ] . 
   to the authors knowledge , this study represents the first demonstration of the ability of diphenhydramine to suppress cough reflex sensitivity in subjects with acute uri . 
   furthermore , the diphenhydramine - containing formulation proved a more effective antitussive than did dextromethorphan , with both agents administered at standard antitussive doses . 
   however , it should be noted that cough reflex sensitivity was measured 2  h after study drug administration , to coincide with near - peak blood concentrations of the agents under investigation . 
   such timing of the cough challenge may not have allowed demonstration of the maximal antitussive effect of dextromethorphan , as a recent study of healthy volunteers found that maximal inhibition of capsaicin cough sensitivity by dextromethorphan was not observed until 6  h after oral administration . 
   the multicomponent diphenhydramine - containing syrup investigated in this study also contains the decongestant phenylephrine at standard otc dose as well as natural cocoa flavoring . to our knowledge , 
   theobromine , a component of cocoa , has been shown to have antitussive effect in healthy volunteers in one previous study , however , the amount of theobromine contained in one dose of the medication evaluated herein is much smaller than that required for cough reflex inhibition . 
   nevertheless , the thickness and cocoa flavor of the diphenhydramine - containing formulation may be contributing to the overall efficacy of the medication by creating a demulcent effect that has been proposed as an important component of the perceived therapeutic effect of cough syrups . 
   the diphenhydramine - containing syrup contained a natural cocoa flavoring ; the dextromethorphan - containing syrup contained licorice and sugar water ; and , the placebo was a dextrose solution . 
   however , we do not feel that the lack of perfect blinding affected our results . 
   subjects knew that during the three study days , they would be receiving two active medications and a placebo . 
   they were unaware , of course , of which flavorings the active and placebo formulations would have . 
   had subjective end points been examined , especially soon after drug administration , then certainly the possibility of a demulcent effect of the various liquids may have contributed to subject perception and experience . 
   however , our study measured only the objective end point of cough reflex sensitivity to capsaicin , 2  h after study drug administration , by which time any local throat sensations and demulcent effects would have dissipated . 
   it is noteworthy that a recent study demonstrated that sweet substances can affect cough reflex sensitivity to capsaicin . 
   thus , our placebo preparation was also sweetened so as to present subjects with sweet liquids on each of the 3  days of testing . 
   although the first - generation antihistamine , diphenhydramine , is classified as an antitussive by the fda and is a component of numerous otc cough and cold preparations , the present study , to our knowledge , contributes the initial evidence demonstrating the ability of this agent to inhibit cough reflex sensitivity in acute pathological cough . 
   further clinical trials are needed to adequately evaluate this and other otc cough and cold products , so as to allow physicians and consumers alike to make informed treatment decisions based on proper scientific data .
summary: background : currently available over - the - counter cough remedies historically have been criticized for lack of scientific evidence supporting their efficacy . 
   although the first - generation antihistamine diphenhydramine is classified as an antitussive by the united states food and drug administration , to the authors knowledge it has never been shown to inhibit cough reflex sensitivity in subjects with pathological cough . 
   objective : to evaluate the effect of diphenhydramine on cough reflex sensitivity . setting : montefiore medical center , an academic medical center in new york city . 
   methods : twenty two subjects with acute viral upper respiratory tract infection ( common cold ) underwent cough reflex sensitivity measurement employing capsaicin challenge on 3  separate days , 2  h after ingesting single doses of study drug ( to coincide with peak blood concentrations ) , administered in randomized , double - blind manner : a multicomponent syrup containing diphenhydramine ( 25  mg ) , phenylephrine ( 10  mg ) , in a natural cocoa formulation ; dextromethorphan ( 30  mg ) syrup ; and , placebo syrup . 
   the standard endpoint of cough challenge was used : concentration of capsaicin inducing 5 coughs ( c5 ) . 
   main outcome measure : effect on cough reflex sensitivity ( c5 ) . 
   results : a significant difference ( p  =  0.0024 ) was established among groups , with pairwise analysis revealing a significant increase in mean log c5 ( 0.4    0.55 ( sd ) ; p  <  0.01 ) for the diphenhydramine - containing medication versus placebo , but not for dextromethorphan versus placebo . conclusions : our results provide the initial evidence of the ability of diphenhydramine to inhibit cough reflex sensitivity in subjects with acute pathological cough . 
   timing of cough reflex sensitivity measurement may not have allowed demonstration of maximal antitussive effect of dextromethorphan .