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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5267_Библиотеки_им_академика_М_И_Перельмана
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Conduct problems CTRS: IOWA: IOWA:
(teacher-rated) SMD 0.68 SMD 1.11 SMD 1.10
(1.18 to 0.18) (1.64 to 0.58) (1.62 to 0.57)
Quality: High Quality: High Quality: High
K 1, N 67 K 1, N 136 K 1, N 136
Conduct problems CPRS: – –
(parent-rated) SMD 0.31
(0.8 to 0.17)
Quality: Moderate
K 1, N 67
Clinical improvement – CGI: CGI:
(clinician-rated) RR 1.98 RR 0.28
(1.11 to 3.52) (0.14 to 0.56)
Quality: High Quality: High
K 1, N 136 K 1, N 136
Harms
Leaving study early NNTB 16 NNTB 10 NNTB 100
due to any reason (NNTB 4 to ∞ to NNTH 11) (NNTB 3 to ∞ to NNTH 12) (NNTB 6 3 to ∞ to NNTH 7)
Quality: Moderate Quality: High Quality: Moderate
K 1, N 67 K 1, N 136 K 1, N 136
279
10.9.5 Clinical evidence summary: clonidine versus methylphenidate
In one study of ADHD with comorbid tics (KURLAN2002) there was a small prefer-
ence for methylphenidate over clonidine in reducing ADHD symptoms and conduct
problems.
10.10 BUPROPION
10.10.1 Pharmacology and prescribing
Bupropion is a selective inhibitor of the neuronal reuptake of noradrenaline and
dopamine. It is licensed as an aid to smoking cessation in combination with motiva-
tional support in nicotine-dependent patients; it is currently not licensed for patients
under 18 years or for the treatment of ADHD (GlaxoSmithKline UK, 2008). The
mechanism by which bupropion enhances the ability of patients to abstain from
smoking is unknown. It is presumed that this action is mediated by noradrenergic
and/or dopaminergic mechanisms (GlaxoSmithKline UK, 2008).
10.10.2 Safety and adverse effects
Many adverse events have been reported: dry mouth, gastro-intestinal disturbances,
taste disturbance; insomnia (reduced by avoiding dose at bedtime), tremor, impaired
concentration, headache, dizziness, depression, agitation, anxiety; fever; rash, pruri-
tus, sweating; less commonly, chest pain, tachycardia, hypertension, flushing, confu-
sion, tinnitus, asthenia, and visual disturbances; rarely jaundice, hepatitis, palpitation,
postural hypotension, hallucinations, depersonalisation dystonia, ataxia, abnormal
dreams, memory impairment, paraesthesia, blood-glucose disturbances, urinary
retention, urinary frequency, Stevens-Johnson syndrome, and exacerbation of psoria-
sis; very rarely delusions and aggression (British Medical Association & the Royal
Pharmaceutical Society of Great Britain, 2007; GlaxoSmithKline UK, 2008). Many
of these adverse events could also be caused by stopping smoking (GlaxoSmithKline
UK, 2008).
Bupropion is associated with a dose-related risk of seizure with an estimated inci-
dence of approximately 0.1%. There have been 184 reports in the UK of seizures
suspected of being associated with the use of bupropion (MHRA, 2002). In approxi-
mately one half of the reports, patients had either a past history of seizure(s) and/or
risk factors for their occurrence. To reduce the risk of seizures, bupropion is
contraindicated in patients with a current seizure disorder or any history of seizures,
with current or previous diagnosis of bulimia or anorexia nervosa, with a known
CNS tumour, and those experiencing abrupt withdrawal from alcohol or benzodi-
azepines (MHRA, 2002).
Pharmacological treatment
280
10.10.3 Clinical evidence for bupropion
Of the 49 trials, five included a comparison of bupropion with placebo. Two of these
studies recruited school-age children with ADHD (a common coexisting condition
was conduct disorder). Three trials involved adults with ADHD (common coexisting
conditions included major depression, anxiety disorders and antisocial personality
disorder).
Study information and evidence from the important outcomes and overall quality
of evidence are presented in Table 29. The full evidence profiles and associated forest
plots can be found in Appendix 19 and Appendix 18, respectively.
