Journal ofhttp://jad.sagepub.com/ Attention Disorders
Effect on Primary Sleep Disorders When Children With ADHD Are Administered Guanfacine Extended Release Thomas A. Rugino Journal of Attention Disorders published online 6 November 2014 DOI: 10.1177/1087054714554932 The online version of this article can be found at: http://jad.sagepub.com/content/early/2014/11/06/1087054714554932
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JADXXX10.1177/1087054714554932Journal of Attention DisordersRugino
Article
Effect on Primary Sleep Disorders When Children With ADHD Are Administered Guanfacine Extended Release
Journal of Attention Disorders 1–11 © 2014 SAGE Publications Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1087054714554932 jad.sagepub.com
Thomas A. Rugino1,2
Abstract Objective: To evaluate children with ADHD and sleep problems with polysomnography (PSG) after guanfacine extendedrelease (GXR) administration. Method: Double-blind, randomized, placebo-controlled study was terminated early due to treatment-emergent concerns after enrolling 29 children aged 6 to 12 years. After >4 weeks dose adjustment and >1 week dose stabilization, 11 children received GXR and 16 controls underwent analyses with PSG. Results: Although GXR improved ADHD symptoms, the primary outcome variable, total sleep time, was shorter in contrast to placebo (−57.32, SD = 89.17 vs. +31.32, SD = 59.54 min, p = .005). Increased time awake after sleep onset per hour of sleep was the primary factor for the reduction. Although rapid eye movement (REM), non-REM, and N3/slow wave sleep times were reduced, these were proportional to the overall sleep reduction. Sedation was common with GXR (73% vs. 6%). Conclusion: Morning-administered GXR resulted in decreased sleep and may contribute to sedation. (J. of Att. Dis. XXXX; XX(X) XXXX) Keywords ADHD, pharmacotherapy, insomnia, sleep, polysomnography, randomized controlled trial
Introduction Disorders of sleep duration and quality are significant comorbidities for 25% to 75% of children and adolescents with ADHD (Bullock & Schall, 2005; Chervin, Dillon, Bassetti, Ganoczy, & Pituch, 1997; Cortese, Faraone, Konofal, & Lecendreux, 2009; Golan, Shahar, Ravid, & Pillar, 2004; Owens, 2009; Weiss & Selpekar, 2010; Yoon, Jain, & Shapiro, 2012). Although initial (onset) insomnia can be exacerbated by medications used to treat ADHD or comorbid conditions (American Academy of Child and Adolescent Psychiatry Work Group on Quality Issues, 2007; Stein, Weiss, & Leventhal, 2007), considerable evidence suggests that the presence of sleep disorders are unrelated to pharmacologic interventions (Cortese et al., 2009). Although sleep disorders are common in children with ADHD, even 1-hr restriction of sleep has been shown to negatively affect neurobehavioral functioning (specifically performance on continuous performance testing); this deterioration is significant enough to cause a substantial number of children to drop from subclinical to clinical ranges of inattention (Gruber et al., 2011). Therefore, finding a treatment that may improve sleep in children with ADHD and sleep problems may provide even greater than expected benefits in core ADHD symptoms.
A mainstay of treatment, sleep hygiene has been shown to improve sleep quality and improve initial (onset) insomnia in children with ADHD (Hryshko-Mullen, Broeckl, Haddock, & Peterson, 2000; LeBourgeois, Giannotti, Cortesi, Wolfson, & Harsh, 2005; Van der Heijden, Smits, Van Someren, & Gunning, 2005; Weiss, Wasdell, Bomben, Rea, & Freeman, 2006). However, when sleep hygiene and behavioral treatments have failed, the use of a sleep-promoting medication may be appropriate as a final resort (Gringras, 2008; Weiss & Selpekar, 2010). The most commonly prescribed sleep aides for children (melatonin, diphenhydramine and H1-blockers, chloral hydrate, benzodiazepines, trazodone, cyproheptadine, mirtazapine, tricyclic antidepressants, L-theanine, nonbenzodiazepine hypnotics such as zolpidem, eszolpiclone, and zalepion; Barrett, Tracy, & Giaroli, 2013; Kratochvil, Lake, Pliszka, & Walkup, 2005; Pelayo & Dubik, 2008) do not have the pharmacologic targets to significantly improve ADHD symptoms. Immediate-release clonidine is effective and has 1
Children’s Specialized Hospital, Toms River, NJ, USA Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA
2
Corresponding Author: Thomas A. Rugino, MD, Children’s Specialized Hospital, 94 Stevens Road, Toms River, NJ 08755, USA. Email: [email protected]
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been commonly prescribed for insufficient sleep (Pelayo & Dubik, 2008). However, its rapid absorption and limited half-life necessitates frequent administration to manifest ADHD symptom improvement during the day; when administered during the day, the resultant peak plasma concentrations often lead to tolerability problems such as sedation (Connor, Fletcher, & Swanson, 1999; Croxtall, 2011; Keranen, Nykanen, & Taskinen, 1978). However, no published reports involving the effects of extended-release clonidine within the context of sleep disorders were evident as of the date of this manuscript. Another, more selective, α-2 agonist, guanfacine (immediate-release tablets, and the more recent extended-release tablets), has been used as a treatment for ADHD for more than a decade, with established safety and efficacy (Biederman et al., 2008; Hunt, Arnsten, & Asbell, 1995; Sallee, Lyne, Wigal, & McGough, 2009; Sallee, McGough, Wigal, Donahue, Lyne, & Biederman, 2009; Scahill, 2009; Silver, 1999). Although several studies cite sedation or somnolence (generally transient and mild to moderate) as common adverse events for guanfacine (Biederman et al., 2008; Kollins et al., 2011; Sallee, Lyne, et al., 2009; Sallee, McGough, et al., 2009; Scahill, 2009), and although previous studies cited no significant differences in reported daytime sleepiness using checklist scales (Biederman et al., 2008; Sallee, McGough, et al., 2009), no published reports involving the effects of guanfacine extended release (GXR) within the context of sleep disorders have been published as of the time of this manuscript. In addition, no studies have reported the effect of guanfacine on direct measures of sleep, such as polysomnography (PSG). The purpose of this investigation was to determine whether morning administration of GXR tablets altered the duration and quality of sleep (as determined by PSG) while reducing daytime ADHD symptoms (as determined by clinician assessment using standard ADHD questionnaires) in a school-age ADHD population with pre-existing sleep problems.
