Parasomnias and sleep‐related movement disorders induced by drugs in the adult a review about iatrogenic medication effects

Authors: Sylvain Dumont, Vanessa Bloch, Agnès Lillo‐Lelouet, Christine Le Beller, Pierre A. Geoffroy, Marc Veyrier

Abstract

Parasomnias and sleep‐related movement disorders (SRMD) are major causes of sleep disorders and may be drug induced. The objective of this study was to conduct a systematic review of the literature to examine the association between drug use and the occurrence of parasomnias and SRMD. Following Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines for reporting systematic reviews, we searched PubMed databases between January 2020 and June 2023. The searches retrieved 937 records, of which 174 publications were selected for full‐text screening and 73 drugs were identified. The most common drug‐induced parasomnias were nightmares and rapid eye movement (REM) sleep behaviour disorders and sleepwalking. In terms of drug‐induced SRMD, restless legs syndrome, periodic limb movement disorders (PLMD), and sleep‐related bruxism were most frequent. Medications that inhibit noradrenergic, serotonergic, or orexin transmission could induce REM sleep (e.g., nightmares). Regarding sleepwalking, dysregulation of serotoninergic neurone activity is implicated. Antipsychotics are mentioned, as well as medications involved in the gamma‐aminobutyric acid (GABA) pathway. A mechanism of desensitisation‐autoregulation of GABA receptors on serotoninergic neurones is a hypothesis. SRMD and PLMD could involve medications disrupting the dopamine pathway (e.g., antipsychotics or opioids). Opioids would act on mu receptors and increase dopamine release. The role of adenosine and iron is also hypothesised. Regarding bruxism, the hypotheses raised involve dysregulation of mesocortical pathway or a downregulation of nigrostriatal pathway, related to medications involving dopamine or serotonin. Parasomnias are rarely identified in drug product labels, likely due to the recent classification of their diagnoses. An analysis of pharmacovigilance data could be valuable to supplement existing literature data.

INTRODUCTION

Sleep is essential for physical and mental well‐being (Matricciani et al., 2017). It is causally linked to the maintenance of every major physiological body system. Improving sleep quality can boost biological process and cognitive performance (Kopasz et al., 2010; Morselli, 2010). The cumulative long‐term effects of sleep deprivation and sleep disorders have been associated with a wide range of deleterious health consequences including an increased risk of premature death, obesity, diabetes, cardiovascular diseases, and mental disorders such as depression or addictions (Cappuccio et al., 2010; Geoffroy et al., 2020; Thase, 2005; Yin et al., 2017).

Parasomnias are a group of sleep disorders characterised by abnormal behavioural, experiential, or physiological events occurring during sleep or sleep–wake transitions (Association AP, 2013). They are highly prevalent in the general population and the lifetime prevalence of the different parasomnia varied from about 4% and 67% of the general population (Akkaoui et al., 2020; Bjorvatn et al., 2010). They can be classified according to the sleep stage of origin. They can occur during the non‐rapid eye movement (NREM) and rapid eye movement (REM) stages of sleep. Sleepwalking is a NREM parasomnia, which consists of complex behaviours that are initiated during slow‐wave sleep and result in ambulation. The lifetime prevalence of sleepwalking is 3.5% in adults (Hublin et al., 1997). Nightmare disorder is characterised by recurrent, highly dysphoric dreams during REM sleep. It is estimated to affect 2–8% of the general population (Akkaoui et al., 2020). Episodic nightmares are very common in the general population with a prevalence of about 35–45% (one nightmare per month) (Akkaoui et al., 2020). Sleep‐related hallucinations are very common unreal experiences that occur at the onset of sleep or upon awakening from sleep. Up to 37% of people experience them (Ohayon et al., 1996).

Sleep‐related movement disorders (SRMD) are characterised by simple, often stereotyped movements during sleep (Merlino & Gigli, 2012; Sateia, 2014). Physiological movements such as hypnic jerks can occur during sleep. However, a high frequency and severity of SRMD can impair sleep quality and cause insomnia, poor sleep quality, fatigue and excessive daytime sleepiness (Merlino & Gigli, 2012). Restless legs syndrome (RLS) is the most common SRMD, which affects between 3.9% and 24% of adults in Western countries (Hadjigeorgiou et al., 2007; Nichols et al., 2003).

Making an accurate diagnosis of parasomnia or substance/medication‐induced sleep disorder (SRMD) requires evaluating various potential causes. Two of international classifications, such as the third edition of the International Classification of Sleep Disorders (ICSD‐3) and the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM‐5), both exclude the iatrogenic effects of drugs for most parasomnias.

