CADTH Health Technology Review
Guanfacine for Autism Spectrum Disorder, Attention-Deficit/Hyperactivity Disorder, and/or Oppositional Defiance Disorder
Rapid Review
Authors: Deepa Jahagirdar, Quenby Mahood
Abbreviations
ASD
autism spectrum disorder
ADHD
Attention-deficit/ hyperactive disorder
ADHD-RS
ADHD rating scale
BRIEF-A
Behavioural Rating Inventory of Executive Function–Adult
BRIEF-P
Behavioural Rating Inventory of Executive Function–Parent
CGI-I
Clinical Global Impressions-Improvement
CGI-S
Clinical Global Impressions-Severity of Illness
CSSRS
Columbia Suicide Severity Rating Scale
DSM
Diagnostic and Statistical Manual
GRADE
Grading of Recommendations, Assessment, Development and Evaluations
HTA
health technology assessment
ICD
International Classification of Disease
MD
mean difference
ODD
oppositional defiance disorder
OR
odds ratio
RCT
randomized controlled trial
YGTSS
Yale Global Tic Severity Scale
Key Messages
This review identified 4 relevant systematic reviews, 2 randomized controlled trials and 1 guideline since 2017.
The systematic reviews and trials suggest that guanfacine is more clinically effective than placebo for improving symptoms of attention-deficit/ hyperactive disorder, however it may be associated with increased adverse events such as abdominal pain and fatigue.
There is some suggestion from 2 systematic reviews that guanfacine may be equally effective as other psychostimulants or non-psychostimulants, with the potential for more greater side effects, but the evidence is highly uncertain.
The included guideline has a strong recommendation to offer guanfacine for use in children and adolescents when psychostimulants have failed, or they are not tolerable.
No evidence was identified on the cost-effectiveness of guanfacine relative to psychostimulants, non-psychostimulants or placebo that met the inclusion criteria.
Context and Policy Issues
Attention-deficit/hyperactivity disorder (ADHD) is 1 of the most commonly diagnosed childhood conditions.1 Autism spectrum disorder (ASD) and oppositional defiance disorder (ODD) are related to ADHD with symptomatic overlap. Symptoms that can be present in all the conditions include hyperactivity, impulsivity, behavioural issues, and inattention. Hyperactivity is more common in young children; this may evolve into impulsivity in adolescence and remain as such throughout the life course. Inattention is often diagnosed later2 and can remain in adulthood.3 The symptoms can affect academics, social skills, and occupational performance. While difficulty keeping up with school and making friends may start in childhood, forgetfulness, prioritization, and difficulty organizing tasks can continue to inhibit executive function as an adult.3
Pharmacological treatment for these conditions includes psychostimulant (simply called stimulant) medications most commonly as a first option, and non-stimulant medications as alternatives. Stimulant medications increase the brain activity of producing dopamine and norepinephrine while the mechanism of non-stimulant medications can vary.4 Selective norepinephrine reuptake inhibitors such as atomoxetine prevent reuptake of the same neurotransmitters, thus increasing concentrations. In contrast, alpha-2-agonists such as guanfacine and clonidine may mimic the effects of the neurotransmitters though their exact mechanism of action is unknown.4 While stimulants are usually the first line treatment, non-stimulant medications can be more desirable in some situations.5 They may be indicated when stimulant medications worsen co-occurring tic disorders, the person has a background of substance use, or have other intolerable side effects. In addition, symptoms may not always respond to stimulants necessitating trials with other options.5
Among the non-psychostimulants, guanfacine hydrochloride (used herein interchangeably with guanfacine) is an emerging and important choice to control ADHD, ASD, and ODD symptoms, but evidence is limited. The aim of this review is to summarize the evidence regarding the clinical and cost-effectiveness of guanfacine compared to stimulants and non-stimulants drugs for ADHD, autism spectrum disorder and ODD, as well as the evidence-based guidelines.
Research Questions
What is the clinical effectiveness of guanfacine versus psychostimulant drugs for attention-deficit/ hyperactivity disorder, autism spectrum disorder, and oppositional defiance disorder?
What is the clinical effectiveness of guanfacine versus other non-psychostimulant drugs for attention-deficit/hyperactivity disorder, autism spectrum disorder, and oppositional defiance disorder?
What is the clinical effectiveness of guanfacine versus placebo or no therapy for attention-deficit/hyperactivity disorder, autism spectrum disorder, and oppositional defiance disorder?
What is the cost-effectiveness of guanfacine versus psychostimulant drugs for attention-deficit/hyperactivity disorder, autism spectrum disorder, and oppositional defiance disorder?
What is the cost-effectiveness of guanfacine versus other non-psychostimulant drugs for attention-deficit/hyperactivity disorder, autism spectrum disorder, and oppositional defiance disorder?
What is the cost-effectiveness of guanfacine versus placebo or no therapy for attention-deficit/hyperactivity disorder, autism spectrum disorder, and oppositional defiance disorder?
What are the evidence-based guidelines regarding the use of guanfacine for attention-deficit/hyperactivity disorder, autism spectrum disorder, and oppositional defiance disorder?
Methods
Literature Search Methods
A limited literature search was conducted by an information specialist on key resources including MEDLINE, Embase, PsycINFO, the Cochrane Library, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy comprised controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was guanfacine. Search filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, or network meta-analyses, randomized controlled trials (RCTs), controlled clinical trials, guidelines, or economic studies. Comments, newspaper articles, editorials, conference abstracts and letters were excluded. Where possible, retrieval was limited to the human population. The search was completed on May 31, 2022 and limited to English language documents published since January 1, 2017.
Selection Criteria and Methods
One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.
Criteria | Description |
|---|---|
Population | People with attention-deficit/hyperactivity disorder, autism spectrum disorder and/or oppositional defiance disorder |
Intervention | Guanfacine |
Comparator | Q1 to Q4. Psychostimulant drugs e.g., short-acting or extended-release amphetamines (including lisdexamfetamine dimesylate, amphetamine, mixed salts, dextroamphetamine), methylphenidate (short acting or extended release), atypical antipsychotics (aripiprazole, clozapine, ziprasidone, risperidone, quetiapine, olanzapine, asenapine, and paliperidone). Q2 to Q5. Non-psychostimulant drugs, i.e., atomoxetine or clonidine (either with or without adjunctive psychostimulants). Q3 to Q6. Placebo and/or no treatment. Q7. Not applicable. |
Outcomes | Q1 to Q3: Clinical effectiveness e.g., behavioural, functional, developmental, or cognitive outcomes assessed by validated scales (e.g., BRIEF-P, ADHD-RS IV, CGI-S, CGI-I); health-related quality of life; safety e.g., harms, AEs (including AEs of particular interest e.g., hypotension, cardiovascular AEs, etc.), SAEs, discontinuations due to TEAEs, mortality. Q4 to Q6: Cost-effectiveness e.g., ICER/ICUR, cost per QALY or other health benefit. Q7: Evidence-based recommendations. |
Study designs | Health technology assessments, systematic reviews, randomized controlled trials, non-randomized studies, economic evaluations, evidence-based guidelines. |
ADHD-RS IV = ADHD Rating Scale IV; AE = adverse event; BRIEF-P = Behavioural Rating Inventory of Executive Function (parent form); CGI-I = Clinical Global Impressions – Improvement scale; CGI-S = Clinical Global Impressions – Severity of Illness scale; ICER = incremental cost-effectiveness ratio; ICUR = incremental cost-utility ratio; QALY = quality-adjusted life-year; SAE = serious adverse event; TEAE = treatment emergent adverse event.
