A wide array of studies has evaluated the efficacy of treatments for AD and concomitant sleep disturbances. These can broadly be arranged into 3 groups, according to whether the treatment modality was systemic, topical, or procedural. Each of the study details, with respective treatment adverse effects, is further delineated in Tables 1 and 2. Sources of funding for each study are provided in Table 3.

Dupilumab, a monoclonal antibody that exerts its effect by blocking interleukin (IL)-4 and IL-13 signaling, is a frequently studied treatment of AD. Using pooled data from 2 RCTs comprising a total of 1379 patients, 1 study using dupilumab found improvements in 2 sleep measures, Scoring Atopic Dermatitis (SCORAD) and Patient-Oriented Eczema Measure (POEM), in 2 treatment groups compared with a control. SCORAD and POEM are clinical tools used to define the eczema severity and monitor its progression [34]. The 2 cohorts either received a once weekly or once every 2 weeks injection of 300 mg dupilumab. Mean decreases in SCORAD were 3.4 (SE 0.14) and 3.3 (SE 0.14) for the weekly and biweekly treatments, respectively. Both significantly outperformed the placebo group (P<.001). In the POEM measure, more patients reported an absence of sleep disturbance in the weekly (n=199, 43.5%) and biweekly (n=234, 51.2%) groups compared with the placebo group (n=81, 17.6%; P<.001) [8].

Another study found significant improvement in visual analog scale (VAS) sleep loss scores for patients with AD undergoing dupilumab treatment. In the 2 pooled RCTs, 300 mg injections were given subcutaneously either weekly or every other week. At week 12, the mean decrease in VAS sleep loss scores for weekly injections was 75% (SD 5.13%) and for biweekly was 52% (SD 10.79%) when compared to the 19.7% (SD 6.17%) and 3.8% (SD 11.55%) reductions for each respective placebo group (P=.001) [10]. Similarly, another study that investigated 300 mg dupilumab implemented SCORAD VAS scores to assess sleep loss. A mean percentage decrease of 66% (SD 17.78%) was observed in the dupilumab group when compared to the placebo group [9]. In a retrospective cohort study, 109 patients received an initial injection of 600 mg dupilumab followed by another 300 mg every other week. A reduction in the Sleep numerical rating scale was seen in the treatment group at 4 weeks (7 to 3) and at 16 weeks (3 to 2; P<.001) [7].

A single ongoing, phase 4 clinical trial using dupilumab for patients with pediatric AD was also found. An estimated 40 participants will be recruited, and a once-weekly subcutaneous injection, based on body weight, will be administered for a total of 12 weeks. Primary sleep outcome measurements include the PROMIS (Patient Reported Outcome Measurement Information System) parent-proxy score, the PROMIS patient score, and a polysomnography-based wake after sleep onset [11].

Melatonin supplementation, given its suppressive effects of autotaxin, has also been attempted as a treatment for sleep disturbance in children with AD [35]. In a double-blinded RCT of 73 children and adolescents, 3 mg of melatonin daily was compared to a placebo. Sleep measures included SCORAD, actigraphy, and subjective assessment. Compared with placebo, melatonin reduced the SCORAD measure by 9.1 (P<.001) and reduced sleep-onset latency by 21.4 minutes (P=.02) [12].

Cyclosporine therapy, given it reduces epidural nerve density, is another potential treatment option for childhood AD [36]. One prospective randomized, parallel study compared short course versus continuous treatment schedules. A total of 40 pediatric patients either underwent multiple 12-week courses or a continued 1-year course of 5 mg/kg/day cyclosporine. Improvement in sleep disturbance was observed in all treatment groups, although no values or P values were given. A tolerability of 80% was observed at week 12 and at the end of the study [13].

Tandospirone citrate, a 5-HT1A receptor agonist, has been used to reduce stress-related symptoms of AD. One RCT of 37 patients assessed the efficacy of tandospirone citrate at a dosage of 10 mg 3 times daily for 4 weeks. Both SCORAD and an insomnia VAS were used to measure changes in sleep. A significant decrease was observed in SCORAD for the treatment group after 4 weeks (P<.001), which was not observed with the control group. However, no significant difference was observed between the groups in either SCORAD or the insomnia VAS [16].

Abrocitinib, a JAK1 inhibitor, was assessed in 1 study using pooled data from 3 RCTs, with a total of 942 patients [37]. Patients received 200 mg, 100 mg, or placebo once daily for 12 weeks, with sleep outcomes measured using the Night Time Itch Scale (NTIS). The percentage of patients reporting a change in NTIS score of >4 was 57% (n=207), 42.7% (n=158), and 12.7% (n=27) for 200 mg, 100 mg, and placebo, respectively. Moreover, the percentage of patients who reported a response in NTIS score after 12 weeks, when compared to placebo, was 44.6% for 200 mg (n=162; P<.001) and 29.8% for 100 mg (n=110; P<.001) [14].

Baricitinib, another JAK inhibitor, was studied in post hoc analysis of data from a phase 3, multicenter, double-blinded RCT of 440 patients, which compared once-daily dosages of 1 mg and 2 mg baricitinib to placebo after 16 weeks. In patients with a baseline body surface area involvement of 10% to 50%, a decrease of at least 1.5 points in the number of nighttime awakenings caused by itch was observed for 2 mg (P=.001) but not 1 mg (P=.15) groups versus placebo. For patients with a baseline Atopic Dermatitis Sleep Scale score ≥1.5, a decrease of at least 1.5 points in the number of nighttime awakenings caused by itch was observed for both 1 mg (P=.04) and 2 mg (P<.001) versus placebo. Adverse effects were not mentioned [15].