Method Sequential children 6 to 12 years of age with ADHD, who had a self- or parent-reported concern with sleep duration or quality despite adequate sleep hygiene practices and caffeine restriction, were recruited for this study at a suburban children’s developmental and rehabilitation referral center. After Institutional Review Board–approved informed consent (and assent when appropriate) was completed in accordance with hospital standard operating procedures, the screening visit included an evaluation for the presence of ADHD and any potentially confounding co-morbidity with the Children’s Schizophrenia and Affective Disorders Scales (Kiddie-SADS; Kaufman et al., 1997). A sheet outlining appropriate sleep hygiene practices was given to the family; this sheet was used as a checklist to
assess sleep hygiene during the interview with the caretaker and the child. If inappropriate sleep hygiene contributed significantly to sleep problems at the time of the screening assessment, the family was counseled, and a follow-up evaluation was repeated in 7 to 14 days. If at the follow-up evaluation, sleep hygiene still significantly contributed to inadequate or poor quality sleep and the family was unable or unwilling to establish adequate sleep hygiene practices, the participant was terminated from the study. A caffeine intake checklist was completed for 7 consecutive days prior to the polysomnogram; excessive caffeine intake (greater than 1.5 mg/kg/day or a single day caffeine intake greater than 2.5 mg/kg/day) resulted in termination from the study. Screening included an evaluation by a subspecialty board-certified neurodevelopmental pediatrician, vital signs including supine and standing blood pressure (BP) and pulse, growth parameters, detailed medical history, medication administration history, and physical examination. Screening also included an electrocardiogram (ECG), routine metabolic profile, complete blood count (CBC), urinalysis (UA), urine drug screen, clinician-conducted interview with the parent for scoring the ADHD Rating Scale–IV (ADHDRS; DuPaul, Power, Anastopoulos, & Reid, 1998), clinician-conducted ADHD Clinical Global Impression of Severity (CGI-S; Guy, 1976), Sleep CGI-S, and completion of a parent-reported Children’s Sleep Habits Questionnaire (CSHQ; Owens, Spirito, & McGuinn, 2000). Females of child-bearing potential had a serum pregnancy test (β-human chorionic gonadotropin [β-HCG]); if pregnant, nursing, or positive for β-HCG, the child was excluded from the study. To be included in the study, the ADHDRS had to confirm the diagnosis of ADHD with >6 inattentive symptoms scoring ≥2 (often) and/or >6 hyperactivity– impulsivity symptoms scoring ≥2 (often), and the ADHD CGI-S score had to confirm at least mild severity (≥3). Children were excluded from the study if the body mass index was less than fifth percentile for age (using the Centers for Disease Control standards as reported by Kuczmarski et al., 2000) or if the body weight was >176 pounds (80 kg). Clinically significant psychiatric pathology, such as autism, autism spectrum disorder, major depression, bipolar disorder, or anxiety, was also exclusionary. Children with clinically significant medical conditions such as hepatic, neurologic, hemodynamic, cardiac, or renal dysfunction (including clinically significant electrocardiographic findings), or with clinically significant laboratory findings were excluded. Medications and supplements with sedative, hemodynamic, or neuropsychiatric properties, or that have known drug–drug interactions with guanfacine had to be discontinued or weaned before baseline assessments. If the child had been administered medications for ADHD at the time of the screening visit, wean or discontinuation was completed so that the child was free of these medications for at least 1 week prior to completion of
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Rugino screening procedures. Although permitted by the protocol, none of the enrolled participants had been administered atomoxetine within a month prior to screening. Although obstructive sleep apnea and periodic limb movement disorders were to be exclusionary, no participant failed screening due to either of these disorders. Children who met inclusion and exclusion criteria who also had a CSHQ total score of >41 underwent a screening overnight multichannel polysomnogram to determine latency to persistent sleep, total sleep time, time awake after sleep onset, and times of sleep phases. Dose optimization was initiated with a flexible-dose, randomized, double-blind, placebo-administered design with study medication administered once a day in the morning. The dose started with either 1 mg GXR or matching placebo starting the morning after the baseline visit. At weekly visits, the dose was adjusted upward by 1 mg (to a maximum dose of 4 mg or matching placebo) if the investigator assessed the response to treatment as being sub-optimal (if either the ADHD Clinical Global Impression of Improvement [CGI-I] was 4), or if a higher dose was not likely to be tolerated based on currently reported side effects. The dose was reduced or discontinued if the investigator assessed the response to study medication to be intolerable; only one dose reduction by 1 mg was permitted before discontinuation. Dose adjustments were permitted until the Week 5 visit. At the early termination visit (when assessments were feasible) or at the termination visit (within 14 days of the Week 4 or 5 visit as long as the dose was stable for at least 7 days), the following data were obtained: a polysomno-gram, a CSHQ, an ADHDRS, ADHD CGI-I, a sleep CGI-I, vital signs, growth parameters, physical examination, detailed interval medical history, ECG, and laboratory investigations. After the termination visit, the study medication was weaned over the course of 7 to 10 days. Follow-up was conducted approximately 30 days following the last dose of study medication to record adverse events. Follow-up continued until all adverse events reached resolution or stabilization. The primary outcome measure was the polysomnographic minutes of total sleep time, although data collected included time of lights out, sleep efficiency, latency to sleep onset, latency to persistent sleep, number of awakenings, time awake after sleep onset, latency to rapid eye movement (REM) sleep, total apnea/hypopnea events, total limb movements, duration of sleep phases (REM, N1, N2, N3, the latter being slow wave sleep). The polysomnogram was conducted using a Sandman system at the Mid-Atlantic School of Sleep Medicine, in a dedicated, electrically insulated, quiet,
individual room, easily accessible from and adjacent to the recording room. Electroencephalographic recordings were obtained from four bilateral cortical electrodes; electrocardiographic electrodes recorded cardiac rhythms; electromyographic electrodes recorded extraocular muscle, chin, and leg movements; and nasal air flow monitoring was conducted throughout the study. Standard preparations assured that electrical impedance did not exceed 5 kΩ. Thirty-second epochs were scored using American Academy of Sleep Medicine criteria (Iber, Ancoli-Israel, Chesson, & Quan, 2007) by a registered Polysomnographic Techno-logist and interpretation was conducted by a physician board-certified in sleep medicine. This project was registered at clinicaltrials.gov (NCT01156051).
Data Analysis Differences between groups at baseline and change from baseline to termination were evaluated using two-sided ANOVA tests for continuous variables. Fisher’s exact test (two-sided) was used to test the difference in categorical variables. IBM SPSS version 21 software was used for analysis, with a significance level of .05. Effect sizes were reported as SPSS calculated partial eta square. Data were reported as value ±SD when appropriate.
Results The plan was to successfully screen 43 participants, anticipating 36 completers. This study was terminated early, when an interim analysis demonstrated treatment-emergent shortening of the polysomnographic minutes of total sleep time. As the population included children with sleep disorders, the medical team determined that it was unethical to continue in light of potential worsening of sleep. Whereas 35 children entered the study, 6 failed screening; no demographic characteristic was statistically significantly different from the 29 children who passed screening (Figure 1). Two females (a 6-year-old receiving treatment was lost to follow-up and a 7-year-old receiving placebo was noncompliant with the protocol) discontinued early from the study without termination (on-treatment) data— neither had any adverse events known to the study staff. As a result, 27 children had adequate pre-treatment and ontreatment data, including a polysomnogram, ADHDRS, and CSHQ data. Randomization resulted in 11 children receiving treatment and 16 children receiving placebo. No characteristics at baseline were statistically significantly different when comparing the treatment group with the placebo group (Tables 1 and 2). Consistent with previously published data and prior pharmacologic studies (Kelsey et al., 2004; Leung &
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Figure 1. CONSORT flow diagram.
Note. PSG = polysomnography; GXR = guanfacine extended release.
Lemay, 2003; Mattingly et al., 2012; Sallee, Kollins, & Wigal, 2012), there was a preponderance of ADHDcombined type in both groups (Table 1). The baseline ADHDRS scores were similar between treatment and placebo groups (inattention scores were 21.3 ± 3.6 and 22.2 ± 3.4 and hyperactive–impulsive scores were 20.0 ± 4.7 and 20.1 ± 4.3); all p values were not statistically significant (ns). None of the CSHQ subscale, problem, and Total Sleep Disruptions scores were statistically significantly different when comparing the treatment group with the placebo group at baseline. Similarly, none of the polysomno-graphic parameters were statistically significantly different when comparing the treatment group with the placebo group at baseline (Table 2). The mean final dose of GXR for children receiving treatment was 3.0 ± 1.0; two children required dose reduction due to intolerance (excessive daytime sleepiness). The final doses for the 11 children receiving treatment were as follows: 4 received 4 mg, 4 received 3 mg, 2 received 2 mg, and 1 received 1 mg. This dosing range is consistent with prior reports (Biederman et al., 2008; Sallee et al., 2012; Sallee, Lyne, et al., 2009; Sallee, McGough, et al., 2009).
The majority of children receiving placebo (13/16) were taking the tablet that matched GXR 4 mg (as expected, since the dose was increased when the clinical picture suggested inadequate effect).
ADHD Outcome Although efficacy was a secondary outcome measure unrelated to the outcome measures for sleep, it was found that children administered GXR demonstrated fewer ADHD symptoms than children administered placebo (Figure 2). Similar treatment-associated improvements were seen for inattention symptoms as well as hyperactive–impulsive symptoms. In addition, significantly more responders (children with termination ADHDRS total scores that have improved 30% or more from baseline) were seen with GXR than with placebo (7/11 vs. 3/16, p = .04).
PSG Outcome The primary outcome measure from the polysomnogram (Figure 2) was the minutes of total sleep time (Figure 3a). From similar (not statistically different) mean baseline total
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Rugino Table 1. Baseline Demographic Characteristics of Enrolled Children.
Age (years) Gender Male (n) Female (n) Ethnicity White Non-White Hispanic Non-Hispanic ADHD subtype ADHD combined ADHD inattentive ADHD hyperactive Stimulant exposure Prior stimulants No prior stimulants Stimulant washout No stimulant washout
GXR (n = 11)
Placebo (n = 16)
p value
9.15, SD = 1.76
8.82, SD = 1.91
ns (1)
9 2
8 8
ns (2) p = .12
10 1 0 11
12 4 2 14
ns (2) ns (2)
8 (72.73%) 3 (27.27%) 0
13 (81.25%) 3 (18.75%) 0
ns (2)
7 4 4 7
5 11 2 14
ns (2) p = .13 ns (2)
Note. Statistical analysis: (a) analysis of variance and (b) Fisher exact. GXR = guanfacine extended release; ns = not statistically significant.
Table 2. Baseline Sleep Polysomnographic Parameters of Enrolled Children.