Therefore, there is limited scientific literature on parasomnias and SRMD induced by medications, although this is a common and challenging clinical scenario (Kierlin & Littner, 2011). Furthermore, due to the complexity of the mechanisms and neurotransmitters involved in sleep, it is important to study which medications can trigger parasomnias and SRMD. A deeper understanding of these adverse events could assist clinicians in their practices and prescriptions.

In this context, the objective of this study was to conduct a systematic review of the literature to examine the association between medication use and the occurrence of parasomnias and SRMD.

METHODS

Literature search strategy

A systematic review was conducted following Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines for reporting systematic reviews (Moher et al., 2009).

Definitions of key terms

We used the following definitions from the ICSD‐3 to characterise parasomnia.

We defined drug‐induced parasomnia as a close temporal relationship between exposure to a drug, medication, or biological substance and the onset of the signs and symptoms of that disorder (World Health Organization, 2015). A likely causal relationship can be inferred if signs and symptoms of the parasomnia or SRMD disappear when the drug or substance is withdrawn and reappears after re‐challenge with the suspected drug or substance. The emergent parasomnia/SRMD can manifest as a de novo condition, the aggravation of a chronic intermittent parasomnia/SRMD, or the reactivation of a previous parasomnia/SRMD (World Health Organization, 2015).

Eligibility

We determined a priori the following inclusion criteria for the Criterion A: studies with patients who had been diagnosed with a parasomnia or SRMD according to the ICSD‐3 caused by a drug.Criterion B: we only selected studies including human subjects aged ≥18 years.Criterion C: we only included original studies (excluded systematic reviews and meta‐analyses)Criterion D: must be in English

Search strategy

We used a systematic search strategy using the PubMed databases. The search in PubMed used the following keyword ((‘sleep‐related movement disorders’[All Fields]) OR (‘parasomnias’[Medical Subject Headings {MeSH} Terms]) OR (‘nocturnal enuresis’[MeSH Terms]) OR (‘sleep related eating disorder’[All Fields]) OR (‘sleep sex’ [All Fields]) OR (‘nightmares’ [All Fields]) OR (‘catathrenia’[All Fields])) AND ((‘drug effects’[MeSH Subheading]) OR (‘adverse effects’ [MeSH Subheading]) OR (‘chemically induced’[MeSH Subheading]) OR (‘iatrogenic disease’[MeSH Terms]) OR (‘side effects’ [All Fields]) OR (‘drug induced’ [All Fields])). We also used PubMed ‘humans, adults’ Filters.

We conducted an analysis of articles published between 2000 and June 2023. We initiated the search in 2000 to coincide with the publication of the first revised edition of the ICSD (ICSD‐1 revised, 2001). Additionally, we reviewed previous studies, reference lists, and related articles in PubMed to identify any potentially overlooked or excluded publications based on the keyword equation.

We aimed to supplement the search by including terms such as nocturnal enuresis, sleep‐related eating disorder, sleep sex, nightmares, and catathrenia, as these terms were not covered in the MeSH Term Parasomnia index.

Two reviewers (S.D., M.V.) independently screened the title, abstract, and keywords of each study identified by our search strategy and applied the inclusion criteria. Subsequently, the same procedure was applied to the full text of eligible studies.

Data extraction

One reviewer (S.D.) extracted and categorised the following data into structured tables. Extracted information included details bibliographic information, type of paper, stated aim, topic/focus of review, study/review methodology, number of patients involved, study results, parasomnias, SRMD, and drugs involved.

For each drug‐induced parasomnia and drug‐induced SRMD, retrospective categorisation of data included focus of Anatomical Therapeutic Chemical (ATC) classification system and frequency of parasomnia frequency if mentioned in the European summary of product characteristics (SPC) and in the United States Food and Drug Administration (FDA) prescribing information (PI) for human prescription drugs.

Judgement of comprehensiveness of description

Our review aim was to find which drugs could induce parasomnias or SRMD. We have developed a method to assess the comprehensiveness of the description of the method or the approach to implication, given that there are no standardised tools for such a task.

RESULTS

The initial search returned 937 articles (Figure 1). After a preliminary screening, 645 records were excluded. In all, 292 articles remained and were reviewed in detail. Upon full‐text eligibility assessment, we further excluded 118 studies that did not meet the full inclusion criteria. Of these, 174 primary studies reporting on the outcomes were included. To classify drugs involved in parasomnias or SRMD we used the ATC drug classification.

