Treatment interventions for co-occurring opioid use disorder, and sleep disturbances: a scoping review

Abstract

Background

Opioid use disorder (OUD) is part of the broader spectrum of substance use disorders often complicated by psychiatric symptoms such as depression, anxiety, PTSD (Post-Traumatic Stress Disorder), and sleep disturbances, with insomnia being particularly frequent. These psychiatric symptoms may act as precipitating factors and consequences of OUD, reinforcing a complex bidirectional relationship that complicates treatment and recovery. Despite the clinical importance of dual disorders, sleep impairments are particularly relevant yet understudied therapeutic targets and literature addressing sleep disturbances in the context of psychiatric symptoms or disorders in OUD remains limited. This scoping review examines pharmacological and non-pharmacological interventions of OUD and sleep disturbances in the presence of psychiatric disorders or symptoms, such as anxiety, depression, and PTSD.

Methods

This review follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews (PRISMA-ScR) guidelines using the following keywords: (“sleep” OR “insomnia”) AND (“depression” OR “anxiety” OR “PTSD” OR “post-traumatic stress disorder” OR “posttraumatic stress disorder”) AND (“opioid use disorder” OR “OUD” OR “opioid addiction. Sleep disordered breathing was excluded. Participants were adults (> 18 years old) with OUD or opioid dependence undergoing withdrawal or treatment. The study focused on quantitative and qualitative study designs.

Results

Fifteen studies including 1,167 adults with OUD or opioid dependence were selected and categorized into pharmacological (targeting opioid or non-opioid receptors) and non-pharmacological interventions. Most interventions were adjunctive to opioid substitution or antagonist therapies. Naltrexone-induced insomnia was common but did not significantly affect mood and could be mitigated with lorazepam. Non-opioid pharmacotherapies yielded mixed results: guanfacine is suggested to increase insomnia risk but reduce stress and craving, while amitriptyline, prazepam, dronabinol, and neurotransmitter-precursor-supplements showed potential in improving sleep and withdrawal symptoms.

Conclusions

Improved characterization and management of impaired sleep in individuals with OUD and psychiatric symptoms may reduce relapse risk, enhance emotional regulation, and decrease self-medication. Clinicians should consider the complex interplay between OUD, psychiatric symptoms, and sleep as part of comprehensive care. Further research is needed to clarify these interactions and support the development of integrated, evidence-based strategies for treatment and prevention.

Clinical trial number

Not applicable.

Background

Opioid use disorder (OUD) is a common condition with a particularly high global prevalence, estimated at approximately 40.5 million people worldwide [1]. It is part of the broader spectrum of substance use disorders, which are characterized by maladaptive patterns of substance use causing distress and significant impairment in interpersonal and social functioning. Within this framework, OUD is defined by a problematic pattern of opioid use associated with unsuccessful attempts to cut down, cravings, tolerance, withdrawal, and continued use despite adverse consequences [2]. OUD is also frequently associated with psychiatric symptoms, which may influence its clinical presentation and may reflect either co-occurring psychiatric disorders or psychiatric manifestations related to OUD itself.

Prior research suggests that OUD results from the combined effects of diverse factors identified across psychiatry, sociology, and neurobiology. The convergence of these factors may determine the severity and course of the addictive process. For instance, psychiatric symptoms often involve sleep disturbances, which are frequently associated with the use of sedative substances such as alcohol, cannabis, or opioids. Substance use can, in turn, exacerbate both psychiatric symptoms and sleep disturbances, contributing to increased social and functional difficulties.