Exclusion Criteria
Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, or were published before 2017. Systematic reviews in which all relevant studies were captured in other more recent or more comprehensive systematic reviews were excluded.6-14 Primary studies retrieved by the search were excluded if they were captured in 1 or more included systematic reviews.15 Guidelines with unclear methodology were also excluded.
Critical Appraisal of Individual Studies
The included publications were critically appraised by 1 reviewer using the following tools as a guide: A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2)16 for systematic reviews, the “Questionnaire to assess the relevance and credibility of a network meta-analysis”17 for network meta-analyses, the Downs and Black checklist18 for randomized and non-randomized studies, and the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument19 for guidelines. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.
Summary of Evidence
Quantity of Research Available
A total of 274 citations were identified in the literature search. Following screening of titles and abstracts, 231 citations were excluded and 43 potentially relevant reports from the electronic search were retrieved for full-text review. 18 potentially relevant publications were retrieved from the grey literature search for full-text review. Of the 61 potentially relevant articles, 54 publications were excluded for various reasons, while 7 publications met the inclusion criteria and were included in this report. These comprised 4 systematic reviews, 2 randomized controlled trials (RCTs), and 1 evidence-based guideline. There were no economic evaluations that met the inclusion criteria. Appendix 1 presents the PRISMA20 flow chart of the study selection.
Additional references of potential interest are provided in Appendix 7. The overlap of primary studies in the included systematic review is available in Appendix 5.
Summary of Study Characteristics
Study Design
All 4 systematic reviews had broader search inclusion criteria than relevant to this report. Two included systematic reviews, 1 with 203 eligible RCTs,21 and the other with 8 eligible RCTs,22 had 1 relevant RCT each reporting about guanfacine. Both these systematic reviews included only double-blinded RCTs. Another systematic review included 12 RCTs related to guanfacine out of 133 studies; open or blinded RCTs were eligible.23 The final systematic review included 13 out of 73 studies pertaining to guanfacine.24 It was not specified whether the included RCTs were blinded.24 The systematic reviews included articles from 1980 to November 2021,21 database inception to April 2021,23 from database inception to September 2017,22 and to up to March 29, 2017.24
The systematic reviews had some overlap. The only guanfacine study in Osland, 201822 was also included in Cortese, 2018,23 which included 12 RCTs. However, the systematic review by Osland, 201822 was retained because it reported outcomes related to tic disorders not reported by Cortese et al.23 Seven primary studies overlapped between Luan, 201724 and Cortese, 201823(Appendix 5).
Of the RCTs, 1 was a multi-centre double-blinded design with 201 participants, where patients were randomized to receive either guanfacine or placebo.25 The other trial was a crossover design with a 10-day washout period, meaning, the participants (40 in total) switched from their initial treatment assignment to the alternative (guanfacine or placebo) after allowing 10 days for the effect of the first to wane.26 The participants received concurrent treatment with a psychostimulant.26
The guideline was developed by the UK’s National Institute for Health and Care Excellence (NICE).27 The guidelines identified evidence through a systematic search of multiple electronic databases. The quality of the evidence was rated according to Grading of Recommendations, Assessment, Development and Evaluations (GRADE). The final recommendations adopted a language-based rating system, where “should offer” and “do not offer” reflect the recommendations with highest level of confidence, while “should consider and should not consider” reflect a lower level of confidence.
Country of Origin
The systematic reviews originated from the UK,22,23 Germany21 and China.24 One RCT was conducted at 71 Japanese centres between October 2016 and July 201725 while the other RCT was conducted at a single centre in Canada though the study period was not specified.26 The guideline was developed by the NICE in the UK.27
Patient Population
One systematic review included children and adults (analyzed separately) diagnosed with ASD using at least Diagnostic and Statistical Manual (DSM)-III or other validated diagnostic tools.21 Two systematic reviews included individuals diagnosed with ADHD.23,24 One systematic review, included children and adults diagnosed with primary ADHD according to DSM-III, DSM-III-R, DSM-IV(TR), DSM-5, International Classification of Disease (ICD)-9, or ICD-10.23 The other systematic review included only children aged 6 to 18 with a DSM-IV diagnosis of ADHD.24 Another systematic review also included only children 18 or younger with a diagnoses of both ADHD and a chronic tic disorder.22 In the systematic reviews without age restriction, the studies pertaining to guanfacine were done in children only.21,23
One of the RCTs was conducted in children aged 6 to 12 years with a primary diagnosis of predominantly inattentive, hyperactive or impulsive, or combined subtype based on DSM-IV diagnosis of ADHD. The children had to be taking a stable methylphenidate or amphetamine (stimulant) regimen for at least 30 days with ongoing executive function difficulties.26 The other trial was done in adults at least 18 years old, with a DSM-V diagnoses of ADHD).25
The guideline targeted health care professionals, commissioners, people with ADHD as well as families and carers.27
Interventions and Comparators
Interventions
The systematic reviews included a variety of pharmacological interventions, though only analyses related to guanfacine were considered for this review. One systematic review included dietary-supplements in addition to medications, except for those given in combination with behavioural interventions or risperidone.21 Findings comparing guanfacine to dietary-supplements were not included in this review. Another systematic review specified amphetamines, atomoxetine, bupropion, clonidine, guanfacine, methylphenidate and modafinil given as oral therapy, alone or in combination with other drugs.23 One systematic review included any pharmacological treatment for ADHD given orally alone or in combination with another drug,22 while the another systematic review included atomoxetine, bupropion, clonidine, guanfacine, methylphenidate and lisdexamfetamine.24 Two studies specified the minimum duration of treatment as 7 days,21,23 while another specified 3 weeks.24
In 1 RCT, the intervention was guanfacine titrated from 2 mg per day to 4 mg to 6 mg per day over 5 weeks to optimize the dose. This period was followed by a 5-week maintenance on the same dose, then tapering over 2 weeks.25 In the crossover RCT, guanfacine was initiated at 1 mg per day and optimized over 4 weeks to a maximum of 4 mg per day. The optimization was followed by an 8-week maintenance period, then tapering over 11 days and a 10-day washout period.26
The guideline considered various pharmacological treatment though in this review only recommendations pertaining to guanfacine were included.27
Comparators
Two systematic reviews included placebo-controlled studies only,21,22 and 2 systematic reviews included studies with placebo or other drugs as comparators.23,24 In 2 systematic reviews, the duration of treatment had to be at least 7 days,21,23 while in another the minimum study duration had to be 3 weeks.24
Both RCTs were placebo-controlled studies.25,26
Outcomes
All the systematic reviews reported change in ADHD symptoms outcomes, assessed by any validated scales and reported the finding using standardized mean difference (SMD).22-24 However, 1 systematic reviews specified only accepting the ADHD Rating Scale (ADHD-RS).24 Where included, parent, teacher and clinician ratings were analyzed separately.21-23 In the systematic review involving people with ASD, changes in repetitive behaviour, and social communication difficulties were reported as additional outcomes.21
Two systematic reviews with network meta-analysis reported SMD and 95% confidence intervals (CIs) based on the different scales.21,23 However, 1 systematic review limited meta-analysis to studies with a common scale, and reported a mean difference (MD) and 95% CI in the change in ADHD-RS.24 The systematic review of studies involving with people with ADHD and a chronic tic disorder reported tic severity using any valid scale such as the YGTSS total tic score as additional an outcome.22 Two systematic reviews measured clinical global functioning as secondary outcomes using the Clinical Global Impression- Improvement (CGI-I) tool.21,23 All reviews collected safety information, e.g., the number of adverse events.