Pharmacological treatment
281
In school-age children In adults
Bupropion versus placebo Bupropion versus placebo
Mixed comorbidity Mixed comorbidity
Total no. of trials 2 (139) 3 (261)
(total no. of
participants)
Study ID CASAT1987 REIMHERR2005A
CONNERS1996B WILENS2001A
WILENS2005B
Diagnosis ADD with hyperactivity ADHD
(common coexisting (common coexisting conditions:
conditions: conduct major depression, anxiety
disorder) disorders, antisocial personality
disorders)
Baseline severity Conners’ TQ Abbrev: Global Assessment
(mean range) Bupropion: 19.93 (4.62) of Functioning:
to 20.35 (5.21) Bupropion: 53.3 (4.6) to
Placebo: 20.67 (7.87) to 57.1 (10.0)
21.50 (4.08) Placebo: 54.6 (3.1) to
58.1 (10.9)
Dose 6 mg/kg (max) 298 to 393 mg/kg
Treatment length 28 days 42–56 days
(mean range)
Table 29: Study information and evidence summary table
for trials of bupropion
Continued
Pharmacological treatment
282
In school-age children In adults
Bupropion versus placebo Bupropion versus placebo
Mixed comorbidity Mixed comorbidity
Benefits
ADHD core CPTQ-T: –
symptoms SMD 0.70
(teacher-rated) (1.11 to 0.29)
Quality: High
K 2, N 139
ADHD core CPTQ-P: –
symptoms SMD 0.88
(parent-rated) (1.89 to 0.13)
Quality: High
K 2, N 139
ADHD core – Various measures:
symptoms (mean SMD 0.36
at endpoint) (0.79 to 0.07)
(investigator- Quality: High
rated) K 2, N 99
ADHD core – ADHD-RS:
symptoms SMD 0.42
(mean change) (0.73 to 0.11)
(investigator- Quality: High
rated) K 1, N 162
Conduct problems CTQ (conduct): –
(teacher-rated) SMD 0.44
(1.21 to 0.32)
Quality: Moderate
K 1, N 30
Conduct problems CPQ: –
(parent-rated) SMD 0.0
(0.76 to 0.76)
Quality: Moderate
K 1, N 30
Table 29: (Continued)
In school-age children In adults
Bupropion versus placebo Bupropion versus placebo
Mixed comorbidity Mixed comorbidity
Clinical – Various measures:
improvement RR 2.01
(clinician-rated) (1.36 to 2.95)
Quality: High
K 3, N 261
Harms
Rash NNTH 10 –
(NNTH 4 to ∞ to
NNTB 34)
Quality: Moderate
K 1, N 109
Dry mouth – NNTH 25
(NNTH 7 to ∞ to NNTB 16)
Quality: High
K 2, N 202
Nausea – NNTH 20
(NNTH 8 to ∞ to NNTB 100)
Quality: Moderate
K 1, N 162
Nasopharyngitis – NNTH 16
(NNTH 7 to ∞ to NNTB 100)
Quality: Moderate
K 1, N 162
Dizziness – NNTH 20
(NNTH 9 to ∞ to NNTB 100)
Quality: Moderate
K 1, N 162
Constipation – NNTH 25
(NNTH 10 to ∞ to NNTB 34)
Quality: Moderate
K 1, N 162
Irritability – NNTH 25
(NNTH 10 to ∞ to NNTB 34)
Table 29: (Continued)
Continued
Pharmacological treatment
283
10.10.4 Clinical evidence summary
For individual outcomes, the quality of the evidence was generally moderate to high.
Bupropion in school-age children
There is no statistically significant evidence that bupropion reduces ADHD core
symptoms or behaviour in children with ADHD.
One study reports an increase of rash in children taking bupropion when
compared with placebo. When compared with placebo, bupropion may increase the
risk of discontinuation.
Conclusion (school-age children)
There is no evidence that bupropion is effective in reducing ADHD core symptoms or
conduct problems in children with ADHD. There is limited evidence that bupropion
may increase the risk of rash.
Pharmacological treatment
284
In school-age children In adults
Bupropion versus placebo Bupropion versus placebo
Mixed comorbidity Mixed comorbidity
Quality: Moderate
K 1, N 162
Tinnitus – NNTH 16
(8 to 100)
Quality: Moderate
K 1, N 162
Chest pain – NNTH 10
(NNTH 4 to ∞ to NNTB 20)
Quality: Moderate
K 1, N 40
Leaving study NNTH 20 –
early due to (NNTH 8 to ∞ to
adverse events NNTB 100)
Quality: High
K 2, N 139
Leaving study NNTH 33 NNTH 20
early due to any (NNTH 7 to ∞ to NNTB 16) (NNTH 6 to ∞ to NNTB 20)
reason Quality: Moderate Quality: High
K 2, N 139 K 2, N 202
Table 29: (Continued)
Bupropion in adults
There is some evidence that bupropion when compared with placebo reduces ADHD
core symptoms and produces clinical improvement in adults with ADHD (mixed
comorbidities).
Bupropion is more likely than placebo to produce the following side effects: dry
mouth, insomnia and chest pain as well as increasing the risk of discontinuation.
Conclusion (adults)
There is some evidence that bupropion is effective in reducing ADHD core symptoms
and producing clinical improvement in adults with ADHD. There is also evidence that
bupropion may increase the risk of side effects.
10.11 MODAFINIL
10.11.1 Pharmacology and prescribing
Modafinil is an antinarcoleptic and mood-enhancing drug; the pharmacological
mechanism by which it acts as both is still under investigation. It has been proposed
that modafinil acts on the GABAergic inhibitory network of the thamalocortical
system, in agreement with the previously described effect on GABAergic networks
in sleep and non-sleep-related areas (Urbano et al., 2007).
