Methylphenidate Dose Titration in ADHD Should Be Based on Outcomes
By Will Boggs MD
NEW YORK—Dose titration of methylphenidate in patients with attention-deficit/hyperactivity disorder (ADHD) should aim to maximize the ratio of benefit to adverse effects, as there appears to be no scientific rationale for published maximum doses, according to a meta-analysis.
"I was surprised that there is so little evidence to support the currently accepted dose range," Dr. Alison S. Poulton of Nepean Hospital, in Penrith, Australia, told Reuters Health by email. "Although there is good safety information that suggests a lack of life-threatening adverse effects at the doses that are being used, we do not know that higher doses would be associated with significantly greater risk."
Various guidelines recommend titrating the dose of methylphenidate for maximal benefit with minimal adverse effects, and they usually specify approved dose ranges in the interests of safety.
There is little consistency, however, in the maximum recommended doses. European guidelines recommend a maximum of 0.7 mg methylphenidate/kg/d for immediate-release formulations and a maximum of 54 mg/d for osmotic-release oral system (OROS) methylphenidate.
The American Academy of Pediatrics defers to the U.S. Food and Drug Administration approval guidelines, which currently recommend a maximum dose of 60 mg/d for immediate-release and extended-release methylphenidate and maximum doses of 54 mg/d in children aged 6-12 years and 72 mg/d in adolescents 13-17 years for OROS methylphenidate.
Australian Therapeutic Guidelines recommend 1 mg/kg/d or 60 mg/d in children aged 4 years or older and dose titration of extended-release or OROS methylphenidate of 0.5-2.0 mg/kg/d in children older than 6 years.
Dr. Poulton's team investigated the doses used in published clinical trials, the clinical justification given by researchers for their selected dose range, and the adverse effects associated with methylphenidate when the dose is established by titration in their systematic review of 49 articles, including 11 randomized clinical trials (RCTs) and 38 cohort studies.
In the RCTs, maximum doses of methylphenidate ranged from 20 to 72 mg/d and 1.4 to 1.5 mg/kg/d. In the cohort studies, maximum doses of methylphenidate ranged from 20 to 60 mg/d and 0.8 to 1.8 mg/kg/d, and maximum doses of OROS methylphenidate varied between 54 mg/d, 72 mg/d and 90 mg/d.
While some studies detailed the method of titration, including maximum dose, only two of the RCTs and eight of the cohort studies reported the justification for the chosen dose range, leaving it unclear whether the doses were selected arbitrarily or were based on evidence, the researchers report in JAMA Pediatrics, online May 28.
In the RCTs, participants treated with methylphenidate were 55% more likely to experience adverse events, compared with those given placebo, and methylphenidate treatment was associated with approximately five-fold higher risks of anorexia and insomnia, with no heterogeneity among studies.
In cohort studies, the overall adverse event rate was 66%, with 33% of participants experiencing anorexia, 15% experiencing insomnia and 14% experiencing headache, with significant heterogeneity among studies.
"Physicians need guidelines that are relevant even for the more difficult patients, who may need higher doses," Dr. Poulton said. "These might be people with more severe ADHD or those who break down the drug more quickly."
"At the moment, prescribing guidelines do not acknowledge that in some patients there could be a conflict between using the most effective dose for treating ADHD and sticking within an authorized dose range," she said. "The worry is that patients may either be under-treated by being given a dose that is too low to be effective, or the doctor may add in other drugs, increasing the risk of drug interactions. This dilemma should be recognized and acknowledged, particularly when guidelines are being updated."
"It is important that doctors test a range of doses to establish the dose that is most effective for treating a patient's ADHD, balancing the beneficial effects against the side effects," Dr. Poulton said. "Although the effects on the appetite and blood pressure increase on higher doses, doctors may like to keep in mind that there is little evidence that higher doses will increase the rate of irreversible or life-threatening adverse effects."
Dr. Mark A. Stein from University of Washington in Seattle, who co-authored an editorial related to this report, told Reuters Health he is "surprised by the lack of detail in published articles on the stimulant titration process. This information would be helpful to prescribing physicians. As a result, it is not surprising that there is wide variation in medication titration in the community, despite the importance of individually titrating due to the wide variability in response and changes over time."
"The vast majority of children respond positively to stimulants within recommended dose ranges, but finding the optimal dose through dose titration processes for each individual patient should be emphasized," he said by email. "Besides clinical characteristics, (it's) important to consider the context that pharmacotherapy is provided within the overall treatment plan. Medication alone and higher doses are a poor substitute for adequate psychosocial treatments, such as behavioral parent training and appropriate educational interventions."
"In the absence of clear empirical evidence, clinicians are currently left with a consensus approach that suggests that, for treating individuals, we need to start low, go slow, and keep going as tolerated, reevaluating approximately every week," write Dr. Stein and colleagues in the editorial.
"We are concerned that this best practice may not be routine in clinical settings, in which lack of resources means that patients are given an appointment up to 3 months after the initial script. Too often, both clinicians and patients may settle for better without an understanding of what best looks like," they add.
"Clinical trials can do a better job of describing their titration process and outlining the rationale for dosing limits in their manuscripts," the editorialists conclude. "As we move toward personalized or precision approaches to ADHD treatment, identifying the factors associated with the variability in dose response effects is a crucial next step."
SOURCE: https://bit.ly/2I22l9y and https://bit.ly/2YZ4cTp
JAMA Pediatr 2019.
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