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Rash
Infection
Nervousness
(10%
population)
Emotional
lability
Pain in limb
High dose: NNTH 20
(NNTH 8 to ∞ to
NNTB 50)
Quality: Moderate
K 1, N 297
High dose: NNTH 16
(8 to ∞)
Quality: Moderate
K 1, N 297
NNTH 12
(NNTH 4 to ∞ to
NNTB 25)
Quality: Moderate
K 1, N 127
10% population:
NNTH 9
(4 to 50)
Quality: Moderate
K 1, N 127
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
Medium dose:
NNTH 50 (20
to ∞)
Quality:
Moderate
K 1,
N 284
–
–
–
–
–
–
–
–
NNTH 25
(11 to ∞)
Quality:
Moderate
K 1, N 229
–
Continued
269
270
In school-age children In adults
Mixed comorbidity Specific comorbidity Mixed Mixed Mixed comorbidity
(tic disorder) comorbidity comorbidity
Atomoxetine versus Atomoxetine Atomoxetine Methylphenidate Atomoxetine Atomoxetine
placebo versus placebo (low dose) versus versus versus placebo (once daily) versus
atomoxetine atomoxetine atomoxetine
(high dose) (twice daily)
Table 27: (Continued)
Sinusitis
Insomnia
Irritability
–
–
–
–
–
–
–
–
–
Medium dose:
NNTH 33 (16
to ∞)
Quality:
Moderate
K 1,
N 284
High dose:
NNTH 14
(9 to 33)
Quality: High
K 2,
N 564
Medium dose:
NNTH 50
(20 to ∞)
Quality:
Moderate
K 1,
N 284
–
–
–
–
–
–
Dry mouth
Constipation
Libido
decreased
Difficulty
getting/
maintaining an
erection
Sweating
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
High dose:
NNTH 7
(5 to 11)
Quality:
Moderate
K 1, N 280
High dose:
NNTH 14
(9 to 33)
Quality:
Moderate
K 1, N 280
High dose:
NNTH 20
(11 to 50)
Quality: High
K 1, N 280
High dose:
NNTH 16
(11 to 50)
Quality: High
K 1, N 280
High dose:
NNTH 25
(14 to 50)
Quality: High
K 1, N 280
–
–
–
–
–
–
–
–
–
–
Continued
271
272
In school-age children In adults
Mixed comorbidity Specific comorbidity Mixed Mixed Mixed comorbidity
(tic disorder) comorbidity comorbidity
Atomoxetine versus Atomoxetine Atomoxetine Methylphenidate Atomoxetine Atomoxetine
placebo versus placebo (low dose) versus versus versus placebo (once daily) versus
atomoxetine atomoxetine atomoxetine
(high dose) (twice daily)
Table 27: (Continued)
Leaving study
early due to
adverse events
Low dose: NNTH 50
(NNTH 12 to ∞ to
NNTB 33)
Quality: Moderate
K 1, N 297
Medium dose:
NNTH 50
(NNTH 20 to ∞ to
NNTB 100)
Quality: High
K 2, N 468
High dose: NNTH 33
(20 to 100)
Quality: High
K 5, N 1189
NNTH 100
(NNTH 16 to ∞ to
NNTB 33)
Quality: Moderate
K 1, N 148
NNTB 33
(0 to 16)
Quality: High
K 2, N 442
High dose:
NNTH 33
(25 to 100)
Quality: High
K 2,
N 536
NNTH 12
(NNTH 5 to ∞ to
NNTB 100)
Quality: Moderate
K 1, N 218
NNTB 100
(NNTB 20 to ∞
to NNTH 25)
Quality:
Moderate
K 1, N 229
Leaving study
early due to
any reason
Low dose: NNTH 12
(NNTH 4 to ∞ to
NNTB 16)
Quality: High
K 1, N 297
Medium dose:
NNTH 50
(NNTH 10 to ∞ to
NNTB 20)
Quality: High
K 2, N 468
High dose: NNTB 25
(NNTB 12 to ∞ to
NNTH 100)
Quality: High
K 8, N 1485
NNTH 100
(NNTH 16 to ∞
to NNTB 33)
Quality:
Moderate
K 1,
N 148
– High dose:
NNTB 100
(NNTB 20
to ∞ to
NNTH 50)
Quality: High
K 2,
N 536
NNTH 25
(NNTH 6 to ∞ to
NNTB 12)
Quality:
Moderate
K 1, N 218
NNTH 14
(NNTH 5 to ∞ to
NNTB 20)
Quality:
Moderate
K 1, N 229
273
The safety review found seven cases of sudden death (three children and four
adults) of which one had lymphocytic myocarditis and two had toxic levels of olan-
zapine or a possible seizure preceding death; none of these patients had prior history
of cardiovascular problems or cardiovascular structural abnormalities. The review
reported that none of the cases appears solely or directly attributable to atomoxetine
at therapeutic doses. The cases were highly confounded. None of the patients had
structural cardiovascular abnormalities. However, the extent of the role of atomoxe-
tine in these deaths is difficult to establish. Further studies were being conducted by
the FDA (2008b) at the time this guideline was being prepared (January, 2008).