Modafinil is licensed for the symptomatic relief of excessive sleepiness associated
with narcolepsy, obstructive sleep apnoea/hypopnoea syndrome and moderate to
severe chronic shift work sleep disorder (Cephalon UK Limited, 2008).
10.11.2 Safety and adverse effects
Reported side effects are: dry mouth, appetite changes, gastro-intestinal disturbances
(including nausea, diarrhoea, constipation and dyspepsia), abdominal pain;
tachycardia, vasodilation, chest pain, palpitation; headache (uncommonly migraine),
anxiety, sleep disturbances, dizziness, depression, confusion, abnormal thinking,
paraesthesia, agitation, asthenia; visual disturbances; less commonly mouth ulcers,
glossitis, pharyngitis, dysphagia, taste disturbance, hypertension, hypotension, brady-
cardia, arrhythmia, peripheral oedema, hypercholesterolaemia, rhinitis, dyspnoea,
dyskinesia, amnesia, emotional lability, abnormal dreams, tremor, decreased
libido, weight changes, hyperglycaemia, urinary frequency, menstrual disturbances,
eosinophilia, leucopenia, myasthenia, muscle cramps, dry eye, sinusitis, epistaxis,
myalgia, arthralgia, acne, sweating, rash, and pruritus (British Medical Association
& the Royal Pharmaceutical Society of Great Britain, 2007; Cephalon UK
Limited, 2008).
For modafinil, statistically significant adverse events and/or with an RR greater
than 5% are displayed in Table 30. For a full list of adverse events see Appendix 18
(forest plot).
Pharmacological treatment
285
Pharmacological treatment
286
In school-age children
Modafinil versus placebo
Mixed comorbidity
Total no. of trials (total 5 (910)
no. of participants)
Study ID BIEDERMAN2005
BIEDERMAN2006B
GREENHILL2006
RUGINO2003
SWANSON2006
Diagnosis ADHD (common coexisting conditions: oppositional
defiant disorder, conduct disorder, learning
disorder, phobias, separation anxiety)
Baseline severity ADHD-RS (total):
(mean range) Modafinil: 27.3 (14.1) to 38.8 (8.9)
Placebo: 24.5 (13.8) to 37.9 (9.0)
Dose 264 to 425mg/day
Treatment length 28 to 63 days
(mean range)
Benefits
ADHD core symptoms ADHD-RS:
(mean at endpoint) SMD 0.52
(teacher-rated) (0.82 to 0.22)
Quality: High
K 1, N 200
ADHD core symptoms ADHD-RS:
(mean change) SMD 0.63
(teacher-rated) (0.84 to 0.43)
Quality: High
K 2, N 438
ADHD core symptoms ADHD-RS:
(mean at endpoint) SMD 0.57
(parent-rated) (0.87 to 0.26)
Table 30: Study information and evidence summary table
for trials of modafinil
In school-age children
Modafinil versus placebo
Mixed comorbidity
Quality: High
K 1, N 200
ADHD core symptoms ADHD-RS:
(mean change) SMD 0.54
(parent-rated) (0.74 to 0.33)
Quality: High
K 2, N 438
Conduct problems CPRS-R-S:
(mean change) SMD 0.31
(parent-rated) (0.57 to 0.04)
Quality: High
K 1, N 248
Clinical improvement CGI:
(clinician-rated) RR 2.79
(2.02 to 3.86)
Quality: High
K 3, N 686
Harms
Insomnia NNTH 4
(3 to 5)
Quality: High
K 2, N 438
Decreased appetite NNTH 8
(5 to 12)
Quality: Moderate
K 1, N 24
Pain NNTH 25
(12 to ∞)
Quality: Moderate
K 1, N 248
Vomiting NNTH 11
(NNTH 3 to ∞ to NNTB 8)
Quality: Moderate
K 1, N 24
Table 30: (Continued)
Continued
Pharmacological treatment
287
Pharmacological treatment
288
In school-age children
Modafinil versus placebo
Mixed comorbidity
Stomach ache NNTH 5
(NNTH 2 to ∞ to NNTB 15)
Quality: Moderate
K 1, N 24
Headache NNTH 11
(NNTH 3 to ∞ to NNTB 8)
Quality: Moderate
K 1, N 24
Tearfulness NNTH 11
(NNTH 3 to ∞ to NNTB 8)
Quality: Moderate
K 1, N 24
Irritability NNTH 11
(NNTH 3 to ∞ to NNTB 8)
Quality: Moderate
K 1, N 24
Tonsillitis NNTH 11
(NNTH 3 to ∞ to NNTB 8)
Quality: Moderate
K 1, N 24
Pharyngitis NNTH 11
(NNTH 3 to ∞ to NNTB 8)
Quality: Moderate
K 1, N 24
Leaving study early due NNTH ∞
to adverse events (NNTH 25 to ∞ to NNTB 33)
Quality:
K 4, N 720
Leaving study early due NNTB 25
to any reason (NNTB 8 to ∞ to NNTH 25)
Quality:
K 4, N 662
Table 30: (Continued)
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