Among psychiatric disorders commonly associated with OUD are polydrug use, depression, anxiety, and post-traumatic stress disorder (PTSD). Regarding depression, its prevalence is estimated at 36,1% (95%CI 32.4%-39.7%) among individuals with OUD [3]. Depressed patients appear more likely to initiate opioid analgesics for chronic pain and tend to remain on it for longer durations than those without depression, possibly as a form of self-medication to alleviate stress and insomnia [4]. This relationship reflects the role of depression as a risk factor for OUD, particularly in individuals with chronic pain [4] and can lead to suicidal behaviors [5]. Depression often co-occurs with anxiety in individuals with OUD [6]. The prevalence of anxiety in this population is estimated at 29% (95%CI 24.0%-33.3%), and both conditions are strongly associated with sleep disturbances. This comorbidity is marked by more severe clinical presentations, poorer treatment outcomes [7], premature discontinuation of substance use treatment [8], and increased lifetime misuse of benzodiazepines [9], which potentiates the risk of overdose. Consequently, anxiety is another critical determinant of OUD severity [10]. Similarly, PTSD is highly prevalent with OUD, with an estimated prevalence of 18.1% (95%CI 15.4–20.9% [3, 11]. It is particularly common in specific populations such as veterans [12]. In these groups, opioids are often used alongside benzodiazepines or sedative-hypnotics to manage sleep disturbances. However, such combinations increase the risk of overdose [13] and contribute to the severity of opioid addiction [11].

In the context of the co-occurrence of multiple psychiatric symptoms, the relationship between sleep and addiction is particularly complex. Sleep disturbances are highly prevalent in OUD, with more than 75% of patients receiving prescription opioids or methadone maintenance therapy classified as poor sleepers [14].

Sleep disturbances occur across acute and protracted phases of opioid use and are associated with poorer recovery outcomes, yet their specific characteristics remain underexplored [15, 16]. The trajectory of these disturbances remains insufficiently characterized. Early opioid use is often associated with sedation and daytime drowsiness, which may diminish over time due to tolerance, although residual sleep impairment may persist [17].

Sleep is an evolving field that influences neural plasticity and is also believed to play an important role in the processes of aging and neurodegeneration. Given its potential as a therapeutic target, a deeper understanding of its relationship with underlying physiological and pathological mechanisms is essential. Despite their clinical importance, the literature addressing sleep disturbances in the context of psychiatric disorders in OUD remains limited. This scoping review examines pharmacological and non-pharmacological interventions addressing OUD and sleep disturbances in the presence of co-occurring psychiatric disorders or symptoms, such as anxiety, depression, and PTSD.

Methods

This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews (PRISMA-ScR) guidelines [18]. Although the PICO framework [19] is primarily used in systematic reviews, it was adapted to help structure the search strategy. Participants were adults with opioid use disorder (OUD); interventions included pharmacological and non-pharmacological treatment interventions; comparisons consisted of either pre-post assessments or comparisons between intervention groups when applicable; and outcomes included sleep-related measures, psychiatric symptoms, and OUD-related outcomes. The objective remained consistent with a scoping review approach aimed at mapping the available evidence.

Searches strategy

A primary search was performed in PubMed on September 4, 2024, using the following keywords: (“sleep” OR “insomnia”) AND (“depression” OR “anxiety” OR “PTSD” OR “post-traumatic stress disorder” OR “posttraumatic stress disorder”) AND (“opioid use disorder” OR “OUD” OR “opioid addiction”). Filters for “clinical trials” and “randomized controlled trials”, were applied, followed by a supplementary search without these restrictions to minimize the risk of missing relevant studies.

A second search was conducted on November 22, 2024, in the French database “Cairn-info” using the keywords in French (“sommeil”) AND (“addiction aux opioïdes”) AND (“santé mentale”). No date restrictions were applied. Titles and abstracts were screened for eligibility. Backward citation searching (snowballing) was subsequently conducted by reviewing the reference lists of included studies and newly identified articles. This process yielded 16 additional articles. The complete study selection process is presented in Fig. 1.

Fig. 1.

PRISMA 2020 flow diagram of the final included studies

Eligibility criteria

Studies published in English or French were eligible for inclusion. Studies were required to: (a) include adults (> 18 years old); (b) investigate individuals with OUD or opioid dependence undergoing withdrawal or treatment; (c) assess symptoms of anxiety, depression, or PTSD, either as formally diagnosed disorders or through measures of anxious or depressive symptoms without a predefined threshold; and (d) address sleep-related outcomes. Both quantitative and qualitative study designs were eligible.

Studies were excluded if they were reviews, observational cohort studies; case reports, case series or study protocols; focused on prescribed opioid treatment without explicitly linking its use to addictive behavior or those focusing on opioid use in the context of prescribed pain medication; addressed substance use disorders without specifically examining OUD; focused solely on sleep-disordered breathing or respiratory depression without mentioning sleep quality or insomnia.

