ADE
AMP (%) (5; 1,226)a
MPH (%) (16; 2,092)a
ATX (%) (21; 3,127)a
GUA (%) (6; 1,150)a
CLO (%) (1; 154)a
Irritability
7–82
1–80
2–12
6–7
8
Crying
76
2–71
1
–
–
Sleeping problems
70
9–64
–
–
–
Decreased appetite
28–59
3–56
3–50
7
–
Daydreams
62
30–62
–
–
–
Anxiety
68
5–61
–
–
–
Emotional disturbances
59
1–56
3–55b
–
4
Social withdrawal
64
27–59
–
–
–
Fingernail biting
40
22–45
–
–
–
Stomachache
40
4–32
5
–
–
Anorexia
17–25
3–15
9–35
–
–
Headache
12–30
2–33
4–28
17–27
–
Insomnia
17–28
2–44
3–19
4
4
Tics
26
1–28
31
–
–
Somnolence
5
1–2
4–36
27–51
35
Mood alteration
–
1–34
44
–
–
Dizziness
5–32
1–30
2–13
5–16
–
Gastrointestinal pain
11–19
4–19
5–47
6–14
–
Nightmares
28
16–21
–
–
6
Unusually happy
26
28
–
–
–
Fatigue
2
1–4
3–33
9–22
14
Dry mouth
5
12–24
–
6
3
Blood pressure changes
–
3–18
18
6
–
Nervousness
6
4–10
6–16
–
–
Changes in heart rate
–
12
11–19
–
–
Abnormal behavior
–
1–5
2–19
–
–
Depression
–
5
3–10
–
–
When compared to placebo (Table 12.2), the short-term effects of lisdexamfetamine and immediate-release methylphenidate are decreased appetite (number needed to harm, NNH = 3 and 4, respectively) and insomnia (NNH = 8 and 7) (Coghill et al. 2014; Schachter et al. 2001), while atomoxetine was associated with significantly decreased appetite (NNH = 9), increased somnolence (NNH = 19) and abdominal pain (NNH = 23) (Cheng et al. 2007).
Table 12.2
Number needed to harm (NNH) estimated from RCTs
ADE | AMP | MPH | ATX | GUA | CLO |
|---|---|---|---|---|---|
Discontinuation | 26 (15–84) | – | 50 (33–100) | 15 (12–21) | 5 (4–10) |
≥1 AE | 6 (4–10) | – | 7 (5–13) | 7 (5–10) | 4 (2–50) |
Decreased appetite | 3 (3–4) | 3 (2–5) | 9 (7–12) | – | – |
Insomnia | 8 (6–10) | 6 (4–12) | n.s. | – | – |
Gastrointestinal pain | – | 11 (6–83) | 10 (8–14) | 22 (14–48) | – |
Somnolence | – | – | 19 (12–44) | 5 (3.5–4.9) | 4 (3–5) |
Fatigue | – | – | 62 (38–182) | 15 (11–21) | 8 (5–15) |
Headache | – | 17 (10–71) | – | 17 (10–52) | – |
Irritability | 19 (13–35) | – | – | 33 (19–112) | – |
Dizziness | 39 (22–186) | 20 (12–45) | 53(33–131) | – | – |
Vomiting | – | – | 30 (16–171) | – | – |
An increased odds ratio was found mainly for somnolence (NNH = 5), fatigue (NNH = 15), and sedation (NNH = 16) in guanfacine-treated patients (Ruggiero et al. 2014) and for somnolence (NNH = 4) and fatigue (NNH = 8) in patients treated with clonidine (Hirota et al. 2014).
12.2.2 Findings from Spontaneous Reporting
ADHD medications were among the drugs most commonly associated with spontaneously reported ADRs in pediatric populations (Blake et al. 2014; Hawcutt et al. 2012; Lee et al. 2014).
Methylphenidate was the most commonly suggested cause of spontaneously reported ADRs in the UK (covering 6 % of drug-related ADRs) (Hawcutt et al. 2012), and in the USA (5 %) (Lee et al. 2014) and the second most commonly suggested cause of ADRs in Europe (2 % of all the pediatric ADRs) (Blake et al. 2014).
Atomoxetine was the drug for which the second largest number of spontaneously reported ADRs was registered in the UK (Hawcutt et al. 2012).
ADHD medications accounted for 14 % of ADRs collected in the World Health Organization global individual case safety report database (VigiBase) during the 2005–2010 period occurring in children aged 2–11 years. ADRs concerned mainly decreased appetite, psychomotor hyperactivity, upper abdominal pain, aggression, somnolence and suicidal ideation (Star et al. 2011).
12.2.3 Regulatory Authorities’ Warnings
Drug regulatory authorities raised several concerns about cardiovascular and psychiatric adverse drug reactions associated with ADHD medications in the last decade (Clavenna and Bonati 2009).