Lights out (24-hr clock) Time of sleep onset (24-hr clock) Time of persistent sleep (24-hr clock) Total sleep time (min) Sleep efficiency (%) Number of awakenings Wake after sleep onset (min) Total apnea/hypopnea events Total limb movements Rapid eye movement sleep (min) N1 duration (min) N2 duration (min) N3 duration (min)
GXR (n = 11)
Placebo (n = 16)
ANOVA p value
21.16, SD = 0.80 21.93, SD = 0.96 22.10, SD = 0.97 528.63, SD = 75.47 85.86, SD = 7.41 9.18, SD = 9.00 39.83, SD = 39.19 5.09, SD = 3.86 22.73, SD = 34.88 135.98, SD = 22.42 65.99, SD = 35.87 193.33, SD = 44.06 133.87, SD = 28.73
21.14, SD = 0.59 21.92 SD = 1.27 22.08 SD = 1.31 525.18 SD = 62.80 87.51 SD = 9.74 7.25 SD = 4.45 26.93 SD = 23.16 4.50 SD = 4.18 15.38 SD = 24.81 129.84 SD = 26.00 50.32 SD = 22.50 205.75 SD = 59.42 115.01 SD = 28.86
ns ns ns ns ns ns ns ns ns ns ns ns ns, p = .11
Note. GXR = guanfacine extended release; ns = not statistically significant.
sleep times, the treatment group total sleep time decreased by 57.32 min (SD = 89.17) as the placebo group increased this parameter by 31.32 min (SD = 59.54). Children administered GXR had later onset of persistent sleep by 10.54 ± 88.44 min compared with 19.94 ± 54.12 min earlier when administered placebo (Figure 3b); however, this difference did not reach statistical significance. Similarly, although the children who were administered GXR awoke earlier than baseline whereas the children administered placebo awoke later than baseline, this difference also did not reach statistical significance (Figure 3d). In contrast, the minutes awake
after sleep onset per hour of sleep showed a statistically significant difference between the two groups, accounting for a significant part of the reduction in total sleep time (Figure 3c). At termination, the children administered GXR were awake for a mean of 4.19 more minutes per hour of sleep (4.64 ± 4.34 min/hr at baseline, 8.83 ± 9.13 min/hr at term), whereas the children administered placebo were awake for a mean of 0.58 min less per hour of sleep (3.11 ± 2.63 min/ hr at baseline, 2.53 ± 1.53 min/hr at term). Nine of 11 children receiving GXR showed a decrease in polysomnographic total sleep time (ranging from 15 to 190
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Discussion
Figure 2. ADHD Rating Scale–IV combined scores for guanfacine extended release and placebo groups at baseline and at endpoint. 2 Note. p < .001, F(1, 25) = 17.67,
ηp
= 0.41.
min less), whereas only 6 of 16 children receiving placebo showed a decrease in this important parameter (ranging from 10 to 43 min less); Fisher’s exact test p = .05. When considering the 12 children whose total sleep time increased, the two in the treatment group ranged from 29 to 131 min, whereas the 10 in the placebo group ranged from 2 to 136 min. Figure 4 demonstrates the effect of GXR and placebo on the phases of sleep during PSG. On one hand, administration of GXR was associated with a statistically significant decrease in REM sleep, decrease in total non-REM sleep, and decrease in N3/slow wave sleep when compared with placebo. On the other hand, REM, non-REM, N1, N2, and N3 sleep as a percentage of total sleep time were not statistically significantly different from placebo. This suggests that these reported differences are attributed to the overall reduction in total sleep time, and do not represent a significantly altered proportion of sleep phases.
Safety Outcome Adverse events from GXR (Table 3) are not significantly different from previous reports (Biederman et al., 2008; Newcorn et al., 2013; Sallee, Lyne, et al., 2009; Sallee, McGough, et al., 2009; Scahill, 2009). Treatmentemergent somnolence was a more frequent concern in this population with pre-existing sleep difficulties than observed in previous publications (Biederman et al., 2008; Newcorn et al., 2013; Sallee, Lyne, et al., 2009; Sallee, McGough, et al., 2009; Scahill, 2009). No electrocardiographic, laboratory, growth, or vital sign parameter was statistically significantly different at termination between the two groups.
This study was designed to evaluate the effects of morningadministered GXR tablets on polysomnographic parameters of sleep. The study was terminated early when an interim analysis demonstrated potential treatment-emergent exacerbation of polysomnographic sleep parameters. The study population reasonably represents the typical ADHD population for this community-based developmental and rehabilitation referral center. As a result of early termination of the study, the randomization did not yield equal numbers of children in each group. Nonetheless, the placebo group and treatment group were reasonably well matched for baseline data (including for overnight polysomnographic parameters). As seen in previous double-blind randomized studies (Biederman et al., 2008; Newcorn et al., 2013; Sallee et al., 2012; Sallee, Lyne, et al., 2009; Sallee, McGough, et al., 2009), GXR improved both inattention and hyperactivity– impulsivity symptoms of ADHD. The average dose and the dosing range are consistent with these prior studies. Polysomnographic evaluations are an objective singlenight assessment conducted in a clinical center, evaluating sleep onset, sleep maintenance, and electroencephalographic sleep phases. This study demonstrated that for this population, morning administration of GXR had an untoward effect on the primary polysomnographic sleep outcome measure compared with morning administration of a matched placebo tablet. The polysomnographic total sleep time decreased (indicating restriction of sleep) in all but 2 of the 11 children administered GXR (in contrast to a shortened total sleep time in less than half of the children administered placebo). Likely due to familiarity and comfort with the sleep center during the second polysomnogram, the placebo group showed more minutes of total sleep time, earlier time to persistent sleep, less time awake after sleep onset per hour of sleep, and a later time of awakening at termination; the effect on these polysomnographic parameters appeared to have been negated for the children having been administered GXR. The GXR group mean total sleep time decreased by almost an hour, primarily due to increased time awake after sleep onset per hour of sleep (accounting for a total of 21.8 min less sleep at termination for the GXR group as opposed to 18.90 min more sleep for the placebo group at termination). Although possibly factors decreasing the minutes of total sleep time for the GXR group, the later time of persistent sleep onset and the earlier time of awakening did not reach statistical significance when compared with the placebo group. Although Gruber et al. (2011) reported that this degree of additional sleep restriction may have a clinically significant negative effect on core ADHD symptoms as measured by continuous performance testing, both inattention and
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Figure 3. Changes in polysomnographic sleep parameters for guanfacine extended release and placebo. (a) Total sleep time (min), p = .005, F(1, 25) = 9.65, η2p = 0.28. (b) Time of persistent sleep (24-hr clock), p = .24, F(1, 25) = 1.45, η2p = 0.06. (c) Wake after sleep onset per hour (min/hr), p = .025, F(1, 25) = 5.66, η2p = 0.19. (d) Time of awakening (24-hr clock), p = .11, F(1, 25) = 2.68, η2p = 0.10. Note. GXR = guanfacine extended release.
hyperactivity ADHDRS scores improved significantly for children receiving GXR compared with children receiving placebo. Of course, it is possible that with improved sleep, the degree of ADHD symptom improvement may have been even greater than reported in this study—in other words, the improvements found in this study do not refute the negative effect of sleep restriction. Although GXR did not significantly alter the proportions of REM and non-REM sleep, the total time spent in nonREM sleep (particularly in N3/slow wave sleep) was significantly decreased for the GXR group when compared with the placebo group. Reduction in N3/slow wave sleep has been associated with increased daytime somnolence (propensity to sleep), decreased daytime performance (Dijik, 2010), and increased reports of nonrestorative sleep
(Walsh, 2009). Therefore, it is possible that a decrease in total sleep time and specifically in slow wave sleep (along with direct drug effects) may contribute to the reports of daytime somnolence following administration of GXR. The significant reduction in overall REM sleep (despite the statistically insignificant reduction in the proportion of REM sleep) is consistent with a previous study in which healthy adults administered 2 mg guanfacine in the evening had a reduction in REM sleep (Spiegel & DeVos, 1980). Similarly, administration of medium-dose (0.15 mg) clonidine (Miyazaki, Uchida, Mukai, & Nishihara, 2004; Spiegel & DeVos, 1980) was found to decrease REM sleep. In contrast, other studies reported that low-dose clonidine increased REM sleep (Miyazaki et al., 2004; Schittecattea et al., 1995) and lower doses of guanfacine (1 mg) had no
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Figure 4. Phases of sleep (min).
Note. REM = rapid eye movement; N3 = slow wave sleep.
Table 3. Adverse Events. Adverse event Any adverse event Somnolence Headache Upper respiratory infection Exacerbation of allergic rhinitis Stomachache Acute gastroenteritis Dermatitis Mood change Febrile illness Cough Enuresis Dizziness Musculoskeletal chest pain Oral pain due to loose teeth Decreased appetite Inguinal hernia Exacerbation of asthma Lightheadedness Stuttering Exacerbation of insomnia Agitation Note. GXR = guanfacine extended release.