The 2 RCTs had different primary outcomes. One used only the Behaviour Rating Inventory of Executive Function–Parent (BRIEF-P) score at all visits outside of the maintenance period.26 Secondary outcomes included changes in total score on the ADHD-RS-IV, Clinical Global Impression-Severity of illness (CGI-S), and the CGI-I. The other RCT25 used the change in baseline score on the Japanese version of the ADHD-RS-IV with adult prompts. Secondary outcomes included the change from baseline in ADHD-RS-IV subscale, and Behaviour Rating Inventory of Executive Function - Adult Version (BRIEF-A) scores for executive function. Safety outcomes in both trials included adverse events, vital sign measurements, physical examinations (weight and height).25,26 The Japanese trial additionally collected electrocardiogram parameters, while the Canadian study also measured safety using the used the Columbia Suicide Severity Rating Scale (CSSRS), which asks a series of ‘yes’ or ‘no’ questions to assess suicide risk.26
The included guideline’s major outcomes were quality of life, ADHD symptoms, and the CGI-I scale. In addition, it collected information on serious adverse events, behavioural and functional outcomes, emotional dysregulation, academic outcomes, substance use and self-harm where available.
Details on the included measurement scales used to assess the outcomes are available in Appendix 6.
Additional details regarding the characteristics of included publications are provided in Appendix 2.
Summary of Critical Appraisal
All 4 systematic reviews had clear research questions and Population, Intervention, Comparator, Outcome (PICO) criteria.21-24 They all searched at least 7 databases for relevant studies, with 3 systematic reviews using supplemental search methods such as handsearching reference lists,21-23 thus, limiting the potential of missing pertinent studies. Risk of bias in studies was assessed using the Cochrane risk of bias tool.21-24 The systematic reviews handled primary studies rated as having high risk of bias in different ways. One systematic review downgraded the overall evidence quality,22 while 2 others conducted sensitivity analyses these studies in meta-analyses.21,23 One systematic review did not present the results of study bias analysis, making it challenging to understand the quality of evidence. This was also the only review that did not provide an overall assessment of evidence quality challenging the interpretation of the findings.24
Three of the systematic reviews conducted random effects pairwise and network meta-analyses.21,23,24 They all compared effect estimates derived from the network versus pairwise analysis, which helps to demonstrate the robustness of the analysis.21,23,24 Three systematic reviews also assessed study heterogeneity,21,23,24 though 2 of these did not discuss the findings or implications.23,24 Two systematic reviews conducted additional sensitivity analyses to ensure robustness of effects against common issues such as different study baseline characteristics and the impact of excluding studies with high risk of bias.21,23 The third systematic review did not conduct sensitivity analysis.24
Both included RCTs had clear research questions and inclusion criteria.25,26 Computerized software was used for treatment assignment and randomization, and both studies had adequate power to detect treatment effects. One study described using sealed envelopes and identical tables for treatment and placebo to maintain blinding,25 while the other trial did not provide specifics of the randomization, making it less clear whether blinding was adequately achieved.26 The study arms were balanced in 1 study,26 while in the other, the treatment group was younger than the placebo group (i.e., age less than 30 years was 47% in the treatment group compared to 39% in placebo group). There was no apparent adjustment for this imbalance, meaning it is unclear if age may have driven some of the observed effects.25 Both RCTs were funded by a grant from Shire, the drug manufacturer of guanfacine, raising concerns of conflict of interest.25,26
The overall quality of the included guideline was high.27 The intended users and target population, scope and purpose were clear, and the methodology for the literature review followed systematic approaches. Members of the committee to develop the guideline had a variety of backgrounds which would bring different perspectives. Where there were conflicts of interests, committee members withdrew from certain discussions. The guideline was also subjected to an online consultation period, which solicited comments from stakeholders on the draft recommendations that were incorporated as appropriate. The limitations of the guideline included lack of clarity on the process of developing the draft recommendations given the evidence, as well as no formal external peer review. There was however an online feedback period open to the public and invited stakeholders.
Additional details regarding the strengths and limitations of included publications are provided in Appendix 3.
Summary of Findings
Clinical Effectiveness of Guanfacine Versus Psychostimulant Drugs
Two systematic reviews compared the effectiveness of guanfacine to psychostimulant drugs.23,24 Guanfacine was not significantly different than methylphenidate in clinician-rated symptoms, parent-rated symptoms, or teacher-rated symptoms.23 from indirect comparisons. Similarly, guanfacine was not significantly different than methylphenidate on the ADHD-RS in both network meta-analysis and pairwise comparisons.24
Indirect comparison in 1 systematic review found that amphetamines were superior to guanfacine to improve ADHD symptoms as rated by both clinicians and parents.23 Amphetamines were also associated with greater positive response on the CGI-I.23 However, another systematic review did not find a statistically significant difference in its indirect comparison of guanfacine to lisdexamphetamine to improve ADHD symptoms.24 No direct evidence for this drug comparison was available.
In terms of safety, the tolerability of guanfacine was similar to methylphenidate and amphetamines in 1 systematic review.23 However, another systematic review found that guanfacine was associated with greater odds of withdrawals due to adverse events compared to methylphenidate.24 The systematic review also found that compared to lisdexamphetamine, the odds were higher with guanfacine for withdrawal due to lack of efficacy and increased abdominal pain.24
Clinical Effectiveness of Guanfacine Versus Non-Psychostimulant Drugs
Three systematic reviews had quantitative comparisons of the efficacy of guanfacine and atomoxetine. Guanfacine was potentially inferior to atomoxetine in 1 systematic review of people with ASD though finding bordered on being statistically insignificant in an indirect comparison.21 Two other systematic reviews did not find a statistically significant difference between guanfacine and atomoxetine in indirect comparisons of clinician, teacher or parent ratings,23 or both indirect and direct comparisons on the ADHD-RS.24
In indirect comparisons, 2 reviews did not find statistically significant differences between guanfacine and clonidine on clinician or teacher ratings of ADHD symptoms,23 or on the ADHD-RS.24 Guanfacine was also not associated with statistically significant differences to ADHD symptoms compared to bupropion or modafinil in an indirect comparison in 1 systematic review.23
One systematic review found that guanfacine was associated with greater improvement to ADHD symptoms compared (indirectly) to 15 different medications among patients with ASD, including riluzole and fluoxetine.21 This same review did not find any statistically significant differences in repetitive behaviours or socio-communication difficulties in indirect comparisons to 21 medications.