10.8.5 Clinical evidence summary: atomoxetine
For individual outcomes, the quality of the evidence was generally moderate to high.
Atomoxetine in school-age children
There is evidence that atomoxetine has a small to medium effect in reducing ADHD
core symptoms in children with ADHD, as rated by both parents and teachers. In one
outcome measure (ADHD core symptoms as rated by teachers) the effect was large
when children were given a high dose of atomoxetine. Regarding conduct problems,
there was a small effect in the reduction of these as reported by parents and no effect
when reported by teachers, although this data was only from one study (MICHEL-
SON2004). There is some evidence of global clinical improvement (RR 1.46) in chil-
dren taking a high dose of atomoxetine when compared with placebo groups.
The evidence suggests there is a slight improvement in reducing children’s
conduct problems when the dose of atomoxetine is reduced.
There is evidence that atomoxetine in children with ADHD causes the following
side effects: nausea, cough, decreased appetite, dyspepsia, vomiting, asthenia, dizzi-
ness, pruritus, somnolence, fatigue, rash, infection, nervousness and emotional labil-
ity. There is also an increased risk of decreased appetite, dyspepsia and vomiting
when dosage is augmented. The evidence suggests there is an increase of risk of
discontinuation of atomoxetine when compared with placebo but this risk is not pres-
ent when children are given high doses of atomoxetine. The safety reviews report
sudden deaths in children taking atomoxetine, but given the lack of background rates,
no conclusions can be drawn from this data.
Atomoxetine versus methylphenidate
One study (WANG2007) indicated that there is little to no difference in efficacy
between methylphenidate and atomoxetine in reducing ADHD core symptoms or
general clinical improvement. Another study (NEWCORN2008) showed that osmot-
ically released methylphenidate was more effective than atomoxetine in children’s
clinical improvement. In terms of leaving the study early due to adverse events, the
evidence from the two studies suggests that there is an increased risk in adverse
events in children taking atomoxetine when compared with methylphenidate.
Pharmacological treatment
274
The effect sizes of the studies comparing methylphenidate with placebo ranged
from SMD 1.40 (1.80 to 1.01) to 0.29 (0.88 to 0.33). The effect sizes for
atomoxetine when compared with placebo were lower, ranging from SMD 0.44
(0.62 to 0.26) to 0.37 (0.54 to 0.19).
Conclusion (school-age children)
Atomoxetine is effective in reducing ADHD core symptoms and clinical improve-
ment in children with ADHD. There is no effect of atomoxetine on children’s conduct
problems as rated by teachers. There is evidence suggesting that atomoxetine may
increase side effects when compared with placebo and when compared with
methylphenidate.
Special circumstances – ADHD comorbid with tic disorder
Only one study (ALLEN2005) compared the effect of atomoxetine with placebo in a
population of children with ADHD comorbid with tic disorder. The results indicate
that there is a medium effect (SMD 0.56) in the reduction of ADHD core symptoms
as rated by parents.
The ALLEN2005 study also suggests that there is increased nausea, decreased
appetite and risk of discontinuation in children taking atomoxetine.
Atomoxetine in adults
There is evidence of the effectiveness of atomoxetine in reducing ADHD core symp-
toms in adults with ADHD (mixed comorbidities) when compared with placebo.
There is evidence that atomoxetine increases the risk of side effects in adults with
comorbid and non-comorbid ADHD when compared with placebo. Atomoxetine is
more likely than placebo to increase the risk of discontinuation. The safety reviews
report cases of sudden death in adults taking atomoxetine. Once again, because of the
lack of background rates the evidence is inconclusive.
Conclusion (adults)
Atomoxetine is effective in reducing ADHD core symptoms in adults with ADHD.
The association between sudden death and the use of atomoxetine in adults is diffi-
cult to establish.
10.9 CLONIDINE
10.9.1 Pharmacology and prescribing
Clonidine is an alpha
2
noradrenergic agonist which is thought to work in ADHD by
affecting noradrenaline transmission in the frontal cortex. Clonidine is licensed
for the treatment of hypertension, migraine (from age 12) and menopausal flushing.