GXR (n = 11)
Placebo (n = 16)
9 (82%) 8 (73%) 4 (36%) 3 (27%) 1 (9%) 1 (9%) 1 (9%) 1 (9%) 1 (9%) 1 (9%) 1 (9%) 1 (9%) 1 (9%) 1 (9%) 1 (9%)
11 (69%) 1 (6%) 2 (13%) 3 (19%) 5 (31%) 2 (13%) 2 (13%) 2 (13%) 1 (6%) 1 (6%) 1 (6%) 1 (6%) 1 (6%) 1 (6%) 1 (6%) 1 (6%)
effect on REM sleep (Spiegel & DeVos, 1980). Considering all of the studies, one can postulate that the α-2 agonist peak blood level may influence the effect on REM sleep: lower peaks may have no effect or an increase in REM sleep whereas higher peaks may suppress REM sleep (in this study, by proportionally reducing overall sleep time). Eight of 11 children in the treatment group developed a spontaneously reported adverse event of sedation, but the parent-completed CSHQ Daytime Sleepiness subscale was not statistically significantly different between the two groups. Two participants with reported sedation resolved the concern with dose reduction; for the other children, this adverse event resolved despite continued administration of a stable GXR dose. The experience during this study is consistent with prior reports suggesting that daytime somnolence is commonly, but not universally, transient (Biederman et al., 2008; Kollins et al., 2011; Sallee, McGough, et al., 2009). When considering the adverse events and the polysomnographic findings seen in this study population with pre-existing sleep disorders, three possible factors may contribute to daytime sedation/somnolence: (a) GXR may disrupt duration and quality of sleep, resulting in daytime somnolence. (b) GXR may promote daytime somnolence and/or reduction of activity level to the point that the influence of exertion/activity on sleep promotion is reduced. (c) As blood guanfacine levels increase for an average of 6 hr after administration (range = 4-8 hr,
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Rugino Shire Pharmaceuticals, Inc., 2011), GXR may promote somnolence through a direct drug effect, whereas a rebound effect on sleep may occur as guanfacine levels decline. This study is limited due to a small sample size, short treatment time, and due to the fact that, considering day to day variability in sleep parameters, a single polysomnogram may not be representative of effect on sleep at home over an extended period of time. Other reports suggest that there may be slightly more daytime somnolence with morning administration (46.7%) than evening administration (42.1%) with similar efficacies (Newcorn et al., 2013); therefore, these data cannot be generalized to children administered GXR in the evening. Similarly, these data cannot be generalized to the ADHD population without a primary sleep disorder. Unequal sample sizes at baseline and at termination need to be taken into consideration when generalizing these results. Additional studies, especially studies evaluating afternoon/evening administration of GXR, will be needed to determine whether timing of the dose reduces the detrimental effect on sleep found in this study and to determine to what degree sleep disruption contributes to daytime somnolence seen after GXR administration. It will also be important for future studies to determine whether these findings generalize to an ADHD population without a pre-existing sleep problem and whether these findings have an impact on children with co-administration of a stimulant.
Conclusion Although ADHD symptoms improved significantly with morning administration of GXR, this treatment worsened important PSG sleep parameters for a group of 6- to 12-yearold children with ADHD and associated primary sleep disorders when compared with placebo administra-tion. Increased time awake after sleep onset per hour of sleep was the greatest factor reducing minutes of total sleep time after GXR administration, as other factors did not reach statistical significance. GXR administration reduced total REM, nonREM, and N3/slow wave sleep times, but these decreases are explained by the decreased total sleep time. This ADHD population with sleep problems had a greater frequency of reported treatment-emergent daytime somnolence than have been reported in previous studies, possibly due to direct medication effect, decreased daytime activity level, and/or due to disrupted sleep patterns. Further studies are needed to assess effects of afternoon/evening dosing on sleep, to assess whether similar findings occur in a population without preexisting sleep difficulties, and to assess the effect on sleep when GXR is co-administered with stimulants. Acknowledgments I would like to thank Kathleen Ryan, MD, for professional and prompt readings of the polysomnograms and consultation. Investigational Review was provided by Western Institutional
Review Board (IRB; www.wirb.com). The statistical expert was Jeffrey Yangang Zhang, PhD.
Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Rugino had no personal financial disclosures within the past 12 months. Children’s Specialized Hospital had received research funding from Shire Pharmaceuticals, Forest Laboratories, Supernus, Inc., Bristol-Myers Squibb, Sunovion, and Eli Lilly and Company within the past 12 months.
Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This manuscript describes the results of an investigator-initiated study funded by ShIre Pharmaceuticals. Facilities support was provided by Children’s Specialized Hospital and SleepCare Centers, Inc.
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DuPaul, G., Power, T., Anastopoulos, A., & Reid, R. (1998). ADHD Rating Scale IV. Los Angeles, CA: Western Psychological Services. Golan, N., Shahar, E., Ravid, S., & Pillar, G. (2004). Sleep disorders and daytime sleepiness in children with attention-deficit/ hyperactive disorder. Sleep, 27, 261-266. Gringras, P. (2008). When to use drugs to help sleep. Archives of Disease in Childhood, 93, 976-981. Gruber, R., Wiebe, S., Montecalvo, L., Brunietti, B., Amsel, R., & Carrier, J. (2011). Impact of sleep restriction on neurobehavioral functioning of children with attention deficit hyperactivity disorder. Sleep, 34, 315-323. Guy, W. (Ed.). (1976). ECDEU assessment manual for psychopharmacology. Rockville, MD: U.S. Department of Health, Education, and Welfare. Hryshko-Mullen, A., Broeckl, L., Haddock, C., & Peterson, A. (2000). Behavioral treatment of insomnia: The Wilford Hall Insomnia Program. Military Medicine, 165, 200-207. Hunt, R., Arnsten, A., & Asbell, M. (1995). An open trial of guanfacine in the treatment of attention-deficit hyperactivity disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 34, 50-54. Iber, C., Ancoli-Israel, S., Chesson, A. L., Jr., & Quan, S. F. (2007). The AASM manual for the scoring of sleep and associated events: Rules, terminology and technical specifications. Westchester, IL: American Academy of Sleep Medicine. Kaufman, J., Birmaher, B., Brent, D., Rao, U., Flynn, C., Moreci, P., . . . Ryan, N. (1997). Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime version (K-SADS-PL): Initial reliability and validity data. Journal of the American Academy of Child & Adolescent Psychiatry, 36, 980-989. Kelsey, D., Sumner, C., Casat, C., Coury, D., Quintana, H., Saylor, K., . . . Allen, A. (2004). Once daily atomoxetine treatment for children with attention-deficit/hyperactivity disorder, including an assessment of evening and morning behavior: A double-blind, placebo-controlled trial. Pediatrics, 111, e1-e8. Keranen, A., Nykanen, S., & Taskinen, J. (1978). Pharmacokinetics and side-effects of clonidine. European Journal of Clinical Pharmacology, 13, 97-101. Kollins, S. H., Lopez, F. A., Vince, B. D., Turnbow, J. M., Farrand, K., Lyne, A., . . . Roth, T. (2011). Psychomotor functioning and alertness with guanfacine extended release in subjects with attention-deficit/hyperactivity disorder. Journal of Child and Adolescent Psychopharmacology, 21(2), 111-120. Kratochvil, C., Lake, M., Pliszka, S., & Walkup, J. (2005). Pharmacological management of treatment-induced insomnia in ADHD. Journal of the American Academy of Child & Adolescent Psychiatry, 44, 499-501. Kuczmarski, R., Ogden, C., Grummer-Strawn, L., Flegal, K., Guo, S., Wei, R., . . . Johnson, C. (2000). CDC growth charts: United States. NCHS Advance Data Report, 314, 1-27. LeBourgeois, M., Giannotti, F., Cortesi, F., Wolfson, A., & Harsh, J. (2005). The relationship between reported sleep quality and sleep hygiene in Italian and American adolescents. Pediatrics, 115(Suppl. 1), 257-265. Leung, A., & Lemay, J. (2003). Attention deficit disorder: An update. Advances in Therapy, 20, 305-318.