In terms of safety and side effects, 1 systematic review found no significant differences in tolerance, or the occurrence of any adverse event compared to atomoxetine among people with ASD.21 However another systematic review found higher odds of withdrawals due to adverse events associated with guanfacine compared to atomoxetine,24 as well as increased likelihood of nausea.24
Guanfacine was also associated with more adverse events compared to sapropterin, dimethylglycine and sertraline in the review of people with ASD.21
Clinical Effectiveness of Guanfacine Versus Placebo or No Therapy
Guanfacine was consistently found to be more effective than placebo to improve ADHD symptoms in the systematic reviews and clinical trials.21-26 Direct and indirect comparisons of guanfacine to placebo were reported in the reviews that conducted network meta-analysis.
Guanfacine was also associated with greater odds of positive response than placebo on the CGI-I in 2 systematic reviews.21,23 and 1 RCT.26 The assessment scales were however inconsistent. For example, guanfacine was associated with a greater improvement to symptoms than placebo based on clinician ratings though not in the teacher or parent-rated scales.23 In 1 systematic review without meta-analysis that assessed the reduction in tic symptoms using the YGTSS total tic score, the treatment with guanfacine was associated with greater symptoms reduction than placebo.22
In the 1 systematic review among people with ASD, the effect of guanfacine was not statistically significantly better than placebo for improving socio-communication difficulties or repetitive behaviours21
In addition to symptoms, guanfacine was more effective to improve executive function than placebo in both the clinical trials. In 1 RCT in children, BRIEF-P scores improved more in the guanfacine group than the placebo group.26 Similarly, the RCT in adults found statistically significant improvements on the Inhibit, Initiate, and Plan/Organize dimensions of the BRIEF-A scales, but not the other dimensions.25
On safety, guanfacine was associated with statistically significantly increased odds of sedation,21 fatigue,24 abdominal pain,24 total adverse events,21 and dropouts due to adverse events23,24 compared to placebo. One systematic review found no statistically significant difference in laboratory test results, weight, or cardiovascular tests though 1 person dropped out of the study due to sedation.22 In 1 RCT in adults, 19.8% (n = 19) of adverse events led to discontinuation in the guanfacine versus 3% (n = 3) in the placebo group, while 81% (n = 82) versus 62% (n = 62) experienced an adverse event in the guanfacine versus placebo group, respectively.25 In the RCT among children, adverse event were 41 (87%) in the guanfacine group and 41 (85%) placebo group. Further, no participant demonstrated suicide risk using the CSSRS while in the treatment arm.26
Cost-Effectiveness of Guanfacine Versus Psychostimulant Drugs
There were no studies identified that met the inclusion criteria available, therefore, no summary can be provided.
Cost-Effectiveness of Guanfacine Versus Non-Psychostimulant Drugs
There were no studies identified that met the inclusion criteria, therefore, no summary can be provided.
Cost-Effectiveness of Guanfacine Versus Placebo or No Therapy
There were no studies identified that met the inclusion criteria, therefore, no summary can be provided.
Evidence-Based Guidelines Regarding the Use of Guanfacine
The 1 included guideline27 recommended offering (i.e., based on strongest evidence) atomoxetine or guanfacine to children aged 5 years and over and young people only if they cannot tolerate methylphenidate or lisdexamfetamine, or their symptoms have not responded to these stimulants. Further, they recommended considering (i.e., based on weaker evidence) changing from a stimulant medication to guanfacine in children aged 5 years and older if they have stimulant-related tics. Finally, they recommended not to offer (i.e., strongest evidence) guanfacine for adults without consulting a tertiary ADHD service.
Appendix 4 presents the main study findings and authors’ conclusions.
Limitations
The main limitation is that the evidence is based on a lot of indirectness and uncertainty in the head-to-head comparisons, limiting the confidence in comparisons of guanfacine versus other non-psychostimulants and stimulant medications. The systematic reviews as well as the included studies were generally of sufficient quality. However, the quantity of primary studies with head-to-head comparisons and in subpopulations is limited. One systematic review concluded that the evidence quality for the guanfacine comparisons was moderate versus placebo, low versus atomoxetine and very for comparisons to clonidine, methylphenidate and modafinil.’23 Two other systematic reviews concluded that the quality of evidence was low for the ASD population due to indirectness and imprecision,21 and very low for children with ADHD and tics.22
Also, only 1 study was conducted in adults, only 1 study was completed in Canada, and there were no studies that explicitly discussed people with ODD. Therefore, the generalizability of the findings to the general Canadian population with ADHD, ASD and ODD is unclear.
Finally, the included RCTs were both funded by Shire, the manufacturer of Intuniv, creating a potential conflict of interest and uncertainty about editorial independence regarding the interpretation of findings.
Conclusions and Implications for Decision- or Policy-Making
This rapid review report included 4 systematic reviews, 2 RCTs and 1 evidence-based guideline. It adds to the current evidence base by synthesizing current evidence for clinical effectiveness and guidelines pertaining to using guanfacine for ADHD, ASD and ODD. The evidence suggests that guanfacine is generally more effective than placebo to improve ADHD symptoms among those with ADHD or ASD,21-26 but with a higher potential for adverse events. Three systematic review found limited evidence of a significant difference in effectiveness between guanfacine and psychostimulants or non-psychostimulants,21,23,24 but there may be greater risk of adverse events such as increased fatigue and abdominal pain.24 The available 2018 guidelines by NICE is in line with these findings, only suggesting guanfacine if children cannot tolerate or do not respond to psychostimulants.27 The evidence among adults with ADHD was limited to 1 clinical trial which found guanfacine was more effective than placebo to improve ADHD symptoms.25
Compared to a previous CADTH report on the same topic,28 this review expands the research questions to more precisely compare guanfacine to psychostimulants and non-psychostimulants. Further, it includes 3 systematic reviews and 2 new RCTs, and a guideline that were unavailable in the previous report. The NICE guidelines identified in the current review recommended guanfacine in situations of intolerability or non-response.27 However, this review aligns with the previous 1 in finding that the comparisons between guanfacine and other drugs for ADHD and related conditions are largely based on indirect evidence.
There is limit evidence about using guanfacine to treat ADHD, autism spectrum disorder, and oppositional defiance disorder in adults. Further, there was no evidence related to using guanfacine in people with ODD, indicating that the generalizability of the findings to this group is unknown. Also, due to the lack of evidence on cost-effectiveness, health care resource utilization studies may be useful to understand cost implications.29 There is a need for studies comparing guanfacine to other medications in adult populations and people with ODD, and for evaluating the comparative cost-effectiveness analyses of the treatments.