Study selection, data extraction, and methodological appraisal

Study selection was conducted in two stages. The first author screened all records and applied the eligibility criteria, while the last author independently reviewed each decision. Disagreements were thoroughly reviewed and discussed until consensus was reached.

For each included study, data were extracted on general information (author, year of publication, country), study objective and type of intervention, study design and quality, population characteristics (sample size, gender, age), outcome measures related to sleep and psychiatric symptoms (clinical interviews for symptom diagnosis, qualitative semi-structured interviews, scales, and questionnaires), the type of opioid use disorder (OUD), and the study’s main findings.

Although formal risk-of-bias assessment is not required in scoping reviews, a structured appraisal of methodological characteristics was conducted to provide context for interpreting the evidence base. This appraisal focused on study design, reporting completeness, clarity of outcome measures, and potential methodological limitations. The aim was not to exclude studies but to provide a descriptive overview of the strengths and limitations of the included literature.

Data synthesis

Studies were presented according to intervention type, as (1) pharmacological interventions targeting opioid receptors (agonists or antagonists), (2) pharmacological interventions targeting non-opioid receptors, and (3) non-pharmacological interventions.

Studies were additionally categorized according to the primary treatment phase addressed by the intervention: (1) withdrawal management, (2) induction/tapering, (3) maintenance treatment, and (4) relapse prevention/protracted abstinence. Classification was based on the clinical objectives and treatment context reported in each study. Because several studies assessed outcomes across more than one stage of treatment, individual studies could be assigned to multiple phases when appropriate.

Results

Search results and study selection

The literature search identified 57 articles from PubMed, and yielded no articles from Cairn.info. An additional 16 articles were retrieved through citation searching. After the title and abstract screening for eligibility, 46 articles were excluded due to lack of relevance. Following this initial screening, 27 full-text manuscripts were assessed for eligibility. Articles were excluded if they were reviews, observational cohort studies, or case reports. Further exclusions were made for articles describing therapeutic interventions that did not address sleep or psychiatric disorders or that did not specifically focus on OUD. After full-text assessment, 12 additional articles were excluded. This step resulted in a total of 15 studies being selected for this scoping review (Fig. 1) [20–34].

Study quality assessment

The 15 included studies comprised pharmacological interventions (n = 12) and non-pharmacological interventions (n = 3). Outcome measures varied significantly, with some studies relying on self-administered questionnaires and others utilizing clinical interviews with or without self-administered questionnaires. One study used a qualitative approach with semi-structured interviews [32]. Among the included studies, 10 used a RCT design, while 5 were CT. Following the database search and quality assessment, we synthesized the findings based on a consensus between the first and last authors.

Characteristics of included studies

The study characteristics are detailed in Table 1. Studies were categorized into three groups based on the type of intervention: (1) pharmacological treatments targeting opioid receptors, (2) pharmacological treatments targeting non-opioid receptors, and (3) non-pharmacological therapeutic interventions. No studies examined the same population. In total, this review included 1,167 adults with OUD: 484 in the first intervention group, 565 in the second, and 118 in the third. Geographically, seven studies (n = 385, 32.99% of the total sample) were conducted in North America [22, 23, 26–29, 34], all from the United States. Five studies (n = 541, 46.36%) were from Asia (Iran: n = 2; China: n = 1; Thailand: n = 1; Russia: n = 1) [20, 24, 25, 31, 33], and three studies (n = 241, 20.65%) were from Europe (Norway: n = 1; Italy: n = 1; United Kingdom: n = 1) [21, 30, 32]. Studies investigating opioid receptor targets, were predominantly from North America and Europe.

Table 1.