In the 174 articles, we 139 nervous system drugs, 10 cardiovascular system drugs, eight anti‐infectives drugs, five respiratory system drugs, five gastrointestinal tract and metabolism drugs, four antineoplastics drugs and immunomodulating agents, three genito‐urinary system and sex hormones drugs, two systemic hormonal preparations (excluding sex hormones and insulins), one blood and blood forming organs drug, and one antiparasitic drug. Data from the 174 included articles were compiled into Table 1.

All identified parasomnias are summarised in Table 2. Nightmares are the most commonly reported parasomnia in the scientific literature, accounting for 37 records or 21% of the included records. Sleepwalking was the second most reported parasomnia, with 28 records representing 16% of the included records, followed by REM sleep behaviour disorders with 16 records, comprising 9% of the included records. These were followed by sleep‐related eating disorder (15 articles), hallucinations (eight articles), and nocturnal enuresis (seven articles).

All identified SRMDs are summarised in Table 3. RLS was the most commonly reported in the scientific literature, accounting for 62 records or 36% of the included records. Periodic limb movement disorders were the second most reported sleep‐related movement disorders, with nine records representing 5% of the included records, followed by sleep‐related bruxism with four records, comprising 2% of the included records.

A total of 113 cases of parasomnias or SRMD induced by drugs was identified in the medical literature. The risk of developing parasomnia or SRMD was mentioned in the SPC or PI for 50 disorders induced by drugs (44%). No mention was found for 63 disorders induced by drugs (56%). When the risk of parasomnia or SRMD was mentioned, the most common frequencies of occurrence uncommon (17 drugs) and undetermined frequency (15 drugs).

A total of 73 distinct drugs have been identified as likely to induce parasomnias or SRMD. In all, 43 drugs were associated with parasomnias and 44 were linked to SRMD, with 14 associated with both adverse effects. Additionally, seven drugs are not available (European Medicines Agency [EMA] and FDA) so classification could not be done.

DISCUSSION

This systematic review highlights the associations between drugs and induced parasomnias/SRMD. Nervous system drugs were found to be the main drug classes reported in association with parasomnias or SRMD. This outcome could be linked with the ability of nervous system drugs to modulate the release of neurotransmitters that are involved in the regulation of sleep–wake cycle (Franco‐Pérez et al., 2012). Noradrenaline, serotonin (5‐hydroxytryptamine [5‐HT]), acetylcholine, gamma‐aminobutyric acid (GABA), histamine, orexin, and adenosine play a major role in sleep–wake cycle (Franco‐Pérez et al., 2012). Agonists and antagonists that interact with these neurotransmitter receptors can increase or decrease the duration of the sleep stages.

Cardiovascular drugs and anti‐infective drugs are also involved in parasomnias. Cardiovascular drugs associated with parasomnias are mostly liposoluble β‐blockers (e.g., propranolol, metoprolol) because of their ability to cross the blood–brain barrier and to modulate the release of neurotransmitters. A reduction in melatonin secretion and symptoms of insomnia have also been reported during long‐term treatment with β‐blockers (Rommel & Demisch, 1994). Other drugs, such as statins, can induce parasomnias through direct effects or pharmacodynamic and pharmacokinetic interactions with other medications such as β‐blockers and can modulate the release of neurotransmitters (Gregoor, 2006), such as serotonin (Yamada et al., 1995). Efavirenz, an anti‐human immunodeficiency virus (HIV) drug, is currently the main driver of parasomnia in anti‐infective drugs. This side‐effect could be due either to the virus, or to underlying psychiatric illnesses that are frequently associated with HIV infection (Drury et al., 2018), or to a direct effect on the central nervous system (Cavalcante et al., 2010). Effects of Efavirenz are dose‐dependent and are influenced by cytochrome P450 2B6 (CYP2B6) polymorphism (Cavalcante et al., 2010; Drury et al., 2018).