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15.Politte LC, Scahill L, Figueroa J, McCracken JT, King B, McDougle CJ. A randomized, placebo-controlled trial of extended-release guanfacine in children with autism spectrum disorder and ADHD symptoms: an analysis of secondary outcome measures. Neuropsychopharmacology. 2018;43(8):1772-1778. PubMed
16.Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008. PubMed
17.Jansen JP, Trikalinos T, Cappelleri JC, et al. Indirect treatment comparison/network meta-analysis study questionnaire to assess relevance and credibility to inform health care decision making: an ISPOR-AMCP-NPC Good Practice Task Force report. Value Health. 2014;17(2):157-173. PubMed
18.Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998;52(6):377-384. PubMed
19.Agree Next Steps C. The AGREE II Instrument. [Hamilton, ON]: AGREE Enterprise; 2017: https://www.agreetrust.org/wp-content/uploads/2017/12/AGREE-II-Users-Manual-and-23-item-Instrument-2009-Update-2017.pdf. Accessed 2022 June 5.
20.Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1-e34. PubMed
21.Siafis S, Ciray O, Wu H, et al. Pharmacological and dietary-supplement treatments for autism spectrum disorder: a systematic review and network meta-analysis. Mol Autism. 2022;13(1):10. PubMed
22.Osland ST, Steeves TD, Pringsheim T. Pharmacological treatment for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders. Cochrane Database Syst Rev. 2018;6:CD007990. PubMed
23.Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry. 2018;5(9):727-738. PubMed
24.Luan R, Mu Z, Yue F, He S. Efficacy and tolerability of different interventions in children and adolescents with attention deficit hyperactivity disorder. Front Psychiatry. 2017;8:229. PubMed
25.Iwanami A, Saito K, Fujiwara M, Okutsu D, Ichikawa H. Efficacy and safety of guanfacine extended-release in the treatment of attention-deficit/hyperactivity disorder in adults: results of a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2020;81(3):14. PubMed
26.van Stralen JPM. A controlled trial of extended-release guanfacine and psychostimulants on executive function and ADHD. J Atten Disord. 2020;24(2):318-325. PubMed
27.National Institute for Health and Care Excellence. Attention deficit hyperactivity disorder: diagnosis and management. (NICE guideline NG87). 2018; https://www.nice.org.uk/guidance/ng87. Accessed 2022 June 5.
28.Harricharan S, Adcock L. Guanfacine hydrochloride extended-release for attention deficit hyperactivity disorder: a review of clinical effectiveness, cost-effectiveness, and guidelines. (CADTH Rapid Response Reports). Ottawa (ON): CADTH; 2018: https://www.cadth.ca/sites/default/files/pdf/htis/2018/RC0969%20Intuniv%20XR%20Final.pdf. Accessed 2022 June 5.
29.Molife C, Haynes VS, Nyhuis A, et al. Healthcare utilization and costs of children with attention deficit/hyperactivity disorder initiating atomoxetine versus extended-release guanfacine. Curr Med Res Opin. 2018;34(4):619-632. PubMed
Appendix 1: Selection of Included Studies
Appendix 2: Characteristics of Included Publications
Note that this appendix has not been copy-edited.
Table 2: Characteristics of Included Systematic Reviews and Network Meta-Analyses
Study citation, country, funding source | Study designs and numbers of primary studies included | Population characteristics | Intervention and comparator(s) | Clinical outcomes, length of follow up |
|---|---|---|---|---|
Siafis, 2022,21 Germany Funding: Innovative Medicines Initiative 2 Joint Undertaking under Grant Agreement No. 777394 for the project AIMS2-TRIALS | Systematic review with network meta-analysis 203 placebo-controlled, parallel RCTs (open or blinded) One relevant RCT related to guanfacine | Children or adults (age unspecified) with a diagnosis of ASD (at least DSM-III) and/or validated diagnostic tools | Intervention: Any pharmacological or dietary supplement interventions for ASD Comparator: Placebo | Primary outcomes:
Secondary outcomes:
Follow up: Minimum duration 7 days |
Cortese, 2018.23 UK Funding: Stichting Eunethydis (European Network for Hyperkinetic Disorders), and the UK National Institute for Health Research Oxford Health Biomedical Research Centre. | Systematic review with network meta-analysis 133 double-blind RCTs with at least 1 week duration 12 relevant RCTs related to guanfacine | Children (aged ≥ 5 years and < 12 years), adolescents (aged ≥ 12 years and < 18 years), or adults (≥ 18 years) with a primary diagnosis of ADHD (DSM-III, DSM-III-R, DSM-IV(TR), DSM-5, ICD-9, or ICD-10). | Intervention: Amphetamines atomoxetine, bupropion, clonidine, guanfacine, methylphenidate and modafinil given as oral therapy. Comparator: Any placebo or other drug | Primary outcomes:
Secondary outcomes:
Follow up: 12 weeks |
Osland, 2018,22 Cochrane Collaboration, UK Funding: Internal sources (of support)
External sources
| Systematic review 8 double-blind RCTs of any pharmacological treatment for ADHD in children with comorbid tic disorders One relevant RCT pertaining to guanfacine | Children 18 years or younger with a clinical diagnosis of ADHD and a chronic tic disorder (Tourette syndrome, chronic motor tic disorder, or chronic vocal tic disorder). | Intervention: Any pharmacological oral treatment for ADHD taken alone or in combination with another drug Comparator: Placebo | Primary outcome:
Secondary outcomes: Adverse effects Follow up: Guanfacine trial was 8 weeks long |
Luan, 2017, 25 China, Funding: unclear | Systematic review 73 “mostly” RCTs with minimum 3-week duration 13 relevant studies of unclear design pertaining to guanfacine | Children and adolescents aged 6 to 18 years diagnosed with ADHD (DSM-IV). | Intervention: Atomoxetine, bupropion, clonidine, guanfacine, methylphenidate and lisdexamfetamine Comparator: Placebo or other drugs | Primary: efficacy measured by the ADHD-RS Secondary: All cause withdrawals, withdraw due to adverse event, withdrawal due to lack of efficacy, nausea, abdominal pain, or fatigue for tolerability Follow up: minimum 3 weeks duration |
ADHD = attention-deficit/hyperactivity disorder; ADHD-RS = ADHD Rating Scale; ASD = Autism Spectrum Disorder; CGI-I = Clinical Global Impressions Scale-Improvement DSM = Diagnostic and Statistical Manual; ICD = International Classification of Disease; RCT = randomized controlled trial.