Summary of the main data from studies included in this review

Author Year Journal	Objectives Treatment phase	Design Study duration Type of OUD	Sample size (N) Gender (M/F) Age (years) Country	Measure of anxiety (A) and/or depression (D)	Measure on sleep	Main results
Group 1: opioid receptor-based treatments
Mysels et al. 2011 Am J Drug Alcohol Abuse	Examine the course of mood symptoms following induction onto naltrexone I/T; M	CT 4 weeks Opioid-dependent	34 M:91.2% 37.2 USA	A, D: Hamilton Depression Scale; individual item “anxiety-psychic”	Individual item “late insomnia”	Naltrexone induction and maintenance in newly abstinent opioid-dependent individuals does not appear to be associated with the onset or worsening of depression; however, it may be associated with sleep impairment early in treatment in line with literature suggesting “sleeplessness” as a component of naltrexone treatment.
Lofwall et al. 2013 Drug Alcohol Depend	Efficacy of extended-release tramadol for treatment of prescription opioid withdrawal WM	RCT 13 days treatment of prescription opioid	36 M:22 18–55 USA	D: observer-rated opioid adjectives withdrawal score	Insomnia: through 10-item short opiate withdrawal scale	Tramadol 200 mg produced significantly lower peak ratings than placebo on ratings of insomnia.
Latif et al. 2019 JAMA Psychiatry	Extended-release naltrexone (XR-NTX) vs. combined buprenorphine-naloxone IT; M; RP/PA	RCT; CT follow-up 12 weeks; 9 months heroin use	159 M: 68.4% 18–60 Norway	A, D: 25-item Hopkins Symptom Checklist	Insomnia: Insomnia Severity Index	No overall differences between treatment groups in anxiety or depression scores; however, insomnia scores were significantly lower in the XR-NTX group. During follow-up participants switching to XR-NTX showed no overall differences.
Neale et al. 2023 Addiction	To evaluate perception of initiating long-acting injectable buprenorphine WM; I/T	CT 72 h 24 heroin use and 2 tramadol + morphine or codeine	26 M: 18 42 (30–62) United Kingdom	Semi-structured interviews	Semi-structured interviews	While most negative effects are well-known, the early benefits of treatment such as improved sleep, mood, and positivity, are less well-documented and may be an overlooked.
Omidvar Tehrani et al. 2023 Front Psychiatry	opium tincture for gradual detoxification WM; I/T; M; RP/PA	CT 11 months OUD and 95.6% history of opium use, 83.3% history of shireh (opium juice) use	90 M: 77 (85.5%) 37.74 ± 7.93 (18–64) Iran	A, D: Beck Anxiety Inventory; Beck Depression Inventory	Sleep: PSQI	Improvement in depression, anxiety, and sleep disorders was observed by the study’s end, with a low 16.7% relapse rate after one year with Opium tincture treatment under the Congress 60 protocol.
Group 2: other pharmacological treatments
Srisurapanont et al. 1998 Acta Psychiatr Scand	To investigate the sedative-hypnotic effects of amitriptyline vs. lorazepam in the treatment of opiate-withdrawal insomnia WM	RCT 5 days Opiate dependence	27 M: 100% 27+/-8.5 Thailand	D, A: HDRS (Hamilton D rating scale)	Sleep Evaluation Questionnaire: 3 items from HDRS	Aside from a hangover effect, amitriptyline is as effective as lorazepam for opiate-withdrawal insomnia. HDRS total scores showed no significant difference between groups.
Stella et al. 2005 Life Sci.	Naltrexone plus benzodiazepine aids abstinence in opioid-dependent patients as NTX results in insomnia RP/PA	RCT 6 months Opioid dependence evaluated according to DSM-IV	56 M: 51/56 Adults Italy	A: clinical symptoms of anxiety or panic attack	Insomnia as defined by ICSD / Thorpy 1990	Many patients remained opioid-free on NTX alone or with prazepam, with the combination showing a significant advantage.
Hillhouse et al. 2010 J Addict Dis	buprenorphine (Suboxone) opioid detoxification; whether in a secondary analysis provision of ancillary medications for opioid withdrawal symptoms affects treatment outcomes WM	CT 13 days opioid dependence	139 F:27% 38 USA	A: Clinical symptoms of anxiety	Clinical symptoms of insomnia	No difference in the number of opioid-free urine samples between groups; receiving ancillary medication group attended fewer days of treatment if they received anxiety medication.
Chen et al. 2012 J Huazhong Univ Sci Technolog Med Sci	Neurotransmitter-precursor-supplement intervention for detoxified heroin addicts WM	RCT 6 days Detoxified heroin addicts	83 M:100% Around 30 China	A, D: Mood states were measured by POMS	Insomnia: Athens Insomnia Scale (AIS)	Improved insomnia, reduced tension-anxiety and depression-dejection in intervention group; neurotransmitter-precursor-supplements show promise for heroin withdrawal and mood symptoms.
Krupitsky et al. 2013 Drug Alcohol Depend	Naltrexone with or without guanfacine for preventing relapse to opiate addiction (stress) RP/PA	RCT 6 months Intravenous heroin	301 M: 82.4% 28.3 Russia	A, D: BDI, SSTA	Insomnia as a clinical symptom	Adverse events occurred in 4.7%, including insomnia in the naltrexone plus guanfacine group.
Bisaga et al. 2015 Drug Alcohol	To examine whether dronabinol reduces opioid withdrawal and increases retention in treatment with extended-release naltrexone (XR-naltrexone) WM; I/T	RCT 7 days Heroin and 16% Prescription opioids	60 M:85% 38 USA	A, D: HAM-D 21	Insomnia: as a clinical symptom	Post-hoc analysis found that 32% of participants who regularly smoked marijuana during outpatient treatment had significantly lower ratings of insomnia and anxiety, with no change in HAM-D.
Reid et al. 2024 Sleep	To examine the effects of suvorexant on sleep-EEG and association with withdrawal severity and depressive symptoms WM/ IT	RCT 11 days Buprenorphine taper	38 M:87% 21–63 USA	D: Hamilton Depression Rating Scale (HAM-D)	Sleep: PSQI; Sleep-EEG band power	During buprenorphine tapering, suvorexant reduced delta power, associated with lower depression and withdrawal severity.
Group 3: non-pharmacological interventions
Lander et al. 2018 J Addict Res Ther	Yoga as an adjunctive intervention to Medication-Assisted Treatment with Buprenorphine+Naloxone RP/PA	CT 12 weeks diagnosis of OUD within the last 12 months	26 NA NA USA	A: Beck Anxiety Inventory (BAI)	Sleep: Sleep scale from the medical outcomes study (MOS-sleep)	Yoga is an effective adjunctive treatment for reducing perceived stress.
Peck et al. 2018 J Trauma Stress	Effectiveness of modified prolonged exposure (mPE) in comorbid PTSD patients, Alcohol use disorder and OUD M	RCT 9–12 sessions of mPE OUD type not specified opioids withdrawn, no substitution therapy	52 M: 50% 31.58 ± 10.12 USA	A, D, PTSD, I: Beck Anxiety Inventory; Beck Depression Inventory; Clinician Administered PTSD Scale	Insomnia: seven-item Insomnia Severity Index	Findings support mPE’s efficacy for PTSD in individuals with problematic drinking and opioid misuse, despite severe baseline symptoms.
Alavi et al. 2023 BMC Psy	Examine the efficacy of brief CBT on opioid users’ general health M	RCT 4 sessions of brief CBT Methadone maintenance therapy	40 39 M/1F Around 40 Iran	A, D, P: general health questionnaire (GHQ − 28) subscores A, D, I	Insomnia as subscore from the GHQ-28	Less anxiety and insomnia after brief CBT.

