Systematic Reviews and Levels of Evidence – Methods and Results
This paper aimed to develop the official recommendations of the Brazilian Sleep Association
(Associação Brasileira do Sono – ABS) to diagnose and treat chronic insomnia in adults. To this end, the ABS board
of directors invited a group of Brazilian professionals experienced in diagnosing
and treating insomnia – hereinafter named the “steering committee,” comprising four
physicians (LFD, MA, AB, and DP), one psychologist (SC), and one methodologist (GNP),
all accredited, qualified, or with a history of relevant research in the area. The
steering committee was responsible for selecting the topics approached in this paper
and inviting coordinators for each one. Lastly, other professionals were invited to
make up each topic's work group.
Methods
Research Questions and Systematic Review
Even though this paper covers both the diagnosis and treatment of insomnia, structured
research questions were developed only for the topics on treatment, not for the ones
on insomnia diagnosis. Developing research questions for diagnostic accuracy – such
as with the PI(R)T approach – requires clearly established reference tests as valid
comparators.[14 ] Since the reference tests are analyzed in this study, the topics on diagnosis were
not addressed with structured research questions – rather, these topics were written
based on theoretical considerations, previous guidelines, and professional experience.
The same is true about topics related to pathophysiological aspects and insomnia classification.
Hence, a series of questions were developed for the topics on insomnia treatment based
on the PICO acronym, following the model, “What is the effect of [INTERVENTION] compared with [CONTROL] on [OUTCOME] in adults
with chronic insomnia without comorbidities? .” Each PICO parameter was defined by the steering committee in a synchronous online
meeting. Concerning pharmacological interventions, only the ones currently available
in Brazil or possibly becoming available in the upcoming years were considered eligible.
Given the large number of interventions to be included in this paper, it was decided
to restrict the research questions to the primary treatment of chronic insomnia in
adults. Other aspects related to the use and implementation of each selected intervention
(e.g., different insomnia phenotypes, comorbidities, combined treatment, etc.) were
not included in the research questions, although they are discussed in the reviews
prepared by each work group. The list of eligible interventions is presented in [Table 1 ]. Each PICO item is detailed in [Table 2 ] and explained in detail along with the inclusion and exclusion criteria.
Table 1
List of eligible interventions.
Non-pharmacological interventions
CBT-I
In-person CBT-I
Online CBT-I
Group CBT-I
Digital CBT-I
Self-help CBT-I
ACT-I
MBCT-I
Alternative
Acupuncture[a ]
treatments
Aromatherapy[a ]
Biofeedback[a ]
Massage[a ]
Meditative practices[a ]
[c ]
Mind-body practices[a ]
[d ]
Physical exercises[a ]
Pharmacological interventions
BZD agonists
Zolpidem
Zopiclone
Eszopiclone
BZD[b ]
Bromazepam
Diazepam
Clonazepam
Alprazolam
Midazolam
Flunitrazepam
Estazolam
Flurazepam
DORA
Suvorexant
Lemborexant
Daridorexant
Antidepressants
Trazodone
Doxepin
Mirtazapine
Amitriptyline
Agomelatine
Melatonin
Melatoninergic agonist
Ramelteon
Anticonvulsants
Gabapentin
Pregabalin
Antipsychotics
Quetiapine
Olanzapine
Clozapine
Periciazine
Levomepromazine
Chlorpromazine
Others
Diphenhydramine
Promethazine
Hydroxyzine
Dimenhydrinate
GABA
Tryptophan
Phytotherapeutics
Valeriana officinalis
Passiflora incarnata
Matricaria recutita
[a ]
Withania somnifera
[a ]
Erythrina mulungu
Cannabinoids
Cannabis sativa
Cannabidiol
Delta-9-THC
Abbreviations: ACT-I: Acceptance and commitment therapy applied to insomnia. BZD: Benzodiazepines.
DORA: Dual orexin receptor antagonists. GABA: Gamma-aminobutyric acid. MBCT-I: Mindfulness-based
cognitive therapy applied to insomnia. CBT-I: cognitive-behavioral therapy applied
to insomnia. THC: Tetrahydrocannabinol.
a Interventions not included in the systematic reviews.
b Recommendations voted in group for the whole class, instead of individually for each
intervention.
c Encompassing meditation and vipassana.
d Encompassing qigong, tai chi, and yoga.
Table 2
Research questions according to PICO criteria.
Population
Interventions
Comparators
Outcomes
Adults diagnosed with chronic insomnia
[Table 1 ]
No treatment
Sleep latency (PSG or actigraphy)
Adults with moderate to severe insomnia symptoms
Waiting list
Total sleep time (PSG or actigraphy)
Placebo
Sleep efficiency (PSG or actigraphy)
Minimum intervention
WASO (PSG or actigraphy)
Pharmacotherapy*
Sleep quality (PSQI)
CBT-I (any format) *
Daytime sleepiness (ESS)
Insomnia symptoms (ISI)
Insomnia diagnosis
Sleep diary*
Self-reported total sleep time, sleep latency, and sleep efficiency*
Abbreviations: CBT-I, Cognitive-behavioral therapy applied to insomnia; ESS, Epworth Sleepiness
Scale; ISI, Insomnia Severity Index; PICO, Population, intervention, comparator, and
outcome; PSG, Polysomnography; PSQI, Pittsburgh Sleep Quality Index; WASO, wake after
sleep onset.
* Items applied only to search strategies related to non-pharmacological interventions.
The results of the systematic reviews based on the research questions were used with
two main purposes: 1. Generating material to analyze the level of evidence for each
intervention and 2. Providing references to each work group to help them prepare their
reviews. No meta-analyses were performed.
Bibliographic Search and Eligibility Analysis
Independent search strategies were developed for each intervention (as seen in [Table 1 ]). Exceptions were made in the following three cases: 1. interventions related to
cannabinoids and cognitive-behavioral therapy applied to insomnia (CBT-I), for which
a general search was made for each group; 2. alternative and complementary interventions,
of which it was decided not to conduct systematic reviews due to the great heterogeneity
in studies using these treatments; and 3. phytotherapy interventions (Matricaria recutita and Withania somnifera ), of which no systematic reviews were conducted because they were included later
in this document.
The strategies combined two search domains, one for insomnia (addressing both population
and outcome) and the other combining each intervention's search strategy. Regarding
specifically non-pharmacological interventions, the search strategies were limited
to CBT-I, acceptance and commitment therapy applied to insomnia (ACT-I), and mindfulness-based
cognitive therapy applied to insomnia (MBCT-I). All search strategies are available
in a supplementary file at:
https://osf.io/p746g/
. The searches were made in two databases (PubMed and Web of Science – full collection),
last updated on June 5, 2023. No secondary search or gray literature evaluation was
made. Search results were exported to Covidence and grouped in a single systematic
review with all interventions. Duplicates were automatically excluded. Each non-duplicate
record was analyzed by two out of six reviewers (AGB, GLRC, IPAL, MPK, VAK, and YML)
in a two-stage process – the first one to analyze titles and abstracts, and the second
stage to analyze full texts. Discrepancies were solved by a third reviewer (GNP).
In each phase, eligibility was analyzed according to the predefined inclusion and
exclusion criteria. As with the research questions, the topics of insomnia diagnosis
were not addressed in the systematic reviews.
Inclusion and Exclusion Criteria
Each article was analyzed based on the following criteria, which were applied in the
same order as presented below.
Abstract and language
Types of articles
o Inclusion: Only original articles (including meta-analyses).
o Exclusion: Non-original articles (including narrative reviews, systematic reviews without meta-analyses,
letters to the editor, editorials, etc.).
Population:
o Inclusion: Articles assessing individuals with primary chronic insomnia, evaluated or diagnosed
with one of the following criteria:
▪ Insomnia diagnosed with standardized criteria, including ICSD-3, the International
Statistical Classification of Diseases and Related Health Problems – 10th version (ICD-10), DSM-5, and previous and posterior editions of this guideline.
▪ Moderate to severe symptoms of insomnia, evaluated with the Insomnia Severity Index
(ISI) or the Athens Insomnia Scale (AIS).
o Exclusion: Articles using any of the following criteria were excluded:
▪ Self-reported insomnia (as long as none of the inclusion criteria had been used).
▪ Insomnia symptoms were evaluated with tools other than ISI or AIS (as long as none
of the inclusion criteria had been used).
▪ Insomnia comorbid with any other condition (regardless of the use of diagnostic
methods indicated in the inclusion criteria). This refers to comorbid conditions evaluated
to define the study population and does not apply to the occasional occurrence of
comorbidities not comprising the study population and not applied to all participants.
▪ Studies in children, adolescents, and older adults. Adults are defined as those
aged 18 to 65 years. Samples with more than one age range were considered eligible,
as long as most of the population were adults, and the analyses enabled conclusions
regarding specifically adults.
Intervention:
o Inclusion : Any of the interventions presented in [Table 1 ]. Studies assessing two or more interventions were considered eligible, as long as
each group received only one intervention, and the results enabled independent conclusions
for each intervention. There were no limitations on the posology or treatment duration
in pharmacological interventions. Likewise, there were no restrictions on the composition,
number of sessions, or session duration in non-pharmacological interventions.
o Exclusion: Interventions not listed in [Table 1 ] or studies in which more than one intervention is used simultaneously in the same
group of individuals.
Comparator:
o Inclusion: Only articles with control groups were considered eligible. Crossover studies were
considered eligible, as long as the order of the interventions was randomized. The
following types of control groups were considered eligible:
▪ No intervention, waiting list, or placebo.
▪ Minimum intervention: Refers to interventions with limited effectiveness or deemed
ineffective, including but not limited to sleep hygiene interventions alone, lectures,
instructional leaflets, and sham therapies.
▪ Pharmacotherapy (only when considered as a control group for non-pharmacological
interventions).
▪ CBT-I (only when considered as a control group for non-pharmacological interventions).
This allows for the inclusion of studies comparing two different non-pharmacological
therapies (such as two different CBT-I modalities).
o Exclusion: Articles with no control groups, before-and-after designs, studies comparing two
pharmacological interventions, and studies whose control group was submitted to a
concomitant intervention.
Outcomes:
o Inclusion : Objective and subjective sleep parameters, as detailed in [Table 2 ].
o Exclusion : Studies without any of the outcomes listed in [Table 2 ].
Full-text articles :
Level of Evidence and Critical Review
The group of articles retrieved in each intervention's systematic review was analyzed
and ascribed a level of evidence, based on the Oxford Centre for Evidence-Based Medicine
(OCEBM) Levels of Evidence.[15 ] A single author (GNP) ascribed the levels of evidence. The structure of analysis
of the levels of evidence is available in [Table 3 ].
Table 3
Levels of evidence, adapted from OCEBM.
Assessment during eligibility analysis
Increase during critical review
Decrease during critical review
Level 1
Systematic reviews of RCTs
Large or very large effect sizes.
Poor-quality, imprecise studies, lacking directionality, or with small effect sizes.
Level 2
RCTs or observational studies with dramatic effects
Level 3
Nonrandomized cohorts/follow-up studies
Level 4
Case series, case-control studies, controlled history studies
Level 5
Mechanism-based assessment
Abbreviations: OCEBM, Oxford Centre for Evidence-Based Medicine; RCT, Randomized clinical trial.
The critical review aims to summarize practical aspects and professional procedures
regarding each intervention, based on the selected references and applied clinical
knowledge. An independent critical review was conducted for each topic (and for each
intervention, when appropriate). Each work group received a selection of articles
resulting from the systematic reviews specifically related to the treatment of primary
chronic insomnia. Additional literature, besides the selected articles, and the package
inserts of the selected drugs were consulted at the discretion of the group responsible
for each critical review.
Recommendations and Consensus
All interventions were voted for consensus in three standardized manners: 1. As a
treatment for sleep-onset insomnia; 2. As a treatment for sleep-maintenance insomnia
and early waking; and 3. As a treatment for insomnia during pregnancy and breastfeeding
(only in round #2). In all cases, the interventions were voted as a primary treatment
for insomnia in adults with no comorbidities. All sentences to be voted on were written
in a standardized positive manner (i.e., avoiding negative sentences). No specific
recommendations were made for the posology or route of administration of pharmacological
interventions – except for zolpidem, for which four different presentations (oral,
sublingual, controlled release, and orodispersible) were voted independently. Also,
each work group formed a special list of recommendations for each intervention and
diagnosis, including subtopics such as specific populations, comorbidities, characteristics,
insomnia phenotypes, posology, and so forth, when relevant. Special recommendations
were voted declaring their direction (in favor or against them).
These statements were used to assess the level of consensus for each possible recommendation
to diagnose and treat insomnia, based on the Delphi method.[16 ]
[17 ]
[18 ] To reach a consensus, each practical recommendation was assessed by all task force
members on a 5-point scale, ranging from 1 (totally agree) to 5 (totally disagree).
A consensus was reached when at least 75% of the task force members voted on the two
agreement options (consensus in favor) or the two disagreement options (consensus
against). The items about which no consensus was reached in the first voting round
were submitted to a second one, being adapted when necessary. Due to limitations and
professional prerogatives, only physicians voted on recommendations related to pharmacological
treatments. All participants voted on the recommendations related to non-pharmacological
treatments, but the psychologists' votes had triple weight. All professionals voted
on recommendations related to diagnoses.
Results
The search results for each intervention were integrated into a single systematic
review with 24,092 articles. After excluding the duplicates, 13,422 articles were
submitted to eligibility analysis, resulting in a final sample of 181 articles – of
which, 133 (73.4%) were randomized clinical trials (RCTs, including crossover studies),
and 44 (24.3%) were meta-analyses. The number of articles per intervention varied
considerably: in-person CBT-I (k = 43), digital CBT-I (k = 43), and zolpidem (k = 28)
had the most articles, whereas 21 interventions had no articles included. In general,
CBT-I (considering all modalities) and the most recent hypnotic drugs (including zolpidem,
dual orexin receptor antagonists [DORAs], and melatoninergic agonists) concentrated
most records. A limited number of articles assessed benzodiazepines (BZDs) and drugs
not primarily intended to treat insomnia (such as antidepressants and antipsychotics),
and many of these interventions were not properly assessed in any study. The number
of articles included in the final sample and specifically per intervention is available
as supplementary material at:
https://osf.io/p746g/
, and the selection process is presented in [Fig. 2 ]. These files were used as a reference to ascribe the levels of evidence and vote
on the recommendations (described in [Tables 4 ]
[5 ]
[6 ]
[7 ]
[8 ] to [9 ]).
Fig. 2 Flowchart of study inclusion.
Table 4
Recommendations for insomnia diagnosis.
Recommendation
Consensus rate
Voting rounds
Insomnia is very prevalent and can lead to impaired quality of life, physical health
and mental health.
100.00%
1
Insomnia is often comorbid with clinical illnesses and psychiatric disorders, requiring
independent treatment.
100.00%
1
The diagnosis of insomnia is essentially clinical, depending on a directed and attentive
anamnesis.
100.00%
1
The most important topics to be evaluated in an anamnesis for diagnosing insomnia
include:
• Difficulties in initiating and maintaining sleep, early morning awakenings, and
non-refreshing sleep.
96.88%
1
• Clinical characteristics of insomnia, such as onset and course.
100.00%
1
• Treatments carried out and responses to them.
90.63%
1
• Patient's daytime and nighttime behaviors and habits: bedtime, sleeping, waking
up, and getting up.
100.00%
1
• Patient's daytime and nighttime behaviors and habits: Daytime naps, voluntary or
not.
100.00%
1
• Patient's daytime and nighttime behaviors and habits: Physical exercise, activity,
intake of alcoholic beverages, and those containing caffeine.
100.00%
1
• Sleeping environment and activities before bed.
100.00%
1
• Consequences of insomnia in different areas of life: cognition, mood, fatigue,
drowsiness, performance, and risk of accidents.
100.00%
1
• Identification of clinical, psychiatric, and other sleep disorders comorbidities.
100.00%
1
Using a sleep diary can help with diagnosis and assessment of response to treatment.
100.00%
1
Sleep questionnaires can be used to identify and assess the severity of insomnia and
identify comorbidities.
100.00%
1
PSG is not routinely indicated in the diagnosis of insomnia.
100.00%
1
PSG may be indicated in the diagnosis of insomnia in the following situations:
• Suspected other sleep disorders and paradoxical insomnia.
100.00%
1
• Treatment failure.
90.63%
1
• Assessment and identification of insomnia with objective short sleep duration.