Mattingly, G., Weisler, R., Dirks, B., Babcock, T., Adeyi, B., Scheckner, B., & Lasser, R. (2012). Attention deficit hyperactivity disorder subtypes and symptom response in adults treated with lisdexamfetamine dimesylate. Innovations in Clinical Neuroscience, 9(5-6), 22-30. Miyazaki, S., Uchida, S., Mukai, J., & Nishihara, K. (2004). Clonidine effects on all-night human sleep: Opposite action of low- and medium-dose clonidine on human NREM-REM sleep proportion. Psychiatry and Clinical Neuroscience, 58, 138-144. Newcorn, J. H., Stein, M. A., Childress, A. C., Youcha, S., White, C., Enright, G., & Rubin, J. (2013). Randomized, doubleblind trial of guanfacine extended release in children with attention-deficit/hyperactivity disorder: Morning or evening administration. Journal of the American Academy of Child & Adolescent Psychiatry, 52, 921-930. Owens, J. (2009). A clinical overview of sleep and attention-deficit/hyperactivity disorder in children and adolescents. Journal of the Canadian Academy of Child & Adolescent Psychiatry, 18(2), 92-102. Owens, J., Spirito, A., & McGuinn, M. (2000). The Children’s Sleep Habits Questionnaire (CSHQ): Psychometric properties of a survey instrument for school-aged children. Sleep, 23(8), 1-9. Pelayo, R., & Dubik, M. (2008). Pediatric sleep pharmacology. Seminars in Pediatric Neurology, 15, 79-90. Sallee, F., Kollins, S., & Wigal, T. (2012). Efficacy of guanfacine extended release in the treatment of combined and inattentive only subtypes of attention deficit/hyperactivity disorder. Journal of Child and Adolescent Psychopharmacology, 22, 206-214. Sallee, F., Lyne, A., Wigal, T., & McGough, J. (2009). Long-term safety and efficacy of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. Journal of Child and Adolescent Psychopharmacology, 19, 215-226. Sallee, F., McGough, J., Wigal, T., Donahue, J., Lyne, A., & Biederman, J. (2009). Guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder: A placebo-controlled trial. Journal of the American Academy of Child & Adolescent Psychiatry, 48, 155-165. Scahill, L. (2009). Alpha-2 adrenergic agonists in children with inattention, hyperactivity and impulsiveness. CNS Drugs, 23(Suppl. 1), 43-49. Schittecattea, M., Garcia-Valentina, J., Charlesa, G., Machowskia, R., Pena-Othaitza, M., Mendlewiczb, J., & Wilmottea, J. (1995). Efficacy of the “clonidine REM suppression test (CREST)” to separate patients with major depression from controls; a comparison with three currently proposed biological markers of depression. Journal of Affective Disorders, 33, 151-157. Shire Pharmaceuticals Inc. (2011). Full prescribing information for Intuniv® (guanfacine) extended-release tablets, version 6/2011. Wayne, PA: Shire US. Silver, L. (1999). Alternative (nonstimulant) medications in the treatment of attention-deficit/hyperactivity disorder in children. Pediatric Clinics of North America, 46, 965-975.
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Rugino Spiegel, R., & DeVos, J. E. (1980). Central effects of guanfacine and clonidine during wakefulness and sleep in healthy subjects. British Journal of Clinical Pharmacology, 10(Suppl. 1), 165S-168S. Stein, M., Weiss, M., & Leventhal, B. (2007). ADHD by night: Sleep problems and ADHD medications. Child & Adolescent Pharmacology News, 12, 1-5. Van der Heijden, K., Smits, M., Van Someren, E., & Gunning, W. (2005). Idiopathic chronic sleep onset insomnia in attentiondeficit/hyperactivity disorder: A circadian rhythm sleep disorder. Chronobiology International, 22, 559-570. Walsh, J. (2009). Slow-wave sleep and its enhancement: Implications for insomnia. Journal of Clinical Sleep Medicine, 5(Suppl. 2), S27-S32. Weiss, M., & Selpekar, J. (2010). Sleep problems in the child with attention-deficit hyperactivity disorder. CNS Drugs, 24, 811-828.
Weiss, M., Wasdell, M., Bomben, M., Rea, K., & Freeman, R. (2006). Sleep hygiene and melatonin treatment for children and adolescents with ADHD and initial insomnia. Journal of the American Academy of Child & Adolescent Psychiatry, 45, 512-519. Yoon, S., Jain, A., & Shapiro, C. (2012). Sleep in attention-deficit/ hyperactivity disorder in children and adults: Past, present, and future. Sleep Medicine Reviews, 16, 371-388.
Author Biography Thomas A. Rugino is a neurodevelopmental pediatrician at Children’s Specialized Hospital, New Jersey. He is an associate clinical professor of pediatrics at Rutgers Robert Wood Johnson Medical School and has published on the topics of ADHD, autism, and other neurodevelopmental disorders.
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Effect on Primary Sleep Disorders When Children With ADHD Are Administered Guanfacine Extended Release Thomas A. Rugino Journal of Attention Disorders published online 6 November 2014 DOI: 10.1177/1087054714554932 The online version of this article can be found at: http://jad.sagepub.com/content/early/2014/11/06/1087054714554932
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research-article2014
JADXXX10.1177/1087054714554932Journal of Attention DisordersRugino
Article
Effect on Primary Sleep Disorders When Children With ADHD Are Administered Guanfacine Extended Release
Journal of Attention Disorders 1–11 © 2014 SAGE Publications Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1087054714554932 jad.sagepub.com
Thomas A. Rugino1,2
Abstract Objective: To evaluate children with ADHD and sleep problems with polysomnography (PSG) after guanfacine extendedrelease (GXR) administration. Method: Double-blind, randomized, placebo-controlled study was terminated early due to treatment-emergent concerns after enrolling 29 children aged 6 to 12 years. After >4 weeks dose adjustment and >1 week dose stabilization, 11 children received GXR and 16 controls underwent analyses with PSG. Results: Although GXR improved ADHD symptoms, the primary outcome variable, total sleep time, was shorter in contrast to placebo (−57.32, SD = 89.17 vs. +31.32, SD = 59.54 min, p = .005). Increased time awake after sleep onset per hour of sleep was the primary factor for the reduction. Although rapid eye movement (REM), non-REM, and N3/slow wave sleep times were reduced, these were proportional to the overall sleep reduction. Sedation was common with GXR (73% vs. 6%). Conclusion: Morning-administered GXR resulted in decreased sleep and may contribute to sedation. (J. of Att. Dis. XXXX; XX(X) XXXX) Keywords ADHD, pharmacotherapy, insomnia, sleep, polysomnography, randomized controlled trial
Introduction Disorders of sleep duration and quality are significant comorbidities for 25% to 75% of children and adolescents with ADHD (Bullock & Schall, 2005; Chervin, Dillon, Bassetti, Ganoczy, & Pituch, 1997; Cortese, Faraone, Konofal, & Lecendreux, 2009; Golan, Shahar, Ravid, & Pillar, 2004; Owens, 2009; Weiss & Selpekar, 2010; Yoon, Jain, & Shapiro, 2012). Although initial (onset) insomnia can be exacerbated by medications used to treat ADHD or comorbid conditions (American Academy of Child and Adolescent Psychiatry Work Group on Quality Issues, 2007; Stein, Weiss, & Leventhal, 2007), considerable evidence suggests that the presence of sleep disorders are unrelated to pharmacologic interventions (Cortese et al., 2009). Although sleep disorders are common in children with ADHD, even 1-hr restriction of sleep has been shown to negatively affect neurobehavioral functioning (specifically performance on continuous performance testing); this deterioration is significant enough to cause a substantial number of children to drop from subclinical to clinical ranges of inattention (Gruber et al., 2011). Therefore, finding a treatment that may improve sleep in children with ADHD and sleep problems may provide even greater than expected benefits in core ADHD symptoms.
A mainstay of treatment, sleep hygiene has been shown to improve sleep quality and improve initial (onset) insomnia in children with ADHD (Hryshko-Mullen, Broeckl, Haddock, & Peterson, 2000; LeBourgeois, Giannotti, Cortesi, Wolfson, & Harsh, 2005; Van der Heijden, Smits, Van Someren, & Gunning, 2005; Weiss, Wasdell, Bomben, Rea, & Freeman, 2006). However, when sleep hygiene and behavioral treatments have failed, the use of a sleep-promoting medication may be appropriate as a final resort (Gringras, 2008; Weiss & Selpekar, 2010). The most commonly prescribed sleep aides for children (melatonin, diphenhydramine and H1-blockers, chloral hydrate, benzodiazepines, trazodone, cyproheptadine, mirtazapine, tricyclic antidepressants, L-theanine, nonbenzodiazepine hypnotics such as zolpidem, eszolpiclone, and zalepion; Barrett, Tracy, & Giaroli, 2013; Kratochvil, Lake, Pliszka, & Walkup, 2005; Pelayo & Dubik, 2008) do not have the pharmacologic targets to significantly improve ADHD symptoms. Immediate-release clonidine is effective and has 1
Children’s Specialized Hospital, Toms River, NJ, USA Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA
2
Corresponding Author: Thomas A. Rugino, MD, Children’s Specialized Hospital, 94 Stevens Road, Toms River, NJ 08755, USA. Email: [email protected]
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been commonly prescribed for insufficient sleep (Pelayo & Dubik, 2008). However, its rapid absorption and limited half-life necessitates frequent administration to manifest ADHD symptom improvement during the day; when administered during the day, the resultant peak plasma concentrations often lead to tolerability problems such as sedation (Connor, Fletcher, & Swanson, 1999; Croxtall, 2011; Keranen, Nykanen, & Taskinen, 1978). However, no published reports involving the effects of extended-release clonidine within the context of sleep disorders were evident as of the date of this manuscript. Another, more selective, α-2 agonist, guanfacine (immediate-release tablets, and the more recent extended-release tablets), has been used as a treatment for ADHD for more than a decade, with established safety and efficacy (Biederman et al., 2008; Hunt, Arnsten, & Asbell, 1995; Sallee, Lyne, Wigal, & McGough, 2009; Sallee, McGough, Wigal, Donahue, Lyne, & Biederman, 2009; Scahill, 2009; Silver, 1999). Although several studies cite sedation or somnolence (generally transient and mild to moderate) as common adverse events for guanfacine (Biederman et al., 2008; Kollins et al., 2011; Sallee, Lyne, et al., 2009; Sallee, McGough, et al., 2009; Scahill, 2009), and although previous studies cited no significant differences in reported daytime sleepiness using checklist scales (Biederman et al., 2008; Sallee, McGough, et al., 2009), no published reports involving the effects of guanfacine extended release (GXR) within the context of sleep disorders have been published as of the time of this manuscript. In addition, no studies have reported the effect of guanfacine on direct measures of sleep, such as polysomnography (PSG). The purpose of this investigation was to determine whether morning administration of GXR tablets altered the duration and quality of sleep (as determined by PSG) while reducing daytime ADHD symptoms (as determined by clinician assessment using standard ADHD questionnaires) in a school-age ADHD population with pre-existing sleep problems.
