Safety of Medicines Used for ADHD in Children
Safety of Medicines Used for ADHD in Children
This is the first review of prospective studies evaluating long-term safety of ADHD medications.
In this regard, few studies were found, monitoring a total of 3000 children, nearly half of whom were taking atomoxetine.
Only for atomoxetine were data regarding treatments lasting longer than 3 years available. On the contrary, for transdermal methylphenidate, the follow-up lasted less than 1 year.
Wide heterogeneity was found regarding the way information concerning AEs was reported, making the comparison between studies not possible.
The rate of discontinuation due to AEs was the only measure reported in all the studies, but with different treatment duration, and three studies did not report the overall incidence of treatment-related AEs.
Different criteria were used in reporting the most common AEs. First of all, the threshold varied between 1% and 10%, which means that only AEs classified as 'common' (frequency >1/100) were described in the papers, or 'very common' (frequency >1/10) in the case of atomoxetine.
Moreover, it is possible that differences exist in the way AE are classified. For example, decrease or loss of appetite was the most common AE with stimulant treatment.
Anorexia occurred very frequently with extended release, but was reported with a lower frequency in the RCTs investigating transdermal methylphenidate, not reported in the subsequent open-label extension period, and, surprisingly, never reported with osmotic-controlled released oral formulation of methylphenidate, despite the fact that, in the 12-month open-label extension, all the treatment-related AEs with an incidence >1% were reported.
When monitoring the long-term safety of extended release amphetamine McGough et al used the term anorexia to group loss of appetite and decreased appetite. On the contrary, in short-term RCTs regarding transdermal methylphenidate McGough et al and Findling et al discriminated between anorexia and decreased appetite.
In studies concerning osmotic-controlled released oral formulation of methylphenidate the following terms were used: loss of appetite, appetite suppression and decreased appetite. Paradoxically, in the paper reporting on a 24-month follow-up period the term used was decreased appetite, while in the previous analysis of the first 12 month the same AE was reported as appetite loss.
The reporting of AEs in clinical trials seems therefore unsatisfactory, as highlighted by other researchers, and more should be done to improve the evaluation of drug safety.
Despite some limitations, the results of this study confirm findings from previous reviews.
Drugs for ADHD seem to be safe and well tolerated. Decreased appetite, insomnia, headache and abdominal pain are the most common AEs observed in the long-term prospective trials (figure 1). Tics were reported in all long-term studies regarding methylphenidate, while emotional lability was reported only with mixed amphetamine salts.
Many AEs are mild or moderate in severity, and the incidence of serious AEs was low. Despite these reassuring results, it should be underlined that lack of tolerability caused the discontinuation of treatment in a proportion of children ranging from one-tenth to one-fourth.
Most of the AEs and discontinuation cases occurred in the first few months of drug treatment.
Given the small sample and the threshold chosen to report the results, few data are available concerning events that occur with a frequency less than 1%. Many psychiatric AEs may be missed or underestimated, in particular the more severe ones (eg, suicide attempts).
Retrieved studies provided scant information concerning the effect of treatments on growth and on the cardiovascular system. However, several ad hoc studies and reviews are available regarding these topics.
Although the medications for ADHD are generally well tolerated, with only mild or minor adverse effects in most cases, their rational use can be guaranteed by implementing and monitoring evidence-based practices, that is, by monitoring the safety and efficacy of treatments in the short and long terms with adequate and appropriate tools and approaches.
Taking into account the wide heterogeneity between studies in the follow-up duration, and the AE reporting criteria, any consideration on which treatment has the least AEs is currently questionable.
Discussion
This is the first review of prospective studies evaluating long-term safety of ADHD medications.
In this regard, few studies were found, monitoring a total of 3000 children, nearly half of whom were taking atomoxetine.
Only for atomoxetine were data regarding treatments lasting longer than 3 years available. On the contrary, for transdermal methylphenidate, the follow-up lasted less than 1 year.
Wide heterogeneity was found regarding the way information concerning AEs was reported, making the comparison between studies not possible.
The rate of discontinuation due to AEs was the only measure reported in all the studies, but with different treatment duration, and three studies did not report the overall incidence of treatment-related AEs.
Different criteria were used in reporting the most common AEs. First of all, the threshold varied between 1% and 10%, which means that only AEs classified as 'common' (frequency >1/100) were described in the papers, or 'very common' (frequency >1/10) in the case of atomoxetine.
Moreover, it is possible that differences exist in the way AE are classified. For example, decrease or loss of appetite was the most common AE with stimulant treatment.
Anorexia occurred very frequently with extended release, but was reported with a lower frequency in the RCTs investigating transdermal methylphenidate, not reported in the subsequent open-label extension period, and, surprisingly, never reported with osmotic-controlled released oral formulation of methylphenidate, despite the fact that, in the 12-month open-label extension, all the treatment-related AEs with an incidence >1% were reported.
When monitoring the long-term safety of extended release amphetamine McGough et al used the term anorexia to group loss of appetite and decreased appetite. On the contrary, in short-term RCTs regarding transdermal methylphenidate McGough et al and Findling et al discriminated between anorexia and decreased appetite.
In studies concerning osmotic-controlled released oral formulation of methylphenidate the following terms were used: loss of appetite, appetite suppression and decreased appetite. Paradoxically, in the paper reporting on a 24-month follow-up period the term used was decreased appetite, while in the previous analysis of the first 12 month the same AE was reported as appetite loss.
The reporting of AEs in clinical trials seems therefore unsatisfactory, as highlighted by other researchers, and more should be done to improve the evaluation of drug safety.
Despite some limitations, the results of this study confirm findings from previous reviews.
Drugs for ADHD seem to be safe and well tolerated. Decreased appetite, insomnia, headache and abdominal pain are the most common AEs observed in the long-term prospective trials (figure 1). Tics were reported in all long-term studies regarding methylphenidate, while emotional lability was reported only with mixed amphetamine salts.
Many AEs are mild or moderate in severity, and the incidence of serious AEs was low. Despite these reassuring results, it should be underlined that lack of tolerability caused the discontinuation of treatment in a proportion of children ranging from one-tenth to one-fourth.
Most of the AEs and discontinuation cases occurred in the first few months of drug treatment.
Given the small sample and the threshold chosen to report the results, few data are available concerning events that occur with a frequency less than 1%. Many psychiatric AEs may be missed or underestimated, in particular the more severe ones (eg, suicide attempts).
Retrieved studies provided scant information concerning the effect of treatments on growth and on the cardiovascular system. However, several ad hoc studies and reviews are available regarding these topics.
Although the medications for ADHD are generally well tolerated, with only mild or minor adverse effects in most cases, their rational use can be guaranteed by implementing and monitoring evidence-based practices, that is, by monitoring the safety and efficacy of treatments in the short and long terms with adequate and appropriate tools and approaches.
Taking into account the wide heterogeneity between studies in the follow-up duration, and the AE reporting criteria, any consideration on which treatment has the least AEs is currently questionable.