78.13%
1
Actigraphy can help differentiate insomnia from circadian rhythm disorder, but alone
cannot diagnose insomnia.
100.00%
1
Table 5
Level of evidence and recommendations of non-pharmacological treatments of insomnia.
Sleep-onset insomnia
Maintenance insomnia and early waking
Category
Intervention
Level of evidence
Recommendation
Consensus rate
Voting rounds
Recommendation
Consensus rate
Voting rounds
CBT-I
In-person CBT-I
1
Recommended
100.0%
1
Recommended
100.0%
1
Online CBT-I
2
Recommended
100.0%
1
Recommended
100.0%
1
Group CBT-I
1
Recommended
96.9%
1
Recommended
96.9%
1
Digital CBT-I
1
Recommended
78.1%
1
Recommended
78.1%
1
Self-help CBT-I
3
No consensus
2
No consensus
2
ACT-I
2
Recommended
87.5%
1
Recommended
84.4%
1
MBCT-I
2
Recommended
87.5%
1
Recommended
81.3%
1
Alternative
Acupuncture[a ]
N/A
NOT Recommended
80.7%
2
NOT Recommended
77.4%
2
treatments
Aromatherapy[a ]
N/A
NOT Recommended
80.7%
2
NOT Recommended
78.1%
1
Biofeedback[a ]
N/A
No consensus
2
No consensus
2
Massage[a ]
N/A
No consensus
2
No consensus
2
Meditative practices[a ]
[b ]
N/A
No consensus
2
No consensus
2
Mind-body practices[a ]
[c ]
N/A
No consensus
2
No consensus
2
Physical exercises[a ]
N/A
No consensus
2
No consensus
2
Abbreviations: ACT-I, Acceptance and commitment therapy applied to insomnia; CBT-I, Cognitive-behavioral
therapy applied to insomnia; MBCT-I, Mindfulness-based cognitive therapy applied to
insomnia; N/A, Not applicable.
a Interventions not included in the systematic reviews.
b Includes meditation and vipassana.
c Includes qigong, tai-chi, and yoga.
Table 6
Special recommendations for non-pharmacological treatment of insomnia.
Recommendation
Consensus rate
Voting rounds
Multicomponent CBT-I is recommended as the gold standard for treating chronic insomnia,
suggesting a greater number of sessions and techniques and observing the clinical
caveats described in the text.
100.00%
1
CBT-I via online services is not inferior to in-person service.
93.75%
1
Sleep hygiene is not recommended as an isolated form of intervention, but should be
included in the practice of CBT-I.
100.00%
1
ACT is recommended as an adjuvant treatment to CBT-I.
93.75%
1
Mindfulness practices are recommended as adjuvants to CBT-I.
96.88%
1
Patients with objectively measured TST < 6h should receive multicomponent CBT-I intervention
associated with mindfulness and/or ACT strategies. At clinical discretion, it can
be associated with pharmacotherapy.
96.88%
1
Biofeedback therapies, although safe, show inconsistent results for the treatment
of chronic insomnia disorder and, therefore, should not be recommended. There is a
clear need for well-designed and adequately powered studies to understand the role
of this form of therapy.
100.00%
1
Acupuncture is safe, but current literature is limited to formally recommend this
therapeutic strategy for treating insomnia.
100.00%
1
Physical exercise (mainly aerobic) appears to have benefits in objective and subjective
parameters in patients with chronic insomnia and can be used as an adjuvant therapy.
87.10%
1
Mind-body techniques are safe but with limited evidence as a therapeutic tool for
treating insomnia. The formal approach can be adopted as an adjuvant practice.
100.00%
1
The use of aromatherapy has limited evidence for treating insomnia and should not
be formally recommended.
94.77%
1
Abbreviations: ACT, Acceptance and commitment therapy; CBT-I, Cognitive-behavioral therapy applied
to insomnia. TST, Total sleep time.
Table 7
Level of evidence and recommendations for pharmacological treatment of insomnia.
Sleep-onset insomnia
Maintenance insomnia and early waking
Category
Intervention
Level of evidence
Recommendation
Consensus rate
Voting rounds
Recommendation
Consensus rate
Voting rounds
BZD agonists
Zolpidem - Oral
1
Recommended
100.00%
1
No consensus
2
Zolpidem - Sublingual
1
Recommended
94.12%
1
NOT Recommended
87.50%
2
Zolpidem - CR
1
No consensus
2
Recommended
100.00%
1
Zolpidem – orodispersible
1
Recommended
100.00%
1
NOT Recommended
87.50%
2
Zopiclone
3
Recommended
94.12%
1
Recommended
82.35%
1
Eszopiclone
1
Recommended
94.12%
1
Recommended
100.00%
1
BZD[a ]
5
NOT Recommended
82.35%
1
NOT Recommended
75.00%
2
DORAs
Suvorexant
1
Recommended
82.35%
1
Recommended
100.00%
1
Lemborexant
2
Recommended
82.35%
1
Recommended
100.00%
1
Daridorexant
1
Recommended
82.35%
1
Recommended
94.12%
1
Antidepressants
Trazodone
2
No consensus
2
Recommended
82.35%
1
Doxepin
2
No consensus
2
Recommended
88.24%
1
Mirtazapine
5
No consensus
2
No consensus
2
Amitriptyline
5
No consensus
2
No consensus
2
Agomelatine
5
NOT Recommended
82.35%
1
NOT Recommended
75.00%
2
Melatonin
Melatonin
2
NOT Recommended
76.47%
1
NOT Recommended
88.24%
1
Melatoninergic agonist
Ramelteon
1
Recommended
88.24%
1
NOT Recommended
76.47%
1
Antipsychotics
Quetiapine
5
NOT Recommended
93.75%
2
NOT Recommended
81.25%
2
Olanzapine
5
NOT Recommended
82.35%
1
NOT Recommended
76.47%
1
Clozapine
5
NOT Recommended
94.12%
1
NOT Recommended
94.12%
1
Periciazine
5
NOT Recommended
100.00%
1
NOT Recommended
100.00%
1
Levomepromazine
5
NOT Recommended
100.00%
1
NOT Recommended
100.00%
1
Chlorpromazine
5
NOT Recommended
100.00%
1
NOT Recommended
94.12%
1
Anticonvulsants
Gabapentin
5
NOT Recommended
88.24%
1
NOT Recommended
82.35%
1
Pregabalin
5
NOT Recommended
88.24%
1
NOT Recommended
82.35%
1
Others
Tienopramine
3
NOT Recommended
94.12%
1
NOT Recommended
94.12%
1
Promethazine
5
NOT Recommended
100.00%
1
NOT Recommended
100.00%
1
Hydroxyzine
5
NOT Recommended
100.00%
1
NOT Recommended
100.00%
1
Dimenhydrinate
5
NOT Recommended
94.12%
1
NOT Recommended
100.00%
1
GABA
3
NOT Recommended
94.12%
1
NOT Recommended
94.12%
1
Tryptophane
5
NOT Recommended
100.00%
1
NOT Recommended
94.12%
1
Phytotherapeutics
Valeriana officinalis
2
NOT Recommended
82.35%
1
NOT Recommended
88.24%
1
Passiflora incarnata
2
NOT Recommended
94.12%
1
NOT Recommended
94.12%
1
Matricaria recutita[a ]
N/A
NOT Recommended
77.78%
2
NOT Recommended
76.47%
1
Withania somnifera[a ]
N/A
NOT Recommended
77.78%
2
NOT Recommended
76.47%
1
Erythrina Mulungu
5
NOT Recommended
76.47%
1
NOT Recommended
82.35%
1
Cannabinoids
Cannabis sativa
3
NOT Recommended
94.12%
1
NOT Recommended
100.00%
1
Cannabidiol
3
NOT Recommended
100.00%
1
NOT Recommended
94.12%
1
Delta-9-THC
3
NOT Recommended
100.00%
1
NOT Recommended
100.00%
1
Abbreviations: BZD, Benzodiazepines; CR, Controlled release; DORAs, Dual orexin receptor antagonists;
GABA, Gamma-aminobutyric acid, N/A, Not applicable; THC, Tetrahydrocannabinol.
a Recommendations voted in group for the whole class, instead of individually for each
intervention. All BZDs were assessed with level of evidence 5, except for flurazepam,
assessed with level of evidence 4.
Table 8
Special recommendations for pharmacological treatment of insomnia.
Recommendation
Consensus rate
Voting rounds
The use of zolpidem should NOT exceed 4 weeks, intermittent use or “if necessary”
is recommended.
100.00%
1
The initial dosage of immediate-release zolpidem for the elderly should be 5 mg.
100.00%
1
In young adults, doses greater than 10 mg of regular-release zolpidem and 12.5 mg
of controlled-release zolpidem are not recommended.
94.12%
1
It is recommended that zolpidem be tapered due to the risk of rebound insomnia.
94.12%
1
Zolpidem is associated with non-REM sleep parasomnias and addiction syndrome.
100.00%
1
Zopiclone should be administered on a short-term basis, if possible intermittently
or on an “as needed” basis.
82.35%
1
The initial dosage of zopiclone for the elderly should be 3.75 mg.
100.00%
1
It is recommended that the dose reduction of zopiclone be gradual due to the risk
of rebound insomnia.
82.35%
1
Eszopiclone should be administered on a short-term basis, if possible intermittently
or on an “as needed” basis.
88.24%
1
The dosage of eszopiclone, for the elderly population, should not exceed 2mg.
100.00%
1
Lemborexant is NOT recommended as a treatment for insomnia in patients with narcolepsy.
82.35%
1
The recommended doses of doxepin should be between 3 and 6 mg used close to bedtime,
even in formulated presentations (since there are no industrialized presentations
in Brazil).
100.00%
1
Doxepin is recommended at the lowest therapeutic dose in adults over 65 years of age.
94.12%
1
Trazodone doses used to treat insomnia should be lower than the doses recommended
for treating major depression, at intervals between 25 and 150mg used close to bedtime.
100.00%
1
Trazodone is NOT recommended for pregnant or breastfeeding women or for use in children
and adolescents.
94.12%
1
Amitriptyline may be useful for managing comorbid insomnia in patients with depressive
disorders.
94.12%
1
Mirtazapine is effective in the management of insomnia comorbid with depressive disorders.
94.12%
1
The long elimination half-life of mirtazapine may cause residual drowsiness with cognitive
and motor impairment.
94.12%
1
Mirtazapine should be avoided in patients with metabolic disorders due to the risk
of weight gain.
100.00%
1
Melatonin can be used to treat initial insomnia in the elderly and children with autism
spectrum disorder.
100.00%
1
Ramelteon is recommended as a treatment for sleep-onset insomnia comorbid with OSA
(COMISA).
100.00%
1
Ramelteon is recommended as a treatment for sleep-onset insomnia comorbid with COPD.
88.24%
1
Quetiapine may be recommended for the management of insomnia in comorbidity with other
psychiatric disorders that justify its prescription.
100.00%
1
Abbreviations: COMISA, Comorbid insomnia and obstructive sleep apnea; COPD, Chronic obstructive
pulmonary disease.
Table 9
Recommendation for insomnia treatment during pregnancy and breastfeeding.
Category
Intervention
Recommendation
Consensus rate
BZD agonists
Zolpidem - Oral
NOT Recommended
93.75%
Zolpidem - Sublingual
NOT Recommended
93.75%
Zolpidem - CR
NOT Recommended
93.75%
Zolpidem – orodispersible
NOT Recommended
93.75%
Zopiclone
NOT Recommended
93.75%
Eszopiclone
NOT Recommended
93.75%
BZD[a ]
NOT Recommended
87.50%
DORAs
Suvorexant
NOT Recommended
87.50%
Lemborexant
NOT Recommended
86.67%
Daridorexant
NOT Recommended
81.25%
Antidepressants
Trazodone
NOT Recommended
81.25%
Doxepin
NOT Recommended
81.25%
Mirtazapine
NOT Recommended
81.25%
Amitriptyline
NOT Recommended
75.00%
Agomelatine
NOT Recommended
93.75%
Melatonin
Melatonin
NOT Recommended
87.50%
Melatoninergic agonists
Ramelteon
NOT Recommended
93.75%
Antipsychotics
Quetiapine
NOT Recommended
81.25%
Olanzapine
NOT Recommended
87.50%
Clozapine
NOT Recommended
93.75%
Periciazine
NOT Recommended
93.75%
Levomepromazine
NOT Recommended
81.25%
Chlorpromazine
NOT Recommended
87.50%
Anticonvulsants
Gabapentin
NOT Recommended
87.50%
Pregabalin
NOT Recommended
87.50%
Others
Difenhydramine
NOT Recommended
87.50%
Promethazine
NOT Recommended
93.75%
Hydroxyzine
NOT Recommended
93.75%
Dimenhydrinate
NOT Recommended
87.50%
GABA
NOT Recommended
93.75%
Tryptophane
NOT Recommended
93.75%
Phytotherapeutics
Valeriana officinalis
NOT Recommended
93.75%
Passiflora incarnata
NOT Recommended
87.50%
Matricaria recutita1
NOT Recommended
93.75%
Withania somnifera1
NOT Recommended
93.75%
Erythrina Mulungu
NOT Recommended
93.75%
Cannabinoids
Cannabis sativa
NOT Recommended
100.00%
Cannabidiol
NOT Recommended
100.00%
Delta-9-THC
NOT Recommended
100.00%
CBT-I
In-person CBT-I
Recommended
100.00%
Online CBT-I
Recommended
100.00%
Group CBT-I
Recommended
100.00%
Digital CBT-I
Recommended
100.00%
Self-help CBT-I
No consensus
ACT-I
Recommended
83.87%
MBCT-I
Recommended
77.42%
Alternative
Acupuncture[a ]
NOT Recommended
87.10%
treatments
Aromatherapy[a ]
No consensus
Biofeedback[a ]
No consensus
Massage[a ]
NOT Recommended
77.42%
Meditative practices[a ]
[b ]
No consensus
Mind-body practices[a ]
[c ]
No consensus
Physical exercises[a ]
No consensus
Abbreviations: ACT-I, Acceptance and commitment therapy applied to insomnia; BZD, Benzodiazepines;
CBT-I, Cognitive-behavioral therapy applied to insomnia; DORA, Dual orexin receptor
antagonists; GABA, Gamma-aminobutyric acid; MBCT-I, Mindfulness-based cognitive therapy
applied to insomnia; THC, Tetrahydrocannabinol.
a Intervention not included in the systematic reviews.
b Recommendations voted in group for the whole class, instead of individually for each
intervention.
c Includes meditation and vipassana.
d Includes qigong, tai-chi, and yoga.
The process of defining levels of evidence revealed that most interventions were not
based on adequate evidence. Most of them (n = 23, 47.9%) were classified as level of evidence 5 (indirect evidence, based only
on action mechanisms), reflecting the absence of studies assessing them appropriately
to treat insomnia. Only eight interventions (16.7%) were assessed with level of evidence
1, and 11 with level of evidence 2 (22.9%). Intervention assessed with the level of
evidence 1 includes two BZD agonists (zolpidem and eszopiclone), two DORAs (suvorexant
and daridorexant), one melatoninergic agonist (ramelteon), and three CBT-I presentations
(in person, in group, and digital). The levels of evidence for each intervention are
shown in [Tables 5 ] and [7 ].
In round #1, 18 non-pharmacological and 39 pharmacological interventions were voted
on, each of them in two contexts (for sleep-onset insomnia and for sleep-maintenance
insomnia and early waking). Also, six special recommendations were made for non-pharmacological
interventions, 23 for pharmacological interventions, and 19 to insomnia diagnosis.
Recommendations related to BZDs were grouped and voted as a collective class, rather
than as separate drugs. Thus, 154 recommendations were voted on in round #1–of which,
a consensus was reached on 123 items (79.9%) – 77 in favor (50.0%) and 46 against
(29.9%). No consensus was reached on the other 31 items (20.13%)
The round #2 had 89 items, encompassing the second voting round on the 31 items that
had not reached a consensus in round #1, five new items related to special recommendations
for alternative and complementary recommendations, 53 items on insomnia treatment
during pregnancy and breastfeeding (14 non-pharmacological and 39 pharmacological
treatments). Items included in round #2 were voted on only once, and a consensus was
reached on 63 items (70.8%) – 11 in favor (12.36%) and 52 against (58.43%). No consensus
was reached on 26 items (29.21%).