Method Sequential children 6 to 12 years of age with ADHD, who had a self- or parent-reported concern with sleep duration or quality despite adequate sleep hygiene practices and caffeine restriction, were recruited for this study at a suburban children’s developmental and rehabilitation referral center. After Institutional Review Board–approved informed consent (and assent when appropriate) was completed in accordance with hospital standard operating procedures, the screening visit included an evaluation for the presence of ADHD and any potentially confounding co-morbidity with the Children’s Schizophrenia and Affective Disorders Scales (Kiddie-SADS; Kaufman et al., 1997). A sheet outlining appropriate sleep hygiene practices was given to the family; this sheet was used as a checklist to
assess sleep hygiene during the interview with the caretaker and the child. If inappropriate sleep hygiene contributed significantly to sleep problems at the time of the screening assessment, the family was counseled, and a follow-up evaluation was repeated in 7 to 14 days. If at the follow-up evaluation, sleep hygiene still significantly contributed to inadequate or poor quality sleep and the family was unable or unwilling to establish adequate sleep hygiene practices, the participant was terminated from the study. A caffeine intake checklist was completed for 7 consecutive days prior to the polysomnogram; excessive caffeine intake (greater than 1.5 mg/kg/day or a single day caffeine intake greater than 2.5 mg/kg/day) resulted in termination from the study. Screening included an evaluation by a subspecialty board-certified neurodevelopmental pediatrician, vital signs including supine and standing blood pressure (BP) and pulse, growth parameters, detailed medical history, medication administration history, and physical examination. Screening also included an electrocardiogram (ECG), routine metabolic profile, complete blood count (CBC), urinalysis (UA), urine drug screen, clinician-conducted interview with the parent for scoring the ADHD Rating Scale–IV (ADHDRS; DuPaul, Power, Anastopoulos, & Reid, 1998), clinician-conducted ADHD Clinical Global Impression of Severity (CGI-S; Guy, 1976), Sleep CGI-S, and completion of a parent-reported Children’s Sleep Habits Questionnaire (CSHQ; Owens, Spirito, & McGuinn, 2000). Females of child-bearing potential had a serum pregnancy test (β-human chorionic gonadotropin [β-HCG]); if pregnant, nursing, or positive for β-HCG, the child was excluded from the study. To be included in the study, the ADHDRS had to confirm the diagnosis of ADHD with >6 inattentive symptoms scoring ≥2 (often) and/or >6 hyperactivity– impulsivity symptoms scoring ≥2 (often), and the ADHD CGI-S score had to confirm at least mild severity (≥3). Children were excluded from the study if the body mass index was less than fifth percentile for age (using the Centers for Disease Control standards as reported by Kuczmarski et al., 2000) or if the body weight was >176 pounds (80 kg). Clinically significant psychiatric pathology, such as autism, autism spectrum disorder, major depression, bipolar disorder, or anxiety, was also exclusionary. Children with clinically significant medical conditions such as hepatic, neurologic, hemodynamic, cardiac, or renal dysfunction (including clinically significant electrocardiographic findings), or with clinically significant laboratory findings were excluded. Medications and supplements with sedative, hemodynamic, or neuropsychiatric properties, or that have known drug–drug interactions with guanfacine had to be discontinued or weaned before baseline assessments. If the child had been administered medications for ADHD at the time of the screening visit, wean or discontinuation was completed so that the child was free of these medications for at least 1 week prior to completion of
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Rugino screening procedures. Although permitted by the protocol, none of the enrolled participants had been administered atomoxetine within a month prior to screening. Although obstructive sleep apnea and periodic limb movement disorders were to be exclusionary, no participant failed screening due to either of these disorders. Children who met inclusion and exclusion criteria who also had a CSHQ total score of >41 underwent a screening overnight multichannel polysomnogram to determine latency to persistent sleep, total sleep time, time awake after sleep onset, and times of sleep phases. Dose optimization was initiated with a flexible-dose, randomized, double-blind, placebo-administered design with study medication administered once a day in the morning. The dose started with either 1 mg GXR or matching placebo starting the morning after the baseline visit. At weekly visits, the dose was adjusted upward by 1 mg (to a maximum dose of 4 mg or matching placebo) if the investigator assessed the response to treatment as being sub-optimal (if either the ADHD Clinical Global Impression of Improvement [CGI-I] was 4), or if a higher dose was not likely to be tolerated based on currently reported side effects. The dose was reduced or discontinued if the investigator assessed the response to study medication to be intolerable; only one dose reduction by 1 mg was permitted before discontinuation. Dose adjustments were permitted until the Week 5 visit. At the early termination visit (when assessments were feasible) or at the termination visit (within 14 days of the Week 4 or 5 visit as long as the dose was stable for at least 7 days), the following data were obtained: a polysomno-gram, a CSHQ, an ADHDRS, ADHD CGI-I, a sleep CGI-I, vital signs, growth parameters, physical examination, detailed interval medical history, ECG, and laboratory investigations. After the termination visit, the study medication was weaned over the course of 7 to 10 days. Follow-up was conducted approximately 30 days following the last dose of study medication to record adverse events. Follow-up continued until all adverse events reached resolution or stabilization. The primary outcome measure was the polysomnographic minutes of total sleep time, although data collected included time of lights out, sleep efficiency, latency to sleep onset, latency to persistent sleep, number of awakenings, time awake after sleep onset, latency to rapid eye movement (REM) sleep, total apnea/hypopnea events, total limb movements, duration of sleep phases (REM, N1, N2, N3, the latter being slow wave sleep). The polysomnogram was conducted using a Sandman system at the Mid-Atlantic School of Sleep Medicine, in a dedicated, electrically insulated, quiet,
individual room, easily accessible from and adjacent to the recording room. Electroencephalographic recordings were obtained from four bilateral cortical electrodes; electrocardiographic electrodes recorded cardiac rhythms; electromyographic electrodes recorded extraocular muscle, chin, and leg movements; and nasal air flow monitoring was conducted throughout the study. Standard preparations assured that electrical impedance did not exceed 5 kΩ. Thirty-second epochs were scored using American Academy of Sleep Medicine criteria (Iber, Ancoli-Israel, Chesson, & Quan, 2007) by a registered Polysomnographic Techno-logist and interpretation was conducted by a physician board-certified in sleep medicine. This project was registered at clinicaltrials.gov (NCT01156051).
Data Analysis Differences between groups at baseline and change from baseline to termination were evaluated using two-sided ANOVA tests for continuous variables. Fisher’s exact test (two-sided) was used to test the difference in categorical variables. IBM SPSS version 21 software was used for analysis, with a significance level of .05. Effect sizes were reported as SPSS calculated partial eta square. Data were reported as value ±SD when appropriate.
Results The plan was to successfully screen 43 participants, anticipating 36 completers. This study was terminated early, when an interim analysis demonstrated treatment-emergent shortening of the polysomnographic minutes of total sleep time. As the population included children with sleep disorders, the medical team determined that it was unethical to continue in light of potential worsening of sleep. Whereas 35 children entered the study, 6 failed screening; no demographic characteristic was statistically significantly different from the 29 children who passed screening (Figure 1). Two females (a 6-year-old receiving treatment was lost to follow-up and a 7-year-old receiving placebo was noncompliant with the protocol) discontinued early from the study without termination (on-treatment) data— neither had any adverse events known to the study staff. As a result, 27 children had adequate pre-treatment and ontreatment data, including a polysomnogram, ADHDRS, and CSHQ data. Randomization resulted in 11 children receiving treatment and 16 children receiving placebo. No characteristics at baseline were statistically significantly different when comparing the treatment group with the placebo group (Tables 1 and 2). Consistent with previously published data and prior pharmacologic studies (Kelsey et al., 2004; Leung &
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Figure 1. CONSORT flow diagram.