Nightmare disorder was the most frequently reported drug‐induced parasomnia, with 37 articles identified. It is mainly considered as a REM‐related parasomnia, although nightmares may occur during all sleep stages. Nervous system drugs were the most frequently associated with drug‐induced nightmares. This result may be linked to neurotransmitters implicated in the REM stage. Although further studies are needed to determine which neurotransmitters are involved. Various β‐blockers were also associated with REM‐related parasomnias. Liposoluble β‐blockers can bind to 5‐HT receptors (Juszczak & Swiergiel, 2005) and to central β‐adrenoreceptors (Yamada et al., 1995) and can promote REM sleep in return (Franco‐Pérez et al., 2012). This suggests that the promotion of REM sleep through the inhibition of noradrenergic and serotonergic transmission can induce REM‐related parasomnias such as nightmares (Franco‐Pérez et al., 2012). A similar pattern can be observed with suvorexant, an orexinergic antagonist, which promotes sleep by increasing slow‐wave sleep and REM sleep and have been reported as causing both nightmares and REM sleep behaviour disorders in a case report (Tabata et al., 2017). This reinforces the previous hypothesis that drugs involving antagonism of neurotransmitters (serotonin, noradrenaline, and orexin) whose levels are physiologically minimal during REM sleep can induce REM sleep‐related parasomnias. Furthermore, medication‐induced REM sleep behaviour disorders are associated with the same category of drugs. REM sleep behaviour disorder ranks third among the most frequent parasomnias in our analysis.

If we hypothesise that nightmares mainly occur during REM sleep, medications that suppress the duration of REM sleep should reduce or eliminate nightmares. However, some selective serotonin re‐uptake inhibitors, such as citalopram and paroxetine, which stimulate 5‐HT2 receptors and should reduce REM sleep duration, seem to induce nightmares (Arora et al., 2012; Parish, 2007). This could be explained by the complex pathophysiology of the conditions that require such treatment and/or associated co‐medication. Another explanation could be related to the initial effect of selective serotonin re‐uptake inhibitors on anxiety. During the first 2 weeks of treatment, these medications increase anxiety, but in the long term, they relieve anxiety.

Sleepwalking was the second most reported parasomnia, with 28 identified articles. According to our study, this non‐REM parasomnia is mainly induced by hypnotics such as zolpidem and zopiclone, which increase GABA activity on the GABAA receptor (Seeman, 2011). The occurrence of sleepwalking when taking short half‐life hypnotics might be explained by the desensitisation‐autoregulation hypothesis of GABA receptors on serotonergic neurones (Juszczak, 2011). This hypothesis suggests that benzodiazepines (or similar drugs) potentiate GABAA receptors and ultimately reinforce the desensitisation of these receptors on serotonergic neurones. The desensitisation increases the activity of serotonergic neurones and reduces with some delay serotonin release using an autoregulation mechanism. The delay between desensitisation and compensatory autoregulation of serotonin release would promote the occurrence of sleepwalking episodes (Juszczak, 2011). Antipsychotics, such as olanzapine and quetiapine, could also induce sleepwalking. This might be explained by the deregulation of serotoninergic activity in the serotonergic neurones of the raphe nuclei and in the serotonergic system, which can modulate the motor system. These two neuronal systems are normally coordinated so that increased excitation of the serotonergic neurones leads to increased motor activity. The dissociation of the activity of the two systems by antipsychotics can lead to sleepwalking (Hafeez & Kalinowski, 2007).

The most reported SRMD in our study was RLS (62 articles). It is not associated with a specific stage of sleep. In most cases, RLS was induced by antidepressants or antipsychotics. According to the literature, RLS is caused by a disruption of dopaminergic neurotransmission (Trenkwalder et al., 2018). Iron deficiency is also a known risk factor for SRMD. In a recent study a possible significant role of adenosine in RLS was reported (Trenkwalder et al., 2018). Opioid withdrawal also induces transient RLS. This could be explained by mu receptor stimulation, associated with increased dopamine release. Dopamine release could abruptly decrease during opioid withdrawal, while a decrease in sensitivity and appropriate intracellular signalling may not have yet restored, leading to complex and transient disturbances in motor behaviour, such as RLS (Park et al., 2010). Moreover, it appears that drugs involved in periodic limb movement disorders belong to the same category of medication as those implicated in SRMD. Genetic studies also seem to show that the risk of RLS is strongly associated with periodic limb movement disorders (Stefansson et al., 2007).

