(This post was written by John Snyder, MD and is reprinted from the blog sciencebasedmedicine.org)
Every drug store has row upon row of medicines designed to treat or prevent an acute upper respiratory tract infection, otherwise known as the common cold. Despite this, very few are able to live up to their promise. In most cases, particularly where children are concerned, the side effects of these medicines can be worse than the symptoms they are intended to treat. Because I am a pediatrician, and because the evidence for cough and cold medicines (I will refer to them here as CCMs) for children is particularly absent and because adverse events due to CCMs are most frequently seen in children, I will focus mainly on this population.
The common cold – a (brief) overview
The term “cold” refers to a complex of signs and symptoms sharing similar characteristics but which may be caused by a variety of different viruses. Usually referred to by clinicians as viral upper respiratory tract infections (URIs), the very familiar features of the common cold include runny nose, nasal congestion, sneezing, cough, and sometimes sore throat and watery eyes. Colds may also be associated with systemic signs and symptoms, such as fever, chills, malaise, and body aches, though these are more typically seen in influenza, or “flu-like syndromes” caused by other viruses. At least 50% of colds are caused by rhinoviruses, of which there are approximately 100 serotypes. Other viruses that can cause colds include adenoviruses, enteroviruses, the respiratory syncytial virus (RSV), coronavirus, influenza and parainfluenza viruses, and human metapneumovirus (hMPV). Rhinoviruses survive best at the cooler temperatures found in the nose as opposed to the warm depths of the body, which is why the primary signs and symptoms of infection occur there. Other viruses can cause disease more systemically, and therefore are capable of producing more severe illness. The typical cold worsens for the first 3-4 days, plateaus for 1-2 days, and then improves over another 3-4 days. Most colds have resolved or significantly improved by day 7-10 of the illness.
An illness begging for a cure
Despite the relatively brief, self-limited, and generally benign nature of colds, they can be extremely uncomfortable nuisances, resulting in a staggering number of missed days from work and school. It is not surprising that many people are willing to try and pay for almost anything to relieve the annoying symptoms of the common cold, resulting in an estimated expenditure of close to $3 billion for over-the-counter CCMs in the US annually. Almost everyone has a favorite over-the-counter (OTC) or home remedy for the common cold. My mother always started me on 1,000mg daily of vitamin C at the onset of any cold symptoms (usually in the form of acerola with rose hips). Unfortunately, notwithstanding all of the marketing, hype and near universal belief in at least some form of cold remedy, there is little to no evidence supporting the efficacy of most CCMs.
The lack of efficacy of CCMs is not surprising when one considers the pathophysiology of common cold symptoms. Those familiar and annoying signs and symptoms are primarily a result of our body’s own inflammatory response to the viral destruction of infected cells in our upper airway. By the time this inflammation has begun, the progression of the illness and the resulting symptoms is inevitable. Our immune system (with the exception of those with congenital or acquired immunodeficiencies) is usually quite capable of rapidly countering the upper airway invasion by these viruses with this robust (though uncomfortable) inflammatory response. Most of the anecdotally reported benefits of CCMs are likely attributable to the self-limited nature of colds – a result our body’s own ability to clear the virus and repair the damage.
Not only is scientific evidence for the efficacy of CCMs lacking, their use in children is responsible for significant morbidity and even mortality. Every year in the US, over 7,000 children under the age of 12 are brought to emergency rooms as a result of an adverse event from a CCM. This is largely a result of incorrect dosing or frequency of administration. One study demonstrated that only 30% of parents were able to both accurately measure and correctly dose OTC CCMs for their child. Also contributing to the occurrence of adverse events is the fact that many children’s CCMs are “multi-symptom” products, containing several different drugs. When parents give more than one medication to their child simultaneously, they may be inadvertently overdosing at least one of these components. For example, many “multi-symptom” CCMs contain acetaminophen as a fever reducer. Unaware of this, parents often simultaneously give their children acetaminophen as a separate medication, resulting in potentially dangerous overdosing.