Note. PSG = polysomnography; GXR = guanfacine extended release.
Lemay, 2003; Mattingly et al., 2012; Sallee, Kollins, & Wigal, 2012), there was a preponderance of ADHDcombined type in both groups (Table 1). The baseline ADHDRS scores were similar between treatment and placebo groups (inattention scores were 21.3 ± 3.6 and 22.2 ± 3.4 and hyperactive–impulsive scores were 20.0 ± 4.7 and 20.1 ± 4.3); all p values were not statistically significant (ns). None of the CSHQ subscale, problem, and Total Sleep Disruptions scores were statistically significantly different when comparing the treatment group with the placebo group at baseline. Similarly, none of the polysomno-graphic parameters were statistically significantly different when comparing the treatment group with the placebo group at baseline (Table 2). The mean final dose of GXR for children receiving treatment was 3.0 ± 1.0; two children required dose reduction due to intolerance (excessive daytime sleepiness). The final doses for the 11 children receiving treatment were as follows: 4 received 4 mg, 4 received 3 mg, 2 received 2 mg, and 1 received 1 mg. This dosing range is consistent with prior reports (Biederman et al., 2008; Sallee et al., 2012; Sallee, Lyne, et al., 2009; Sallee, McGough, et al., 2009).
The majority of children receiving placebo (13/16) were taking the tablet that matched GXR 4 mg (as expected, since the dose was increased when the clinical picture suggested inadequate effect).
ADHD Outcome Although efficacy was a secondary outcome measure unrelated to the outcome measures for sleep, it was found that children administered GXR demonstrated fewer ADHD symptoms than children administered placebo (Figure 2). Similar treatment-associated improvements were seen for inattention symptoms as well as hyperactive–impulsive symptoms. In addition, significantly more responders (children with termination ADHDRS total scores that have improved 30% or more from baseline) were seen with GXR than with placebo (7/11 vs. 3/16, p = .04).
PSG Outcome The primary outcome measure from the polysomnogram (Figure 2) was the minutes of total sleep time (Figure 3a). From similar (not statistically different) mean baseline total
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Rugino Table 1. Baseline Demographic Characteristics of Enrolled Children.
Age (years) Gender Male (n) Female (n) Ethnicity White Non-White Hispanic Non-Hispanic ADHD subtype ADHD combined ADHD inattentive ADHD hyperactive Stimulant exposure Prior stimulants No prior stimulants Stimulant washout No stimulant washout
GXR (n = 11)
Placebo (n = 16)
p value
9.15, SD = 1.76
8.82, SD = 1.91
ns (1)
9 2
8 8
ns (2) p = .12
10 1 0 11
12 4 2 14
ns (2) ns (2)
8 (72.73%) 3 (27.27%) 0
13 (81.25%) 3 (18.75%) 0
ns (2)
7 4 4 7
5 11 2 14
ns (2) p = .13 ns (2)
Note. Statistical analysis: (a) analysis of variance and (b) Fisher exact. GXR = guanfacine extended release; ns = not statistically significant.
Table 2. Baseline Sleep Polysomnographic Parameters of Enrolled Children.
Lights out (24-hr clock) Time of sleep onset (24-hr clock) Time of persistent sleep (24-hr clock) Total sleep time (min) Sleep efficiency (%) Number of awakenings Wake after sleep onset (min) Total apnea/hypopnea events Total limb movements Rapid eye movement sleep (min) N1 duration (min) N2 duration (min) N3 duration (min)
GXR (n = 11)
Placebo (n = 16)
ANOVA p value
21.16, SD = 0.80 21.93, SD = 0.96 22.10, SD = 0.97 528.63, SD = 75.47 85.86, SD = 7.41 9.18, SD = 9.00 39.83, SD = 39.19 5.09, SD = 3.86 22.73, SD = 34.88 135.98, SD = 22.42 65.99, SD = 35.87 193.33, SD = 44.06 133.87, SD = 28.73
21.14, SD = 0.59 21.92 SD = 1.27 22.08 SD = 1.31 525.18 SD = 62.80 87.51 SD = 9.74 7.25 SD = 4.45 26.93 SD = 23.16 4.50 SD = 4.18 15.38 SD = 24.81 129.84 SD = 26.00 50.32 SD = 22.50 205.75 SD = 59.42 115.01 SD = 28.86
ns ns ns ns ns ns ns ns ns ns ns ns ns, p = .11
Note. GXR = guanfacine extended release; ns = not statistically significant.
sleep times, the treatment group total sleep time decreased by 57.32 min (SD = 89.17) as the placebo group increased this parameter by 31.32 min (SD = 59.54). Children administered GXR had later onset of persistent sleep by 10.54 ± 88.44 min compared with 19.94 ± 54.12 min earlier when administered placebo (Figure 3b); however, this difference did not reach statistical significance. Similarly, although the children who were administered GXR awoke earlier than baseline whereas the children administered placebo awoke later than baseline, this difference also did not reach statistical significance (Figure 3d). In contrast, the minutes awake
after sleep onset per hour of sleep showed a statistically significant difference between the two groups, accounting for a significant part of the reduction in total sleep time (Figure 3c). At termination, the children administered GXR were awake for a mean of 4.19 more minutes per hour of sleep (4.64 ± 4.34 min/hr at baseline, 8.83 ± 9.13 min/hr at term), whereas the children administered placebo were awake for a mean of 0.58 min less per hour of sleep (3.11 ± 2.63 min/ hr at baseline, 2.53 ± 1.53 min/hr at term). Nine of 11 children receiving GXR showed a decrease in polysomnographic total sleep time (ranging from 15 to 190
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Journal of Attention Disorders
Discussion
Figure 2. ADHD Rating Scale–IV combined scores for guanfacine extended release and placebo groups at baseline and at endpoint. 2 Note. p < .001, F(1, 25) = 17.67,
ηp
= 0.41.
min less), whereas only 6 of 16 children receiving placebo showed a decrease in this important parameter (ranging from 10 to 43 min less); Fisher’s exact test p = .05. When considering the 12 children whose total sleep time increased, the two in the treatment group ranged from 29 to 131 min, whereas the 10 in the placebo group ranged from 2 to 136 min. Figure 4 demonstrates the effect of GXR and placebo on the phases of sleep during PSG. On one hand, administration of GXR was associated with a statistically significant decrease in REM sleep, decrease in total non-REM sleep, and decrease in N3/slow wave sleep when compared with placebo. On the other hand, REM, non-REM, N1, N2, and N3 sleep as a percentage of total sleep time were not statistically significantly different from placebo. This suggests that these reported differences are attributed to the overall reduction in total sleep time, and do not represent a significantly altered proportion of sleep phases.
Safety Outcome Adverse events from GXR (Table 3) are not significantly different from previous reports (Biederman et al., 2008; Newcorn et al., 2013; Sallee, Lyne, et al., 2009; Sallee, McGough, et al., 2009; Scahill, 2009). Treatmentemergent somnolence was a more frequent concern in this population with pre-existing sleep difficulties than observed in previous publications (Biederman et al., 2008; Newcorn et al., 2013; Sallee, Lyne, et al., 2009; Sallee, McGough, et al., 2009; Scahill, 2009). No electrocardiographic, laboratory, growth, or vital sign parameter was statistically significantly different at termination between the two groups.
