2024 Volume 47 Issue 6 Pages 1204-1208
Guanfacine, used as a medication for attention-deficit/hyperactivity disorder (ADHD), leads to a high incidence of somnolence, in contrast to methylphenidate, which leads to a high incidence of insomnia. The impact of somnolence on continuing guanfacine treatment is unclear. Therefore, we investigated the reasons for discontinuing guanfacine and analyzed the factors associated with discontinuation caused by somnolence. We surveyed 96 patients under guanfacine from July 2017 to December 2021 at the Saga University Hospital. Patients who discontinued guanfacine by the end date of our study were divided into a median early and late group. We compared the reasons for discontinuation in both groups. Of all patients, 47 continued and 49 discontinued guanfacine. A higher percentage of patients discontinued guanfacine caused by somnolence for ≤70 d than for >70 d of treatment (44.0 vs. 8.3%; p = 0.008). When stratified by the concomitant use of other ADHD drugs, somnolence resulted in a higher discontinuation rate for ≤70 d than for >70 d of treatment without concomitant use (55.0 vs. 7.1%; p = 0.009). Nonetheless, concomitant use resulted in no difference. In conclusion, somnolence affects the early discontinuation of guanfacine as an ADHD drug. The combination of methylphenidate or atomoxetine may decrease withdrawal caused by somnolence.
Attention-deficit/hyperactivity disorder (ADHD) is a common behavioral disorder characterized by symptoms such as inattention, hyperactivity, and impulsivity. The inattention subtype is more common in girls despite ADHD prevalence in boys.1,2) By contrast, ADHD becomes less sex-specific with increasing age. Moreover, it is recognized that many patients with ADHD have other psychiatric comorbidities and that a timely diagnosis of ADHD is crucial to reduce the risk of developing ADHD-related comorbidities.3)
Several pharmacological treatment options have been identified for ADHD.4) Guanfacine is a selective alpha 2A adrenergic receptor agonist that suppresses hyperactivity and impulsivity by reducing sympathetic overexcitation.5) Two meta-analyses demonstrated guanfacine as an effective and safe treatment for ADHD.6,7) Therefore, it is recommended as a pharmacotherapy for patients with difficulty using psychostimulants because of tolerability or other factors. By contrast, guanfacine leads to a higher incidence of somnolence, contrary to methylphenidate, which leads to a higher incidence of insomnia. The impact of somnolence on continuing guanfacine treatment remains unclear. Results of previous randomized controlled trials (RCTs) indicated few adverse events leading to discontinuing guanfacine.8) Hypotension and somnolence are the primary adverse events resulting in guanfacine discontinuation.9) However, the factors associated with guanfacine discontinuation caused by somnolence are unclear.
We investigated the reasons that lead to guanfacine discontinuation. Moreover, we analyzed the factors related to discontinuation caused by somnolence.
Patients under guanfacine for ADHD from July 2017 to December 2021 at the Saga University Hospital were enrolled. Patients without known outcomes were excluded. Finally, 96 patients were included in this study (Fig. 1). ADHD diagnoses were conducted comprehensively by a specialist using the ADHD-rating scale completed at home and school, considering daily living conditions and the course of previous medical interviews. All data were anonymized, and patient confidentiality was protected. This retrospective study was approved by the Institutional Review Board of Saga University Hospital (Approval No. 2023-02-02). Informed consent was obtained in the form of opt-out consent on the hospital website.
Data on the age, sex, treatment line, concomitant drugs, adverse events, and outcomes were obtained from medical records. In this study, somnolence was defined as an overall assessment made by the attending physician based on complaints of daytime sleepiness by the patient or family members. Furthermore, we included drowsiness as part of somnolence since the superordinate term somnolence encompasses the subordinate term drowsiness, which is defined as being generally synonymous in the Japanese version of the Medical Dictionary for Regulatory Activities. The efficacy of guanfacine was based on the overall judgment of the physician and was discontinued when clinically ineffective. The study termination date was set for June 2022, and patients who discontinued guanfacine by this date were divided into early and late stages in the median. They were compared for sex, age, treatment line, concomitant drugs, adverse events, and outcomes.