Common treatments for a common illness
By far, the most common diagnosis I make each day in my practice as a pediatrician is “viral URI”, otherwise known as the common cold. And every day, many times per day, I am asked by parents what they can give their suffering child to make them better faster. And every day, many times per day, my advice is far from modern or high-tech. That is because I am trying, as best as I can, to limit my advice to that which can be supported by the best science-based evidence. Too often, that leaves parents dissatisfied and sometimes even frustrated or angry. Some parents are thankful, however, for my honesty and for staying true to my oath to “first do no harm”. But the number of children who are prescribed or who are given OTC CCMs in the US is truly staggering. Every week approximately 10% of children (that’s over 82 million according to the 2012 US census) take these medicines without evidence of efficacy, and at significant risk.
In October of 2007, concerned about the lack of evidence supporting the efficacy of CCMs in children, and out of a growing concern about the safety of these products, the FDA’s Nonprescription Drugs Committee and Pediatric Advisory Committee unanimously recommended against the use of CCMs in children under 2 years of age. In response, US manufacturers voluntarily withdrew those products marketed for infants under age 2. In 2008, manufacturers revised their labeling to warn against use by children under age 4. Though a majority of the original FDA Advisory Committee members voted against the use of CCMs in children under age 6 years, the FDA has not yet officially ruled on that recommendation. The American Academy of Pediatrics, however, has officially recommended against their use in children under 6 years of age.
Even though the majority of randomized controlled trials show no difference in endpoints when CCMs are compared to placebo, and despite the potential for serious adverse events, these products remain ubiquitous on pharmacy shelves, and parents and many pediatric practitioners still turn to them for treating colds in children. Though the labeling changes noted above have resulted in a significant decline in reported adverse events from CCMs in children under 4, their use remains high.
The A-to-Z of OTC CCMs
In my practice, I find that parents frequently give acetaminophen or ibuprofen to their children with colds as if it were some sort of cure-all elixir. Although they may help with fever or muscle aches, they do not affect the upper respiratory signs and symptoms of a cold. Acetaminophen may actually suppress virus-neutralizing antibodies, potentially prolonging viral shedding and cold symptoms.
Antibiotics and antivirals
Being caused by viruses, it should be of no surprise that antibiotics do nothing for treatment of the common cold. There are upper respiratory tract infections for which antibiotics may be indicated, for example some ear and sinus infections, which are potential complications of colds. However, what we all know as the common cold is not treatable with antibiotics. Unfortunately, treatment of colds with antibiotics is not uncommon, and has contributed (along with the addition of antibiotics to livestock feed) to the very dangerous reality of antibiotic resistance. But that is a topic for another post.
There are major obstacles to the development of an effective antiviral agent for colds. These include the enormous number of viruses and virus serotypes that are known to cause colds, and the ease with which these viruses mutate and thus potentially evade any drug with which they may interact. For similar reasons, the development of a vaccine against the common cold remains elusive. One antiviral agent, pleconaril, has shown some promise in preliminary studies (mostly in adults), but was rejected by the FDA in 2002 due to its poor side effect profile.
Some studies have demonstrated a modest decrease in sneezing and runny nose with the use of antihistamines in adults. While these drugs are helpful for the treatment of allergies, the signs and symptoms of which can resemble a cold, they have not been found to be effective when used to treat colds in children. Many OTC products marketed for use in children as “multi-symptom” cough and cold medicines contain first-generation antihistamines, which can have significant anticholinergic side effects. These can include gastrointestinal upset, dry mouth, increased heart rate, and even cardiac arrhythmias, central nervous system depression (or excitation), hallucinations, and respiratory depression.
Antitussives (cough medicines)
When I was training, I was taught never to treat a cough because coughing is a protective mechanism which clears the airway of mucus and pathogens. At that time, however, we weren’t aware that it probably didn’t matter, since no cough medicines have been shown to actually work better than placebo. But because they do contain drugs, however, they can have potentially serious side effects.
Dextromethorphan (think Robitussin-DM) is one of the most common “cough suppressants” on the market. It is a narcotic derivative which, when dosed correctly, has a low potential for side effects. At higher doses, however, it can have serious effects on the central nervous system, including hallucinations and dissociative states. Because of this, dextromethorphan has become a drug of abuse. Unfortunately, it doesn’t actually work. In a 2004 study, neither dextromethorphan nor the antihistamine diphenhydramine was found to outperform placebo at improving nighttime cough or sleep difficulty in children with colds. Other studies have shown that increasing the dose of dextromethorphan does not improve its efficacy, and can result in an increased risk of side effects. There is some evidence that dextromethorphan may even be responsible for some infant deaths.