Group 1 - opioid receptor-based treatments (n = 5); Group 2 - other pharmacological treatments (n = 7); Group 3 - non-pharmacological interventions (n = 3). Treatment phase: withdrawal management (WM); induction/taper (I/T); maintenance (M); relapse prevention/protracted abstinence (RP/PA). Abbreviations: OUD: opioid use disorder; A: anxiety; D: depression; N: sample size; M: male; F: female; NA: not available; CT: controlled trial; RCT: randomized controlled trial; XR-NTX: extended-release naltrexone; PSQI: Pittsburgh Sleep Quality Index; HDRS: Hamilton Depression Rating Scale; ICSD: International Classification of Sleep Disorders; AIS: Athens Insomnia Scale; BDI: Beck Depression Inventory; SSTA: Subjective Sleep Total Time; HAM-D-21: 21-item Hamilton Depression Rating Scale; EEG: electroencephalogram; BAI: Beck Anxiety Inventory; MOS-sleep: sleep scale from the medical outcomes study; mPE: modified prolonged exposure; CBT: cognitive behavioral therapy; GHQ-28: 28-item General Health Questionnaire

Demographic characteristics

Most study participants were between 30 and 40 years old, though mean or median age was not consistently reported. Gender distribution was largely skewed toward male participants, with most studies reporting at least two-thirds of the sample as male, and one study including only male participants. Only one study [29], conducted in the United States of America and focusing on a non-pharmacological therapy for PTSD, reported a balanced gender distribution.