Altogether, considering both voting rounds, 214 items were voted on – 21 on insomnia
diagnosis, 53 on non-pharmacological treatment (14 interventions in three different
conditions – sleep-onset insomnia, sleep-maintenance insomnia and early waking, and
insomnia during pregnancy and breastfeeding – and 11 special recommendations), and
140 on pharmacological treatment (39 interventions in the three different conditions
and 23 special recommendations).
A consensus was reached for all 21 recommendations (100%) on insomnia diagnosis ([Table 4 ]). As for non-pharmacological treatments ([Table 5 ]), six interventions (42.8%) were recommended for both sleep-onset and maintenance
insomnia (including four modalities of CBT-I, ACT-I, and MBCT-I), and two (14.3%)
were not recommended (acupuncture and aromatherapy).
Regarding the pharmacological treatment ([Table 7 ]), nine interventions (23.1%) were recommended to treat sleep-onset insomnia, including
three zolpidem presentations (oral, sublingual, and orodispersible), zopiclone, eszopiclone,
suvorexant, lemborexant, daridorexant, and ramelteon. Eight interventions (20.5%)
were recommended to treat maintenance insomnia and early waking, including prolonged-release
zolpidem, zopiclone, eszopiclone, suvorexant, lemborexant, daridorexant, trazodone,
and doxepin.
Only six interventions (11.3%) were recommended for insomnia treatment during pregnancy
and breastfeeding ([Table 9 ]), all of them non-pharmacological. Four presentations of CBT-I, ACT-I, and MBCT-I
were included.
The mean consensus rate was 88.0 ± 13.4% – 97.7 ± 5.6% for diagnosis, 82.5 ± 14.9%
for non-pharmacological interventions, and 88.7 ± 12.7% for pharmacological interventions.
Considerations of the Results
This study is based on methods commonly used for evidence synthesis and guidelines
development, encompassing systematic reviews, levels of evidence, and standardized
methods to reach consensus. Nonetheless, some considerations must be made to properly
interpret these results, especially in the case of comparisons with other guidelines
to diagnose and treat insomnia, such as the ones issued by the American Academy of
Sleep Medicine (AASM), the European Sleep Research Society (ESRS), and other societies.[19 ]
[20 ]
[21 ]
[22 ]
[23 ]
[24 ]
[25 ]
The list of pharmacological and non-pharmacological interventions to treat insomnia
may differ from interventions assessed in other guidelines for two main reasons. First,
due to the focus on interventions available in Brazil, which left out some interventions
present in other studies (e.g., zaleplon and temazepam) and included interventions
not commonly found in other guidelines (especially some phytotherapeutics). Moreover,
this guideline is more recent than the ones mentioned above, thus including interventions
developed more recently (e.g., cannabinoids and ACT-I).
The list of studies selected based on systematic reviews for each intervention may
differ from lists included in other guidelines, mainly due to the inclusion and exclusion
criteria used in this guideline. Particularly, the definition of the population (only
adults with insomnia and no comorbidities), the criteria to diagnose insomnia, eligible
types of control groups, and the list of outcomes may have limited the list of references,
excluding from this guideline some studies that may have been included in other ones.
This observation is especially valid for BZDs and other non-primarily hypnotic drugs,
for which few or no references were found.
The method to ascribe levels of evidence was essentially based on the experimental
design used in the selected studies. Even though the level of evidence can be raised
or lowered based on other aspects (as described in [Table 3 ]), this is not done in a structured and parameterized manner. Other methodologies
would have allowed the assessment of other aspects associated with the level of evidence,
such as the quality of the studies or the level of the certainty of evidence (e.g.,
using the GRADE tool [Grading of Recommendations Assessment, Development, and Evaluation]).
Despite these observations, this guideline presents recommendations to diagnose and
treat insomnia robustly and based on evidence, primarily applicable to Brazil, but
certainly extensible to other countries and contexts. The following sections present
the critical reviews developed for each topic included in this guideline.
Non-Pharmacological Insomnia Treatment
Various authors have proposed theoretical models to explain the psychological phenomenon
of insomnia and understand sleep patterns and complaints associated with insomnia
disorder. They mostly explain or approach more in-depth factors involved in the etiology
of insomnia described by Spielman and colleagues in the 3P model.[46 ] Based on this model, CBT-I explains the vicious cycle of insomnia perpetuated by
the impairment of the homeostatic sleep pressure, the disorganization of the circadian
rhythm, and the wakefulness conditioned by associations between the environment, cognitive
and somatic excitability, and dysfunctional beliefs and thought patterns about sleep.
Using techniques derived from the cognitive and behavioral approach and practices
to promote relaxation,[47 ]
[48 ] the literature has documented well CBT-I's effectiveness in treating insomnia comorbid
with medical and psychiatric conditions.[47 ]
[49 ] Hence, it is considered the first line of treatment to address chronic insomnia.[50 ]
[51 ]
[52 ] Other CBT-I settings and modalities have been proposed to increase its dissemination,
including videoconference or phone calls, messages in virtual chat rooms or e-mail,
bibliotherapy, self-guided books, and digital platforms.[52 ]
[53 ]
[54 ] Moreover, other non-pharmacological approaches have been developed and tested independently
or combined with CBT-I, such as interventions based on ACT[55 ] and mindfulness techniques.[56 ]
[57 ]
This chapter aims to recommend the approaches with the highest level of scientific
evidence for clinical outcomes and follow-up, considering objective parameters assessed
with PSG and actigraphy and subjective ones obtained from sleep diaries and questionnaires
that assess the severity of insomnia symptoms and the quality of sleep, especially
ISI and PSQI, respectively.
Main Non-pharmacological Approaches and Therapeutic Planning
CBT-I
Central CBT-I components include psychoeducation and sleep hygiene, stimulus control,
sleep restriction technique, cognitive therapy, cognitive restructuring, and relaxation
techniques.[48 ]
[58 ] They generally take four to eight sessions, lasting 60 to 90 minutes on average.[57 ]
[59 ] The lower the intervention frequency and duration, the fewer the techniques it includes
– among which sleep restriction and stimulus control are the most used. [Table 11 ] presents other CBT-I application modalities described in the literature.[54 ]
[59 ]
[60 ]
[61 ]
[62 ]
[63 ]
[64 ]
[65 ]
[66 ]
Table 11
CBT-I modalities: application formats and settings.
Modality
Description
In-person CBT-I
Individual or group care by a trained professional.
Online CBT-I
Real-time videoconference care from a trained healthcare professional.
Digital CBT-I
Digital material organized and made available through an application for mobile devices
or a web system. It can include a communication channel with a specialist professional
(email or chat inserted in the application/system).
Bibliotherapy
Reading material with guidance based on the CBT-I protocol (guided or not by a health
professional).
Self-help therapy for insomnia
Printed or recorded structured audio and/or video material based on CBT-I.
Abbreviations: CBT-I, Cognitive-behavioral therapy applied to insomnia.
Acceptance and Commitment Therapy (ACT)
ACT belongs to the third wave of Behavioral Psychology and aims to develop psychological
flexibility (i.e., the capacity to respond in an adapted way to life challenges with
an ample awareness of and engagement in personal values) through six main processes:
acceptance, defusion, being present, self as context, values, and committed action.[67 ]
ACT has been recently tested to treat insomnia either alone or in combination with
CBT-I behavioral components, such as stimulus control and sleep restriction.[68 ] Both interventions approach the six processes that make up the construct of psychological
flexibility.
Mindfulness Techniques
Mindfulness is defined as a state of full attention, deprived of judgment, capable
of promoting attentional and emotional regulation, and cultivating attitudes associated
with openness, acceptance, compassion, curiosity, and peace. This process is grounded
on the process of widening body, mental, and environmental perception and awareness.
Jon Kabat-Zinn developed a Mindfulness-based Stress Reduction Program with eight weekly
encounters that include practices, discussions on applications and challenges, and
guidance to individual daily practice.[69 ] This program has been adopted and adapted for supplementary use in various health
interventions, including insomnia.
The mindfulness-based insomnia intervention program encompasses mindfulness techniques
with CBT-I components,[70 ]
[71 ] aiming to change the relationship with psychosomatic suffering associated with the
condition and change dysfunctional thoughts and habits unfavorable to healthy sleep,
thus transforming reactive responses into adaptative ones and improving emotional
management.[72 ]
Clinical Reservations on non-pharmacological approaches to insomnia
The decision for an intervention approach must consider the therapeutic response after
the treatment and follow-up, resource availability, physical and mental health conditions,
and the patient's openness and readiness to adhere to the proposed therapy. Since
non-pharmacological interventions depend on the patient's active participation, different
managements must be aligned to ensure their greater effectiveness and efficiency.
Non-pharmacological insomnia treatments are usually well-tolerated, but they may require
some precautions, and there may be some contraindications to applying them to older
adults – for instance, stimulus control and sleep restriction mental changes pose
a risk of falls.[73 ]
If there are no time or trained professionals to apply multicomponent CBT-I, the recommendation
is to apply its components separately (especially the sleep restriction and stimulus
control technique) or use digital CBT-I. Unwanted effects, such as excessive daytime
sleepiness, fatigue, and concentration difficulties, may be associated with sleep
deprivation resulting from the application of the sleep restriction technique. These
are short-lasting effects, extinguished as the ideal TST is reached. This technique
may be contraindicated to shift or high-risk workers, such as machine operators and
drivers, and patients with psychiatric or neurological conditions, predisposed to
episodes of mania/hypomania or convulsion. Older patients or those with chronic pain
or depression may have difficulties filling in the time awake resulting from the sleep
restriction protocol.[52 ]
[74 ]
Regarding insomnia phenotypes based on objective sleep duration, CBT-I is less effective
among patients with TST < 6 hour than in those with TST > 6 hour.[75 ]
[76 ]
[77 ] The recommendation for the former is to apply multicomponent CBT-I associated with
mindfulness strategies and ACT to favor the autonomic modulation promoted by somatic-cognitive
hyperarousal. It can also be combined, at the clinician's discretion, with pharmacotherapy
to aid its management.[78 ]
[79 ]
Clinical Outcomes of Non-pharmacological Intervention Approaches to Insomnia
Randomized studies and meta-analyses assessed the effect of multicomponent CBT-I on
sleep parameters and mental health of patients with chronic insomnia compared with
active and passive control conditions. The results of multicomponent CBT-I proved
to decrease the severity of insomnia and improve the quality of life, and subjective
parameters of sleep, particularly sleep latency, the number of wakes, WASO, and sleep
efficiency.[47 ]
[50 ]
[53 ]
[80 ]
[81 ]
[82 ]
[83 ]
[Table 12 ] presents these effects and the ones measured with PSG.[54 ]
[84 ]
Table 12
Effect of multicomponent CBT-I on subjective sleep parameters.
CBT-I modality (vs. control conditions)
Sleep quality (PSQI)
Insomnia severity (ISI)
Sleep latency
Number of wakes
WASO
Sleep efficiency
Total sleep time
In-person CBT-I
Increases
Decreases
Decreases*
Decreases
Decreases
Increases*
Decreases*
Online CBT-I
Increases
Decreases
Decreases
–
Decreases
Increases
Decreases
Digital CBT-I
N/A
Decreases
Decreases
Decreases
Decreases
Increases
–
Abbreviations: CBT-I, Cognitive-behavioral therapy applied to insomnia; ISI, Insomnia Severity Index;
N/A, not applicable; PSQI, Pittsburgh sleep quality index; WASO, wake after sleep
onset.
* Corresponding effect measured with polysomnography.
The effects of CBT-I on increasing TST are evident in some studies, with sensitivity
indicated by the sleep diary[50 ]
[62 ]
[64 ]
[66 ]
[83 ]
[85 ] and PSG,[62 ]
[84 ] though with no such correspondence in actigraphy analysis.[62 ] The effects of CBT-I are more substantial on subjective than objective sleep parameters,[54 ]
[62 ] suggesting greater sensitivity of subjective recordings to detect the effect of
decreasing hyperarousal present in insomnia, more reliably reflecting increases in
TST.[62 ] It is worth pointing out that clinical outcomes are maintained in follow-ups of
3 to 12 months.[47 ]
[80 ]
[83 ]
[86 ]
[87 ]
When compared with control conditions and isolated CBT-I techniques, multicomponent
CBT-I has also been shown to improve daytime symptoms such as fatigue and sleepiness,[80 ]
[88 ]
[89 ] as well as symptoms of anxiety, depression, and/or stress[82 ]
[83 ]
[85 ]
[88 ]
[89 ] and dysfunctional beliefs and attitudes toward sleep.[63 ]
[82 ]
[85 ]
[86 ]
Online and digital CBT-I services compared with control conditions demonstrate improvement
in subjective sleep parameters.[63 ]
[64 ]
[85 ]
[89 ]
[90 ]
[Table 12 ] discriminates these effects per CBT-I modality. Although Soh and colleagues[90 ] indicate a greater effect of in-person CBT-I to reduce the severity of insomnia
and WASO compared with digital CBT-I, the clinical outcomes promoted by both modalities
demonstrated post-treatment and follow-up equivalence compared with in-person CBT-I.[64 ]
[89 ] Moreover, Arnedt and colleagues[89 ] found equivalence in the levels of satisfaction, credibility, and therapeutic alliance
of the CBT-I modality via online care when compared with in-person CBT-I.
Given the scarce availability and accessibility of sleep psychologists and health
professionals trained in CBT-I, online and digital modalities emerge as alternatives
for intervention in the treatment of chronic insomnia. Concerning digital CBT-I, Zhang,
and colleagues[66 ] demonstrated the relevance of cultural adaptation – i.e., adaptation to language,
communication style (expressions), day and night life habits, and pre-sleep activities
– and scientific validation of systems.
Bibliotherapy and self-help therapy as CBT-I modalities, when compared with non-intervention,
demonstrate positive effects on the main subjective sleep parameters (ISI, PSQI, sleep
latency, sleep efficiency, and/or WASO)[54 ] but with limited effectiveness when compared with other CBT-I modalities,[54 ] limiting their use as isolated approaches, but serving as support for interventions
that demonstrate superior effectiveness.
The sleep hygiene approach alone has limited clinical outcomes in improving primary
chronic insomnia when compared with control,[52 ]
[91 ] with no effect on comorbid insomnia or when compared with CBT-I and mindfulness
approaches for treating insomnia.[91 ]
It is observed that the more structured and frequent the intervention with CBT-I techniques,
the greater the effects on sleep parameters.[50 ]
[64 ]
[83 ] These effects are long-lasting and independent of comorbidity, age, and sex,[49 ]
[64 ]
[92 ] especially in the presence of clinical support during follow-up.[64 ] The adherence rate to CBT-I is higher than other active interventions.[93 ] The outcome of CBT-I in patients with more years of chronic insomnia and medication
use is inferior to those in the opposite condition.[83 ]
Compared with a waiting list and a psychoeducation control group, ACT reduced the
severity of insomnia[55 ]
[68 ] and improved sleep parameters and secondary outcomes such as dysfunctional beliefs
and attitudes about sleep, acceptance of sleep problems, daytime sleepiness, and cognitive
suppression.[55 ]
[68 ] When compared with CBT-I, ACT showed no differences in subjective sleep parameters.[55 ]
[68 ] Chapoutot and colleagues[94 ] observed reduced hypnotics, Z-drugs, and BZDs consumption in response to ACT. Although
studies involving ACT suggest promising results for the intervention of chronic insomnia,
they do not present the same empirical support as CBT-I, recommending its use as an
adjuvant to CBT-I.
Studies involving mindfulness-based intervention protocols compared with controls
demonstrate improvements in ISI,[56 ]
[95 ]
[96 ]
[97 ] PSQI,[97 ]
[98 ]
[99 ] and subjective sleep parameters: sleep latency, sleep efficiency, WASO,[97 ]
[98 ] with improvement in mental health parameters during follow-up.[56 ]
[86 ] A comparison of these approaches with CBT-I demonstrated inferior results about
sleep parameters.[56 ]
[86 ] A meta-analysis conducted by Entrambasaguas and colleagues[95 ] identified inconclusive results of the mindfulness approach combined with CBT-I
on clinical outcomes in the evaluation parameters of chronic insomnia due to the lack
of standardization in the methodological designs that compromise the evaluation of
the effectiveness of the combined therapy.
