Wednesday, March 9, 2016

Stimulant Medications for treating ADHD: A comparison

ADHD medication is a big business in the world today.  Annual sales of ADHD medication are projected to be 15-20 billion dollars by 2020, increasing at a rate of about 8% per year.   To put this in perspective, this is similar to the value of the worldwide market for fresh vegetables
 ( ).

 It is an amount of money that would pay for the salaries of
 400 000 teachers, each of whom paid $50 000 per year. 

 A relevant article to look at about this is by Alan Schwartz, published in the New York Times in 2013:

I am not meaning this post to be a discussion of the controversies of ADHD diagnosis.  Instead, this post will focus mainly about ADHD medication.   I think the rising rate of ADHD diagnosis, and the rising rate of stimulant prescription,  is a very concerning trend, particularly if these diagnoses and treatments are offered without attending adequately to other biopsychosocial factors, and particularly if these treatments are being offered under the influence of un-recognized biases due to the financial power and influence of the manufacturers.

On the other hand, the rising awareness and acceptance of ADHD can allow those children, adults, and families who are dealing with ADHD-related issues to feel less stigmatized, judged, and unfairly treated.  In families, knowledge and acceptance of ADHD can help child-rearing practices to be adapted, so as to avoid a harshly punitive stance towards those children with attention problems.  

The newer ADHD medications are, not surprisingly, very popular, frequently prescribed, are often touted as being better than the older medications, and are listed first on medication advice guideline sheets (such as the CADDRA recommendations).

Here is a comparison of costs per day between the different ADHD drugs, looking at a typical full therapeutic dose for an adult.  These cost estimates come from a site called "Pharmacy Compass" which searches for the best local prices for medications at pharmacies.   

1. Newer drugs (CADDRA considers these to be the only "first line" medications):

Adderall XR 30 mg:$3.91 per day
Biphentin 80 mg:$4.36 per day
Concerta 72 mg:$5.92 per day
Vyvanse 60 mg:  $5.14 per day
Strattera 100 mg: $5.51 per day

2. Older drugs (CADDRA considers these "second line"):

Dexedrine spansules 40 mg: $3.59 per day

Ritalin (methylphenidate) 60 mg: $0.81 per day
 Ritalin SR 60 mg $0.66 per day

So we see that the least expensive option is methylphenidate or methylphenidate SR.  Dexedrine is over 5 times as expensive.  Concerta and Vyvanse are about 8 times as expensive, per day.

I mention these expense differences not necessarily in an effort to favour the cheaper medication, but rather to heighten your anticipation that there could be bias in any research results regarding these medications--especially if the research is sponsored by the manufacturers-- due to the huge profit motives involved.

It would be fair to look for studies which carefully and prospectively treat ADHD patients with Ritalin vs. one of the newer medications, in randomized comparisons.

1) Vyvanse vs. Ritalin.  Almost no studies in the literature!  In one study, all they looked at was whether patients stuck to a dosing regimen, in which case the Vyvanse group did "better." ( ) But this measure had nothing to do with the patients actually feeling better or improving more!

A better study compared Vyvanse with Oros-MPH, a long-acting version of Ritalin (though not plain old Ritalin itself!)

In this study, at first glance it certainly appears that Vyvanse is better!  But looking carefully, one finds statements such as this: "At endpoint, the difference between lisdexamfetamine and OROS-MPH in the percentage of patients with an ADHD-RS-IV total score less than or equal to the mean for their age was not statistically significant." (p.747)   This statement was tucked into the results section but left out of the conclusion.  Looking at side-effects, we find a lower total rate of adverse effects in the Ritalin group.  Reduced appetite, insomnia, and nausea were more common in the Vyvanse group.  Notably, there is a long list of conflicts of interest at the end of this paper, including some of the authors being employees of the Vyvanse manufacturer, and owning stocks in the company!

In conclusion here, there is no doubt that Vyvanse is an effective medication for ADHD.  The dosing regime is very convenient, which may be particularly effective and helpful for many.  But it is not necessarily superior to much cheaper alternatives.  For some people (including many patients I have seen), regular methylphenidate (Ritalin) allows better fine control of symptoms during the course of the day, without being "stuck" with a continuous sustained-release effect.  For others, they certainly do prefer the Vyvanse.  I just think that Vyvanse should not be assumed to be better, as the evidence is very weak that it is, while it is 8 times more expensive than Ritalin!

2) Concerta vs. Ritalin
This is a good early study, directly comparing the two medications, published in Pediatrics in 2001.  Here is the authors' concise summary: "On virtually all measures in all settings, both drug conditions were significantly different from placebo, and the 2 drugs were not different from each other."   The reason to choose Concerta over Ritalin would be convenience.  The authors do point out that "compliance" is more likely on a long-acting formulation.  But remember that "compliance" is a very, very indirect, and possibly irrelevant, measure of health and well-being!!  Why is it important that there be better "compliance?"   Should the only criteria not be well-being?   Certainly this is not a reason to classify Concerta as "better" or "first line".  Concerta is 9 times more expensive than Ritalin!

3) Adderall vs Ritalin
In this study, published in Pediatrics in 1999, Adderall comes out as looking better than Ritalin.  But, once again, the study was sponsored by the manufacturer.  On a close look, a couple of problems:  first, the doses of the medications were fixed.  The ritalin doses appear too low, so as not to match the equivalent doses of Adderall given.  At this point, one would usually give Ritalin doses at least twice that of Adderall (i.e. 100% higher) but in this study the Ritalin dose was only 40% higher than the Adderall dose.  In accordance with this under-dosing, the Adderall group not surprisingly had more side effects such as insomnia.

In conclusion, there is no doubt that Adderall XR is a good medication for ADHD.  Many of my patients have preferred it over other alternatives.  But it is not fair, once again, to assume that it is better.  It does not deserve to be considered "first line" while a similarly-effective alternative that is one-sixth the cost is considered "second line."

4) Meta-analytic comparison:
Faraone and Glatt (2010) have published a good meta-analytic review paper, which is worth reading in detail, with particular attention to the data tables and graphs:
In the conclusion of this paper, the authors state that they "found no significant differences between short- and long-acting stimulant medications."

Addendum:  a recent Cochrane review, published in February 2016 by Punja et al., concludes that there is a lot of evidence that amphetamines reduce core symptoms of ADHD, but cause a variety of problematic side-effects.  They note that there was evidence of a lot of bias in the studies they looked at, with the quality of evidence being low to very low.

Here is a direct quote from their conclusion:   "This review found no evidence that supports any one amphetamine derivative over another, and does not reveal any differences between long-acting and short-acting amphetamine preparations."