Bruxism was the third most reported SRMD, with four identified articles. Antidepressants appear to be the class of medications that is the most likely to cause bruxism in our literature review. According to Uca et al. (2015), the incidence of antidepressant‐induced bruxism was 14%. It seems that the central dopaminergic system, which regulates motor activity, could play a role in the pathophysiology of bruxism (Lavigne et al., 2003). It has been hypothesised that the mechanism of antidepressant‐induced bruxism involves excessive serotoninergic activity on mesocortical neurones originating from the ventral tegmental area (Milanlioglu, 2012). This activity results in a dopamine deficit, leading to a particular form of akathisia and akathisia‐like movements of the jaw muscles, resulting in bruxism (Milanlioglu, 2012). Antipsychotics are also associated with bruxism due to their inhibitory effect on dopamine‐2 receptors (Clark & Ram, 2007; Fratto & Manzon, 2014). Falisi et al. (2014) proposed a hypothesis to explain the link between drugs and bruxism. Dopamine agonists, such as L‐DOPA, stimulate dopamine receptors in the basal ganglia, thus increasing dopaminergic control of motor functions via nigrostriatal pathways and preventing the onset of bruxism. Selective dopamine antagonists, such as typical antipsychotics, cause dysfunction of motor control and bruxism phenomena. Psychostimulants sensitise dopamine receptors in the frontal cortex and reduce the functionality of the mesocortical pathway, thereby reducing inhibition of motor control. Serotonin re‐uptake inhibitors alter serotoninergic control of the raphe nucleus on the mesocortical pathway, with a similar effect to psychostimulants. Medications that inhibit serotoninergic neurotransmission, such as atypical antipsychotics, suppress bruxism through the opposite mechanism, by normalising mesocortical pathway activity (Falisi et al., 2014).

Analysis of the information provided in the SPC and PI shows that the risk of developing parasomnia or SRMD is rarely this risk was not mentioned in the SPC or PI for 56% of the drugs identified in our study. This could be explained by the following factors. Some drugs were created before the emergence of the ICSD diagnostic criteria, thus ICSD diagnostic criteria were not considered when they were marketed. Although the post‐marketing period of a drug involves monitoring adverse reactions based on reports, the diagnosis is rarely specific in these reports. Most of the time, the report indicate sleep disorders without specifying the precise diagnosis. Moreover, the development of sleep medicine is relatively recent, thus parasomnia assessment according to ICSD criteria may not always be applied to adverse drug reaction reports.

In our study, drugs were classified according to their effects on the release of neurotransmitters and their possible specific role with each parasomnia. However, many drugs have either multiple mechanisms of action, or their mechanisms are not entirely understood. Moreover, the pharmacological action of some drugs changes depending on the plasma concentration. An illustrative example is it has antipsychotic effects at high concentrations, antidepressant effects at intermediate concentrations, and anxiolytic effects at low concentrations. For this reason, only a pharmacodynamic analysis of the data was conducted. Furthermore, patients prescribed such medications are likely to be taking other medications that can cause potential interactions and complicate data analysis. As our study did not address these factors, we cannot precisely identify which neurotransmitters are involved in inducing parasomnias. Therefore, no causal conclusions can be drawn from this analysis. It must be emphasised that the data in this analysis may be underestimated as pharmacovigilance data have not been analysed.

CONCLUSION

In conclusion, our study found that the most common drug‐induced parasomnias were nightmare and REM sleep behaviour disorders. Regarding drug‐induced SRMD, RLS, periodic limb movement disorders, and sleep‐related bruxism were most frequent. While our study did not establish a direct correlation between a particular neurotransmitter and a distinct parasomnia or SRMD, certain drug classes such as antidepressants, antipsychotics, hypnotics and sedatives, β‐blockers, and anti‐infectives emerged as the most frequently reported in the literature for inducing parasomnias. Parasomnias showed associations with neurotransmitter pathway‐altering drugs, such as those affecting dopamine, noradrenaline, and serotonin. SRMD seemed mostly associated with dopamine‐related drugs. An analysis of pharmacovigilance declarations should be carried out soon to achieve a more comprehensive coverage of cases and to further understand the relationship between drugs and sleep disorders.

AUTHOR CONTRIBUTIONS

Sylvain Dumont: Writing – original draft; writing – review and editing; formal analysis; methodology; conceptualization; data curation; project administration. Vanessa Bloch: Writing – review and editing. Agnès Lillo‐Lelouet: Writing – review and editing. Christine Le Beller: Writing – review and editing. Pierre A. Geoffroy: Conceptualization; methodology; validation; writing – review and editing; project administration. Marc Veyrier: Conceptualization; methodology; validation; writing – original draft; writing – review and editing; project administration.

CONFLICT OF INTEREST STATEMENT

Pierre A. Geoffroy received speaker honorarium from Biocodex, Bioprojet, Ibsa, Idorsia, Janssen‐Cilag, Isis Medical, Jazz pharmaceuticals, Lundbeck, MySommeil, Withings; fees for consulting from Apneal, Biocodex, Dayvia, Idorsia, Janssen‐Cilag, Jazz pharmaceuticals, Myndblue, Mysommeil, Posos, ResilEyes, Withings; and is advisory board member of Apneal, Idorsia, Janssen‐Cilag, Myndblue, Sleepify. The other authors have no conflicts of interest to declare.