Unlicensed uses of clonidine include the treatment of tics, Tourette’s syndrome
and ADHD.
Pharmacological treatment
275
10.9.2 Safety and adverse effects
Common adverse effects of clonidine include sedation and reduction in heart rate.
10.9.3 Clinical evidence for clonidine
Two trials were found that included a comparison of clonidine with placebo. One trial
(HAZELL2003) was done with a sample of school-age children with ADHD
(common coexisting conditions included oppositional defiant disorder and/or conduct
disorder). The second study (KURLAN2002) involved adults with ADHD and
comorbid Tourette’s syndrome, chronic motor tic disorder or chronic vocal tic disor-
der. This same study (KURLAN2002) also included a comparison of clonidine with
methylphenidate.
For clonidine, statistically significant adverse events and/or with an RR greater
than 5% are displayed in Appendix 19. For a full list of adverse events refer to
Appendix 18 (forest plot).
Study information and evidence from the important outcomes and overall quality
of evidence are presented in Table 28. The full evidence profiles and associated forest
plots can be found in Appendix 19 and Appendix 18, respectively.
10.9.4 Clinical evidence summary: clonidine
For individual outcomes, the quality of the evidence was moderate reflecting the
paucity of the data.
Clonidine in school-age children
There is evidence that clonidine reduces children’s ADHD core symptoms and
conduct problems as well as producing general clinical improvement. When
outcomes were measured by teachers the effect sizes were medium; when measured
by parents, they were small to no effect.
Clonidine is more likely than placebo to decrease the risk of discontinuation.
Special circumstances – ADHD comorbid with Tourette’s syndrome, chronic motor tic
or chronic vocal tic disorder
In children with ADHD and comorbid Tourette’s syndrome, chronic motor tic or
chronic vocal tic disorder, clonidine produced a large effect in reducing ADHD core
symptoms and conduct problems. These results are based on only one study
(KURLAN2002).
As in the mixed comorbid ADHD population, clonidine is more likely than
placebo to decrease the risk of discontinuation.
Pharmacological treatment
276
277
In school-age children
Clonidine versus placebo Methylphenidate versus clonidine
Mixed comorbidity Specific comorbidity Specific comorbidity
(Tourette’s syndrome, chronic (Tourette’s syndrome, chronic
motor tic disorder or chronic motor tic disorder or chronic
vocal tic disorder) vocal tic disorder)
Total no. of trials 1 (67) 1 (136) 1 (136)
(total no.
of participants)
Study ID HAZELL2003 KURLAN2002 KURLAN2002
Diagnosis ADHD with oppositional ADHD with Tourette’s syndrome, ADHD with Tourette’s syndrome,
defiant disorder or chronic motor tic disorder or chronic motor tic disorder or
conduct disorder chronic vocal tic disorder chronic vocal tic disorder
Baseline severity Number of inattentive Conners’ ASQ-T: Conners’ ASQ-T:
(mean range) symptoms: Clonidine: 18.4 (5.9) Methylphenidate: 18.9 (6.3)
Clonidine: 7.16 (1.54) Placebo: 16.0 (6.2) Clonidine: 18.4 (5.9)
Placebo: 7.32 (1.54)
Dose 0.18mg/day 0.6 mg/day (max) 0.6 mg/day (max)
Treatment length 42 days 112 days 112 days
(mean range)
Table 28: Study information and evidence summary table for trials of clonidine
Continued
278
In school-age children
Clonidine versus placebo Methylphenidate versus clonidine
Mixed comorbidity Specific comorbidity Specific comorbidity
(Tourette’s syndrome, chronic (Tourette’s syndrome, chronic
motor tic disorder or chronic motor tic disorder or chronic
vocal tic disorder) vocal tic disorder)
Benefits
ADHD core CTRS: ASQ-T: ASQ-T:
symptoms SMD 0.57 SMD 2.42 SMD 2.18
(teacher-rated) (1.06 to 0.08) (3.07 to 1.76) (2.81 to 1.56)
Quality: High Quality: High Quality: High
K 1, N 67 K 1, N 136 K 1, N 136
ADHD core CPRS: ASQ-P: ASQ-P:
symptoms SMD 0.16 SMD 2.41 SMD 2.41
(parent-rated) (0.64 to 0.32) (3.07 to 1.75) (3.09 to 1.73)
Quality: Moderate Quality: High Quality: High
K 1, N 67 K 1, N 136 K 1, N 136
Table 28: (Continued)
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