This study was designed to evaluate the effects of morningadministered GXR tablets on polysomnographic parameters of sleep. The study was terminated early when an interim analysis demonstrated potential treatment-emergent exacerbation of polysomnographic sleep parameters. The study population reasonably represents the typical ADHD population for this community-based developmental and rehabilitation referral center. As a result of early termination of the study, the randomization did not yield equal numbers of children in each group. Nonetheless, the placebo group and treatment group were reasonably well matched for baseline data (including for overnight polysomnographic parameters). As seen in previous double-blind randomized studies (Biederman et al., 2008; Newcorn et al., 2013; Sallee et al., 2012; Sallee, Lyne, et al., 2009; Sallee, McGough, et al., 2009), GXR improved both inattention and hyperactivity– impulsivity symptoms of ADHD. The average dose and the dosing range are consistent with these prior studies. Polysomnographic evaluations are an objective singlenight assessment conducted in a clinical center, evaluating sleep onset, sleep maintenance, and electroencephalographic sleep phases. This study demonstrated that for this population, morning administration of GXR had an untoward effect on the primary polysomnographic sleep outcome measure compared with morning administration of a matched placebo tablet. The polysomnographic total sleep time decreased (indicating restriction of sleep) in all but 2 of the 11 children administered GXR (in contrast to a shortened total sleep time in less than half of the children administered placebo). Likely due to familiarity and comfort with the sleep center during the second polysomnogram, the placebo group showed more minutes of total sleep time, earlier time to persistent sleep, less time awake after sleep onset per hour of sleep, and a later time of awakening at termination; the effect on these polysomnographic parameters appeared to have been negated for the children having been administered GXR. The GXR group mean total sleep time decreased by almost an hour, primarily due to increased time awake after sleep onset per hour of sleep (accounting for a total of 21.8 min less sleep at termination for the GXR group as opposed to 18.90 min more sleep for the placebo group at termination). Although possibly factors decreasing the minutes of total sleep time for the GXR group, the later time of persistent sleep onset and the earlier time of awakening did not reach statistical significance when compared with the placebo group. Although Gruber et al. (2011) reported that this degree of additional sleep restriction may have a clinically significant negative effect on core ADHD symptoms as measured by continuous performance testing, both inattention and
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Rugino
Figure 3. Changes in polysomnographic sleep parameters for guanfacine extended release and placebo. (a) Total sleep time (min), p = .005, F(1, 25) = 9.65, η2p = 0.28. (b) Time of persistent sleep (24-hr clock), p = .24, F(1, 25) = 1.45, η2p = 0.06. (c) Wake after sleep onset per hour (min/hr), p = .025, F(1, 25) = 5.66, η2p = 0.19. (d) Time of awakening (24-hr clock), p = .11, F(1, 25) = 2.68, η2p = 0.10. Note. GXR = guanfacine extended release.
hyperactivity ADHDRS scores improved significantly for children receiving GXR compared with children receiving placebo. Of course, it is possible that with improved sleep, the degree of ADHD symptom improvement may have been even greater than reported in this study—in other words, the improvements found in this study do not refute the negative effect of sleep restriction. Although GXR did not significantly alter the proportions of REM and non-REM sleep, the total time spent in nonREM sleep (particularly in N3/slow wave sleep) was significantly decreased for the GXR group when compared with the placebo group. Reduction in N3/slow wave sleep has been associated with increased daytime somnolence (propensity to sleep), decreased daytime performance (Dijik, 2010), and increased reports of nonrestorative sleep
(Walsh, 2009). Therefore, it is possible that a decrease in total sleep time and specifically in slow wave sleep (along with direct drug effects) may contribute to the reports of daytime somnolence following administration of GXR. The significant reduction in overall REM sleep (despite the statistically insignificant reduction in the proportion of REM sleep) is consistent with a previous study in which healthy adults administered 2 mg guanfacine in the evening had a reduction in REM sleep (Spiegel & DeVos, 1980). Similarly, administration of medium-dose (0.15 mg) clonidine (Miyazaki, Uchida, Mukai, & Nishihara, 2004; Spiegel & DeVos, 1980) was found to decrease REM sleep. In contrast, other studies reported that low-dose clonidine increased REM sleep (Miyazaki et al., 2004; Schittecattea et al., 1995) and lower doses of guanfacine (1 mg) had no
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Journal of Attention Disorders
Figure 4. Phases of sleep (min).
Note. REM = rapid eye movement; N3 = slow wave sleep.
Table 3. Adverse Events. Adverse event Any adverse event Somnolence Headache Upper respiratory infection Exacerbation of allergic rhinitis Stomachache Acute gastroenteritis Dermatitis Mood change Febrile illness Cough Enuresis Dizziness Musculoskeletal chest pain Oral pain due to loose teeth Decreased appetite Inguinal hernia Exacerbation of asthma Lightheadedness Stuttering Exacerbation of insomnia Agitation Note. GXR = guanfacine extended release.
GXR (n = 11)
Placebo (n = 16)
9 (82%) 8 (73%) 4 (36%) 3 (27%) 1 (9%) 1 (9%) 1 (9%) 1 (9%) 1 (9%) 1 (9%) 1 (9%) 1 (9%) 1 (9%) 1 (9%) 1 (9%)
11 (69%) 1 (6%) 2 (13%) 3 (19%) 5 (31%) 2 (13%) 2 (13%) 2 (13%) 1 (6%) 1 (6%) 1 (6%) 1 (6%) 1 (6%) 1 (6%) 1 (6%) 1 (6%)
effect on REM sleep (Spiegel & DeVos, 1980). Considering all of the studies, one can postulate that the α-2 agonist peak blood level may influence the effect on REM sleep: lower peaks may have no effect or an increase in REM sleep whereas higher peaks may suppress REM sleep (in this study, by proportionally reducing overall sleep time). Eight of 11 children in the treatment group developed a spontaneously reported adverse event of sedation, but the parent-completed CSHQ Daytime Sleepiness subscale was not statistically significantly different between the two groups. Two participants with reported sedation resolved the concern with dose reduction; for the other children, this adverse event resolved despite continued administration of a stable GXR dose. The experience during this study is consistent with prior reports suggesting that daytime somnolence is commonly, but not universally, transient (Biederman et al., 2008; Kollins et al., 2011; Sallee, McGough, et al., 2009). When considering the adverse events and the polysomnographic findings seen in this study population with pre-existing sleep disorders, three possible factors may contribute to daytime sedation/somnolence: (a) GXR may disrupt duration and quality of sleep, resulting in daytime somnolence. (b) GXR may promote daytime somnolence and/or reduction of activity level to the point that the influence of exertion/activity on sleep promotion is reduced. (c) As blood guanfacine levels increase for an average of 6 hr after administration (range = 4-8 hr,
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Rugino Shire Pharmaceuticals, Inc., 2011), GXR may promote somnolence through a direct drug effect, whereas a rebound effect on sleep may occur as guanfacine levels decline. This study is limited due to a small sample size, short treatment time, and due to the fact that, considering day to day variability in sleep parameters, a single polysomnogram may not be representative of effect on sleep at home over an extended period of time. Other reports suggest that there may be slightly more daytime somnolence with morning administration (46.7%) than evening administration (42.1%) with similar efficacies (Newcorn et al., 2013); therefore, these data cannot be generalized to children administered GXR in the evening. Similarly, these data cannot be generalized to the ADHD population without a primary sleep disorder. Unequal sample sizes at baseline and at termination need to be taken into consideration when generalizing these results. Additional studies, especially studies evaluating afternoon/evening administration of GXR, will be needed to determine whether timing of the dose reduces the detrimental effect on sleep found in this study and to determine to what degree sleep disruption contributes to daytime somnolence seen after GXR administration. It will also be important for future studies to determine whether these findings generalize to an ADHD population without a pre-existing sleep problem and whether these findings have an impact on children with co-administration of a stimulant.
Conclusion Although ADHD symptoms improved significantly with morning administration of GXR, this treatment worsened important PSG sleep parameters for a group of 6- to 12-yearold children with ADHD and associated primary sleep disorders when compared with placebo administra-tion. Increased time awake after sleep onset per hour of sleep was the greatest factor reducing minutes of total sleep time after GXR administration, as other factors did not reach statistical significance. GXR administration reduced total REM, nonREM, and N3/slow wave sleep times, but these decreases are explained by the decreased total sleep time. This ADHD population with sleep problems had a greater frequency of reported treatment-emergent daytime somnolence than have been reported in previous studies, possibly due to direct medication effect, decreased daytime activity level, and/or due to disrupted sleep patterns. Further studies are needed to assess effects of afternoon/evening dosing on sleep, to assess whether similar findings occur in a population without preexisting sleep difficulties, and to assess the effect on sleep when GXR is co-administered with stimulants. Acknowledgments I would like to thank Kathleen Ryan, MD, for professional and prompt readings of the polysomnograms and consultation. Investigational Review was provided by Western Institutional
Review Board (IRB; www.wirb.com). The statistical expert was Jeffrey Yangang Zhang, PhD.
Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Rugino had no personal financial disclosures within the past 12 months. Children’s Specialized Hospital had received research funding from Shire Pharmaceuticals, Forest Laboratories, Supernus, Inc., Bristol-Myers Squibb, Sunovion, and Eli Lilly and Company within the past 12 months.
Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This manuscript describes the results of an investigator-initiated study funded by ShIre Pharmaceuticals. Facilities support was provided by Children’s Specialized Hospital and SleepCare Centers, Inc.
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Author Biography Thomas A. Rugino is a neurodevelopmental pediatrician at Children’s Specialized Hospital, New Jersey. He is an associate clinical professor of pediatrics at Rutgers Robert Wood Johnson Medical School and has published on the topics of ADHD, autism, and other neurodevelopmental disorders.
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