Codeine has been used for a long time to treat cough in children despite no evidence that it is actually superior to placebo for this purpose. Codeine is an opioid compound that is converted in the liver to morphine, its active metabolite. Central nervous system effects of codeine are well described, as are serious, sometimes deadly events in infants and children. Individuals who are genetically predisposed to rapidly metabolize codeine into morphine are at particularly high risk of serious adverse events from the use of codeine-containing products. The American Academy of Pediatrics recently reaffirmed its prior policy statement that there are no well-controlled scientific studies to support the efficacy and safety of codeine for the treatment of cough in children, and that the use of codeine-containing products should therefore be avoided.
Aromatic vapor therapies
Vapor therapies containing some combination of menthol, camphor, and eucalyptus oil (such as Vicks VapoRub) are commonly used to treat cold symptoms in infants and children (though they are not recommended for use in children under the age of 2 years). These products are typically placed on the chest, neck, or under the nostrils (I have also encountered parents who swear by placing it on the soles of their infant’s feet). One study looking at inhalation of menthol vapor in school-age children showed no improvement over control in terms of cough or nasal airway flow or volume, though interestingly there was an improvement in the perception of nasal patency. Another study of colds in school-age children compared Vicks VapoRub, petrolatum, and no treatment. Parents gave Vicks the highest score in improving their child’s night time cough, congestion, and sleep difficulty. For obvious reasons this was not a blinded study, and the survey results should be interpreted in that light. After treating an 18 month old child with severe respiratory distress believed to be triggered by the application of Vicks VapoRub under her nostrils, a group from Wake Forest University School of Medicine studied the effect of this product on an experimental animal airway model. They found that Vicks increased mucin secretion and tracheal mucociliary transport velocity, and decreased ciliary beat frequency. Based on their findings, the authors hypothesized that Vicks may actually lead to mucus obstruction of small airways and increased nasal resistance to air flow.
There are so many so-called complementary and alternative therapies that are claimed to prevent and treat colds that I cannot possibly do justice to a discussion of them all here. I do discuss Echinacea below because this is the most commonly used and most studied CAM modality for treating colds. I will not even discuss homeopathy as there is no scientific plausibility for its efficacy.
These drugs (pseudoephedrine and phenylephrine) act on the sympathetic nervous system to cause constriction of capillaries, thereby decreasing swelling of the nasal and sinus mucosa. In adults, pseudoephedrine has been shown to decrease mucus production and runny nose. Similar evidence has not been demonstrated for phenylephrine, even though this drug has been steadily replacing pseudoephedrine in many products. This is because products containing pseudoephedrine can now only be sold at the pharmacy counter in an effort to prevent their use in the production of methamphetamine. There are no studies demonstrating the efficacy of decongestants in children, and dosing has been extrapolated from adult trials. One study by Hutten et al. and another by Clemens et al. found no difference between an oral antihistamine-decongestant combination containing phenylephrine and placebo. There are no studies on the use of pseudoephedrine in children. Unfortunately, the action of these drugs on the nervous system can produce serious side effects, including elevation of blood pressure, sleeplessness, headache, nausea, vomiting, and even cardiac arrhythmias and seizures. One drug once commonly used in OTC cough and cold medications, phenylpropanolamine, was taken off the market in 2000 because it could cause potentially fatal intracranial hemorrhages.
Echinacea is frequently touted as an effective, natural cold remedy. There are many published studies on the use of Echinacea for both treating and preventing colds. Most of these studies have significant methodological flaws. They also utilize different parts of the plant and at different doses, have produced conflicting results, and are difficult to interpret as a whole. The highest quality study to date, however, demonstrated no benefit over placebo in treating or preventing symptoms of the common cold in young adults.