Study duration

One short term study assessed outcomes at one, two and 3 months with a longer term follow up period of 9 months [30]. Seven studies assessed outcomes for less than 2 weeks with a range between 72 h and 13 days [20, 22, 23, 26, 27, 32, 34]; 2 studies had a duration of one month [23, 30], 2 studies tracked outcomes for 3 months follow-up [28, 30], and 4 studies had a follow-up period longer than 3 months though none followed participants for more than one year [21, 25, 32, 33]. In two non-pharmacological studies [29, 31] the precise time frame was not detailed; it was only described in terms of number of sessions. Study duration did not impact on the effect size or included number of study participants.

Study design

Study design varied and included randomized controlled trials (RCT) [20, 21, 24–27, 29–31, 34] and controlled trials (CT) [22, 23, 28, 32, 33]. In most studies, sleep was assessed as a predefined outcome, either as a symptom or a clinical diagnosis. In contrast, in one study [25], insomnia was reported solely as a tolerability-related adverse event, without systematic assessment of sleep outcome. In most studies, add-on therapies targeting opioid receptors were used alongside standard treatment, either to support substitution or to induce an aversive response. These interventions were typically compared with placebo or with the absence of an add-on therapy, with only one study including an active comparator [20]. The aim of these add-on therapies was to improve short- and long-term abstinence outcomes. Study design did not impact the number of enrolled participants.

Only one study used a qualitative approach to explore patient-reported experiences and perceived effects [32], whereas all other studies assessed outcomes using quantitative measures.

Results structured by intervention type

Impaired sleep and presence of psychiatric disorders are considered risk factors for negative outcome in withdrawal and abstinence in individuals with OUD. Given that maintenance therapies may contribute to insomnia, and that both insomnia and psychiatric comorbidities are known risk factors for relapse, some studies focused on interventions aimed at reducing insomnia and/or psychiatric symptoms such as anxiety, depression or PTSD to support successful withdrawal or long-term abstinence. These studies aimed to augment success rates in a variety of ways. For example, some studies targeted withdrawal symptoms with a personalized approach [22], or a generalized approach targeting multiple systems [22, 24, 28, 31]; others targeted specific symptoms of withdrawal like insomnia and hyperarousal [20, 21, 27, 34], on stress [25], on anxiety [27], depression [27] or PTSD [29].

Studies were grouped according to intervention type: (1) pharmacological interventions targeting opioid, or non-opioid receptors, and (2) non-pharmacological interventions. In most studies, the intervention was administered as an adjunct to opioid substitution therapy or opioid antagonist treatment [20–22, 25, 27, 28, 31].

Pharmacological interventions targeting opioid receptors

Studies have examined opioid receptor agonists including buprenorphine [30, 32], tramadol [26], and opium tincture [33], as well as the opioid antagonist naltrexone [23] in relation to sleep and psychiatric symptoms.

Opioid agonists

Although methadone is an established treatment for OUD, none of the included studies directly assessed its effects on sleep outcomes and psychiatric symptoms. Buprenorphine has demonstrated benefits for anxiety and depressive symptoms. Latif et al. evaluated whether discontinuing buprenorphine, used as an add-on to naltrexone (NTX), would reveal underlying anxiety or depression [30]. Over 12-weeks, anxiety and depression scores did not differ between patients receiving extended-release NTX (XR-NTX) alone and those receiving combined buprenorphine-NTX. Insomnia scores, however, were significantly lower in the XR-NTX group. No group differences emerged during follow‑up. In this study, insomnia was viewed mainly as a correlate of psychiatric morbidity. In contrast, a qualitative study by Neale et al. reported early improvements in sleep, mood, and overall well‑being during the first 72 h of long‑acting injectable buprenorphine initiation [32]. Extended-release (ER) tramadol (200 mg) significantly reduced peak insomnia ratings key withdrawal symptom compared with placebo during prescription opioid withdrawal without affecting depression scores [26]. In an Iranian detoxification study, opium tincture improved sleep disturbances, reduced anxiety and depressive symptoms, and was associated with a low relapse rate (16.7%) over one year [33].