However, some studies have indicated that mindfulness practices improve dose-dependent
sleep quality (PSQI) (i.e., the longer the practice, the greater the effect on sleep
quality or decreased excitability),[57 ]
[86 ]
[96 ] suggesting preventive power for insomnia in healthy and clinical populations and
adjuvant practice to CBT-I with or without comorbidity.[57 ]
“Alternative” treatments
Biofeedback
Biofeedback is a therapeutic tool that aims to develop the capacity for self-regulation
by electronically monitoring physiological processes, such as peripheral temperature,
blood pressure, heart rate, muscle tone, or brain waves. The collected signals associated
with stress conditions are immediately returned to the patient through images and/or
sounds to promote ess of the stress condition and promote voluntary regulation of
physiological and emotional reactions, breaking the vicious cycle of stress, promoting
relaxation, and improving symptoms associated with anxiety and other mood disorders,
possibly acting on the reduction of sympathetic activation.[100 ]
Different biofeedback modalities have been described, such as neurofeedback, which
aims to influence the occurrence of sleep-related brain waves, and heart rate variability
biofeedback, which aims to reduce sympathetic activity by training breathing in the
context of heart rate oscillations.[100 ]
Recent systematic reviews on the application of biofeedback to treat insomnia demonstrate
inconsistent results and general limitations regarding the quality of available studies,
such as small sample size and lack of control group.[101 ]
[102 ]
[103 ] Few randomized studies have tested biofeedback techniques alone or in combination
for insomnia. One of the first studies, conducted by Nicasio and colleagues,[104 ] tested progressive relaxation and neurobiofeedback with electrodes in the frontal
region, versus simulated neurobiofeedback (placebo) in 40 adult patients. Relaxation
and neurobiofeedback led to significant reductions in both self-reported sleep latency
and depressive symptomatology. However, this result did not show significant differences
when compared with the control group, suggesting a potential placebo effect.[104 ] A similar result of a potential placebo effect was observed in a double-blind study
in patients with primary insomnia.[105 ] A recent randomized study by Kwan and colleagues[106 ] suggested that a neurofeedback protocol was comparable in efficacy to CBT-I, but
the small sample size precludes any conclusions in this regard.
Acupuncture
Acupuncture has been used in clinical practice as an alternative to the treatment
of insomnia in some countries such as China. Systematic reviews and meta-analyses[107 ]
[108 ]
[109 ]
[110 ]
[111 ]
[112 ]
[113 ]
[114 ] from the past 4 years evaluating different acupuncture techniques suggest that acupuncture
is safe compared with no treatment or sham procedures and has produced reduced PSQI scores, increased TST, and sleep efficiency.
However, in practically all analyses, there are criticisms about the quality of the
available studies, suggesting the need for studies with more consistent protocols
in this context.[107 ]
[108 ]
[109 ]
[110 ]
[111 ]
[112 ]
[113 ]
[114 ]
Physical Exercises
Physical exercise, with emphasis on aerobic practice, is cited as an adjuvant therapy
in the treatment of insomnia, especially as it is associated with increased energy
expenditure, promoting well-being, facilitating weight loss, and improving mood and
cognition. However, to date, few randomized studies have tested the effect of physical
exercise on insomnia.[115 ]
[116 ]
[117 ] One of the studies tested a monitored program of at least 150 minutes of physical
exercise per week, of moderate intensity (brisk walking, in the chosen environment
for at least 30 minutes per day, on at least 5 days of the week), for 6 months. At
the end of the follow-up, the physical exercise group showed an average reduction
of 4 points in the ISI.[115 ] More recently, Baron and colleagues showed that moderate to vigorous aerobic training
for 12 weeks also improved the severity of insomnia symptoms.[116 ] In another investigation, Zhang and colleagues compared aerobic exercise three to
five times a week with implementing a balanced diet and with non-treatment for 6 months
in 72 patients with insomnia.[117 ] Both physical exercise and diet improved sleep quality and reduced objective sleep
latency and sleep efficiency in relation to the baseline period.[117 ] However, no significant differences were shown compared with the control group.[117 ]
Evidence on resistance exercise or strength exercise is even scarcer, although it
suggests a benefit in objective and subjective parameters in patients with chronic
insomnia.[118 ] Meta-analyses point to safety and some favorable effects on insomnia symptomatology;
however, they also report inconsistencies and significant quantity and quality limitations
of the studies.[119 ]
[120 ]
Mind-body techniques
Mind-body techniques include meditative practices, yoga, Tai Chi, qigong, and so forth.
These are ancestral practices that aim to train the mind, especially attention, through
contemplation, body movement, and/or posture, focused on breathing to integrate mind
and body. In general, studies on the effect of these techniques involve practices
with a frequency of one to three times a week (60–120 minutes per session) for 12
or more weeks.[57 ]
Although some studies evaluating the effect of practicing Yoga and Tai-chi point to
improvements in sleep quality, some parameters of sleep architecture,[57 ]
[121 ]
[122 ]
[123 ]
[124 ] and psychiatric symptoms,[124 ] the evidence is very limited due to studies with small samples, relatively short
follow-up, high response heterogeneity, and the lack of standardized techniques.
However, some studies have indicated that mind-body approaches, including mindfulness
practices, improve dose-dependent sleep quality (PSQI) (i.e., the longer the practice,
the greater the effect on sleep quality or decreased excitability).[57 ]
[86 ]
[96 ] These results indicate that such approaches can be adopted as preventive practices
for insomnia in healthy and clinical populations,[57 ]
[124 ] and can be adjuvants to CBT-I with or without comorbidity.
Aromatherapy
Aromatherapy is a therapeutic approach based on the principle that substances that
make up the aroma of essential oils release particles capable of generating favorable
stimuli to brain areas related to emotions, helping to treat symptoms of anxiety,
depression, and insomnia, among other medical and psychological conditions. Preliminary
studies limited to a few patients and short follow-up suggest that aromatherapy (mainly
using lavender) may have benefits on sleep quality in patients with mild forms of
insomnia.[125 ]
[126 ]
[127 ]
Pharmacological Insomnia Treatment
The pharmacological treatment of insomnia today consists of several classes of medications
with different mechanisms of action, sometimes specific to a certain type of insomnia.
As detailed below, some classes have greater scientific support for safety and efficacy
while others lack greater scientific evidence and are often used “off-label.” In this
guideline, we will divide the classes into the items presented below.
Selective Benzodiazepine Receptor Agonists and Benzodiazepines
Selective Benzodiazepine Receptor Agonists (Z-drugs)
Selective BZD receptor agonists marketed so far in Brazil – zolpidem, zopiclone, and
eszopiclone – constitute a class approved for the treatment of insomnia, acting as
hypnotics.
Zolpidem
Mechanism of action: hypnotic agent of the imidazopyridine class, acts on the α1 subunit of type A gamma-aminobutyric
acid (GABA) receptors.[128 ]
[129 ] Immediate-release presentations have a short half-life (0.5–3.5 hours), with peak
plasma concentrations of 45 to 60 minutes. Controlled-release presentations have biphasic
absorption, with rapid initial absorption and prolonged plasma concentration, lasting
more than 3 hours.[128 ]
Available presentations: in Brazil, available presentations include immediate-release tablets, 10 mg; sublingual,
5 mg and 10 mg; 5 mg and 10 mg orodispersible; controlled-release tablets of 6.25 mg
and 12.5 mg; oral solution 10 mg/mL (0.5 mg/drop).[128 ]
Patient assessment: it is indicated for acute night sleep-onset insomnia (immediate release – dose of
5 to 10 mg) and for sleep maintenance (prolonged release – dose of 6.25 mg), in adults.
For older adults, it is recommended to start with half this dose.[1 ] The initial dose should be lower for women. Use for children, adolescents, pregnant
women, or during breastfeeding is not recommended.
Therapeutic planning: should be administered at bedtime, over no more than 4 weeks.[129 ]
Expected outcomes: In a meta-analysis (n = 1,068), zolpidem resulted in increased TST, reduced sleep latency, and improved
sleep quality, with no difference in WASO.[129 ] Evaluating different doses of zolpidem (5; 7.5; 10; 15; and 20mg), it was shown
that doses of 7.5 and 10 mg decreased sleep-onset latency and the number of nighttime
wakes and increased TST, without impact on psychomotor performance.[130 ]
Comparing sublingual and oral zolpidem, 10 mg, the sublingual presentation reduced
sleep onset latency by 8.6 minutes, with no differences in TST and WASO, compared
with oral zolpidem.[131 ] In individuals with chronic insomnia, oral (10mg) and sublingual (5mg) zolpidem
led to a similar reduction in the number of wakes and an increase in TST, but with
a greater reduction in sleep latency with sublingual zolpidem.[132 ]
For maintenance insomnia, with nighttime wakes, sublingual zolpidem (5 mg) increased
TST, without significant changes in sleep latency, WASO, or sleep quality, and with
sleepiness and reduced alertness in the morning.[133 ]
Extended-release zolpidem (12.5 mg), in individuals with chronic insomnia, increased
TST and sleep efficiency, while reducing latency to persistent sleep, wakes, and WASO.
The following morning, there was no impairment of psychomotor performance.[134 ]
[135 ]
Drug interactions, contraindications, and side effects: zolpidem is metabolized by cytochrome p450 (CYP). Use with CYP3A4 inhibitors (fluvoxamine,
ciprofloxacin, and ketoconazole) is not recommended due to the potential increase
in the sedative effect. Use with CYP3A4 inducers (rifampicin and St. John's wort)
may decrease zolpidem levels.
Side effects of zolpidem include sleepiness (5%), dizziness (5%), headache (3%), gastrointestinal
symptoms (4%), sleepwalking (1%), nightmares (1–2%), and mental confusion (1–2%).[128 ]
[131 ]
[132 ]
[135 ] The risk of falls and fractures is increased, especially among older people.[128 ] Non-REM (NREM) sleep parasomnias, and behavioral changes (disinhibition, aggressiveness,
impulsivity, visual and auditory hallucinations, driving) are possible effects, more
prevalent in association with alcohol.[128 ] There is an increased risk of suicide, especially with high doses and psychiatric
comorbidities.[128 ] The prevalence of rebound insomnia with discontinuation of zolpidem was not greater
than that observed with placebo after daily use for one year,[136 ] but it may be observed with abrupt discontinuation of higher doses.[128 ]
Zolpidem can cause dependence syndrome. Abrupt interruption is associated with headache,
myalgia, irritability, anxiety, mental confusion, and, in more serious cases, derealization,
depersonalization, hyperacusis, hypersensitivity to light, noise, and tactile stimuli,
hallucinations, and epileptic seizures. There has been a recent increase in zolpidem
abuse and the use of high doses, with tolerance, particularly in individuals with
reported dependence and abuse of other drugs.[137 ] In Brazil, between 2018 and 2022, there was a 161% growth in zolpidem sales, reaching,
almost 22 million boxes sold in 2022, according to data provided by the National Controlled
Products Management System, managed by the National Health Surveillance Agency (ANVISA).
In this same period, comparatively, the sale of clonazepam increased by just over
9%. Therefore, measures to combat indiscriminate use, as well as the correct assessment
and reassessment of patients during the use of zolpidem, are priorities in the treatment
of patients.
Zopiclone
Mechanism of action: It is a non-benzodiazepine hypnotic agent from the cyclopyrrolone family. It has
a high affinity for the α-1 and α-2 subunits of the GABA-A receptor.[128 ] After oral administration, zopiclone is rapidly absorbed, with maximum plasma concentrations
of 30 and 60 ng/mL reached within 1.5 to 2 hours, after administration of 3.75 and
7.5 mg, respectively. Its terminal elimination half-life (t1/2) is ∼5 hour.
Available presentations: Zopiclone is available in Brazil in the form of 7.5 mg coated tablets.[128 ]
Patient assessment: Due to its mechanism of action, zopiclone is indicated for adult patients with acute,
onset, and/or maintenance insomnia. Older people should start with half the dosage
(3.75 mg).
Therapeutic planning: The recommended administration is 1 tablet, orally, only at bedtime (considering
that the patient must adopt a regular pattern in the times they go to bed and get
up). Treatment should be short-term, trying not to exceed 4 weeks.
Expected outcomes: A systematic review evaluated the use of zopiclone in 12 double-blind, placebo-controlled
RCTs, two open studies, and two observational reports, and concluded that it can be
an effective and relatively safe treatment to treat insomnia in adults and older people,
with and without comorbidities.[138 ] Zopiclone reduced sleep latency, nighttime wakes, and WASO, increasing TST, with
probable effects on sleep architecture, at dosages of 3.75 mg, 5 mg, 7.5 mg, and 10 mg.
It was compared with placebo or BZDs in different populations (older people living
in the community, residents of long-term care institutions, and those admitted to
hospitals). Zopiclone was well tolerated, with a low rate of adverse events and low
impact on psychomotor or cognitive performance, as long as the dosages and guidelines
established for its use were respected. However, the quality of most studies was low
or unclear.[138 ] There are two RCTs – one compared the effectiveness of zopiclone with zolpidem and
the other, with eszopiclone, demonstrating that both substances were effective in
decreasing sleep latency and increasing TST and sleep efficiency, respectively.[139 ]
[140 ]
Drug interactions, contraindications, and side effects : The binding of zopiclone to plasma proteins is weak and non-saturable; therefore,
the risk of drug interactions is very small. Reducing the dose of zopiclone is necessary
when used concomitantly with potent CYP3A4 inhibitors, such as erythromycin and ketoconazole.
The opposite was also observed with rifampicin, carbamazepine, phenobarbital, phenytoin,
and St. John's wort, drugs that induce CYP3A4, decreasing the action of racemic zopiclone
by 80%. Ethanol should not be consumed concomitantly with zopiclone due to the risk
of parasomnia such as sleepwalking, food intake, telephone calls, and amnesia, in
addition to increasing the sedative effect of zopiclone.
This medicine should not be used by pregnant women as there are no adequate and well-controlled
studies in these conditions. The use of this medication in women who are breastfeeding
is also not recommended. Likewise, the use of zopiclone in children and adolescents
is not recommended.
Very common adverse events (> 10%): bitter taste; common ones (> 1% and ≤ 10%): dizziness,
headache, residual sleepiness, dry mouth, dyspepsia, nausea. Nightmares or inappropriate
behaviors such as sleepwalking were rarely recorded.
Other considerations: 1) Withdrawal syndrome has been reported upon discontinuation of zopiclone and may
cause rebound insomnia, anxiety, tremors, sweating, agitation, confusion, palpitations,
and tachycardia; 2) The risk of dependence or abuse increases with the dose and duration
of treatment, history of abuse with alcohol or other drugs and concomitant use of
alcohol or other psychotropic drugs. 3) Continued use of zopiclone can reduce its
effectiveness, generating tolerance. 4) Anterograde amnesia may occur, especially
when sleep is interrupted or when the time to lie down is delayed after taking the
zopiclone tablet.
Eszopiclone
Mechanism of action: Eszopiclone, an S-enantiomer of racemic zopiclone, is a nonbenzodiazepine hypnotic
agent from the cyclopyrrolone family.[1 ]
[128 ] After oral administration, it is rapidly absorbed and reaches maximum concentration
(Tmax) in ∼1 hour. Its terminal elimination half-life (t1/2) is ∼6 hours. It has a
high affinity for the α-1, α-3 and α-5 subunits of the GABA-A receptor.[142 ]
[143 ]
Available presentations: Eszopiclone is available in Brazil as 2 and 3 mg coated tablets. The 1mg presentation
is expected to arrive soon, which could be attractive for older patients.
Patient assessment: Due to its mechanism of action, eszopiclone is indicated for adult patients with
acute, onset, and/or maintenance insomnia.[1 ]
Therapeutic planning: The recommended administration is one tablet only when going to bed (considering
that the patient must adopt a regular pattern in the times they go to bed and get
up). Always try to start with the lowest dosage. Intermittent dosing or “treatment
as needed” may be an alternative to the treatment.[143 ]
Expected outcomes: There are already numerous RCT studies and two meta-analyses. The first reviewed
14 RCTs with 4,732 participants and demonstrated that eszopiclone reduced sleep latency
by 12 minutes and WASO by 17 minutes, helping increase TST by at least 30 minute,
increasing sleep efficiency and improving functioning the next day when compared with
placebo.[142 ]
[143 ] This effect was observed in different age groups (3 mg being administered to adults
and 2 mg to older adults) and in different types of insomnia, including comorbid conditions.