Statistical AnalysesCategorical variables (sex, concomitant drugs, adverse events, and outcomes) were compared between the early and late stages using the chi-squared test. Age was treated as a continuous variable and compared using the Mann–Whitney U test. All statistical analyses were performed using JMP®16 software (SAS Institute, Cary, NC, U.S.A.). p < 0.05 indicated statistical significance.
Table 1 summarizes the characteristics of 96 patients. Of them, 72 were boys or men and 24 were girls or women, with a mean age of 11.9 years. Fifty-six patients had been treated previously, and 29 were treated concomitantly with other ADHD drugs while initiating guanfacine. The most common concomitant psychiatric disorder was autism spectrum disorder, affecting 66.7% of the patients. Adverse events were reported in 59 patients, the most common being somnolence. Figure 2 presents the Kaplan–Meier curve of guanfacine continuation rates. Approximately 30% of all patients discontinued guanfacine within 100 d. Forty-seven patients continued and 49 discontinued guanfacine until study termination. The median treatment duration in the discontinuation group was 70 d.
| Factor | n [%] or mean ± S.D. |
|---|---|
| N | 96 |
| Sex | |
| Boys or men | 72 (75.0) |
| Girls or women | 24 (25.0) |
| Age | 11.9 ± 9.8 |
| Treatment line | |
| First | 40 (41.7) |
| Non first | 56 (58.3) |
| Concomitant psychiatric disorders | |
| Autism spectrum disorder | 64 (66.7) |
| Other developmental disability | 19 (19.8) |
| Depression | 2 (2.1) |
| Epilepsy | 5 (5.2) |
| Tic disorder | 3 (3.1) |
| Concomitant drugs | |
| Other ADHD drugs | 29 (30.2) |
| Methylphenidate | 24 (24.0) |
| Atomoxetine | 5 (5.2) |
| Psychotropic drugs | 28 (29.2) |
| Antipsychotic drugs | 24 (25.0) |
| Antidepressant drugs | 2 (2.1) |
| Hypnotics | 2 (2.1) |
| Adverse events | 59 (61.4) |
| Somnolence | 45 (46.9) |
| Headache | 8 (8.3) |
| Constipation | 2 (2.1) |
| Low blood pressure | 2 (2.1) |
| Staggering | 2 (2.1) |
| Abdominal pain | 1 (1.0) |
| Sleeplessness | 1 (1.0) |
| Loss of appetite | 1 (1.0) |
| Dizziness | 1 (1.0) |
| Fatigue | 1 (1.0) |
| Nocturia | 1 (1.0) |
| Nausea | 1 (1.0) |
| Abnormal behavior | 1 (1.0) |
| Outcome at endpoint | |
| Continuation | 47 (49.0) |
| Discontinuation | 49 (51.0) |
ADHD, attention-deficit/hyperactivity disorder; S.D., standard deviation.
The discontinuation group was divided into two subgroups, namely, ≤70 d and >70 d of treatment. Table 2 summarizes the results of the comparison of several factors. Adverse events accounted for 48% of the reasons for guanfacine discontinuation in the ≤70 d group. Of these, discontinuation caused by somnolence was higher in the ≤70 d group than in the >70 d group (44.0 vs. 8.3%; p = 0.008). In contrast, the percentage of concomitant use of other ADHD drugs was higher in the >70 d group than in the ≤70 d group (20.0 vs. 41.7%; p = 0.13). Other ADHD drugs included methylphenidate and atomoxetine.
| Factor | Duration of guanfacine use | p-Value | |
|---|---|---|---|
| ≤70 d | >70 d | ||
| N | 25 | 24 | |
| Sex | |||
| Boys or men | 20 (80.0) | 16 (66.7) | 0.35 |
| Girls or women | 5 (20.0) | 8 (33.3) | |
| Age | 15.4 ± 15.0 | 10.2 ± 4.5 | 0.33 |
| Treatment line | |||
| First | 10 (40.0) | 8 (33.3) | 0.77 |
| Non first | 15 (60.0) | 16 (66.7) | |
| Concomitant psychiatric disorders | |||
| Autism spectrum disorder | 15 (60.0) | 17 (70.8) | 0.55 |
| Other developmental disability | 7 (28.0) | 5 (20.8) | 0.74 |
| Depression | 0 (0.0) | 1 (4.2) | 0.49 |
| Epilepsy | 2 (8.0) | 0 (0.0) | 0.49 |
| Tic disorder | 0 (0.0) | 2 (8.3) | 0.23 |
| Concomitant drugs | |||
| Other ADHD drugs | 5 (20.0) | 10 (41.7) | 0.13 |
| Methylphenidate | 4 (16.0) | 8 (33.3) | 0.20 |
| Atomoxetine | 1 (4.0) | 2 (8.3) | 0.61 |
| Psychotropic drugs | 5 (20.0) | 5 (20.8) | 1 |
| Antipsychotic drugs | 4 (16.0) | 4 (16.7) | 1 |
| Antidepressant drugs | 0 (0.0) | 1 (4.2) | 0.49 |
| Hypnotics | 1 (4.0) | 0 (0.0) | 1 |
| Reason for discontinuance | |||
| Adverse events | 12 (48.0) | 6 (25.0) | 0.67 |
| Somnolence | 11 (44.0) | 2 (8.3) | 0.008 |
| Headache | 0 (0.0) | 2 (8.3) | 0.23 |
| Staggering | 0 (0.0) | 1 (4.2) | 0.49 |
| Sleeplessness | 1 (4.0) | 0 (0.0) | 1 |
| Loss of appetite | 0 (0.0) | 1 (4.2) | 0.49 |
| Fatigue | 1 (4.0) | 0 (0.0) | 1 |
| Nocturia | 0 (0.0) | 1 (4.2) | 0.49 |
| Nausea | 0 (0.0) | 1 (4.2) | 0.49 |
| Abnormal behavior | 1 (4.0) | 0 (0.0) | 1 |
| Insufficient effect | 10 (40.0) | 9 (37.5) | 1 |
| Patient request | 5 (20.0) | 6 (25.0) | 0.74 |
| Unknown | 2 (8.0) | 3 (12.5) | 0.67 |
n [%] or mean ± S.D.; ADHD, attention-deficit/hyperactivity disorder.
We compared the percentage of discontinuations caused by somnolence in both ≤70 d and >70 d groups, stratified by the concomitant use of other ADHD drugs. In the absence of concomitant drug use, discontinuation caused by somnolence was significantly higher in the ≤70 d group than in the >70 d group (55.0 vs. 7.1%; p = 0.009). In contrast, in the presence of concomitant drug use, there was no difference in the rate of discontinuation caused by somnolence in both groups (Table 3).
| Factor | Duration of guanfacine use | p-Value | |||
|---|---|---|---|---|---|
| ≤70 d | >70 d | ||||
| Other ADHD drugs | (−) | N | 20 | 14 | |
| Somnolence, n [%] | 11 (55.0) | 1 (7.1) | 0.009 | ||
| (+) | N | 5 | 10 | ||
| Somnolence, n [%] | 0 (0.0) | 1 (10.0) | 1 | ||
ADHD, attention-deficit/hyperactivity disorder.
We observed a high percentage of guanfacine discontinuation caused by somnolence at a relatively early stage. However, discontinuation caused by somnolence was mitigated by other concomitant ADHD drugs. The association of methylphenidate with insomnia has been reported previously.10,11) Atomoxetine causes less severe insomnia than methylphenidate.12,13) Guanfacine and these combination therapies may offset somnolence and insomnia.
Researchers have demonstrated the efficacy and safety of combined guanfacine and methylphenidate. In an RCT, combination therapy with guanfacine and methylphenidate demonstrated an ADHD Rating Scale IV total score advantage over guanfacine monotherapy; moreover, it improved the inattention subscale compared with methylphenidate monotherapy.14) These combination therapies were superior to guanfacine monotherapy regarding cognitive function.15) By contrast, cardiovascular events are a matter of concern, and the combination of guanfacine and methylphenidate may reduce the risk of these events, compared with guanfacine alone.16) Combination therapy resulted in mild to moderate adverse events without safety or tolerability issues.14) However, the incidence of somnolence was almost equal, 23.5% for guanfacine alone and 21.4% for combination therapy.14) Our results demonstrate a difference in the incidence of somnolence, namely, 35.3% for guanfacine monotherapy and 6.7% for combination therapy, despite no classification by the treatment duration. Possible factors contributing to the varied differences include race, drugs, foods, and drinks that affect sleepiness. The survey may also have been influenced by the inclusion of patients who discontinued because of somnolence. However, considering the adverse event profiles of these agents, combination therapy may prevent worsening sleep status. Somnolence was observed in 45 patients during guanfacine use, and 32 (71.1%) of them continued treatment throughout the study period. Although our study does establish a causal relationship between continued guanfacine use and a reduction in somnolence, it may support existing reports indicating a decrease in adverse events, including somnolence with continued guanfacine.17,18) Nevertheless, somnolence was the most common reason for guanfacine discontinuation regarding adverse events. We believe this issue needs to be resolved to maintain efficacy.
In our study, children and adolescents were combined with adults, whereas existing RCT typically analyzed these age groups separately. The incidence of somnolence in RCT has been reported to be 27.0% in children and adolescents and 34.7% in adults.8,9) However, the incidence of somnolence in this study was 48.9% in children and adolescents and 25.0% in adults. The difference in rates between children and adolescents may be attributed in part to racial differences and the absence of assessment of somnolence using measures such as the Epworth Sleepiness Scale.
Adverse events may cause the discontinuation of medication on an individual case basis. A network meta-analysis demonstrated that guanfacine resulted in a higher risk of dropout because of adverse events and was less well tolerated than placebo in children and adolescents.19) Somnolence was supposedly one of the adverse events that led to dropout. Children and adolescents have classes at school, and excessive somnolence may interfere with their daily lives. Notably, existing reports have shown that somnolence during the day affects academic performance,20,21) and somnolence associated with guanfacine use may also have this adverse effect. Thus, the management of somnolence may be important for the efficacy of guanfacine.
The strength of this study is that it demonstrated practical reasons for discontinuing guanfacine and factors supposedly associated with somnolence. Nevertheless, this study has some limitations. First, we performed a single-center retrospective study, and consequently, the results may be biased. The exclusion criteria were minimal to limit this bias. Second, patient adherence was unclear. Furthermore, the duration of administration was determined by the number of prescription days, which may vary. Third, concomitant medications that induce somnolence might have influenced the study results. However, if patients had received prescriptions outside of our hospital, we might lack comprehensive information regarding their concomitant medications. Finally, we used a limited sample size. Therefore, it was challenging to perform multivariate analysis in the comparisons in Table 2. Moreover, we cannot exclude the presence of unadjusted confounding factors. However, the stratified analysis suggested that other ADHD medications may have influenced dose discontinuation caused by early somnolence. Further studies with larger sample sizes are required to improve the credibility of these results.
We identified somnolence as a factor for early guanfacine discontinuation and that the combination of methylphenidate or atomoxetine may decrease discontinuation caused by somnolence. This finding supports previous evidence for combination therapies and is useful for ADHD pharmacotherapy.
The authors declare no conflict of interest.