Opioid antagonists

Naltrexone (NTX) is commonly used as a maintenance treatment following detoxification. In the study by Mysels et al., NTX did not induce or worsen depression compared with placebo but was associated with early-treatment sleep impairment, consistent with reports of NTX-related “sleeplessness” [23].

Pharmacological interventions not targeting opioid receptors

Non-opioid medications studied include benzodiazepines, tricyclic antidepressants, cannabinoids, and neurotransmitter precursors [20–22, 24, 25, 27, 34]. Ancillary, individualized medications are often prescribed during withdrawal. In a secondary analysis, Hillhouse et al. assessed whether ancillary medications influenced outcomes during buprenorphine-assisted detoxification [22]. 70% of participants received ancillary medications: 59% for insomnia, 45% for anxiety, 40% for bone pain, 35% for nausea, and 28% for diarrhea. Ancillary medication use did not affect opioid-free urine samples, though those treated for anxiety attended fewer treatment days. Chen et al. evaluated neurotransmitter-precursor-supplement intervention (NPSI) - targeting dopamine, acetylcholine, GABA, and serotonin pathways - in individuals who had completed seven days of heroin detoxification [24]. Compared with placebo, NPSI significantly improved insomnia (Athens Insomnia Scale), withdrawal severity, and tension–anxiety and depression–dejection scores. Srisurapanont et al. compared the sedative‑hypnotic agents, amitriptyline and lorazepam, over five days of opioid withdrawal to determine whether amitriptyline could serve as a benzodiazepine alternative [20]. Both effectively reduced withdrawal-related insomnia, without differences in depression scores. Amitriptyline produced more difficulty awakening (“hangover effect”). Stella et al. tested whether adding prazepam could mitigate NTX-induced insomnia [21]. The NTX-prazepam group showed higher abstinence rates (12/14 vs. 6/14 patients) and significant reductions in insomnia, anxiety, and panic attacks. Insomnia was diagnosed using ICSD‑3 criteria; anxiety and panic were assessed via DSM‑IV. Bisaga et al. evaluated dronabinol during opioid withdrawal, in combination with XR-NTX [27]. Although dronabinol reduced acute withdrawal severity, it did not improve XR-NTX initiation or retention. Regular marijuana smokers reported fewer sleep disturbances and lower anxiety regardless of treatment assignment. Reid et al. investigated suvorexant (20 or 40 mg) during buprenorphine tapering [34]. Reductions in delta power were associated with decreases in depressive symptoms and withdrawal severity. Finally, Krupitsky et al. assessed guanfacine, an alpha-2 agonist with better tolerability than clonidine, for acute and protracted withdrawal symptoms [25]. When combined with NTX, guanfacine was associated with reduced stress and craving at later follow-up assessments (weeks 10 and 18), but did not improve retention or opioid-free urine outcomes. Insomnia occurred as an adverse event in 4.7% of participants, alongside mild symptoms such as headache, poor appetite, and dizziness. Insomnia was not evaluated as an independent symptom, and no significant changes were observed in depression or anxiety scores.

Non-pharmacological interventions

Three studies evaluated non-pharmacological interventions: yoga in volunteer participants [28], modified prolonged exposure (mPE) therapy in individuals with OUD and co-occurring PTSD [29], and brief cognitive behavioral therapy (CBT) [31] as an adjunct to methadone maintenance treatment.

Lander et al. investigated yoga as an adjunctive intervention to buprenorphine/naloxone in participants recruited from an outpatient program [28]. Yoga was associated with reduced perceived stress, but was not associated with significant changes in opioid craving, treatment retention, relapse rates, sleep quality, or anxiety symptoms.

Peck et al. evaluated mPE therapy in individuals with co-occurring PTSD, alcohol use disorder, and OUD [29]. Participants were not permitted to receive concurrent opioid replacement therapy during the study. Improvements were reported in PTSD symptoms, sleep disturbances, anxiety, depression, and alcohol craving during the study period.