Table 3: Characteristics of Included Primary Clinical Studies
Study citation, country, funding source | Study design | Population characteristics | Intervention and comparator(s) | Clinical outcomes, length of follow up |
|---|---|---|---|---|
Iwanami, 2020,25 Japan, Funding: Shire International GmbH (manufacturer/licensee of Intuniv) | Phase 3, double-blind, placebo-controlled RCT | Japanese patients aged ≥ 18 years with ADHD (DSM-5) | Intervention: Guanfacine (n = 101) titrated from 2 mg per day to 4 to 6 mg per day (dose- optimization; 5 weeks), followed by 4 to 6 mg per day (dose-maintenance; 5 weeks), then tapered doses to 2 mg per day (2 weeks). Comparator: placebo (n = 100) | Primary Outcome: Change from baseline in total score on the Japanese version of the ADHD-RS-IV with adult prompts Secondary outcomes: Symptoms and improvement as measured by CGI-I, BRIEF-A, CAARS, CGI-S, AAQoL, PGI-I Safety outcomes: Adverse events, vital signs, body weight, ECG parameters, and clinical laboratory test values Length of follow up: 10 weeks |
Van Stralen, 2020,26 Canada, Funding: an investigator-initiated grant from Shire Canada Inc (manufacturer/licensee of Intuniv) | Single centre, double-blind placebo-controlled crossover trial | Children aged 6 to 12 years with:
| Intervention: Guanfacine initiated at 1mg per day and optimized over 4 weeks to a maximum of 4 mg per day. 8-week maintenance period, then tapering over 11 days and a 10-day washout period. Comparator: Placebo | Primary outcome: Executive function measured by the BRIEF-P Secondary outcomes: ADHD symptoms and behaviours measured using ADHD-RS-IV, CGI-S, and the CGI-I. Safety outcomes: Adverse events, vital sign measurements, physical examinations (weight and height), and Columbia Suicide Severity Rating Scale Length of follow up: Final visit to measure outcomes at 21 days after the last visit (15 visits total, varying from 7 days to 8 weeks between visits with more frequent visits on visit 2 to 6 to optimize the dose, then 8 weeks to sustain the dose before tapering off) |
AAQoL = adult attention-deficit hyperactivity disorder quality-of-life scale; ADHD = attention-deficit/hyperactivity disorder; ADHD-RS-IV = attention-deficit/hyperactivity disorder rating scale; BRIEF-A = Behaviour Rating Inventory of Executive Function–Adult Version; BRIEF-P = Behaviour Rating Inventory of Executive Function–Parent Version; CAARS = Conners' Adult ADHD Rating Scales, CGI-I = Clinical Global Impressions-Improvement; CGI-S = Clinical Global Impressions-Severity, DSM = Diagnostic and Statistical Manual; PGI-I = Patient Global Impressions-Improvement, RCT = randomized controlled trial.
Table 4: Characteristics of Included Guideline
Intended users, target population | Intervention and practice considered | Major outcomes considered | Evidence collection, selection, and synthesis | Evidence quality assessment | Recommendations development and evaluation | Guideline validation |
|---|---|---|---|---|---|---|
NICE, 201827 | ||||||
Intended users: Health care professionals Commissioners and providers, People with ADHD, and their families and carers Target population: People with ADHD | Clinical and cost-effectiveness of pharmacological treatment | Quality of life, ADHD symptoms, CGI, serious adverse events, behavioural, functional, emotional dysregulation, academic outcomes, substance use and self-harm |
| Evidence was rated according to GRADE | Committee discussed evidence to arrive at recommendations, including the trade-off between benefits and harms, economic consideration and resources, and feasibility of the intervention |
|
ADHD = attention-deficit hyperactivity disorder; CGI = Clinical Global Impressions; GRADE = Grading of Recommendations, Assessment, Development and Evaluations; NICE = The National Institute for Health and Care Excellence; RCT = randomized controlled trial.
Appendix 3: Critical Appraisal of Included Publications
Note that this appendix has not been copy-edited.
Table 5: Strengths and Limitations of Systematic Reviews and Network Meta-Analyses Using AMSTAR 216 and the ISPOR Questionnaire17
Strengths | Limitations |
|---|---|
Siafis, 202221 | |
|
|
Cortese, 201823 | |
|
|
Osland, 201822 | |
| |
Luan, 201724 | |
|
|
AMSTAR 2 = A MeaSurement Tool to Assess systematic Reviews 2; GRADE = Grading of Recommendations, Assessment, Development and Evaluations; ISPOR = International Society for Pharmacoeconomics and Outcomes Research; ITT = Intention to treat; NMA = network meta-analysis; PICO = Population, Intervention, Comparator, Outcome; RCT = randomized controlled trial.
Table 6: Strengths and Limitations of Clinical Studies Using the Downs and Black Checklist18
Strengths | Limitations |
|---|---|
Iwanami, 202025 | |
|
|
Van Stralen, 202026 | |
|
|
Table 7: Strengths and Limitations of Guideline Using AGREE II19
Item | NICE27 |
|---|---|
Domain 1: Scope and Purpose | |
1. The overall objective(s) of the guideline is (are) specifically described. | Yes |
2. The health question(s) covered by the guideline is (are) specifically described. | Yes |
3. The population (patients, public, etc.) to whom the guideline is meant to apply is specifically described. | Yes |
Domain 2: Stakeholder Involvement | |
4. The guideline development group includes individuals from all relevant professional groups. | Yes |
5. The views and preferences of the target population (patients, public, etc.) have been sought. | Unclear: The background of the commentors was not described |
6. The target users of the guideline are clearly defined. | Yes |
Domain 3: Rigour of Development | |
7. Systematic methods were used to search for evidence. | Yes |
8. The criteria for selecting the evidence are clearly described. | Yes |
9. The strengths and limitations of the body of evidence are clearly described. | Yes |
10. The methods for formulating the recommendations are clearly described. | No: While there were general processes described on the NICE website, the methods for formulating recommendations were vague |
11. The health benefits, side effects, and risks have been considered in formulating the recommendations. | Yes |
12. There is an explicit link between the recommendations and the supporting evidence. | No: The evidence review was separate to the guideline, making the links difficult to specify |
13. The guideline has been externally reviewed by experts before its publication. | No |
14. A procedure for updating the guideline is provided. | Yes |
Domain 4: Clarity of Presentation | |
15. The recommendations are specific and unambiguous. | Yes |
16. The different options for management of the condition or health issue are clearly presented. | Yes |
17. Key recommendations are easily identifiable. | Yes |
Domain 5: Applicability | |
18. The guideline describes facilitators and barriers to its application. | Yes |
19. The guideline provides advice and/or tools on how the recommendations can be put into practice. | Yes |
20. The potential resource implications of applying the recommendations have been considered. | Yes |
21. The guideline presents monitoring and/or auditing criteria. | No |
Domain 6: Editorial Independence | |
22. The views of the funding body have not influenced the content of the guideline. | Yes |
23. Competing interests of guideline development group members have been recorded and addressed. | Yes |
AGREE II = Appraisal of Guidelines for Research and Evaluation II; NICE = The National Institute for Health and Care Excellence.
Appendix 4: Main Study Findings and Authors’ Conclusions
Note that this appendix has not been copy-edited.
