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Honey Boo Boo

My son has been coughing for several weeks, and the cough will probably persist for another 2 or 3 weeks. Coughs last a long time. Patients think a cough will go away in less than a week but in reality they are likely to last several weeks.

Coughs are a pain for the patient and an annoyance for the people around them. You never really know if the cougher in the row behind you has asthma,  a post infectious cough or  is actively spewing TB or influenza all over the airplane.  I learned from Clinton the importance of not inhaling, especially on airplanes.

I tend to leave most symptoms alone if the they are not life threatening or otherwise unbearable for the patient. Codeine is the only really good cough suppressant and none of the over the counter cough medications are effective.  I assume that coughing with infection, like diarrhea, is beneficial. Key to treating all infections is to physically remove it. Undrained pus doesn’t heal, and a good cough is the most efficient way I know to remove potential pathogens from the lungs.

If there are benefits to suppressing the cough associated with acute respiratory infections I can’t find any and we have all seen people who, because of inability to cough secondary to rib fractures, develop severe pneumonia.  As a resident I had an elderly male die of just such a series of unfortunate events.

I suffer from a mild form the the naturalistic fallacy. I tend to let normal physiologic processes run their course unimpeded as long as they pose no harm to the patient.  So I do not treat infectious coughs, in part because medications are not effective, in part there is no benefit  and in part because the medications that are effective, and those that are not, have side effects. 

Not only has my son been coughing, but, thanks to flu-like illness season, almost everyone around me is coughing as well and someone asked me about honey as a cough treatment, pointing to a recent article in Pediatrics.

I like honey. Of the roughly 40,000 PB&J sandwiches I estimate I have consumed in my life, I bet half have been made with honey. For a variety of reasons I occasionally recommend honey for wounds. But as a cough therapy? Why would honey have an effect on cough? Whatever the active ingredient, it would have to survive gastric acid and pancreatic enzymes, be absorbed and have sufficient half life to have an effect.

Given that honey is >95% water and sugar there is little room for any ‘active’ ingredients. I went looking for a coherent, plausible mechanism for how honey might suppress cough but failed. Much was written about the complexity of honey, its antioxidant and antibacterial effects:

Honey is a remarkably complex natural liquid that is reported to contain at least 181 substances. It has well-established antioxidant and antimicrobial effects.

True and interesting, but it has little to with suppressing cough. The link between antioxidants and cough is tenuous at best, most of my Google-fu found references to asthma. It was also suggested that the sweetness of the honey is key:

Because of the close anatomic relationship between the sensory nerve fibers that initiate cough and the gustatory nerve fibers that taste sweetness, an interaction between these fibers may produce an antitussive effect of sweet substances via a central nervous system mechanism.

Neither seem particularly likely to me as a mechanism for cough suppressant.

There is a strong placebo effect when treating cough:

Placebo treatment has been reported to improve subjective and objective measures of disease in up to 30-40% of patients with a wide range of clinical conditions. A review of 8 clinical trials on the effects of antitussive medicines on cough associated with acute upper respiratory tract infection shows that 85% of the reduction in cough is related to treatment with placebo, and only 15% attributable to the active ingredient.

Although any author who routinly uses the word ‘powerful’ in conjunction with placebo, as Dr. Eccles does, probably has a stronger bias in favor of placebo effects than I. Coughs improve with time. Because of the favorable natural history of cough, a “positive” response in medication trials should not be assumed to be due to the medication.

The ever questionable Cochrane Reviews had evaluated honey as an anti-cough therapy and concluded

We included two RCTs of high risk of bias involving 265 children. The studies compared the effect of honey with dextromethorphan, diphenhydramine and ‘no treatment’ on symptomatic relief of cough using the 7-point Likert scale. Honey was better than ‘no treatment’ in reducing frequency of cough (mean difference (MD) -1.07; 95% confidence interval (CI) -1.53 to -0.60; two studies; 154 participants). Moderate quality evidence suggests honey did not differ significantly from dextromethorphan in reducing cough frequency (MD -0.07; 95% CI -1.07 to 0.94; two studies; 149 participants). Low quality evidence suggests honey may be slightly better than diphenhydramine in reducing cough frequency (MD -0.57; 95% CI -0.90 to -0.24; one study; 80 participants). Adverse events included mild reactions (nervousness, insomnia and hyperactivity) experienced by seven children (9.3%) from the honey group and two (2.7%) from the dextromethorphan group; the difference was not significant (risk ratio (RR) 2.94; 95% Cl 0.74 to 11.71; two studies; 149 participants). Three children (7.5%) in the diphenhydramine group experienced somnolence (RR 0.14; 95% Cl 0.01 to 2.68; one study; 80 participants) but there was no significant difference between honey versus dextromethorphan or honey versus diphenhydramine.

Since all over the counter medications for cough are essentially worthless, if honey is equal to dextromethorphan and dextromethorphan does nothing, then honey does nothing. Or does it?

Enter Effect of Honey on Nocturnal Cough and Sleep Quality: A Double-blind, Randomized, Placebo-Controlled Study, which received a lot of press, most of it favorable.

The study was simple and really, really flawed. Really.

First, it was partially funded by Big Honey (sounds like a New Orleans madame), and we know the Honey Board of Israel has their hooks into every aspect of honey-related therapies and has corrupted medicine in pursuit of good outcomes in clinical trials.  I am sure they are suppressing the negative studies and side effects, information they do not want you to know.

They enrolled children 1-5 years old with uncomplicated upper respiratory infection. Children with asthma, pneumonia, sinusitis, or allergic rhinitis were excluded. There were pre- and post intervention questionnaires with 5 items that evaluated the child’s cough and degree of sleep difficulty the night before and the night of the intervention.