Alavi et al. examined brief CBT, a four-session intervention designed to improve general health outcomes in individuals with OUD [31]. Participants reported reductions in anxiety and insomnia scores of the General Health Questionnaire following treatment, whereas, no significant changes were observed for depressive symptoms. The study did not evaluate substance use outcomes or relapse, and the short follow-up period limits conclusions regarding long-term effects.

Results structured by treatment phase

Studies were categorized according to the primary treatment phase targeted by the intervention: withdrawal management, induction/taper, maintenance treatment, and relapse prevention/protracted abstinence. Because many studies followed participants longitudinally, several studies contributed data across more than one treatment phase.

During withdrawal management, characterized by severe insomnia, several pharmacological interventions were evaluated to alleviate withdrawal-related sleep disturbances. Opioid agonists, including extended-release tramadol, buprenorphine, and opium tincture, were associated with improvements in insomnia symptoms [26, 32, 33]. Additional interventions, including amitriptyline, lorazepam, and prazepam, were also reported to improve sleep-related outcomes [20, 21]. Other approaches, such as neurotransmitter-precursor supplements, dronabinol, and suvorexant, were investigated for their potential effects on sleep during this phase [24, 27, 34].

During induction and tapering, sleep may initially worsen, with increased fragmentation and sedation, before stabilizing. Naltrexone was not associated with increased anxiety or depression but may transiently impair sleep early in treatment [23]. Extended-release naltrexone (XR-NTX) was associated with lower rates of insomnia than naltrexone combined with buprenorphine [23]. Buprenorphine and opium tincture were associated with improvements in insomnia symptoms [30, 33]. Additional findings included lower insomnia ratings among participants reporting regular cannabis use, and improved sleep outcomes during buprenorphine tapering with suvorexant [27, 34]. However, given the study designs and sample sizes, the findings should be interpreted cautiously.

During maintenance treatment, sleep generally improves compared to earlier stages, although chronic insomnia often persists. Naltrexone was associated with early sleep impairment, whereas opium tincture was associated with improved sleep outcomes [23, 33]. Among non-pharmacological interventions, mPE was associated with improvements in PTSD symptoms, while brief CBT was associated with reduced insomnia [29, 31].

During relapse prevention and protracted abstinence, sleep disturbances often persist and may contribute to relapse risk. No significant changes in sleep outcomes were observed among participants switching from combined naltrexone and buprenorphine treatment to naltrexone alone [23]. Opium tincture and naltrexone, (including in combination with prazepam,) were associated with improved sleep outcomes, whereas guanfacine was associated with increased insomnia [21, 23, 25, 33]. Yoga was associated with reduced perceived stress [28].

Discussion

This scoping review identified a limited but heterogeneous body of evidence examining pharmacological and non-pharmacological interventions addressing sleep disturbances in individuals with OUD and psychiatric symptoms or co-occurring psychiatric disorders. The included studies varied substantially in terms of treatment phase, intervention type, outcome measures, and study design, limiting direct comparisons across studies. Overall, the review highlights the diversity of approaches that have been explored while underscoring the limited evidence available to guide clinical management of sleep disturbances in this population.

Most included studies evaluated pharmacological interventions. Sleep outcomes varied across interventions and treatment phases. Some studies reported poorer sleep during initiation of opioid agonists during treatment initiation [35], whereas more favorable self-reported sleep outcomes were observed during longer-term follow-up, alongside improvements in mood and anxiety symptoms [36]. In studies evaluating opioid antagonists such as naltrexone, insomnia was frequently reported, and adjunctive treatments such as benzodiazepines were associated with improvements in sleep complaints without notable effects on mood [30].

Several studies explored non-opioid receptor-targeting medications. Personalized, ancillary medications used to manage withdrawal symptoms, such as insomnia, anxiety, nausea, and pain, did not show clear benefits on treatment outcomes [22]. Guanfacine combined with NTX was associated with reduced craving and stress but also with an increased incidence of insomnia [25]. Other interventions, including NPSI, amitriptyline, prazepam, and dronabinol were associated with improvements in selected sleep- or withdrawal-related outcomes [20, 21, 27], although the evidence remains limited and requires confirmation in larger studies.

Only a small number of studies evaluated non-pharmacological interventions, including mPE, yoga, and CBT [28, 29, 31]. Given the limited number of studies and their methodological heterogeneity, no conclusions can be drawn regarding their relative effectiveness. