WHAT IS ALREADY KNOWN ON THIS TOPIC

Melatonin is commonly prescribed in UK services for children and adolescents, principally for the management of sleep disorders. The number of prescriptions for melatonin has increased exponentially in primary care in England in the last 10 years or so.29

WHAT THIS STUDY ADDS

The study provides data about the prescription of melatonin in a large audit sample of children and adolescents and reveals the extent to which current use aligns with evidence-based practice standards. The findings indicate a relative lack of systematic review by clinicians of the therapeutic response to melatonin treatment and emergent side effects in routine clinical practice.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

Processes for reviewing the efficacy, tolerability and continuing need for melatonin treatment should be embedded in care pathways for children and adolescents with sleep-related problems; these pathways should be resourced appropriately. Studies investigating the utility of planned melatonin breaks are warranted.

Background

A variety of sleep problems in children and adolescents are commonly encountered in clinical practice, including difficulty getting to sleep, difficulty maintaining sleep, reduced duration of sleep, circadian rhythm disorders and obstructive sleep apnoea. Compared with their healthy peers, sleep disturbances are far more common in children with neurodevelopmental or psychiatric disorders, affecting 50–80%.1–4 These disorders can adversely affect the daytime functioning of a child and impact on family life5 prompting parents to seek medical help.

A growing body of evidence suggests that abnormalities in the timing and quantity of endogenous melatonin production might underlie some of the sleep onset, maintenance and circadian rhythm problems that commonly occur in children with neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD).6 7

In contrast to the USA where melatonin of uncertain quality is readily available over the counter as a health food supplement,8 in the UK and most of Europe, melatonin is a prescription-only medicine. It has a more extensive evidence base than any other drug used for paediatric sleep disorder. Although uncertainties about its optimal use remain, there is an emerging consensus that for children with circadian rhythm disorders, particularly delayed sleep phase syndrome, melatonin, with regular follow-up and assessment, can be a useful treatment,2 9 10 particularly in those with neurodevelopmental disorders.3 11 However, the benefits are generally modest.12 Whether or not sleep disorders are associated with ASD or ADHD as underlying conditions, it has been recommended that melatonin should only be used where sleep problems persist after non-pharmacological interventions have been implemented.13 Melatonin appears to be relatively well tolerated, at least in the short to medium term14 and, for children with neurodevelopmental disorders, only mild transient adverse effects, such as headache, hyperactivity, dizziness and abdominal pain, have been reported.15

Objective

In 2022, a clinical audit of melatonin use was conducted in a range of UK clinical services for children and adolescents, as part of a quality improvement (QI) programme run by the Prescribing Observatory for Mental Health (POMH). The data collected provided the opportunity to assess the quality of evidence-based prescribing practice with melatonin.

Methods

POMH invited all 65 member healthcare organisations (predominantly National Health Service (NHS) Mental Health Trusts) to participate in a clinical audit, as part of a QI programme addressing the use of melatonin in children and adolescents. The audit was limited to children and adolescents treated with melatonin, under the care of child and adolescent mental health services (CAMHS), community paediatric services or intellectual disability (ID) services. All Trusts and clinical teams were self-selected in that they chose to participate.

The clinical practice standards for the audit included the following: (1) the target symptoms for melatonin treatment should be documented (eg, sleep onset, sleep duration, night-time awakenings, sleep quality); (2) evidence-based, non-pharmacological interventions should be tried before melatonin is prescribed; (3) the efficacy and safety/tolerability of melatonin medication should be reviewed within 3 months of starting; and (4) the need for continuing melatonin treatment should be reviewed annually, based on efficacy and side effects. These standards were derived from good practice recommendations in a review of the use of melatonin for sleep problems in children with neurodevelopmental disorders that was published in the Drug and Therapeutics Bulletin.2

Information related to performance against these practice standards was collected using a bespoke data collection tool. The data collected on each eligible patient included the following: age, sex, ethnicity, nature of clinical service providing care and clinical diagnoses. In addition, detailed information was collected on the melatonin prescriptions, including formulation, total daily dosage, whether melatonin had been prescribed for less than 3 months, 3–12 months or more than a year, and details of early on-treatment and longer-term medication review, as well as documentation of the clinical reasons for use in the individual patients. The data on prescribing practice for melatonin reported in this paper relate to children and adolescents who were 18 years of age or younger.

Clinicians and clinical audit staff in each Trust collected the audit data.

Statistical analyses

Anonymised data were submitted online using Formic software16 and stored and analysed using SPSS (V.26.0).17 Simple descriptive statistics were used to describe the total audit sample and clinical subsamples. Differences between the clinical subsamples were explored using X2 and independent samples t-tests.

Findings

Data were submitted by 59 Trusts for 4151 children and adolescents prescribed melatonin who were 18 years of age or younger; 2711 (65%) of whom were under the care of CAMHS, 1202 (29%) community paediatric services and 238 (6%) ID services. Of the total sample, 2129 (51%) had a diagnosis of ASD, 1744 (42%) ADHD (including hyperkinetic disorder) and 853 (21%) an ID. The comorbidity of these disorders in our audit sample is shown in figure 1. In the 945 (23%) cases where none of these diagnoses were documented, the most common International Classification of Diseases 10th Edition (ICD)-10 diagnostic categories were ‘anxiety, dissociative, stress-related, somatoform and other non-psychotic mental disorders’ (F40–F48: n=408), ‘affective disorders’ (F30–F39: n=244), ‘other insomnia’ (F51: n=69), ‘circadian rhythm sleep disorders, including delayed sleep phase syndrome’ (G47.2: n=66) and ‘other behavioural syndrome’ (F50, F52–59: n=41).

Figure 1

Most common clinical diagnoses in children and adolescents prescribed melatonin. ADHD, attention deficit hyperactivity disorder.

We identified four diagnostic subsamples of patients, as follows: (1) those with a diagnosis of an ASD (but no ADHD), with or without a comorbid ID (n=1309); (2) those with a diagnosis of ADHD (but no ASD), with or without a comorbid ID (n=924); (3) those with both ASD and ADHD, with or without a comorbid ID (n=820); and (4) those with neither ASD nor ADHD, with or without comorbid ID (n=1098). The demographic characteristics of the total audit sample and the four diagnostic subsamples are shown in table 1. In the three subsamples of children and adolescents with neurodevelopmental disorders (subsamples 1, 2 and 3), the patients were predominantly male (n=2159; 71%), while in the subsample with other clinical diagnoses (subsample 4), they were predominantly female (n=653; 59%): X2=314.812, p<0.001. There were relatively more adolescents in the subsample without neurodevelopmental disorders than in the subsamples with these diagnoses.

Table 1

Demographic characteristics of four diagnostic subgroups of children and adolescents who were prescribed melatonin (n=4151)

Melatonin was prescribed to be taken regularly in 3651 (88%) of cases, a small minority of whom (n=140; 4%) were also prescribed melatonin on a PRN (pro re nata; as required) basis. In the remaining 500 cases (12%), melatonin was prescribed on a PRN basis only; these proportions did not differ between the diagnostic subgroups. The doses and formulations of melatonin prescribed to be taken regularly and the clinical reasons for these prescriptions are shown in table 2. There were only minor numerical differences in these variables across the diagnostic subgroups. For example, children and adolescents with both an ASD and ADHD diagnosis were less often prescribed a dose of melatonin that was lower than 4 mg/day, a controlled release formulation was more often prescribed for those with ADHD, and sleep latency as a target symptom was slightly less common in those with neither an ASD nor an ADHD diagnosis. In the total sample, the mean daily dose of melatonin regularly prescribed for adolescents who were 13 years of age or older (mean 4.7 mg, SD 2.4 mg) was significantly higher than that in children who were 12 years of age or younger (mean 4.0 mg, SD 2.1 mg); t=−8.743, df=3649, p<0.001.

Table 2

Dose, formulation and clinical reasons for regular prescriptions for melatonin in the four diagnostic subgroups of children and adolescents

Performance against the practice standards was assessed in relevant subgroups, as follows. With respect to the reason for prescribing melatonin being documented in the clinical records (practice standard 1), this was examined in the 3651 patients who were prescribed melatonin to be taken regularly and the standard was met in 3192 (87%) of these cases overall with little difference between the clinical subsamples (see table 2). The documented use of non-pharmacological interventions prior to prescribing melatonin (practice standard 2) was assessed in the 409 patients who had been treated with melatonin for less than 3 months, as recently documented information should be more reliably accessed in the clinical records and will be reflective of current practice. This standard was met in 279 (68%) of these cases; 106 (78%) of the 136 with a diagnosis of ASD but no ADHD, 43 (62%) of the 69 with a diagnosis of ADHD but no ASD, 26 (59%) of the 44 with both diagnoses and 104 (65%) of the 160 patients with neither of these diagnoses. Cognitive–behavioural therapy for insomnia (CBTi) had been used in only eight cases. Comparing those with a neurodevelopmental disorder with those without, there was no difference in the overall proportions who received a non-pharmacological intervention before melatonin was prescribed (n=175; 70% vs n=104; 65%; X2=1.253, df=1, p=0.263). With respect to the documentation of a clinical review, quantifying the effectiveness of melatonin in the first 3 months of treatment (practice standard 3), this was assessed in the 889 patients who had been prescribed melatonin for between 3 months and a year and the standard was met in in 321 (36%) cases (see table 3); while a clinical review in the last year, quantifying the effects of melatonin (practice standard 4) was assessed in the 2353 patients treated with melatonin for more than a year and this standard was met in 729 (31%) cases (see table 3). Table 3 also shows data relating to the assessment of side effects and consideration of treatment breaks in the national subsamples in each of the diagnostic groups. The data in tables 2 and 3 show some modest numerical differences in adherence to the practice standards between the different diagnostic subsamples. For example, an assessment of early response to melatonin was documented numerically most often in the subsample with a diagnosis of both ASD and ADHD.

Table 3

Documented review of the benefits and side effects of melatonin treatment within 3 months of treatment initiation in the four diagnostic sub-groups of children and adolescents who had been (A) prescribed melatonin for between 3 months and a year and (B) been prescribed melatonin for more than a year

Discussion

The data reported in this paper were collected in the context of a retrospective audit of melatonin prescribing practice. The large sample size, drawn from 59 different NHS Trusts, means that our findings are likely to be representative of prescribing practice with melatonin for children and adolescents up to 18 years of age in the UK.

The most common clinical reasons for prescribing melatonin were to decrease sleep latency (time taken to fall asleep), reduce night-time awakenings and increase the overall duration of sleep; these treatment goals were consistent, irrespective of the underlying psychiatric diagnosis. Melatonin has proven efficacy in reducing sleep latency along with more modest effects on total sleep duration and night-time awakenings,4 18 and our data suggest that melatonin is essentially used for these evidence-based indications. The daily dose of melatonin was between 2 and 6 mg in half of the cases, with adolescents prescribed a slightly higher dose than children, particularly in the subsample with both ASD and ADHD, suggesting that sleep problems may be more refractory in such patients. Melatonin was prescribed as a controlled release preparation in three-fifths of cases, likely reflecting recommendations in local treatment guidelines that direct prescribers towards formulations with the lowest acquisition cost.19 20

Use of non-pharmacological interventions before prescribing melatonin

There are a large number of non-pharmacological interventions aimed at improving various aspects of sleep disturbance in different clinical populations of children and adolescents. Clinical guidelines generally recommend that such interventions are tried before medication is prescribed2 13 20: in some cases, response to non-pharmacological interventions may be adequate, thus avoiding the need for melatonin.21 In our subsample of patients treated with melatonin for less than 3 months, there was documented evidence in the clinical records to suggest that non-pharmacological interventions had been tried in just over two-thirds. This proportion did not differ significantly between those children and adolescents with a neurodevelopmental disorder and those without.

For the children and adolescents with ASD, parental education programmes have been shown to be more effective than melatonin in improving co-sleeping and morning wakening times, but such non-pharmacological interventions have only weak evidence for efficacy for a reduction in sleep latency and increase in sleep duration, compared with melatonin.4 In our sample, reducing night-time awakenings was a target symptom for melatonin in one-third. For such patients, it is therefore possible that in some cases of ASD where no non-pharmacological intervention before starting melatonin had been documented, clinicians may have opted first line for the treatment they perceived to be supported by the strongest evidence. An alternative explanation is that the system was insufficiently resourced to provide the extra appointments that would be needed to support parents to implement non-pharmacological interventions.

Regarding the use of cognitive–behavioural therapy (CBT) alone or in combination with melatonin, there are relevant data from a randomised controlled trial: Cortesi et al 22 randomised 160 children with ASD to receive melatonin alone, CBT alone, melatonin and CBT or placebo alone. At 12 weeks, sleep latency was less than 30 min (or had decreased by more than 50%) in 39%, 10%, 84% and 0%, respectively, demonstrating that 1 in 10 children responded to CBT alone and that the combination of CBT and melatonin was much more effective than either treatment alone. There are other promising results supporting the effectiveness of CBTi in children and adolescents.23 However, despite this encouraging evidence, we found that CBT was rarely tried before melatonin was prescribed. The most likely reason for such low use is lack of timely access to services providing this treatment.