Guaifenesin is the most common drug marketed as an expectorant. These agents purportedly work by drawing water into mucus, thinning it out and thus aiding clearance from the airway. It is found in products such as Mucinex, Robitussin DAC, Benalyin, and DayQuil mucus control. In one study, adults with colds reported subjective improvement in the thickness and quantity of sputum, but no decrease in cough. There are no studies demonstrating the efficacy of guaifenesin in children.
Perhaps the most promising treatment for cold related cough in children is turning out to be the golden sweet elixir, honey. In a well-designed, randomized, partially double-blind study, children receiving buckwheat honey showed significant improvement in cough symptom score compared to those receiving dextromethorphan or placebo. Another study demonstrates that honey given at bedtime was more effective than placebo in reducing the frequency and severity of nighttime cough. This was true whether the honey administered was eucalyptus, labiatae, or citrus honey. A criticism of other studies looking at the efficacy of honey has been the lack of a similarly sweet and viscous control group. In this study, the placebo compound was made from dates, and had similar sweetness, appearance, and texture.
>> Note: it is important to remember that honey should never be given to infants under 12 months of age due to the risk of botulism.
Probiotics have been in the news quite a bit lately for a variety of applications, including for the prevention of colds in children. A study of young children at a day care center in China found that those who received daily Lactobacillus acidophilus NCFM for 6 months had lower fever and less runny nose and cough during colds, as well as shorter colds and a reduced chance of being prescribed an antibiotic compared to those receiving placebo. Study children also missed fewer school days during colds. A recent Cochrane meta-analysis of randomized controlled trials exploring the use of probiotics in children found that they may significantly reduce the likelihood of developing a cold or requiring an antibiotic. One criticism of this analysis was the heterogeneity amongst the studies reviewed for the primary outcome of number of colds in children. It was also unclear which probiotic might be conferring the protection from colds. It was suggested that the heterogeneity of the study outcome findings might be due to the fact that the immune-modulating effects of probiotics are likely to be species- and strain-specific. The current consensus is that more data for specific probiotic species and strains is required before generalized recommendations can be made.
Saline nasal sprays and washes
Perhaps the most commonly used treatment for colds in infants is the application of saline drops and sprays to the nasal passages, often followed by bulb suction. Though this is not likely to result in anything more than transient improvement in nasal obstruction, one study looked at symptomatic relief during a cold as well as prevention of colds in children receiving instillation of nasal saline wash. Their result showed significant improvement in sore throat, cough, nasal obstruction, and secretions when given as treatment for a cold, as well as fewer illness days, school absences, and complications in children receiving the saline as a preventative.
While zinc has the ability to inhibit rhinovirus replication in the test tube, clinical trials for the treatment of colds have been disappointing. While there was a very modest improvement in symptom score in one study of adults, the benefit was seen only when zinc was taken in large doses 5-6 times per day. At these doses, GI side effects were significant and patients complained of a bad taste in their mouth. Needless to say, 5-6 times per day dosing with these side effects would preclude this as a viable option in children. Additionally, a well-designed, randomized, double-masked, placebo-controlled study demonstrated no effectiveness of zinc on cold symptoms in children and adolescents.
Prevention is the best medicine
The common cold is caused by a large number of different viruses and virus serotypes, and these viruses mutate rapidly in the human host. This makes finding effective treatments and vaccines elusive. Since finding a cure for the common cold is unlikely, the best approach is to prevent infection. Spread of inflection occurs primarily via aerosol droplet (from sneezing and coughing) or by touching a contaminated object or person and then auto-inoculating oneself (by then touching the nose or eyes for example). There is scant evidence to support any dietary or medicinal prophylaxis for the common cold. If one existed, it would need to be taken chronically to be effective, and the risk-benefit ratio would have to be very low. The best way to prevent the common cold is to limit transmission. That means frequent hand washing, staying away from others as much as possible when sick, and avoidance of those with colds. The now-ubiquitous use of alcohol-based hand sanitizers does not prevent secondary transmission of colds due to rhinovirus (the most common cause of colds in children), and “antibacterial” soaps (usually containing triclosan or triclocarban) have no evidence of efficacy for preventing colds, and are now under close scrutiny by the FDA.
Modern medicine is sometimes quite limited in its capabilities. We need to be honest and humble when faced with these limitations. This, ultimately, is what distinguishes science-based medicine from pseudoscience and belief.