To Tamiflu or Not To Tamiflu...

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During flu season we have many requests for Tamiflu (oseltamivir) because of flu exposure or disease. I have rarely complied with these requests, though in recent years more often due to the powers that set the guidelines recommending it more. It is more common in my experience to hear negative feedback about side effects than it is to see patients get better faster. (Note: this is a very biased view, since those who are better would not call, but since so many call with side effects it seems fair to say I don't like the drug.)

I am not alone in my dislike of Tamiflu. I follow a listserv of pediatricians around the country and many share my views. A recent topic thread on treatment of flu has peaked my interest. One doctor suggested watching a TED Talk by Dr. Ben Goldacre: What doctor's don't know about the drugs they prescribe.  Dr. Goldacre starts talking about Tamiflu specifically about 10:10, but the entire lecture is done in an entertaining and informative manner if you have the time.

I feel deceived. When I practice medicine, I follow standard recommendations and guidelines that are based on peer reviewed articles and data. The question is, what important data is left out? There is a movement to solve this problem of unpublished studies. You can see updates at the Tamiflu Campaign of the British Medical Journal.

Back to influenza treatment...

First, current influenza treatment guidelines regarding the use of antivirals: 

The current guidelines basically say every child should be considered a candidate for an antiviral treatment. I understand the reasoning behind the first two conditions of antiviral use (except that studies don't really support even those indications), but I am very confused about the third highlighted below.

(from http://aapnews.aappublications.org/content/early/2013/09/02/aapnews.20130902-1)

ANTIVIRALS CONTINUE TO BE IMPORTANT IN THE CONTROL OF INFLUENZA.

Treatment should be offered for:

• any child hospitalized with presumed influenza or with severe, complicated or progressive illness attributable to influenza, regardless of influenza immunization status; and
• influenza infection of any severity in children at high risk of complications of influenza.

Treatment should be considered for:

• any otherwise healthy child with influenza infection for whom a decrease in duration of clinical symptoms is felt to be warranted by his or her pediatrician; the greatest impact on outcome will occur if treatment can be initiated within 48 hours of illness onset.

Then look at what a search for "unpublished tamiflu trials" shows.

For those of you unfamiliar with the Cochrane group, I need to take a quick sideline. They are a well respected group that reviews all the studies within certain parameters on one topic to evaluate the overall findings of several independent studies. 

From the Cochrane Group: A review of unpublished regulatory information from trials of neuraminidase inhibitors (Tamiflu - oseltamivir and Relenza - zanamivir) for influenza. These results are from a review of published and unpublished studies that they could find. From the abstract: "The authors have been unable to obtain the full set of clinical study reports or obtain verification of data from the manufacturer of oseltamivir (Roche) despite five requests between June 2010 and February 2011. No substantial comments were made by Roche on the protocol of our Cochrane Review which has been publicly available since December 2010. 

They found several problems with Tamiflu from the studies they were able to review:

• Drug manufacturers sponsored the trials, leading to publication and reporting biases. One of the authors reported that 60% of the data was never published. This is over half of the research, and I suspect it didn't support use of the medicine (remember the company that benefits from selling the medicine was doing the trials...)
• There was no decrease in hospitalization rate for influenza in people treated with Tamiflu.
• There was not enough evidence of prevention of complications from influenza. Design of the trials (again by the people who make the drug) did not report the prevention of complications from influenza, such as secondary infections.
• There is not evidence in the trials to support that Tamiflu reduces spread of the virus. One of the main reasons people request the medication is after exposure to prevent illness! (Note: this might have changed because the indications on the package insert now say it can be used to prevent illness in those over 1 year of age and they were previously not allowed to mention prophylaxis.) 
• Tamiflu reduced symptoms by 21 hours. Yep. Less than one day of fewer symptoms. For the cost of the drug and the potential side effects, is feeling sick for 1 day less really worth it? 
• There was a decreased rate of being diagnosed with influenza in those randomized to get Tamiflu, probably due to an altered antibody response. The authors suspect a body becomes less able to make its own antibodies against influenza when taking Tamiflu. 
• Side effects were not well documented.

A review study done in children exclusively Neuraminidase inhibitors for treatment and prophylaxis of influenza in children: systematic review and meta-analysis of randomised controlled trials focused on treatment of disease and prevention of illness after exposure. Findings included:

• Symptom duration decreased between 0.5 and 1.5 days, but only significantly reduced symptoms in 2 of 4 trials. That means in 2 of 4 trials there was no significant reduction in symptoms.
• Prophylaxis after exposure decreased incidence by 8% of symptomatic influenza. This means for every 13 people given Tamiflu to prevent disease, one case will be prevented. Not great odds.
• Treatment was not associated with an overall decrease in antibiotic use, suggesting it did not alter the complication of bacterial secondary infections.
• Tamiflu was associated with in increased risk of vomiting. About 1 in 20 children treated with Tamiflu had an increased risk of vomiting over the baseline vomiting due to influenza.
• There was little effect on the number of asthma exacerbations or ear infections by treating influenza with Tamiflu.