Early on-treatment review of the benefits and side effects of melatonin

Clinical trials that have tested the efficacy of melatonin have used a number of standard measures to compare the effects of this medication with placebo. These include time taken to fall asleep, number of night-time awakenings, longest period of unbroken sleep and time of morning wakening. As with all medication, individual response will differ; for example, a 1-year open-label study of melatonin in children with ASD reported that a quarter gained little benefit, even with a daily dose of up to 10 mg.24 An early on-treatment review is therefore essential to determine whether the response of the target symptoms is sufficient to justify continuing treatment. Our data show that while an early on-treatment review addressing therapeutic response to melatonin had been documented in just under two-thirds of cases overall, the clinical effect of melatonin had been quantified in only one-third.

There was documentation in the clinical records that there had been a review of possible treatment emergent side effects in just under half of cases. Melatonin is generally considered to be well tolerated in the short term, although dizziness, sedation, gastrointestinal symptoms and headaches can occur.9 25 Side effects may be difficult to elicit from some children and adolescents due to underlying conditions and/or communication barriers, but direct inquiries should be made with the patient where possible and parents/carers prompted to report concerns as appropriate.

Review of the benefits and side effects of long-term melatonin treatment

Of the patients who had been prescribed melatonin for more than a year, just over two-thirds had had their response to treatment reviewed in the past year, with the response being quantified in less than half. Side effects had been reviewed in the past year in just under a half of those on long-term treatment. Consideration of the need for continuing treatment had been documented in almost two-fifths. Whether or not patients had a diagnosis of ASD and/or ADHD did not seem to have any clear or consistent association with the profile of medication review.

It has been reported that for a proportion of children prescribed melatonin for chronic sleep onset insomnia in the absence of neurodevelopmental disorders, the medication can be successfully withdrawn.26 Such findings prompted the recommendation that melatonin, as a treatment for delayed sleep–wake phase disorder, should be stopped ‘at least once a year’ to assess whether it should continue to be prescribed.27 However, there is a lack of studies testing the risks and benefits of such treatment breaks as a routine strategy in clinical practice, across the different clinical populations prescribed melatonin; a National Institute for Health and Care Excellence Clinical Knowledge Summary addressing the prescription of melatonin for insomnia28 makes no mention of them. Despite this, one international consensus guideline25 has a standard recommendation for annual treatment breaks and many NHS Trusts have endorsed a range of treatment break strategies.19 20 In our subsample of cases who had been prescribed melatonin for more than a year, it was reported that a treatment break had been tried in the past year for around one in eight. Possible explanations for this low proportion may be that a treatment break had been tried more than a year ago, that some treatment breaks in the past year had not been documented in the clinical records, that clinicians considered the risk of destabilising sleep to be too great to justify, that services lacked the resources to oversee treatment breaks, and that clinicians were unaware of or unconvinced by recommendations to stop the medication at least once each year.

Clinical implications

Our findings suggest that just under one-third of children and adolescents starting melatonin will not have had a non-pharmacological intervention. But disturbance in more than one aspect of sleep was common, and on the basis that no single intervention is likely to be effective for all problems, it may be reasonable to suppose that the greater use of non-pharmacological strategies could lead to better outcomes in this patient group.

Our data also reveal that following the initiation of melatonin for sleep disorder, the nature and extent of the initial effects on sleep are not consistently assessed and recorded. A lack of quantification of the therapeutic response will make it more challenging to develop and review a systematic treatment plan over time, potentially resulting in unnecessary long-term treatment for some patients.

Treatment breaks were relatively infrequently documented despite the common inclusion of such a strategy in guidelines for melatonin use developed by UK healthcare providers. Given the lack of published evidence for a favourable risk–benefit balance for routine planned breaks in melatonin treatment, a review of such guidelines may be warranted.

Data availability statement

No data are available. The aggregated dataset that supports these findings is not openly available. Membership agreements between POMH and participating mental health services state that each mental health service owns its own dataset and that this will not be shared by POMH with any third party. POMH is restricted to reporting on analyses based on the aggregated national dataset.

Ethics statementsPatient consent for publication

Not required.

Ethics approval

Ethical approval is not required for audit-based quality improvement initiatives.30

Acknowledgments

Thanks are due to all the clinicians and clinical audit staff from the UK clinical services who collected and submitted data as part of this quality improvement initiative, and to Gavin Herrington, the POMH programme manager.