Table 8: Summary of Findings Included Systematic Reviews and Network Meta-Analyses
Main study findings | Authors’ conclusion |
|---|---|
Siafis, 202221 | |
Network meta-analysis (other medication comparisons that were not statistically significant: mirtazapine, valproate, risperidone, aripiprazole, L1 to 79, atomoxetine, memantine, bumetanide, tideglusib, sapropterin, fluoxetine, n-acetylcysteine, sertraline, buspirone, citalopram, mecamylamine, lamotrigine, oxytocin, lurasidone, arbaclofen, simvastatin) Primary outcomes (ref: placebo), results from comparisons in network meta-analysis) Socio-communication difficulties: SMD (95% CI) = 0.04 (−0.46 to 0.54) Repetitive behaviours: SMD (95% CI) = 0.55 (−0.02 to 1.11) Secondary outcomes (ref: placebo (95% CI), results from comparisons in network meta-analysis unless otherwise specified)
Note: Confidence in evidence was low, due to concerns regarding the imprecision and more minor concerns regarding indirectness | “Among ADHD medications, atomoxetine and guanfacine improved ADHD symptoms and potentially repetitive behaviors, but not social communication difficulties. Guanfacine was also associated with more adverse events and sedation.” (p 9) |
Cortese, 201823 | |
Network Meta-analysis Primary outcomes:
Tolerability (OR (95% CI): findings > 1 mean the first drug is less tolerable): GUA vs placebo: 2.64 (1.20,5.81) (no difference: amphetamines, ATX, BUP, clonidine, MPH) Secondary outcomes
Acceptability (OR (95% CI): findings > 1 mean lower acceptability for the first drug): GUA vs placebo: 0.81 (0.54,1.23) (no difference: amphetamines, ATX, BUP, Clonidine, MPH, MOD)
| “In children and adolescents, all compounds were superior to placebo on the CGI-I scale” (p 733) “With respect to tolerability, in children, only amphetamines and guanfacine were less well tolerated than placebo.”(p 734) “[Guanfacine] was not superior to placebo according to parents’ ratings (SMD –0·23, 95% CI –0·90 to 0·45) (p 733) “With respect to ADHD core symptoms rated by clinicians in children and adolescents, all drugs were superior to placebo” (p 731) |
Osland, 201822 | |
Primary outcomes:
Secondary outcomes:
| “Methylphenidate, clonidine, guanfacine, desipramine, and atomoxetine appear to reduce ADHD symptoms in children with tics though the quality of the available evidence was low to very low. Although stimulants have not been shown to worsen tics in most people with tic disorders, they may, nonetheless, exacerbate tics in individual cases. In these instances, treatment with alpha agonists or atomoxetine may be an alternative.” (p 2) |
Luan, 201724 | |
Network meta-analysis Primary outcome (ADHD-RS: value > 0 favours the first drug): GUA vs placebo: MD = 6.58 (2.32, 10.94) (no difference: ATX, CLON, MPH, LDX, MPH Secondary outcomes (95% credible interval) (all comparisons: ATX, CLON, MPH, LDX, MPH; no statistically significant difference unless otherwise noted): All cause withdrawal: GUA vs placebo: OR = 0.83 (0.63 to 1.09) Withdrawals due to adverse events: GUA vs placebo: OR = 3.39 (1.93 to 6.30) (additional: GUA vs ATX: OR = 2.29 (1.20, 4.57); GUA vs MPH: OR = 0.39 (0.18 to 0.83)) Withdrawal due to lack of efficacy: GUA vs placebo: OR = 0.37 (0.26 to 0.54) (additional: GUA vs LDX: OR = 3.46 (1.70 to 7.60) Nausea: GUA vs placebo: OR = 1.45 (0.83 to 2.64) (additional: GUA vs ATX: OR = = 0.51 (0.26 to 0.96)) Abdominal pain: GUA vs placebo: OR = 2.18 (1.55 to 3.19) (additional: GUA vs LDX: OR = 4.85 (2.25 to 10.1)) Fatigue: GUA vs placebo: OR = 4.22 (2.56 to 7.54) (additional: MPH vs GUA: OR = 0.19 (0.08 to 0.45)) | “ATX and [GUA] are located at moderate positions under symptom improvement and rate of withdrawal. There are not significant differences in ADHD-RS when compared with another therapy, which indicated comparable efficacy. ” (p. 11) “In summary, according to the results obtained from our NMA, the stimulants LDX and MPH are still highly recommended because they are highly efficacious and well tolerated by patients. Among the non-stimulants, CLON should be taken into consideration for its appreciable effectiveness and tolerability. ATX and [GUA] can be seen as moderate choices. We failed to evaluate BUP because of the lack of enhanced evidence.” (p. 12) |
ADHD = attention-deficit/hyperactivity disorder; ADHD-RS = ADHD Rating Scale; ATX = atomoxetine; BUP = bupropion; BSP = buspirone; CLON = clonidine; DEX = dexamphetamine; EDX = edivoxetine; GUA = guanfacine; LDX = lisdexamfetamine; MPH = methylphenidate; MAS = mixed amphetamine salts; MOD = modafinil; PDL = pindolol; OR = odds ratio; 95% CI = 95% confidence interval; RBX = reboxetine; SLG = selegiline; SD = standard deviation; SMD = standardized mean difference; MD = mean difference; VEN = venlafaxine; YGTSS = Yale Global tic Severity Scale.
Table 9: Summary of Findings of Included Primary Clinical Studies
Main study findings | Authors’ conclusion |
|---|---|
Iwanami, 202025 | |
Primary outcome: ADHD-RS-IV total score: Change of −11.55 (1.10) vs −7.27 (1.07); MD = −4.28 (–6.67 to –1.88) in treatment vs placebo group respectively(P = 0.0005) Secondary outcomes (MD (95% CI): value < 0 favours GUA) ADHD-RS-IV inattention: MD = −2.51 (–4.16 to –0.85) (P = 0.0032) ADHD-RS-IV hyperactivity-impulsivity: MD = −1.74 (–2.84 to –0.64) (P = 0.0021) CAARS scores:
AAQoL: no statistically significant changes in total score or sub-dimensions (life outlook, relationships, psychological health) except for life productivity (MD = 6.78 (1.86 to 11.71), P = 0.0072) BRIEF-A: statistically significant changes for Inhibit (MD = −2.91 (–5.30 to –0.52) 0.0173), Initiate (MD = −3.32 (–6.49 to –0.14)), Plan/Organize (MD = −3.76 (–6.85 to –0.67) P = 0.0174) but not Shift, Emotional Control, Self-Monitor, Behavioural Regulation Index, Working Memory, Task Monitor or Organization of Materials Metacognition Index: MD = −3.04 (–6.11 to 0.03) 0.0519 Global Executive Function Index: MD = −3.06 (–5.99 to –0.14) 0.0404 Safety outcomes: n = 82 (81%) in GUA vs n = 62 (62%) in placebo had adverse event, 19.8% lead to discontinuation in GUA group vs 3% in placebo group. 2% had severe in GUA group vs 0 in placebo group. | “The superiority of [guanfacine] compared with placebo was demonstrated for ADHD symptoms as measured by the ADHD-RS-IV and CAARS. Furthermore, the improvement in ADHD symptoms was associated with physician- and patient-rated clinical improvement (CGI-I and PGI-I) as well as patient-rated quality of life (life productivity on the AAQoL) and executive functioning (some BRIEF-A subscales). The most commonly observed [treatment related adverse events] were mild to moderate in severity and consistent with the known safety profile of GXR. The favorable benefit-risk profile of [guanfacine] in the treatment of ADHD was established in pediatric patients, and these results support its profile in adult patients.” (p e7) |
Van Stralen, 202026 | |
Primary outcome: BRIEF-P: MD = −3.0, 95% CI [−5.9, −0.2]; p value = 0.0392 (change of −9.2% (SE = 2.11%) vs. −6.9% (SE = 1.94%) in the treatment vs placebo arm, respectively) Secondary outcomes (MD [95% CI]; negative MD favours GUA):
Safety outcomes: Any adverse event: n = 41 (87%) vs n = 41 (85%) in GUA vs placebo respectively. Headache most common (49% vs 33%) followed by abdominal pain (30% vs 10%) No “yes” responses to the CSSRS during the GUA arms of the study. | “The results of this study show that adjunctive administration of the selective α2A-adrenoceptor agonist, [guanfacine], to a psychostimulant in patients with suboptimal response to psychostimulants improves executive function...This adjunct therapy also improved the ADHD symptom control as assessed by the ADHD-RS-IV and the CGI-I and CGI-S scales.” (p 322) |
AAQoL = adult attention-deficit/hyperactivity disorder quality-of-life scale; ADHD = attention-deficit/hyperactivity disorder; ADHD-RS-IV = ADHD Rating Scale IV; BRIEF-A = Behaviour Rating Inventory of Executive Function–Adult Version; BRIEF-P = Behavioural Rating Inventory of Executive Function; CAARS = Conners' Adult ADHD Rating Scales; CGI-S = Clinical Global Impressions of Severity of Illness; CGI-I = Clinical Global Impressions-Improvement; CSSRS = Columbia Suicide Severity Rating Scale; MD = mean difference.