So what do I recommend during the cold and flu season?

1. Get vaccinated! The influenza vaccines have been shown to help prevent influenza and are very well tolerated with few side effects. If you or your children are due for other vaccines, be sure to get caught up.
2. If you get sick, stay home until you're fever free without the use of a fever reducer for at least 24 hours! Don't spread the illness to others by going to work or school. The influenza virus is spread for several days, starting the day before your symptoms start until 5-7 days after symptoms start-- kids may be contagious for even longer. You are most contagious the days you have a fever.
3. Wash hands well and frequently. If you can't use soap and water, use hand sanitizer.
4. Cover your cough and sneeze with your elbow or a tissue.
5. Avoid close contact with people who are sick. But remember that people spread the virus before they feel the first symptoms, so anyone is a potential culprit!
6. Don't share food, drinks, or towels (such as after brushing teeth to wipe your mouth) with others. 
7. Don't touch your eyes, nose, and mouth -- these are the portals for germs to get into your body. 
8. Keep infants away from large crowds during the sick season.
9. Frequently clean objects that get a lot of touches, such as keyboards, phones, doorknobs, refrigerator handle, etc.
10. Avoid smoke. It irritates the airway and makes it easier to get sick.
11. Remember that many germs make us sick during the flu season. Just because you've been sick once doesn't mean you won't catch the next bug that comes around. Use precautions all year long!

Because the guidelines recommend Tamiflu as above, I will probably be forced to prescribe it by worried parents who hope that their kids will feel better. (You've heard of defensive medicine, right?) 

Influenza is a miserable illness. The key is prevention. I've had my vaccine, how about you? 

Further Reading:

Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children: A link is available to the full text of the study by T Jefferson, MA Jones, P Doshi, CB Del Mar, CJ Heneghan, R Hama, and MJ Thompson.

Update 2016:

The CDC continues to recommend Tamiflu (oseltamivir) and other anti-viral medications. I continue to wonder why.

There continues to be a lot of confusion about unpublished studies. Investigators have documented their discussions with the maker of Tamiflu on Tamiflu correspondence with Roche.

Recent studies have tried to compile all that is known about how oseltamivir works:

• Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. 

Results from this study include:

• In the treatment of adults, oseltamivir reduced the time to first alleviation of symptoms by 16.7 hours, 29 hours in children.
• There was no difference in rates of admission to hospital between treatment groups in both adults and children.
• Oseltamivir relieves symptoms in otherwise healthy children but has no effect on children with asthma who have influenza-like illness.
• Oseltamivir had no significant effect on admissions to the hospital.
• Oseltamivir causes gastrointestinal disturbances in both prophylaxis and treatment roles. In prophylaxis, it caused headaches, renal events (especially decreased creatinine clearance), and psychiatric effects. 

Update 2016/2017 Season:

The CDC recommendations for the use of antiviral medications remain essentially unchanged.

I have heard early reports that this year's flu vaccine is about 60% effective, but it is too early in the season to be sure. For up to date information on this season's flu, check out the CDC website.

Cough Medicine: Which one's best?

This is the time of year I get a lot of requests for an over the counter cough suppressant suggestion or a prescription cough medicine for kids so they can sleep. Despite my attempts at educating the family about why I don't recommend any cough medicines, many parents are upset leaving without a medicine. I have collected numerous articles that show why I treat cough the way I do. Links are included throughout this blog. Click away to learn more!

First, a little background...

Most cough medicines were studied in adults and the dosing for kids was calculated from the adult dosage. Kids are not small adults. Their bodies handle illness and metabolize drugs differently. But few studies have been done to show if medicines work at all, and if they do, what the best dose is for kids of various ages and sizes.

In 2008 the FDA stated that toddlers and babies should not use cold and cough medicines. Drug makers voluntarily changed the labeling of over the counter (OTC) cough and cold products, recommending them only for children aged 4 and older. The American Academy of Pediatrics says there is no reason that parents should use them in children under age 6 because of the risks without benefit. Despite this, studies show that 60% of parents of children under 2 years have given a cough and cold medicine. Why? In my opinion, they are desperate to help their child and don't think it is enough risk to not at least try.

I know it is frustrating when your child is up all night coughing. It is frustrating when my kids and I are up all night coughing. But you know what we do in my house?