Two 6-month studies indicated that therapeutic benefits can be maintained for prolonged
periods.[145 ]
[146 ]
A dosage of 1mg of eszopiclone is enough to reduce sleep latency and increase sleep
efficiency. However, only with 3 mg was there a significant difference in WASO, number
of wakes, and wake-up time (with PSG) when compared with placebo.[147 ] A study in a Japanese population observed a statistical difference with a dosage
of 2 mg.[148 ]
The most recent meta-analysis, from 2019, brought together 6 RCTs involving 2,809
patients with insomnia disorder and concluded that eszopiclone is an effective and
safe therapeutic option, especially for older patients. Eszopiclone was associated
with significant improvements in subjective sleep latency, WASO, number of wakes,
TST, increasing sleep quality, ability to function, daytime alertness, and sense of
physical well-being in studies with follow-ups of 1 week, 2 weeks, 1 month, 3 months,
and 6 months.[146 ] Roth and Walsh described the same results, but with follow-ups of 12 months, the
last 6 months being an open study.[149 ]
Drug interactions, contraindications, side effects : Eszopiclone is weakly bound to plasma proteins. The high fraction of free drugs
in plasma suggests that its distribution is not affected by interactions with other
medications related to binding to these proteins. Eszopiclone did not show any inhibitory
potential on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, or 3A4A.
Reducing the dosage of eszopiclone is necessary when used concomitantly with potent
CYP3A4 inhibitors, such as ketoconazole. The opposite was also observed with rifampicin,
a drug that induces CYP3A4, decreasing the action of racemic zopiclone by 80%. Ethanol
should not be consumed concomitantly with eszopiclone due to a potentiation of the
effect on psychomotor performance up to 4 hours after use.[143 ]
This drug should not be used by pregnant women as there are no adequate and well-controlled
studies in these conditions. Its use in women who are breastfeeding is also not recommended.
Likewise, the use of eszopiclone in children and adolescents is not recommended.
Very common adverse events (> 10%): Headache, and unpleasant taste; common ones (>
1% and ≤ 10%): sleepiness, dry mouth, viral infection, dyspepsia, and nausea.[143 ]
Other considerations: 1) Discontinuation of eszopiclone after several weeks and months of treatment did
not result in withdrawal symptoms; 2) Rebound effect was reported in a minority of
studies; 3) The efficacy of eszopiclone has been proven in patients with insomnia
comorbid with severe depression, generalized anxiety, rheumatoid arthritis, and OSA,
with improvement in sleep parameters.[145 ]
[150 ] 4) Eszopiclone provided significant improvements in sleep, mood, and menopause-related
symptoms in perimenopausal and early postmenopausal women.[151 ]
Benzodiazepines (BZDs)
BZDs' history began in 1955 with the discovery of chlordiazepoxide and in 1963 with
the launch of diazepam. The expectation of a new variety of drugs with more effective
and safer psychic effects than the predominant barbiturates and opioids meant that
BZDs dominated the neuropsychopharmacology market from the 1960s and 1970s onwards.
The perception of medical society about these drugs began to change after the second
half of the 1970s and into the following decade due to side effects, mainly abuse,
addiction, and accidents.[152 ] Although there has been a decline in prescription in the past 20 years,[153 ] BZDs remain popular[153 ]
[154 ]
[155 ] with new formulations emerging as recreational drugs, the so-called designer BZDs.[156 ]
Mechanism of action
: They act as allosteric agonists of GABA-A type A receptors – i.e., they bind to the
same receptor, but in different GABA sites, facilitating the effect of the agonist
neurotransmitter. This effect is predominantly in postsynaptic neurons, where there
is a cellular influx of chloride leading to neuronal hyperpolarization. BZDs demonstrate
different effects depending on the α subunits that make up the GABA-A receptor and
their locations in the different GABAergic pathways of the central nervous system
(CNS): anxiolytic, hypnotic, myorelaxant, amnesic, antiepileptic, and respiratory
depressant.[157 ] In the mesolimbic dopaminergic system, GABA inhibition in the ventral tegmental
area leads to an increase in the dopaminergic signal, resulting in a reward effect,
which is related to the mechanism of abuse and dependence.[158 ]
Available presentations
: Several BZDs are sold in Brazil. This study will evaluate those for outpatient use
and aiming to treat insomnia – thus, only oral and sublingual tablet presentations
and drop bottles will be mentioned. Those for injectable hospital use, intravenously
and intramuscularly, will not be listed, as well as the presentations absent in our
country, nasal spray and rectal gel. The BZDs analyzed were bromazepam (3 mg, 6 mg
oral tablets and 2.5 mg/mL solution), diazepam (5 mg and 10 mg oral tablets), clonazepam
(0.25 mg sublingual tablets, 0.5 mg oral tablets, 2 mg and 2.5 mg/mL solution), alprazolam
(0.25 mg, 0.5 mg, 1 mg and 2 mg oral tablets), midazolam (7.5 mg and 15 mg oral tablets),
flunitrazepam (1 mg oral tablets), estazolam (oral tablets 2 mg), flurazepam (30 mg
oral tablets), nitrazepam (5 mg oral tablets), clobazam (10 mg and 20 mg oral tablets)
and lorazepam (1 mg and 2 mg oral tablets). It is noteworthy that temazepam is the
only BZD indicated for the treatment of insomnia according to the AASM guidelines,[19 ] not available in Brazil and for this reason not included in this Brazilian guideline.
Patient assessment
: Due to their mechanism of action, BZDs have hypnotic potential for onset, maintenance,
and early morning awakening insomnia. However, the risks of abuse, dependence and
withdrawal, intoxication, enhancement of other substances with a hypnotic effect,
accidents, and death mean that they are not drugs of choice for the treatment of insomnia.[105 ]
[106 ]
[107 ]
Therapeutic planning: Only in cases of insomnia comorbid with diseases of which BZDs are treatment options
(e.g., epilepsy, some psychiatric and sleep disorders) is it possible to seek their
therapeutic hypnotic effect according to the clinical standard. It is not recommended
to use a benzodiazepine for more than 4 weeks as almost half of patients using it
daily for more than a month can develop dependence.[161 ] In early-night insomnia, BZDs with a short and intermediate half-life (alprazolam,
flunitrazepam, estazolam, midazolam, and bromazepam) are usually more used, with those
with prolonged effect duration (clonazepam, diazepam, and flurazepam) being options
for cases of maintenance and early-morning insomnia. Sublingual administration presentations
can be an option for early-night insomnia as it is a faster absorption route than
oral. One difficulty regarding the duration of the drug's effect is that some of them
have active metabolites, such as alprazolam and diazepam.[159 ]
[160 ]
[162 ]
[163 ] Furthermore, short-acting BZDs present a greater risk of abuse by users.[159 ]
[160 ]
[162 ]
[163 ] It is noteworthy that the option is also linked to the disease that primarily requires
the use of benzodiazepine.
Expected outcomes: There are no recent studies with a sufficient level of evidence for BZDs marketed
in Brazil to be recommended for the treatment of insomnia.
Drug interactions, contraindications, and side effects: Drugs that interfere with CYP3A4 may influence the metabolism of BZDs. The main pharmacological
interactions are with phenothiazines, opioids, barbiturates, monoamine oxidase inhibitors,
antidepressants with hypnotic effects, and alcohol and illicit drugs. Interaction
may also occur with some foods, grapefruit, St. John's wort, and Kava.[164 ]
BZDs can exacerbate symptoms such as respiratory depression, incoordination and imbalance,
behavioral changes, and sleepiness. Therefore, the use of this pharmacological class
is not recommended in patients with myasthenia gravis, ataxic syndrome, OSA, chronic
respiratory failure, CNS depressant intoxication, angle-closure glaucoma, older people
presenting agitation, or patients in delirium. The use of BZDs by pregnant and breastfeeding
women is also not recommended.[164 ] Populations with psychiatric comorbidities are those at greatest risk of abuse and
dependence.[160 ]
[161 ]
The most common side effects are sleepiness, lethargy, fatigue, daytime sleepiness,
impaired attention and concentration, amnesia, abuse, dependence and withdrawal, hypotonia,
and ataxia. Falls, fractures, accidents, memory impairment, and a greater risk of
paradoxical reactions can occur in older people.[162 ]
[163 ]
Dual Orexin Receptor Antagonists (DORA)
Orexins or hypocretins are hypothalamic neuropeptides that have a role in regulating
the sleep-wake cycle and maintaining wakefulness.[165 ] The orexin/hypocretin system is considered a target for the treatment of insomnia.
Suvorexant
Suvorexant was the first DORA approved for the treatment of insomnia.[166 ]
Mechanism of action: Suvorexant is DORA that promotes sleep through selective antagonism of the OX1R and
OX2R orexin receptors. Its half-life is ∼12 hours and the time to reach the maximum
concentration (Tmax) is ∼1 to 2 hours (if ingested on an empty stomach) and ∼3 hours
(with food).
Available presentations: Suvorexant is available in the following doses: 5, 10, 15, and 20 mg oral tablets.
Patient assessment: It is indicated to treat sleep-onset and maintenance insomnia in adults and older
adults.
Therapeutic planning: According to the American Food and Drug Administration (FDA), the recommended dose
is 10 mg taken once at night, 30 minutes before going to bed, and at least 7 hours
before the planned time to get up the next morning. The dose can be increased to up
to 20 mg if the 10 mg dose is not effective, although well tolerated. The total daily
dose should not exceed 20 mg per day. In patients using moderate CYP3A4 inhibitors,
the maximum recommended dose is 10 mg per day (starting with 5 mg).
Expected outcomes: As this was the first DORA approved, more studies and systematic reviews exist on
this medication.[167 ]
[168 ] Outcomes such as sleep onset latency, TST, WASO reduction, maintenance of sleep
architecture, as well as global and patient clinical impression, have been systematically
evaluated with suvorexant in placebo-controlled trials involving more than 1,000 patients.[168 ] A review that included 1,824 patients using suvorexant revealed significant improvement
in sleep, as assessed with ISI when compared with the placebo group. Improvement in
sleep (onset/maintenance), as well as a reduction in the impact of sleep problems
on daytime function, contributed to the overall improvement observed in the ISI total
score.[169 ] A double-blind RCT conducted in 522 patients aged ≥ 18 years (322 used suvorexant
versus 162 placebo) for 1 year showed that patients who received suvorexant had subjective
improvement in sleep latency and maintenance when compared with the placebo group.
The perception of improved sleep was evident in the first week of sleep and was maintained
after 1 year at the end of it. According to this study, suvorexant improves the perception
of sleep quality and the feeling of morning well-being, with no effect on mood, and
there were no marked differences between the groups in the occurrence of adverse events.[170 ] Suvorexant was also evaluated in patients with insomnia and probable Alzheimer's
disease, maintaining the same efficacy and safety profile observed in studies in patients
with primary insomnia.[170 ]
Suvorexant significantly reduces sleep-onset latency, increases TST, and decreases
WASO,[167 ] being effective and safe compared with placebo.
Drug interactions, contraindications, and side effects
: According to the FDA, the most common adverse effects include sleepiness, fatigue,
and headache. Other less common adverse effects are dry mouth, coughing, increased
incidence of respiratory tract infections, and changes in dream patterns. The risk
of adverse effects is dose-dependent and appears to occur more frequently in women.
There is no significant difference between young people and older adults in relation
to the risk of adverse effects.
When evaluating this drug in patients with insomnia, no significant differences were
observed in the occurrence of narcolepsy symptoms, such as hypnagogic or hypnopompic
hallucinations or sleep paralysis. No events suggestive of cataplexy were observed.[167 ]
Daridorexant
Mechanism of action: Daridorexant binds to G protein-coupled orexin (hypocretin) receptors A and B to
promote wakefulness – like the other DORAs mentioned in this section. Hence, daridorexant
suppresses excessive vigilance during the sleep period by selectively targeting and
blocking the binding of orexin neuropeptides to the two receptors.[171 ] Its half-life is ∼8 hour, and Tmax is ∼1 to 2 hour. The rapid absorption of daridorexant
associated with its rapid elimination allows a rapid onset of action and maintenance
of nighttime sleep, avoiding sleepiness the next morning.
Available presentations: Daridorexant is available as 25 and 50mg oral tablets.
Patient assessment: It is indicated for the treatment of insomnia, sleep-onset, or maintenance difficulties
in adults and older adults.
Therapeutic planning: Daridorexant was approved by the FDA for the treatment of insomnia in adults aged
≥ 18 years in doses of 25 to 50 mg, with a recommendation for use 30 minutes before
bedtime, with this medication taking at least 7 hours before the planned time to wake
up.
Expected outcomes: The main randomized, placebo-controlled study, lasting 52 weeks, showed that daridorexant
was generally safe and well tolerated, without inducing residual morning sleepiness
at the doses studied. One of the study results showed that daridorexant improved sleepiness
the next morning. Reports of adverse events were rare in all groups studied (active
and placebo). Narcolepsy symptoms were not reported by study participants, as monitored
for all DORAs already approved for insomnia. Finally, there were no signs of rebound
insomnia upon withdrawal.[172 ] In summary, it was concluded that in patients with insomnia, daridorexant administered
for up to 1 year was generally safe, with no signs of tolerance, physical dependence,
or rebound after withdrawal.
A secondary analysis of the study evaluated the efficacy and safety in a subpopulation
of older people with insomnia, demonstrating that, as in younger patients, the efficacy
of daridorexant is maximum in nighttime and daytime variables at the highest dose
of 50 mg. Older patients particularly required this dose to improve daytime functioning.
They did not present an increased risk of adverse events or residual effects the following
morning after the evening administration of 50 mg.[173 ]
A systematic review with meta-analysis gathered data from 2,271 patients from 4 RCTs,
showing that 50 mg of daridorexant was superior to placebo for the four efficacy outcomes,
including WASO, sleep latency, subjective TST and Insomnia Daytime Symptoms and Impacts
Questionnaire domain score. Furthermore, there were no significant differences in
adverse events between daridorexant and placebo.[174 ] Daridorexant is effective and safe for the treatment of insomnia when compared with
placebo.
Drug interactions, contraindications, and side effects: The most common side effects are sleepiness, fatigue, headache, and nasopharyngitis.
Lemborexant
Lemborexant is a new DORA used for the treatment of adults and older people with insomnia,
characterized by sleep-onset and/or maintenance difficulties. Lemborexant was approved
in 2019 for use in the United States, Japan, and Canada.
Mechanism of action: It acts as a reversible competitive antagonist at both orexin 1 and 2 receptors (OX1R
and OX2R). Compared with suvorexant, it has a greater affinity for the orexin 2 receptor
and, therefore, has a more potent inhibition effect for this receptor in addition
to faster dissociation of both receptors, providing a shorter duration of action and
faster elimination in initial phases. These differences corroborate the lower risk
of residual sleepiness the next day.[175 ]
Available presentations : Lemborexant is available as 5 and 10 mg oral tablets.[175 ]
Patient assessment: It is indicated for the treatment of sleep-onset and sleep-maintenance insomnia in
adults and older people. Use for children, adolescents, pregnant women, or during
breastfeeding is not recommended.[175 ]
Therapeutic planning: The recommended dose is 5 mg administered at bedtime, at least 7 hours before the
planned wake-up time. The dosage may be increased to 10 mg based on clinical response
and tolerability.
Expected outcomes: In randomized, double-blind, placebo-controlled studies and objective and subjective
assessments, lemborexant 5 mg and 10 mg provided efficacy with minimal residual sleepiness
the following morning in adult and older participants with insomnia. Individuals treated
with lemborexant experience improvement in all sleep parameters - i.e., reduced sleep-onset
latency, increased sleep efficiency, and increased TST when compared with placebo.
The benefits are observed at dosages of 5 mg and 10 mg from the first week of use
and maintained for 12 continuous months of treatment.[176 ]
[177 ]
Roth and colleagues evaluated changes in insomnia severity in 949 individuals with
moderate to severe insomnia (ISI score > 15) treated for 12 months with both dosages
of lemborexant. It reduced the severity of insomnia (reduction > 7 points in ISI),
which was maintained at the end of the analysis for 12 months, versus placebo.[178 ]
There is no evidence of rebound insomnia or withdrawal after stopping 12 months of
treatment. Furthermore, no deaths or falls were recorded. No suicidal tendencies,
suicidal ideation, suicidal behavior, or self-injurious behavior are reported with
up to 12 months of treatment.[179 ]
In a randomized, double-blind study of 1,006 participants aged ≥ 55 years or older
with insomnia, Rosenberg and colleagues found that lemborexant therapy significantly
improved both sleep latency and maintenance compared objectively via PSG with placebo
and extended-release zolpidem treatment (6.25mg). Therapy with 5 mg and 10 mg lemborexant
was well tolerated in older adults and proved to be effective, especially in the last
half of the night, compared with placebo. Benefits for sleep onset and maintenance
were also observed from the beginning of treatment and maintained throughout treatment
for 30 days.[180 ] Also in older people, the use of lemborexant led to significant increases in the
percentage of rapid eye movement (REM) sleep and significant reductions in baseline
latency to REM sleep compared with placebo and zolpidem.[180 ] These findings suggest that Lemborexant may modify some of the changes in sleep
architecture normally observed in older people with insomnia.[181 ]
Drug interactions, contraindications, side effects: The effective half-life is 17–19 hour and reaches peak concentration in ∼1 to 3 hour.
It is predominantly eliminated via CYP3A-mediated metabolism and the major metabolites
are physiologically inactive.[175 ]
[182 ] Concomitant use with CYP3A inhibitors (itraconazole, clarithromycin, fluconazole,
verapamil, and ranitidine) increases bioavailability and maximum concentration and
risk of adverse reactions. Concomitant use with a CYP3A inducer (rifampin, carbamazepine,
modafinil) decreases lemborexant exposure, which may reduce efficacy. The association
with alcohol increases the maximum concentration and bioavailability of lemborexant,
increasing the sedative effect and adverse reactions. Sleep onset may be delayed if
administered concomitantly with or after a meal. The 5 mg dosage is recommended in
cases of mild and moderate hepatic insufficiency and is contraindicated in severe
hepatic insufficiency.
Doses of 5 mg and especially 10 mg lemborexant were beneficial for the treatment of
patients with insomnia, being well tolerated. Adverse effects are considered mild
and moderate, the most common being sleepiness, nasopharyngitis, and headache.[176 ] Sleepiness is the most common adverse reaction reported in 5% or more of patients
(10% for 10 mg lemborexant versus 7% for 5 mg lemborexant and 1% for placebo).[182 ]
Adverse reactions considered uncommon (incidence < 2%) were sleep paralysis (1.6%
and 1.3% for 10 mg and 5 mg, respectively), hypnagogic hallucinations (0.7% and 0.1%
of patients who received 10 mg and 5 mg, respectively), compared with no reports of
patients receiving placebo. Although rare, complex behaviors during sleep have been
reported with the use of lemborexant at a dose of 10 mg.[182 ]
Observations
1) DORAs are not available in Brazil, sofar, but are expected to be launched. 2) Like
most data and studies presented in this guideline, very rare studies evaluated patients
with comorbid insomnia. Therefore, caution should be taken in extending these results
to this population. 3) Drug interactions between DORAs and antidepressants may occur,
and suicide risk in serious patients has not been well evaluated. 4) This class of
hypnotic is contraindicated for the treatment of insomnia in patients with narcolepsy.
Melatoninergic Agonists
Melatoninergic receptor agonists, represented in Brazil by Ramelteon, are an approved
class for the treatment of insomnia, acting as a chronohypnotic.
Mechanism of action: They are sleep promoters acting on the sleep-wake cycle by stimulating melatonin
receptor (MT) MT1 (attenuating the alert signal in the suprachiasmatic nucleus) and
the MT2 receptor (synchronizing the circadian clock).[183 ] Although there are no direct comparison studies, there is evidence from experimental
data that ramelteon is 3 to 16 times more powerful than melatonin.[184 ]
Available presentations: Ramelteon is available in 8 mg doses. Ramelteon is absorbed rapidly; therefore, its
low bioavailability is due to the extensive first-pass metabolism, with cytochrome
p450 being the largest isoenzyme involved in the liver metabolism of Ramelteon – which
is highly lipophilic and allegedly spread quickly to tissues including CNS. Its half-life
is 1 to 2.6 hour.
Patient assessment: Ramelteon can be indicated for adult patients with sleep-onset insomnia.
Therapeutic planning: The recommended administration is one tablet a day, 30 minutes before bedtime (considering
that the patient should adopt a regular sleep pattern). The tablet should not be broken,
and there is no evidence of the need to adjust doses for specific cases.
Expected outcomes: To date, there are two systematic reviews[185 ]
[186 ] (one of them with meta-analysis [185]) and several randomized studies lasting up
to 12 months of treatment that evaluated the effect of ramelteon on insomnia.[187 ]
[188 ]
[189 ]
[190 ]
[191 ]
[192 ]
[193 ]
[194 ]
[195 ]
[196 ]
[197 ]
[198 ] In that meta-analysis, Kuriyama and colleagues[185 ] reported 13 studies involving > 5,800 patients with insomnia or insomnia symptoms
with an average follow-up duration of 38 days. Ramelteon was associated with reduced
sleep latency (a weighted average difference of 4.30 minute [95% CI, 7.01 to 1.58])
and improved sleep quality, but was not associated with subjective TST increase. Ramelteon
has also been associated with improving persistent sleep latency (time from lights
off to the first sleep lasting at least 10 minutes), improving sleep efficiency, and
objective TST.
Drug interactions, contraindications, and side effects: When co-administered with ramelteon, fluvoxamine (strong CYP1A2 inhibitor) significantly
increased the concentration and half-life when compared with ramelteon administered
alone. Thus, ramelteon and fluvoxamine should not be co-administered. Ramelteon should
be administered with caution in patients taking other CYP1A2 inhibitors (such as ciprofloxacin),
as well as CYP3A4 inhibitors (such as ketoconazole), and CYP2C9 inhibitors (such as
fluconazole).
This medicine should not be used by pregnant women as there are no adequate and well-controlled
studies under these conditions. The use of this medicine in women who are breastfeeding
is also not recommended. Similarly, the use of ramelteon is not recommended in children
and adolescents due to the lack of studies focused on these populations.
The most common adverse events seen with ramelteon, with at least one difference in
incidence with 2% placebo, were sleepiness (5% versus 3% placebo); dizziness (5% versus
3% placebo), and fatigue (4% versus 2% placebo). Although very rare, there are reports
of serious allergic reactions such as angioedema with the use of ramelteon.
Other considerations: 1) Toxicity and relatively low abuse potential compared with other hypnotic agents[199 ]; 2) Evidence of safety with more prolonged use and no evidence of rebound insomnia
in 12-month-use studies[189 ]; 3) Safety in older patients and patients with comorbidities such as chronic obstructive
pulmonary disease (COPD)[200 ]
[201 ] and mild to moderate OSA,[202 ] without worsening their severities (including hypoxemia).
Melatonin
Endogenous melatonin (N-Acetyl-5-metoxytryptamine) is a neurohormone synthesized mainly
in the pineal gland and known for its chronobiotic effects. Melatonin biosynthesis
has a circadian rhythm, being synchronized by the light/dark cycle by the suprachiasmatic
nuclei. During the night, the absence of light allows the activation of noradrenergic
neurons that stimulate the production of melatonin in the pineal gland. During the
day, the luminous stimulus activates the retinal-hypothalamic tract that projects
an inhibitory signal for these noradrenergic neurons, limiting the production of the
molecule. Thus, endogenous melatonin acts as a marker of the dark phase, synchronizing
biological functions to the day/night cycle.[203 ]
[204 ]
Exogenous melatonin has been marketed for ∼30 years, being a chronobiotic suitable
for circadian rhythm disorders.[205 ] However, melatonin has erroneously become one of the most used substances in the
world to induce sleep.[206 ]
Mechanism of action: Endogenous melatonin and exogenous melatonin act on the sleep-wake cycle by stimulating
the MT1 receptor (attenuating the alert signal in the suprachiasmatic nucleus) and
the MT2 receptor (synchronizing the circadian clock).[203 ]
[204 ]
Available presentations: Exogenous melatonin is marketed in various presentations in the forms of immediate-release
tablets (2 mg, 3 mg, 5 mg, and 10 mg), sublingual use tablets (0.21 mg) and drops
(0.21 mg/drop), and the molecule is available for formulation in compounding pharmacy.
marketing in the form of drops (0.21 mg/drop and 0.20 mg/6 drops) has been approved
in Brazil.
In oral immediate-release formulations, exogenous melatonin reaches maximum plasma
concentration in ∼50 minutes and bioavailability is low and variable. Metabolism is
hepatic by the p450 system and excretion is urinary. The half-life is ∼60 minutes
(40 minutes - 2 hours).[207 ]
[208 ]
Patient assessment: There is no consistent evidence supporting melatonin use to treat insomnia in healthy
young adults. Although evidence is not robust, melatonin can be indicated in the management
of insomnia in older adults and children with autistic spectrum disorder. Melatonin
has proven effective in the management of circadian rhythm disorders.
Therapeutic planning: There is no recommended therapeutic planning for the use of melatonin in chronic
insomnia in adults since there is no proven effectiveness.
Expected outcomes: There are three systematic reviews[186 ]
[209 ]
[210 ] and some recent randomized studies that evaluated the effect of melatonin on insomnia
in adults.[211 ]
[212 ]
[213 ] The results are heterogeneous, encompassing effects on reduced sleep latency,[209 ] reduced sleep latency only in older people,[212 ] increased TST in comorbid insomnia,[186 ] reduced early waking,[213 ] and even the absence of effectiveness.[213 ]
[214 ]
There is evidence suggesting that melatonin can effectively treat chronic insomnia
in children with neurological diseases, especially autism and attention-deficit/hyperactivity
disorder (ADHD), as well as older adults. However, a broader assessment of possible
long-term consequences is still needed.[213 ]
[214 ]
[215 ]
[216 ]
[217 ]
Drug interactions, contraindications, side effects: Exogenous melatonin administration is considered quite safe in relation to potential
drug interactions, risk of intoxication, abuse potential, and significant short and
medium-term side effects.[206 ] The most common adverse events reported are headaches and sleepiness.[207 ]
Exogenous melatonin should not be used by pregnant women as it crosses the placental
barrier, and there are no adequate and well-controlled studies under these conditions.
The use of this medicine in women who are breastfeeding is likewise not recommended.
Clinical observations: As a chronobiotic, exogenous melatonin delays or advances phases in the sleep-wake
cycle, depending on the time when it is administered. Delayed phases can occur if
it is ingested around the end of the usual sleep period, and advanced phases when
ingested 3 to 5 hours before the usual sleep onset.[218 ]
[219 ]
Other considerations: In some countries, including in Brazil, exogenous melatonin has been released by
regulatory agencies as a food supplement and is therefore not subject to the same
quality rules of drugs. In 2017, after testing 30 different types of exogenous melatonin
sold in Canada, Erland and Saxena reported disagreements between label specifications
and formulation content – large differences in the actual amount of melatonin, presence
of serotonin in 26% of formulations, addition of herbal extracts and variations between
lots of the same manufacturer.[220 ]
Antidepressants
The use of sedative antidepressants to treat chronic insomnia is widespread, but none
is approved for insomnia by ANVISA. Hence, its prescription is considered off-label
and based on scientific evidence of non-systematized trials, which limits the power
of generalizing their effectiveness.[221 ]
[222 ] This unlicensed medicine use can be motivated by concern for the prolonged use of
hypnotics and the limited availability of psychological treatments. Although few studies
evaluate the effect of antidepressants on insomnia symptoms, with limited sampling,
short-term follow-up, and design limitations, the long-term safety profile of antidepressants
makes them empirically chosen, instead of other medications, for the treatment of
chronic insomnia.[221 ]
[222 ] High-quality antidepressants for insomnia treatment are required. It is important
to clarify that indicating the use of sedative antidepressants to treat insomnia is
independent of the presence of psychiatric comorbidity and that the doses used for
this purpose are significantly lower than those originally recommended to treat depression.[20 ]
[223 ]
Doxepin
Mechanism of action : Tricyclic antidepressant, whose mechanism of action as an antidepressant is to block
the reuptake of monoaminergic neurotransmitters for pre-synaptic terminals, having
anticholinergic activity and modulating the antagonism of histamine (H) H1 and H2[221 ] receptors. Due to the very high affinity of doxepin by the H1 receiver, its effect
as a selective antagonist of the H1 receiver can be ensured when used at low doses
and promoting its hypnotic action (1 to 6 mg of doxepin as a hypnotic, compared with
150 to 300 mg of doxepin as an antidepressant).[221 ] In addition, doxepin is actually a mixture of two chemical forms, one of which (and
its active metabolites) has a shorter half-life (8 to 15 hour) than the other, which
has the traditionally long half-life tricyclic antidepressants (24 hour). From a functional
point of view, the mix of the two agents means that their night administration produces
substantially lower residual drug plasma levels in the morning, thus reducing possible
residual daytime effects.
Available presentations : Doxepin is available in Brazil only for compounding in registered pharmacies upon
specific prescription. As it is an FDA-approved drug for insomnia treatment, the usually
recommended dose should be that of the same industrialized presentation in the United
States – i.e., 3 and 6 mg.[19 ]
[20 ]
Patient assessment : Due to pharmacokinetic characteristics, doxepin can be indicated for different clinical
insomnia phenotypes in adults and can, therefore, be used in sleep-onset and maintenance
insomnia and early waking.[19 ]
[20 ]
[221 ] There are no specific contraindications for different age groups and can also be
used in adults over 65 years.[222 ]
[223 ]
Therapeutic planning : The recommended initial dose is 3 mg used ∼30 minutes before the planned sleep onset
time.[19 ]
[20 ]
[221 ] In the absence of response in the first weeks, the dose should be raised to 6 mg.[221 ] The recommended therapeutic dose for adults over 65 is 3 mg.[221 ] Patients should be suggested to allow for ∼7 hours of sleep to avoid residual morning
sleepiness, at least in the first nights of treatment. Unfortunately, there is no
evidence in studies or guidelines recommending the time of use to treat chronic insomnia.
Due to its exclusively compounding presentation in Brazil, pharmacokinetic characteristics
will be potentially different from those found in the industrialized presentation[222 ] (doxepin Tmax occurs 3.5 hours after oral administration; it has liver metabolization
with renal elimination of inactive metabolites; apparent terminal half-life (t½) of
doxepin is 15.3 hours).
Expected outcomes : Five studies have compared doxepin with placebo,[224 ]
[225 ]
[226 ]
[227 ]
[228 ] using doses between 1 and 6 mg, revealing a moderate improvement in the subjective
quality of sleep compared with placebo, improved sleep efficiency, increased TST,
and discreet impact on sleep latency, with better responses in the 6 mg dose.[224 ]
[225 ]
[226 ]
[227 ]
[228 ] The systematic review published in 2015 with RCTs comparing doxepin with placebo[229 ] concluded that doxepin had a mean effect size compared with placebo for sleep maintenance
and sleep duration, without significant residue the next day, being considered safe
and effective, particularly for maintenance insomnia, to improve sleep in short-term
evaluations.[229 ]
Drug interactions, contraindications, side effects, and observations: In adults over 65 years old, side effects were similar to those of placebo and included
sleepiness (8–9%), nausea (4–5%) and dizziness (2%).[223 ] There are no association reports with complex sleep behaviors or memory impairment
in older patients treated with doxepin.[223 ] Drug interactions may occur with cytochrome inductors and inhibitors, considering
that it is metabolized by CYP2C19 and CYP2D6. Patients with decreased renal function
may have delayed doxepin clearance, leading to prolonged sedation.[223 ] Its use in the third trimester of pregnancy may increase the risk of neonate poor
adaptation symptoms (respiratory discomfort, temperature instability, diet difficulties,
hypotonia, tremor, irritability); use during breastfeeding is not recommended; use
in children is not recommended, as safety and effectiveness have not been evaluated.[221 ]
[223 ] Attention must be paid to the dose scaling in patients with liver failure or a tendency
to urinary retention.[221 ]
[223 ] Unlike other tricyclic antidepressants, doxepin does not pose a risk of worsening
symptoms of restless leg syndrome or periodic limb movement disorder.[230 ]
Other considerations: 1) no evidence supports long-term effectiveness (up to 5 weeks); 2) Safe, low-toxicity
medicine, without evidence of abuse behaviors; 3) Considering doxepin tests as an
antidepressant, it is a usually safe medication in clinical comorbidities; 4) Doxepin
is not recommended for pregnant or breastfeeding women, as well as children and adolescents.
Agomelatine
Mechanism of action : It is an antidepressant whose mechanism of action is its performance as an agonist
in MT1 and MT2 receptors and antagonist actions in histaminergic (H) receptors 5H2c.
Available presentations : It is available in Brazil in 25 mg coated tablets.
Patient assessment : There are no RCTs with any methodology assessing agomelatine specifically in the
treatment of insomnia without comorbidities. Some publications evaluate the outcomes
of sleep quality in patients with depression treated with agomelatine.[221 ]
[231 ]
[232 ] Thus, there are no specific recommendations for the evaluation of patients with
insomnia treated with agomelatine.
Therapeutic planning : The 25 mg initial dose to treat depression with agomelatine should be recommended
when going to bed, planning to increase doses to 50 mg when going to bed after 4 weeks,
in the persistence of depressive symptoms.
Expected outcomes : A 24-week, double-blind, controlled randomized study evaluated the efficacy of agomelatine
and escitalopram in depression and subjective sleep perceptions in patients with major
depression. It reported a subjective improvement in sleep-onset latency but did not
find differences between escitalopram and agomelatine in relation to sleep latency
in 12 and 24 weeks.[232 ] A review that brought together the results of three randomized studies comparing
agomelatine with selective serotonin reuptake inhibitor antidepressants or venlafaxine
established that agomelatine increases slow-wave sleep, improves sleep efficiency
in patients with major depressive disorder while not changing REM sleep amount or
latency.[233 ]
Drug interactions, contraindications, side effects, and observations: Agomelatine is metabolized by cytochrome p450 1a2 (CYP1A2) (90%) and CYP2C9/19 (10%).
Other medications that interact with these isoenzymes may decrease or increase the
bioavailability of agomelatine. It should not be used in association with other medicines
such as fluvoxamine, estrogens, and ciprofloxacin, as they can modify their serum
level, as well as propranolol, and exaggerated smoking.[223 ] At the 25 mg dose, the average maximum concentration was ∼4 to 13 times higher for
patients aged ≥ 75 years compared with patients aged < 75 years. This medicine is
contraindicated in the presence of liver failure with transaminases greater than three
times the upper limit of the normal interval, as well as in children and adolescents.
It should be avoided in pregnancy and breastfeeding.
Other considerations: When used in the treatment of major depression, agomelatine can improve subjective
and objective sleep parameters when compared with other antidepressants.
Trazodone
Mechanism of action: The effect of trazodone as a hypnotic is due to its moderate antihistamine activity
in the H1 receptor, and its partial agonism in the hydroxytryptamine receptor (HT)
5HT1a.[233 ] As an antidepressant, it promotes 5HT1C and 5HT2 receptor antagonism and post-synaptic
a1-adrenergic receptor antagonism.[221 ]
[233 ] It also exerts relatively weak, although specific reuptake inhibition, acting on
the 5-HT carrier. Thus, trazodone is classified as serotonin antagonist 2A/2C and
serotonin reuptake inhibitor. Trazodone doses lower than those effective for antidepressive
action are often used for the effective treatment of insomnia. Low doses explore powerful
trazodone action as 5HT2a antagonist, as well as its properties as an antagonist of
H1 and α1-adrenergic histamine receptors, but do not adequately explore their properties
of serotonin carrier inhibition or 5HT2C receptors, which are weaker.[221 ]
[231 ]
Available presentations : Trazodone is available in 50 mg and 100 mg immediate-release and 150 mg and 300 mg
extended-release presentations. Importantly, extended-release presentations minimize
the known sedative effect of the drug.[221 ]
[231 ]
Patient assessment : Considering the pharmacokinetic characteristic of immediate-release trazodone, it
can be recommended to treat different clinical presentations of chronic insomnia:
sleep-onset and maintenance insomnia and early waking.[79 ]
[221 ]
[234 ]
[235 ] It is not recommended for use in children under 18, as safety and effectiveness
have not been determined. It can be used in adults over 65 but with lower doses.[221 ]
[231 ]
Therapeutic planning : Recommended therapeutic doses of trazodone to treat insomnia are in the interval
between 50 and 100 mg taken near going to bed, with an expanded interval of doses
between 25 and 150 mg when lying down.[221 ]
[231 ]
[234 ]
[235 ] The time to take trazodone for sleep-onset insomnia should be individualized, usually
between 30 and 90 minutes before bedtime. Trazodone half-life is ∼7 hour after oral
administration and has linear pharmacokinetics within the dosage range of 50–150 mg/day.[231 ] Its absorption is irregular in fasting individuals, but improves when taken after
meals, although no differences were found in the total amount of trazodone absorbed
with and without food: its bioavailability values.[231 ] It is metabolized mainly by the hepatic enzyme CYP3A4 and inhibition of this enzyme
by other drugs leads to high blood levels of trazodone.[231 ]
Expected outcomes : A relevant number of RCTs are available evaluating trazodone in the treatment of
insomnia, compared with placebo or other hypnotic medications, as well as CBT-I.[79 ]
[234 ]
[235 ] A meta-analysis published in 2018[234 ] specifically evaluated the role of trazodone in the treatment of insomnia in placebo-controlled
randomized studies and included seven studies involving 429 patients. Patients receiving
trazodone perceived better subjective quality of sleep than those who received a placebo,[234 ] as well as a significantly reduced number of wakes throughout the night with trazodone,
compared with placebo. No important differences were found for sleep latency or TST
between trazodone and placebo.[234 ] A systematic review and meta-analysis published in 2022 evaluated the effect of
trazodone on PSG objective findings in insomnia patients. It included 11 studies,
evaluating a total of 466 patients.[235 ] Compared with the control group, trazodone significantly increased TST and stage
3 (NREM sleep), significantly reducing sleep-onset latency, stage 1 time (NREM sleep),
the number of wakes, and WASO.[235 ]
Drug interactions, contraindications, side effects, and observations: There are reports of changes in coagulation exams in patients receiving warfarin
and trazodone.[231 ]
[236 ] Concomitant use of antihypertensive can cause an important drop in blood pressure.
There are reports of increased concentrations of digoxin and phenytoin in the blood
of patients who received trazodone along with one of these medications.[231 ]
[236 ] It is not recommended for patients recovering from a myocardial infarction.[231 ]
[236 ] Trazodone is associated with the occurrence of priapism (prolonged or inadequately
lasting erections),[221 ]
[231 ]
[236 ] with a risk of occurrence in 1 per 6,000 patients treated with trazodone.[231 ]
[236 ]
Other considerations: 1) Trazodone should be considered in the treatment of the comorbidity between insomnia
and OSA, due to its safety profile.[235 ] 2) Trazodone is not recommended for pregnant or breastfeeding women, as well as
children and adolescents.
Amitriptyline
Mechanism of action : Amitriptyline is commonly used off-label for insomnia because of its sedative properties.
Like other tricyclic antidepressants, its antidepressant action mechanism is to block
reuptake bombs of serotonin and norepinephrine neurotransmitters. Sedative properties
are caused by antagonism on muscarinic-cholinergic receptors, α1-adrenergic, and histaminergic,
being present in low doses such as 10 mg. The antidepressant effect requires doses
greater than 75 mg/day to recruit serotonergic and noradrenergic receptors.[237 ]
Available presentations: Amitriptyline is available in 10 mg, 25 mg, and 75 mg tablets.
Patient assessment: No RCT has assessed amitriptyline to treat specifically insomnia with no comorbidities.
Therefore, there are no specific recommendations for the evaluation of patients with
insomnia in treatment with amitriptyline.
Expected outcomes: There are no systematic reviews, meta-analyses, or randomized studies that specifically
evaluated the effect of amitriptyline on insomnia without psychiatric comorbidities.
Studies with objective research with PSG conducted in patients with major depression
undergoing amitriptyline treatment had reduced sleep latency, fewer night wakes, and
increased sleep efficiency.[238 ]
[239 ]
[240 ] It is important to emphasize that tricyclic antidepressants suppress REM sleep and
are associated with the triggering or aggravation of periodic limb movements, restless
leg syndrome, and REM sleep behavioral disorder.[237 ] Considering its pharmacokinetic and pharmacodynamic characteristics, the sedative
effect of amitriptyline occurs with doses considered subtherapeutic for depression,
around 25 and 25 mg used near the intended time for sleep.
Drug interactions, contraindications, and side effects: Amitriptyline is metabolized in the liver by cytochrome p450 2D6 enzymes. Combined
use of amitriptyline with other nervous system depressors increases the risk of sedation
to ataxia. Oral contraceptives, selective serotonin inhibitors, antipsychotics, and
acetylsalicylic acid reuptake increase the serum levels of amitriptyline. Use with
medications that extend the QT interval should be avoided due to the synergistic effect
of amitriptyline in this condition. The main side effects of amitriptyline are dry
mouth, constipation, increased appetite, postural hypotension, sedation, dizziness,
blurred vision, reduced sexual drive, cognitive deficit, heart conduction abnormalities,
reduced seizure threshold, and blurred vision. Amitriptyline is contraindicated for
patients with acute myocardial infarction, cardiac conduction disorders, prostatism
or urinary retention, paralytic ileum, closed-angle glaucoma, and concomitant use
of monoaminoxidase inhibitors. Use in pregnancy should be avoided in the first trimester,
and the risk-benefit must be assessed in cases of severe depression. Use during breastfeeding
is safe.
Other considerations: 1) Due to the evidence that antidepressant amitriptyline treatment reduces sleep
latency and night waking and increases sleep efficiency, it may also be useful to
treat insomnia, in off-label conditions, if no other pharmacological options with
robust scientific evidence are available.
Mirtazapine
Mechanism of action: Mirtazapine is an antidepressant antagonist of presynaptic α2-noradrenergic self-receptors
and α2-serotoninergic hetero-receptors, acting on the disinhibition of synaptic release
of noradrenaline and serotonin. In addition to stimulating the release of serotonin
and noradrenaline, mirtazapine is an antagonist of the 5HT2A and H1 postsynaptic receptors,
with effects associated with increased slow-wave sleep and sedation, respectively.[241 ] Antidepressant doses range from 30 to 60 mg/day, and the sedative effect is more
pronounced with lower doses (7.5–15 mg); doses greater than 30 mg are less sedative
due to the largest noradrenergic effect. Its half-life ranges from 20 to 40 hours
and may cause residual sedation.[241 ]
[242 ]
Available presentations: 15, 30, and 45 mg orodispersible and coated tablets.
Patient assessment: No RCT has assessed mirtazapine specifically to treat insomnia with no comorbidities,
Hence, there are no specific recommendations for the evaluation of patients with insomnia
in treatment with mirtazapine.
Expected outcomes: In a double-blind, placebo-controlled RCT with healthy volunteers, the effects of
7.5 mg mirtazapine and 50 mg quetiapine were comparatively evaluated, both in normal
sleep and sleep disturbed by acoustic stress (traffic noise) as a model for transient
insomnia.[243 ] Under acoustic stress, both mirtazapine and quetiapine increased TST by half an
hour and reduced the number of wakes by 35–40% compared with placebo. While quetiapine
specifically increased the duration of stage N2, mirtazapine mainly increased stage
N3. Individuals reported that both mirtazapine and quetiapine facilitated sleeping
and improved sleep quality. Both drugs caused daytime sleepiness and diminished sustained
attention.[243 ] Studies with clinical samples of depressed patients using mirtazapine show increased
sleep, reduced latency, increased TST, reduced waking, increased efficiency, and increased
slow-wave sleep.[244 ]
[245 ]
[246 ]
Drug interactions, contraindications, side effects: Mirtazapine is a substrate of cytochrome enzymes p450 1 A2, 2 D6, and 3 A4 and weakly
inhibits 1A 2 and 3A4. Sedation is increased when mirtazapine is used in association
with other CNS depressors. The combination of mirtazapine with other antidepressants
such as selective serotonin reuptake inhibitors should be avoided due to the risk
of serotonergic syndrome. Mirtazapine may increase the appetite, raise triglyceride
cholesterol levels and liver enzymes, and cause dry mouth, constipation, excessive
sedation, dizziness, nightmares, vivid dreams, and restless leg syndrome.
Other considerations: 1) Considering small studies, particularly with evidence that antidepressant treatment
with mirtazapine improves different sleep parameters in patients with comorbid insomnia,
it may also be useful to treat insomnia in off-label conditions, if no other pharmacological
options with robust scientific evidence are available. Long-elimination half-life
can cause residual sleepiness with cognitive and motor deficits. Avoid using it in
patients with metabolic disorders due to the potential risk of weight gain.
Antipsychotics
Both typical and atypical antipsychotics differ regarding the affinity in receptors
and the predominance of action in different pathways, such as the nigra-striatal,
mesolimbic, mesocortical, and tuberoinfundibular ones. Thus, one can understand the
various profiles of adverse effects such as sedation, hypotension, extrapyramidal
symptoms, dystonia, hyperprolactinemia, and so on, which should be considered when
prescribing medications of this class. Phenothiazines, such as chlorpromazine and
levomepromazine, tend to cause sedation as an adverse effect, but this is not sufficient
to indicate them to treat insomnia, in the absence of scientific evidence that promotes
this support.[19 ]
[20 ]
[247 ] Considering atypical antipsychotics, a 2023 meta-analysis evaluated eight controlled
RCTs on the impact of the use of this class of sleep drugs during the treatment of
schizophrenia.[247 ] The findings indicate that among the antipsychotics, olanzapine, quetiapine, risperidone,
and ziprasidone were associated with a significant increase in insomnia symptoms,
concluding that clozapine is less associated with insomnia compared with other antipsychotics.[247 ] In guidelines for the treatment of insomnia without psychiatric comorbidities, few
studies are available assessing the use of antipsychotics, limiting orientations due
to the scarcity of data.[19 ]
[20 ]
[128 ] In recent years, there has been an increase in studies assessing the effect of quetiapine
on sleep and its possible role in the treatment of insomnia,[243 ]
[248 ]
[249 ]
[250 ] which is why we will discuss this medication and its role in the treatment of insomnia
below.
Quetiapine
Mechanism of action: It has a high affinity with 5-HT2a receptors. Regarding dopamine receptors, it has
a relatively lower affinity with D2 and D receptors compared with antipsychotic-standard
agents and a high affinity with D4 receptors. It has affinity with histaminergic and
α-1adrenergic receptors and lower affinity for adrenergic α-2 receptors and 5-HT1a
serotonin receptors. Quetiapine resembles other second-generation antipsychotics but
has particular affinity by different CNS receptors in a dose-dependent way. Low doses
have a predominance of action in H1, α-1adrenergic, and α-2 receptors by mediating
sedative action. In intermediate and high doses, affinity is added by serotonergic
receptors (5-HT1a, 5-HT2a, 5-HT2b, 5-HT2c) and dopamine D2 receptors providing mood
stabilization, anxiety and psychosis improvement.[251 ]
Available presentations: Quetiapine is available in the form of immediate-release 25 mg, 100 mg, 200 mg, and
300 mg tablets and extended-release 50 mg, 200 mg, and 300 mg tablets.
Patient assessment : Due to pharmacokinetic characteristics, quetiapine could be indicated for different
forms of insomnia presentation in adults and can, therefore, be used in sleep-onset
and maintenance insomnia and early waking.[19 ]
[128 ]
[248 ]
[250 ] Given its adverse effects profile, its prescription to adults over 65 years should
be avoided or performed more carefully.[128 ]
[250 ] However, there is an evident need for further studies using it as a treatment of
insomnia without psychiatric comorbidities[249 ]
[252 ] and assessing the safety profile of adverse effects using long-term low quetiapine
doses.[252 ]
Therapeutic planning : The possibly recommended administration for the treatment of insomnia is once a
day, close to bedtime, between 25 and 100 mg/day.[243 ]
[248 ]
[249 ]
[250 ] After oral administration, rapid absorption occurs, reaching peak serum concentration
in 1.2 to 1.8 hour, and its bioavailability is not significantly affected by food
intake. It is metabolized in the liver by CYP 3 A 4, and its elimination half-life
is ∼6–7 hour. The elimination occurs through renal (73%) and fecal (27%) routes.