In the USA, the Food and Drug Administration (FDA) issued a black box warning for amphetamines (risk of serious cardiovascular events and risk of drug dependence), methylphenidate (risk of drug dependence), and atomoxetine (risk of suicidal ideation). Other related warnings not leading to a black box warning concerned psychiatric adverse events, effects on growth, heart rate and blood pressure (Table 12.3).
Table 12.3
Adverse drug events for ADHD medications that were highlighted in warnings issued by the Food and Drug Administration
MPH | AMP | ATX | GUA | CLO |
|---|---|---|---|---|
Drug dependencea | Drug dependencea | Suicidal ideationa | Hypotension, bradycardia and syncope | Hypotension, bradycardia and syncope |
Serious cardiovascular events | Serious cardiovascular eventsa | Serious cardiovascular events | Sedation and somnolence | Sedation and somnolence |
↑ Blood pressure and heart rate | ↑ Blood pressure and heart rate | ↑ Blood pressure and heart rate | Cardiac conduction abnormalities | Cardiac conduction abnormalities |
Psychiatric adverse events (psychosis, aggression, bipolar disorder) | Psychiatric adverse events (psychosis, aggression, bipolar disorder) | Psychiatric adverse events (psychosis, aggression, bipolar disorder) | ||
Long-term suppression of growth | Long-term suppression of growth | Long-term suppression of growth | ||
Priapism | Priapism | Priapism | ||
Seizures | Seizures | Severe liver injury | ||
Peripheral vasculopathy | Peripheral vasculopathy | Allergic events | ||
Visual disturbance | Visual disturbance | Urinary retention | ||
Potential for gastrointestinal obstruction | Potential for gastrointestinal obstruction |
The most recent warning issued by the FDA concerned the risk of priapism in males treated with methylphenidate (Food and Drug Administration 2013). According to the FDA statement, this risk is also associated with atomoxetine and amphetamine use.
12.2.4 Adverse Events of Particular Concern
As stated above, despite the fact that most of AEs observed in clinical trials were mild and temporary, physicians should be aware of some uncommon severe events (e.g. cardiac AEs, psychiatric AEs, suicidal ideation) and on the potential impact of drug treatment on child growth and development.
Guidelines on this were published in 2011 by the European Network for Hyperkinetic Disorders regarding the management of clinically relevant adverse effects of ADHD medication (Graham et al. 2011).
The following paragraphs address the most relevant AEs that clinicians should be aware of and monitor when deciding on drug therapy for ADHD.
12.2.4.1 Sleep Disturbances
Sleep disturbances may be associated both with ADHD medication and with ADHD itself. Higher rates of sleep problems were reported by parents in a systematic review, but few of these were confirmed by objective sleep data (Cohen-Zion and Ancoli-Israel 2004; Cortese et al. 2009).
Studies on the relationship between psychostimulants and ‘sleep disturbance’ assessed with objective methods (e.g. polysomnography, actigraphy) reported inconsistent findings (Stein et al. 2012). The heterogeneity in results may be explained by several factors, including differences in the length of the trial, the dose of the drug and duration of exposure. It should be taken into account, however, that a meta-analysis of eight studies (393 patients) recording homogeneous actigraphic outcomes found that children taking methylphenidate had a decreased mean activity, a decreased total sleep time and a longer sleep latency compared with children taking placebo (De Crescenzo et al. 2014). A history of any sleep problems should therefore be taken before starting ADHD medication, and if this is a significant concern, then atomoxetine could be considered as the first choice. Sleep hygiene should be encouraged and a switch of medication should be considered when sleep problems persist after dose adjustment and dose scheduling of the original medication (Graham et al. 2011).
12.2.4.2 Growth
Treating ADHD children with stimulants generally results in a reduction in height and weight gain. A systematic analysis of psycho-stimulant effects in 18 studies found height and weight deficits. The height reduction was approximately 1 cm/year during the first 1–3 years of treatment, while the decrease of weight is estimated to be around 3 kg over a 3-year period (Faraone et al. 2008).
However, the number of children who fall below the fifth growth percentile did not increase. The initial effect of stimulants on growth appears to slow down over time, and final adult height does not seem to be affected (Biederman et al. 2010).
A longitudinal study monitoring 243 ADHD cases and 394 controls did not find an association between ADHD or treatment with stimulants and differences in magnitude of peak height velocity (PHV) during adolescence (Harstad et al. 2014). The mean age of PHV was slightly later in boys treated with stimulants (13.6 years in those treated with stimulants for at least 3 years versus 12.9 years in ADHD cases never receiving stimulants), but no correlation was found between treatment duration and change in height for age Z scores, and the adult height was not different in ADHD patients treated with stimulants compared with ADHD stimulant naive and controls (Harstad et al. 2014). A slower body mass index (BMI) growth in childhood was observed in children with ADHD and children undergoing stimulant treatment compared with untreated ADHD and non-ADHD (Schwartz et al. 2014). However, during adolescence, the rate of BMI increase was more rapid in the first group, with BMIs eventually exceeding those of controls (Schwartz et al. 2014). With regard to atomoxetine, a meta-analysis of seven double blind placebo-controlled and six open-label studies found that height and weight at 24 months of treatment were 2.5 cm and 2.7 kg lower than the expected values (Kratochvil et al. 2006). Patient weight, height and body mass index should be monitored every 6 months, and a growth chart should be used (Graham et al. 2011; National Collaborating Centre for Mental Health 2008).