• Humidify the air of the bedroom (unless it's a spring or summer cough)
• Extra water to drink all day
• Honey before bedtime in an herbal tea (No honey before 1 year of age!)
• Encourage cough during the day to help clear the airways
• Nasal rinse with saline (I love this, but my family is not so keen on it)
• Sleep with water next to the bed to sip on all night long (even when I still had bedwetters)
• Back rubs, hugs, kisses, reminders that it will get better, etc
• Nap during the day as needed to catch up on lost sleep
• Watch for signs of wheezing or distress

That's about it for the cough. If something hurts, we use a pain reliever like ibuprofen or acetaminophen. We use those only if something hurts, not just because and not for fever without discomfort.

Why don't I give my family cough medicines?

Because they don't work.

The OTC options:

A Cochrane Review in 2007 was done to look at over the counter cough medicine effectiveness in both children and adults. These reviews look at many studies and analyze the data. Unfortunately there are very few studies, and many were of poor quality because they relied on patient report. In studies that included children, they found:

• Antitussives were no more effective than placebo for kids. (one study) In adults codeine was no more effective than placebo. Two studies showed a benefit to dextromethorphan, but another study did not, so mixed results.
• Expectorants had NO studies done in children. In adults guaifenesin compared to placebo did not show a statistically different response. 
• Mucolytics more effective than placebo from day 4-10 in kids. (one study) In adults cough frequency was decreased on days 4 and 8 of the cough. (Note: I am not sure what OTC mucolytic was studied. I am only aware of pulmozyme and mucomyst, both used by prescription in children with cystic fibrosis.)
• Antihistamine-decongestant combinations offered no benefit over placebo. (2 studies) One of two studies showed benefit in adults. The other did not.
• Antihistamine shows no benefit over placebo. (one study) In adults antihistamines did not help either.

Another Cochrane Review in 2012 once again failed to show any real benefits of cough medicines, especially given the risks of side effects.

What about some specific studies on OTC medicines? I cannot report them all here, but here's a few:

A study comparing dextromethorphan (the DM in many cough medicines), diphenhydramine (AKA benadryl), and placebo in 2004 showed no difference in effectiveness of controlling cough for sleep. That means the placebo worked just as well as the medicines. Insomnia was more common in those who got dextromethorphan.

Does guaifenesin help? It is thought to thin mucus to help clear the airways. It does not stop the cough. Studies vary in effectiveness and are typically done in adults, but it may be helpful in children over 4 years of age. Do not use combination cough medicines though, for all the reasons above.

In 2007 honey was shown to be a more effective treatment than dextromethorphan or no treatment. Another study in 2012 showed benefit with 2 tsp of honey 30 minutes before bedtime. A side effect of honey? Cavities... Be sure to brush teeth after the honey!

What side effects and other problems are there from over the counter cough medicines?

As stated above, the dosages for children were extrapolated from studies in adults. Children metabolize differently, so the appropriate dosage is not known for children. Taking too much cold medicine can produce dangerous side effects, including shallow breathing and death.

Many cough medicines have more than one active ingredient. This can increase the risk of overdosing. It also contributes to excess medicines given for problems that are not present. For instance if there is a pain reliever plus cough suppressant, your child gets both medicines even if he only has pain or a cough. Always choose medicines with one active ingredient.

Accidentally giving a child a too much medicine can be easy to do. Parents might use two different brands of medicine at the same time, not realizing they contain the same ingredients. Or they can measure incorrectly with a spoon or due to a darkened room. Or one parent forgets to say when the medicine was given and the other parent gives another dose too soon. 

And then there's non-accidental overdose. There is significant abuse potential: One in 20 teens has used over the counter cough medicines to get high. Another great reason to keep them out of the house!

Side effects of cough medicines include:

• Nausea and vomiting
• Stomach pain
• Confusion
• Dizziness
• Double or blurred vision
• Slurred speech
• Shallow breathing
• Impaired physical coordination
• Rapid heart beat
• Drowsiness
• Numbness of fingers and toes
• Disorientation
• Death, especially in children under 2 years of age and those with too high of a dose

What about prescription cough suppressants? 

In 1993 a study comparing dextromethorphan or codeine to placebo showed that neither was better than the placebo. Codeine belongs to a class of medications called opiate analgesics and to a class of medications called antitussives. When codeine is used to reduce coughing, it works by decreasing the activity in the part of the brain that causes coughing. It can make breathing too shallow in children. Codeine has several serious side effects which could be life threatening in children. Combination products with codeine and promethazine (AKA phenergan with codeine) should never be used in children under 16 years. In my opinion, why use it in older children and adults, since it hasn't been shown to work?

How about antibiotics for the cough?

Antibiotics may be used to treat bacterial causes of cough (such as some pneumonia or sinusitis illnesses) but antibiotics have no effect on viruses, which cause most coughs. If your child has a cold, antibiotics won't help.