Three types of honey were used: eucalyptus honey, labiatae honey, and citrus honey. The placebo was Silan, a syrup made from dates, because it was brown and sweet like honey. The children received 10 g (10 ml) of the honey or placebo 30 minutes before going to sleep. The next day the parents were called and completed the post intervention questionnaire. Parents were asked the following:

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So parents were asked about cough before enrollment, given the therapy, then quizzed the next day. Like veterinary medicine the researchers relied on second hand information as to efficacy and there is ample opportunity for bias. I would say, and this is without data, people tend to play up the symptoms at the beginning and play down their symptoms after the intervention.

But the data was impressive, despite the fact it seems like a minor intervention. Cough was better in all four groups and the honey outperformed the placebo:

 

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There were  big flaws in the study. First, of course, is they relied on the parents’ impression of efficacy. Not a reliable technique. There has been some interesting work with cough recognition software that, for example, can determine if the cough is likely due to pertussis. It would have been nice to have an objective measure of the cough severity before and after.  Just a recorder in the child’s room would have been sufficient.  It is also possible that they were seeing the natural history of cough, but I doubt it was a significant component of the response. Coughs do not get better that fast on their own.

And think about the parents. Your kid is ill. Is it serious? You are hyper-alert to your kids every cough and wheeze and are up all night. When my kids had fevers I would check them every 10 minutes for purpura, Meningococcal infection was always my worst infectious fear.  Being up all night with the kid you are tired. The next day you find out the child has a trivial, self limited disease, nothing to worry about. Reassured,  the next night you are not going to pay as much attention to the child’s cough and you need, and get, a better night’s sleep as a result.  You will be paying less attention.  It would have been so much better to get a baseline after the assessment, preferably with cough recognition software as back up, then the next night do the intervention.

But the big question they did not ask, and should have, is what did you think your child received? Could the parents tell if the kids were getting honey or Silan date extract? I expect they could.

The article says “The parents, the physicians, and the study coordinator did not know the content of the preparation that was dispensed.”

I like to cook and honey is a royal pain. It is thick and sticks to the measuring cup and spoon. I always end up some honey on my finger from trying to scrape it off the cup or the spoon or the spatula and that finger goes in the mouth. The honey was

packed in small plastic containers of 10 g each and marked with the letters A, B, C, or D. The study preparations were distributed to the pediatric community clinics in blocks of 4. Parents were instructed to administer 10 g of their child’s treatment product within 30 minutes of the child going to sleep. The parents were instructed that the preparation could be given undiluted or together with a noncaffeinated beverage.

You are going to squirt something in your ill fussy kids mouth, and being honey it almost certainly would have to be milked out of the container and in the process get it on the fingers. What parent would not smell it, taste it or otherwise check it out? No one. There is no way almost every parent, unless blind and anosmiac, would not know if their child received honey.  The question is whether they would know if they had the date extract.

It wasn’t an o-ring in ice water moment, but I went hunting and found 2 different date extracts. It wasn’t easy. Only one store in Portland sold the product and I had to get the other from Amazon. The date syrup I could find is darker than honey, looks more like molasses, is not as viscous as honey and tastes good but nothing like honey.  It tasted like sweet dates. No way did the products I found resemble honey. Too much datey goodness. To say the date syrup was a reasonable placebo for honey because it was sweet and brown is like saying my bicycle could be a mistaken for my car because it has wheels and is red.

As I read the paper, there is no way for the parents to have not known what their kids were receiving, honey or date extract, especially as the study was done in Israel where use of date syrup is common. There is the caveat that I do not know for sure if the products I sampled were equivalent to the ones in the study, but I strongly suspect it would be simple enough to know if you child received honey or date.

As they note in the final paragraph

The dropout rate was higher for children receiving citrus and eucalyptus honey. The exact reason for the higher dropout rate in these groups is not known. Because these types of honey are more aromatic, it is possible that some children disliked the honey taste.

For placebo to be a valid control it has to be indistinguishable from the active therapy, and, after tasting some date syrup, I call horsefeathers. The parents were almost certainly aware of whether their children were getting honey or date extract and that would render the conclusions of the paper fatally flawed.  The key characteristic in most studies of implausible or impossible therapies that demonstrate benefit is there is no placebo.  People know what they are getting and respond accordingly.  Bias central.  As in this study. Calling something a placebo does not make it so.  Placebo.  You keep using that word, I do not think it means what you think it means.

So did the paper demonstrate honey is better than placebo? I suspect not. I suspect the parents knew very well what their children were taking and bias flooded in. Someone, and I can’t find the quote, suggested I thought the placebo effect was the patient lying to themselves and/or to their doctors. Not quite. People will convince themselves that they are better when they are not and report the imagined improvement to their doctors. Humans are most expert at convincing themselves that what is not real is real. I always think the archetype is the Penn and Teller show with the the gutter downspout bent and painted to look like a giant magnet and the person telling the man in the white coat her arthritis was better (13:30 in). The same effect is probably occurring in this study.

Does the study demonstrate that honey is better than date extract? Yes.  But in a study to compare honey and placebo where the patients almost certainly know what they are getting.  Like acupuncture, it is effective only when the patient knows they are getting needles.

Does it demonstrate when you do not have an adequate placebo and make it simple for someone to break the blinding that it renders a study nearly worthless? Yes.

Does it suggest that neither the editors and reviewers of Pediatrics nor those reporting the study took the time to think about the validity of the study?  Yes. It is the new peer review. Peer: to appear partially or dimly.

Posted in: Clinical Trials, Herbs & Supplements, Science and Medicine

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