Expected outcomes: Quetiapine has been approved by the FDA for the treatment of schizophrenia and manic
episodes and as an adjuvant treatment for major depressive episodes. Quetiapine has
been used, in off-label prescription, to treat insomnia, and studies have evaluated
the effectiveness of treatment and sleep impact.[243 ]
[248 ]
[249 ] In 2010, an RCT evaluated the use of 25 mg quetiapine at night for the treatment
of primary insomnia.[250 ] In this study, there was no statistically significant difference in sleep parameters
such as TST and sleep latency in relation to the placebo group.[250 ] Since then, other studies have been developed. A review published in 2009 suggested
that quetiapine could reduce sleep-onset latency and improve TST and sleep efficiency
in patients with psychiatric disorders, but findings are still insufficient to propose
it as a pharmacological option in the treatment of insomnia without psychiatric comorbidities.[248 ] Meta-analysis results published in 2023 point out that quetiapine, in doses lower
than those used in the treatment of schizophrenia or acute manic episodes, effectively
managed insomnia.[249 ] However, the authors point out that long-term effectiveness and safety need to be
investigated, especially in groups of patients without psychiatric disorders.[249 ] According to a meta-analysis, doses ranging from 50–150 mg/day are recommended,
particularly for symptoms of insomnia in comorbidity with generalized anxiety disorder
and major depressive episodes.[249 ]
Drug interactions, contraindications, and side effects : Compared with other medications of the same class of antipsychotics, quetiapine
is less associated with dystonia and extrapyramidal symptoms, but may promote weight
gain, metabolic syndrome, and QT interval prolongation.[252 ] The body mass index, weight, blood pressure, fasting blood glucose, and lipid profile
before starting treatment should be monitored in patients who use it, following control
regularly.[251 ] During concomitant administration of potential CYP3A4 inhibitor drugs (such as blue
antifungals, macrolide antibiotics, and protease inhibitors), their plasma concentrations
may be significantly increased as observed in patients in clinical studies.[252 ] Long-term safety data on quetiapine treatment are not available for children and
adolescents.[252 ]
Other considerations: 1) Despite the further cited and recently developed studies, other ones are needed
with more individuals, evaluating the effect of continuous treatment and response
profile in insomnia without comorbidity; 2) it is always necessary to consider risks
associated with adverse effects when prescribing antipsychotic for other purposes;
3) the safety and effectiveness of quetiapine were not established for children and
adolescents (10 to 17 years old); 4) the safety and effectiveness of quetiapine during
human pregnancy were not established; 5) there are reports on the excretion of quetiapine
in breast milk during breastfeeding. However, the level of excretion was not consistently
detectable at low doses such as those used to treat insomnia. According to records
in the package leaflet of manufacturing industries, women who are breastfeeding should
be advised to prevent breastfeeding while using quetiapine. Still, the Center for
Programmatic and Strategic Actions of the Department of Healthcare of the Brazilian
Ministry of Health, in its publication on breastfeeding and the use of medicines and
other substances,[253 ] states that the use of quetiapine is compatible with lactation, at the discretion
of the prescribing physician, given the risk-benefit assessment.
Anti-epileptic Drugs
The anti-epileptic drugs, previously named anticonvulsants, included in this manuscript
are: gabapentin and pregabalin.
Gabapentin
Gabapentin is an anti-crisis medication discovered in the 1970s and approved by ANVISA
for the treatment of neuropathic pain in adults and as monotherapy or adjuvant therapy
for epilepsy with focal seizures, with and without secondary generalization, in pediatric
patients from 12 years and adults. In addition to the above indications, the FDA includes
the treatment of post-herpetic neuralgia and moderate to severe restless leg syndrome.
Mechanism of action: Gabapentin has a structure analogous to the inhibitory neurotransmitter (GABA) and,
although its mechanism of action is not fully understood, it inhibits the action of
α-2delta subunits of the voltage-dependent calcium channels, inhibiting calcium currents
and decreasing neuronal excitability.
Expected outcomes: Two studies on the efficacy of gabapentin have been included in this review, both
with low-quality evidence. An open clinical study, without a control group, studied
18 patients with chronic insomnia who used gabapentin at a dose of 200 to 900 mg at
night (average of 540 mg, most patients taking 600 mg) for 28 days. In this study,
improved sleep efficiency, decreased WASO, increased N3, and decreased awakening rate,
were reported, as measured with PSG, when compared with pre-treatment data. However,
the changes were not statistically significant. There was a significant improvement
in PSQI after starting the treatment.[254 ]
Another double-blind randomized study evaluated 237 adults (placebo: n = 115; gabapentin: n = 122) with transient insomnia, defined as at least one night with sleep-onset or
maintenance difficulties in the preceding month. This study, with a dose of 250 mg
of gabapentin for 28 days at 5 pm (∼5 hour on average before the usual time of sleep), showed with PSG on days 1 and
28 a significantly decreased WASO and increased TST. Residual effects during the day
after use were not statistically significant. The authors concluded that 250 mg of
gabapentin taken on average 5 hour before the usual time of sleep can improve the
maintenance and quality of sleep in patients with transient insomnia.[255 ]
Pregabalin
Pregabalin is approved by ANVISA for the treatment of neuropathic pain, as an adjuvant
in the control of focal-onset epileptic seizures with or without secondary generalization,
generalized anxiety disorder, and adult fibromyalgia.
Mechanism of action: Pregabalin is an enantiomer analogous to GABA with a mechanism of action similar
to gabapentin. No RCT so far has assessed this medication focused on the specific
study of chronic insomnia.
Expected outcomes: There are no controlled pregabalin studies for chronic insomnia. A systematic review
of gabapentin and pregabalin, also called α-delta ligands or gabapentinoids, for bipolar
disorder, generalized anxiety, and insomnia showed inconclusive results in relation
to outcomes for insomnia. This review shows that α-delta ligands appear to improve
sleep in patients with insomnia associated with clinical conditions such as anxiety
and neuropathic pain. However, it is unclear whether improvement occurs by direct
or indirect sleep effects. There is moderate evidence of gabapentinoid efficacy in
anxiety states and minimal evidence in bipolar disorder and insomnia.[256 ]
Cannabinoids
Cannabinoids are compounds found in Cannabis sp . Since 2019, ANVISA has allowed the registration, importation, marketing, and prescription
in the national territory of products derived from cannabis.
Mechanism of action: There are ∼100 phytocannabinoids in Cannabis sp . Preclinical and clinical studies were done only with Cannabidiol (CBD) and Delta-9-tetrahydrocannabinol
(THC). Therefore, we do not know the action of other cannabinoids on human sleep,
besides the two described above. CBD has a biphasic action – it promotes alertness
in lower doses and sedation in higher ones. Acute THC administration reduces sleep
latency, and chronic administration increases sleep fragmentation, WASO, and probably
reduced REM sleep.
Available presentations: 18 cannabinoids have been currently approved (ANVISA's Joint Board decisions no.
327/2019 and no. 335/2020). Cannabinoids in Brazil have several presentations: CBD
alone (20 mg/mL to 200 mg/ml); extracts containing CBD/THC (0.2% or 0.24% THC); or
cannabis extracts containing medicinal cannabinoids without specifications.
Patient assessment: There are no scientific guidelines, even though cannabinoids have been used for the
treatment of insomnia with or without comorbidities.
Therapeutic planning: No quality study so far has addressed their effectiveness and safety to guide the
posology.
Expected outcomes: To date, there are three systematic reviews with meta-analysis and some randomized
studies lasting up to 8 weeks of treatment that evaluated the effect of cannabinoids
on insomnia.[257 ]
[258 ]
[259 ]
[260 ] A meta-analysis with 219 adult patients with insomnia, evaluating objective (PSG
or actigraphy) and subjective outcomes, showed that the use of cannabinoid, CBD, and
THC-analogous extracts, improved PSQI sleep quality by up to 8 weeks.[259 ] Another meta-analysis, with more than 5,000 patients, evaluated the impact of different
cannabinoids on patients with sleep complaints under various medical conditions. It
found that a discreet proportion of patients reported an improvement in sleep complaints
compared with placebo after the use of cannabinoids, especially in the “cancer” patient
subgroup.[257 ] In the studies described above, it is not known whether the improvement of insomnia
stems from anxiolytic effects (CBD), painkillers (Δ 9-TC), or a direct effect on CNS
pathways that help regulate sleep. There are also other ongoing studies (for example
NCT0534170, NCT05041647, NCT05237037 - https://clinicaltrials.gov/ ) that can help improve evidence in the upcoming years.[261 ]
Drug interactions, contraindications, and side effects : Small clinical safety studies were performed only with CBD and CBD/THC extracts.[262 ] CBD and Δ 9-TC are metabolized in the liver and use the cytochrome p450 pathway
and may interact with various drugs that use the same pathway, as well as patients
with liver failure. Concomitant use of CBD with valproate increases transaminase levels
and the risk of hepatotoxicity, as well as clobazam (with reciprocal interaction).
CBD inhibits the enzyme responsible for its degradation by increasing its half-life
by 2 times. CBD use is associated with frequent though mild to moderate and self-limited
adverse events, such as sedation, epigastralgia, diarrhea, and increased transaminases.
THC use, in turn, induces known pleiotropic effects, such as sedation in small doses,
euphoria, and even psychotic outbreaks with high doses, which can lead to abuse and
abstinence. Regarding other phytocannabinoids and synthetic cannabinoids, their mechanisms
of action are still not well understood, as well as their drug interactions, contraindications,
and side effects.
Phytotherapeutics
Valeriana (Valeriana officinalis )
Mechanism of action: Valerian's most likely mechanism of action involves an agonist role of GABA-A receptors,
probably due to GABA's relatively high content in valerian extracts.[263 ] Recent research also points to adenosine receptor activity as the main contributor
to its relaxing and sleep-inducing effects.
Available presentations: It can be found in capsules or tablets or compounding presentations containing valerian
extracts (50 to 100 mg).
Patient assessment: There are no scientific guidelines, even though valerian is used to treat insomnia
symptoms.
Therapeutic planning: Package inserts suggest 50 to 300 mg standardized Valerian extract administrations,
30 to 60 minutes before going to bed. The tablet should not be broken and there is
no evidence of the need to adjust doses for specific cases.
Expected outcomes: A systematic review with meta-analysis demonstrated inconsistent valerian effects,
possibly due to the irregularity and variability in the quality of the extracts used.
Nonetheless, no significant adverse events were observed in the evaluated populations.[264 ]
[265 ]
Drug interactions, contraindications, and side effects: No residual effects and significant serious adverse events were observed with valerian.
Rebound insomnia after its discontinuation was not observed. Herbal or herbal products
should not be used by pregnant or breastfeeding women, as there are no adequate and
well-controlled safety and toxicity studies in these conditions.
Passiflora (Passiflora incarnata Linnaeus )
Mechanism of action: Passiflora extract probably exerts its sedative effect modulating the GABAergic activity.
Available presentations: It can be found in capsules or tablets or compounding presentations containing dry
passiflora extracts in variable quantities and with different flavonoid concentrations.
It is also available in different liquid formulations.
Patient assessment: There are no scientific guidelines, even though passiflora has also been used to
alleviate insomnia symptoms.
Therapeutic planning: No scientific guidelines instruct therapeutic planning.
Expected outcomes: A placebo-controlled, double-blind RCT demonstrated increased TST with PSG in patients
with insomnia taking passiflora extracts for 2 weeks.[266 ]
Drug interactions, contraindications, and side effects: Passiflora possibly enhances the effect of barbiturates, and concomitant use is not
recommended. Studies, which are still inconclusive, suggest an interaction with coumarin
medications, such as warfarin, and concomitant use is not recommended.
Chamomile (Matricaria recutita)
Mechanism of action: Chamomile extract possibly exerts its sedative effects by modulating GABAergic activity.
Available presentations: No formulations are available in capsules, tablets, or liquids in Brazil.
Patient assessment: No scientific guidelines so far indicate the use of chamomile to treat insomnia or
comorbid insomnia.
Therapeutic planning: No scientific guidelines instruct therapeutic planning with chamomile.
Expected outcomes: A placebo-controlled RCT used chamomile but did not find significant effects in comparison
with the placebo group.[267 ]
Drug interactions, contraindications, and side effects: chamomile did not have more adverse effects than the placebo group in the abovementioned
RCT.
Ashwagandha (Withania somnifera L. Dunal )
Mechanism of action: Ashwagandha possibly exerts its sedative effects by modulating GABAergic activity.
Available presentations: Compounding presentations can be found in capsules with 300 mg ashwagandha root extract.
Patient assessment: No scientific guidelines so far indicate the use of ashwagandha to treat insomnia
disorders or comorbid insomnia.
Therapeutic planning: No scientific guidelines support therapeutic planning.
Expected outcomes: A placebo-controlled, double-blind RCT demonstrated the effects of ashwagandha to
treat insomnia. There were improvements in actigraphy parameters (TST, sleep latency,
sleep efficiency, and WASO), sleep quality, and anxiety scores.[268 ]
Drug interactions, contraindications, and side effects: No significant adverse effects have been described from using ashwagandha extract.
Mulungu (Erythrina mulungu)
Mechanism of action: The mechanism of action of mulungu has not been described yet.
Available presentations: Compounding presentations can be found in capsules with various doses (200 mg is
the most common) of mulungu bark extract.
Patient assessment: No scientific guidelines so far indicate the use of mulungu to treat insomnia or
comorbid insomnia.
Therapeutic planning: No study has suggested therapeutic planning.
Expected outcomes: No study has assessed the effect of mulungu on any sleep-related outcome.
Drug interactions, contraindications, and side effects: No significant adverse effects have been described by using mulungu extract.
5.10. Others
Various other medications and dietary supplements are used as treatments for insomnia
symptoms, some of which are common in popular use and without a prescription. Medications
in this category generally induce sleepiness as a side effect parallel to their primary
use and are not formally indicated for the treatment of insomnia by any international
guideline. This condition includes antihistamines (including diphenhydramine, promethazine,
and hydroxyzine) and antiemetics (such as dimenhydrinate). Supplements are often based
on pharmacological assumptions, including precursors of related hormones or analogs
of sleep-related neurotransmitters (such as tryptophan and GABA). Specific information
on antihistamines is described below, as they are the most representative medications
in this category.
Antihistamines
Antihistamines, designed to treat allergies, were developed from anticholinergic medications
more than 70 years ago. Over the years and with the emergence of new classes of antihistamines,
they have been divided into first and second generations according to their pharmacokinetic
properties, structural characteristics, and adverse effects. First-generation antihistamines
are known to have sedation and anticholinergic effects. Second-generation drugs have
few adverse effects due to their high affinity for H1 receptors, low passage through
the blood-brain barrier, and little or no anticholinergic effect.[269 ]
[270 ] The sedative effect of first-generation antihistamines led to popular dissemination
as over-the-counter drugs for the treatment of insomnia despite the lack of scientific
evidence of efficacy and safety. The antihistamines selected for this article were
diphenhydramine, promethazine, hydroxyzine, and dimenhydrinate, which are first-generation
drugs.
Mechanism of action: They act as inverse agonists rather than H1 (histamine) receptor antagonists. The
effects on the CNS are basically determined by its ability to cross the blood-brain
barrier and bind to central H1 receptors. The ability to cross the blood-brain barrier
will depend on the lipophilic quality of the molecule and affinity with P-glycoprotein.
Furthermore, it has anticholinergic, α-adrenergic, and serotonergic actions.[269 ]
Most antihistamines available for oral administration in Brazil have a long half-life,
such as hydroxyzine (20–25 hours) and promethazine (16–19 hours). Compared with the
previous ones, oral diphenhydramine (not available) has a shorter half-life (6–9 hours).
Expected outcomes: Due to the lack of well-designed studies, expected outcomes for insomnia are not
adequately quantified.[271 ]
[272 ] Off-label use of this class can generate residual symptoms the next day and compromise
everyday situations (reflexes, ability to drive, etc.).
Drug interactions, contraindications, side effects: Common adverse effects (1 to 10%) include daytime sleepiness, fatigue, impaired attention,
vigilance, working and sensory memory, motor performance, and anticholinergic symptoms
(insomnia, tremors, nervousness, irritability, palpitation, blurred vision, constipation,
retention urinary tract, tachycardia, xerostomia, and dry throat and nose).
CNS-damaging effects of first-generation antihistamines cause impaired performance
in children and impaired ability in adults to work, drive, and pilot aircraft. The
association with alcohol or CNS depressants such as hypnotics causes additive sedation
effects. Concomitant use with MAO inhibitors prolongs and intensifies the anticholinergic
effects of antihistamines. Antihistamines may increase the arrhythmogenic effect of
psychotic agents and should be used with caution in patients with narrow-angle glaucoma.
Smaller doses in addition to cautious use are recommended in the elderly due to the
greater potential for anticholinergic effects and sedation. Dosages should be reduced
in liver failure.