Chlorpheniramine, an antihistamine, was assessed in 1 RCT of 151 patients with AD, with no significant difference being observed in AD symptoms when compared to placebo. Dosages included 2.5 mL versus 5 mL, given once at night. There was also no difference in the severity of daytime drowsiness and the number of episodes of sleeplessness [17].

Ebata et al [18] investigated nitrazepam, a benzodiazepine believed to reduce itch by sedation, and found no significant effects on nocturnal scratching behavior. Ten patients either took 5 mg nitrazepam once nightly for 2 consecutive days or 10 mg for 1 night, followed by a 4-day washout period. A decrease in frequency in nocturnal scratching bouts was observed at the 10 mg dosage; however, this coincided with an increase in mean scratching duration. Hence, no significant difference was observed in TST% when compared to placebo [18].

Trimeprazine, an antihistamine and sedative, and trimipramine, a tricyclic antidepressant, were tested against a placebo in 1 double-blinded randomized trial of 12 patients with severe AD. Patients underwent a 3-day treatment course of either 20 mg trimeprazine tartrate, 50 mg trimipramine maleate, or placebo once at night. Electroencephalogram recordings were used to measure wakefulness and stages of sleep. No significant differences were found in total time asleep, sleep latency, or wakefulness once asleep [19].

Sertaconazole, an antifungal that inhibits ergosterol synthesis, was studied in 1 double-blind RCT with 70 subjects [33]. Topical 2% sertaconazole cream was applied twice daily for 4 weeks. The SCORAD measure was used to assess changes in sleep. No significant differences were observed between sertaconazole and the vehicle control [21].

Given AD has been hypothesized to arise from immune dysregulation, studies have also examined tacrolimus, a calcineurin inhibitor that inhibits T-cell proliferation [38]. In 1 study, 28 patients were treated with sequential application of topical tacrolimus and corticosteroids in a 4-phase treatment process. In phase 1, patients applied 0.03% tacrolimus ointment every morning and a corticosteroid ointment every night for 2 weeks. In phase 2, the same concentration of tacrolimus ointment was applied twice daily for 2 weeks, with the addition of the corticosteroid ointment on weekends. Phase 3 eliminated the corticosteroid treatment while continuing tacrolimus twice daily for 2 weeks. The fourth and final phase involved the application of an emollient once daily, with tacrolimus application as needed for a total of 6 weeks. A 4-point sleep disturbance scale was used to assess changes in sleep disturbance. A decrease was observed from a baseline of 1.0 to 0.03 and 0.04 at 6 and 12 weeks, respectively (P<.001) [22].

Topical tacrolimus has also been compared to topical fluticasone, a corticosteroid agent and T-cell proliferation inhibitor [39]. Tacrolimus or fluticasone was applied twice daily until the clearance of lesions. If lesions persisted by week 3, the application was continued once daily for an additional 3 weeks. Sleep quality, measured with VAS, improved in both groups but with no significant difference [23].

Another immunomodulatory agent, which inhibits calcineurin, pimecrolimus, has also been tested for AD treatment [40]. In 1 RCT of 19 pediatric patients experiencing AD, pimecrolimus cream was not shown to be effective in improving sleep parameters, specifically sleep duration and wakefulness. Moreover, no difference was observed in sleep parameters between the treatment and control groups [24].

Colloidal oatmeal, an anti-inflammatory and antihistaminergic agent via avenanthramide, is another potential treatment option for AD [41]. In 1 study, 23 infants and toddlers with AD received colloidal oatmeal lotion for 14 days. Sleep quality was assessed “clinically and instrumentally,” with improvement noted in continuous sleep duration and number of wakings. The degree and timing of these improvements were not specified [20].

UV phototherapy is a common treatment for dermatoses by stimulating prostaglandins and cytokine synthesis [42]. One study compared the efficacy of UV-B and cyclosporine on sleep disturbance secondary to AD, by implementing the Athens Insomnia Scale. UV-B dosage began at 0.22-0.26 J/cm² and was increased every second session until erythema appeared. Doses were given 3 times a week, with a maximum dose of 0.56 J/cm². The baseline cyclosporine dosage was 3.5 mg/kg/d, divided in 2 doses, and increased after 2 weeks, with a maximum dose of 5 mg/kg/d. Patients either received UV-B or cyclosporine for a period of 12 weeks. Itch reduction was achieved in both treatment groups, with more significant itch reduction in the UV-B cohort (P<.001). Moreover, UV-B treatment resulted in a reduction from 13.5 to 4 in mean Athens Insomnia Scale scores (P<.001). Cyclosporine, likewise, led to a mean reduction of 13.9 (SD 1.8) to 5.9 (SD 0.9; P<.001) [25].

Progressive muscle relaxation (PMR) therapy is a form of psychological therapy primarily used for stress management [43]. In 1 RCT, 25 patients were randomly assigned to either receive 1 month of PMR therapy in addition to conventional treatment or only undergo 1 month of conventional treatment. A significant decrease in sleep loss horizontal VAS scores was observed in the PMR group but not the control group (P=.007) [27].

Structured parental intervention, which consisted of a 2-hour physician lecture, was evaluated for improving sleep in 1 study of 134 children with AD. Sleep parameters were measured using SCORAD, patient-oriented (PO) SCORAD index, and sleeplessness and evaluated at the second visit (2 mo after initial evaluation). By the second visit, the mean SCORAD scores for the intervention group were 23.08 (SD 15.188) versus 36.44 (SD 16.760) for the control group (P=.001), and PO SCORAD index scores were 24.92 (SD 16.572) and 38.31 (SD 16.253), respectively (P=.001). Likewise, sleep disturbance means were 2.94 (SD 2.981) for the intervention group and 4.69 (SD 2.943) for the control group (P=.001) [26].