Table 10: Summary of Recommendations in Included Guideline
Recommendations and supporting evidence | Quality of evidence and strength of recommendations |
|---|---|
NICE, 201827 | |
“1.7.10 Offer atomoxetine or guanfacine to children aged 5 years and over and young people if:
“1.7.17 Do not offer any of the following medication for ADHD without advice from a tertiary ADHD service:
“1.8.14 If tics are stimulant related, reduce the stimulant dose, or consider changing to guanfacine (in children aged 5 years and over and young people only)...” (p 31) Supporting evidence: “Atomoxetine and guanfacine were the non-stimulant drugs with the most convincing evidence. The committee noted that atomoxetine is more widely used and that there was stronger evidence for a benefit of atomoxetine compared with placebo than guanfacine compared with placebo.” (p. 46) | The word ‘offer’: clear and strong evidence of benefit (1.7.10, 1.7.17) The word 'consider': evidence is less certain (1.8.14) |
ADHD = attention-deficit/hyperactivity disorder; NICE = The National Institute for Health and Care Excellence.
Appendix 5: Overlap Between Included Systematic Reviews
Note that this appendix has not been copy-edited.
Table 11: Overlap in Relevant Primary Studies between Included Systematic Reviews
Primary study citation | Osland, 2018 22 | Cortese, 2018 23 | Luan, 201726 |
|---|---|---|---|
Scahill L, et al. American Journal of Psychiatry 2001;158(7):1067 to 74. | Yes | Yes | — |
Biederman J, et al. Pediatrics. 2008;121(1):e73 to 84. | — | Yes | Yes |
Connor DF, et al. CNS Drugs. 2010;24(9):755 to 768. | — | Yes | Yes |
Newcorn JH, et al. J Am Acad Child Adolesc Psychiatry. 2013;52(9):921 to 930. | — | Yes | Yes |
Rugino TA. J Atten Disord. 2014. | — | Yes | Yes |
Sallee FR, et al. J Am Acad Child Adolesc Psychiatry. 2009;48(2):155 to 165. | — | Yes | Yes |
Hervas A, et al. Eur Neuropsychopharmacol. 2014;24(12):1861 to 1872. | — | Yes | Yes |
Wilens TE, et al.J Am Acad Child Adolesc Psychiatry. 2015;54(11):916 to 925.e912. | — | Yes | Yes |
Appendix 6: Details on included scales
Note that this appendix has not been copy-edited.
ADHD Rating Scale, ADHD Rating Scale IV (ADHD-RS)24-26: completed independently by a parent or teacher, and scored by a clinician. The scale consists of 2 subscales: inattention (9 items) and hyperactivity-impulsivity (9 items) for a total of 18 items. The total score can range from 0 to 54; a higher score means worse ADHD symptoms.
Behaviour Rating Inventory of Executive Function–Parent (BRIEF-P)26: an 86-item questionnaire completed by parents to assess executive function in children. Raw scores are transformed to T-scores of which above 65 is considered clinically significant.
Behaviour Rating Inventory of Executive Function - Adult Version (BRIEF-A)25: like the BRIEF-P but for adults, it includes 75 items to assess adult executive function behaviours.
Clinical Global Impressions- Severity of illness (CGI-S)21,23,25,26: Scale ranges from 1 (no symptoms) to 7 (very severe symptoms).
Clinical Global Impressions-Improvement (CGI-I)21,23,25,26: Scale ranges from 1 (most improvement) to 7 (least improvement): Three or less means improvement, 4 means no change, 5 to 7 means worse.
Yale Global Tic Severity Scale (YGTSS) total tic score22: tool to quantify the severity of tic symptoms in children aged 6 to 17. A higher score indicates more severe tics symptoms: the Total Tic Severity Score has a range of 0 to 50, and the Global Severity Score has a range of 0 to 100.
Appendix 7: References of Potential Interest
Note that this appendix has not been copy-edited.
Previous CADTH Reports
Harricharan S, Frey N. Intravenous acetaminophen for the management of short-term post-operative pain: a review of clinical effectiveness and cost-effectiveness. (CADTH rapid response report: summary with critical appraisal). Ottawa (ON): CADTH; 2018: https://www.cadth.ca/sites/default/files/pdf/htis/2019/RC1023%20IV%20Acetaminophen%20v2%20Revised%20Final.pdf. Accessed 2022 June 5.
Additional References
American Academy of Neurology. Practice guideline recommendations summary: treatment of tics in people with Tourette Syndrome and chronic tic disorders. 2019; https://www.aan.com/Guidelines/Home/GuidelineDetail/958. Accessed 2022 June 5.
Molife C, Haynes VS, Nyhuis A, et al. Healthcare utilization and costs of children with attention deficit/hyperactivity disorder initiating atomoxetine versus extended-release guanfacine. Curr Med Res Opin. 2018;34(4):619-632. .PubMed
Newcorn JH, Huss M, Connor DF, Hervás A, Werner-Kiechle T, Robertson B. Efficacy of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder. J Dev Behav Pediatr. 2020 Sep;41(7):565-570. .PubMed
United States Department of Veteran Affairs. Management of posttraumatic stress disorder and acute stress reaction 2017. (VA/DoD Clinical Practice Guidelines). 2017; https://www.healthquality.va.gov/guidelines/MH/ptsd/. Accessed 2022 June 5.
ISSN: 2563-6596
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This disclaimer and any questions or matters of any nature arising from or relating to the content or use (or misuse) of this document will be governed by and interpreted in accordance with the laws of the Province of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusive jurisdiction of the courts of the Province of Ontario, Canada.
The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document for non-commercial purposes only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors.
About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system.
Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.
Questions or requests for information about this report can be directed to Requests@CADTH.ca