12.2.4.3 Tics
Psychostimulants increase dopamine levels and can therefore theoretically aggravate tic severity.
A meta-analysis including nine double-blind placebo-controlled trials evaluating the efficacy of medications in treatment of ADHD in patients with comorbid tic concluded that there is no evidence that methylphenidate worsens tic severity in the short-term, that supra-therapeutic doses of dextroamphetamine worsen tics and that atomoxetine improves tics (Bloch et al. 2009).
However, psychostimulants may exacerbate tics in individual cases. Since tics are common in childhood and tend to wax and wane spontaneously, an observation period of at least 3 months is needed before making a clinical decision. If tics are troublesome, clinicians should consider a dose reduction or drug substitution. If these measures are ineffective, an antipsychotic could be added to control tics (Graham et al. 2011).
12.2.4.4 Cardiac Adverse Events
In June 2009, the Food and Drug Administration issued a safety communication to warn health professionals about a possible association between stimulant medications and an increased risk of sudden deaths in healthy children. The alert was issued after the completion of a study funded by the FDA and the National Institute of Mental Health (NIMH) that compared the use of stimulant medications in 564 healthy children with a registration of sudden death and in 564 children who died as passengers in a motor vehicle accident. Stimulant use was reported by ten out of 564 children with sudden death versus two out of ten children in the control group (Gould et al. 2009). Due to the limitation of the study, the FDA was unable to evaluate the presence of a causal association. However, subsequent studies did not find an increased risk of cardiovascular events. In a cohort of 1,200,438 children and young adults aged 2–24 years, a total of 81 subjects had a serious cardiovascular event (3.1 per 100,000 person-years) including 33 sudden cardiac deaths (1.3 per 100,000 person-years). As compared with the nonusers, the adjusted rate of serious cardiovascular events did not differ significantly among current users of ADHD drugs (hazard ratio, HR 0.75; 95 % CI 0.31–1.85) or among former users (HR 1.03; 95 % CI 0.57–1.89) (Cooper et al. 2011). In a cohort of 241,417 incident ADHD medication users, no statistically significant difference in the rate of validated sudden death or ventricular arrhythmia was found compared to nonusers (HR 1.60; 95 % CI 0.19–13.60) or all-cause death (HR 0.76; 95 % CI 0.52–1.12) (Schelleman et al. 2011). Similar findings, i.e. no increased risk of cardiovascular events, were also found in a study performed in the adult population (25–64 years) (Habel et al. 2011).
All stimulant medications and atomoxetine are reported to increase blood pressure. An average increase of 1–5 mmHg of blood pressure and an increase of ≤10 heart beats per minute have been observed with stimulants (Hammerness et al. 2015). An average increase of 1–4 mmHg of systolic pressure and 1–2 mmHg in diastolic pressure was observed.
An increase in blood pressure was observed with atomoxetine, with a standardised mean difference (SMD) of 0.27 mmHg (95 % CI 0.19–0.35) in diastolic blood pressure and 0.15 mmHg (95 % CI 0.06–0.23) in systolic blood pressure (Schwartz and Correll 2014). Elevation of blood pressure above the 95th percentile occurred in 6.8 % of patients (systolic) and 2.8 % (diastolic) treated with atomoxetine in comparison with 3 and 0.5 % patients treated with placebo (Hammerness et al. 2011; Wernicke et al. 2003). Immediate-release clonidine was associated with a significant SMD drop of 0.52 mmHg (95 % CI −0.15 to −0.89) in systolic blood pressure and an SMD of – 0.49 mmHg (95 % CI −0.02 to −0.097) in diastolic blood pressure.
Change in QTc interval showed no significant differences between alpha-2 agonists and placebo (SMD = 0.12, 95 % CI – 0.18–0.43). In a subgroup analyses, however, extended-release guanfacine significantly prolonged the QTc interval by a mean of 5.3 ms (95 % CI 2.7–7.9) compared to placebo (SMD = 0.33, 95 % CI 0.12–0.43) (Hirota et al. 2014). Pretreatment monitoring of pulse and blood pressure is recommended with any ADHD medication. Blood pressure should be measured prior to treatment and at each visit and converted to a percentile score using the appropriate chart. If BP is elevated and above the 95th percentile after at least three measurements, patients should be referred to a pediatric cardiologist. Moreover, before starting any ADHD drug treatment, family history of cardiac diseases and history of exercise syncope, undue breathlessness and any other cardiovascular symptoms should be assessed (Graham et al. 2011; National Collaborating Centre for Mental Health 2008). Routine electrocardiographic screening of ADHD patients prior to initiation of medication is not recommended (Graham et al. 2011; National Collaborating Centre for Mental Health 2008).
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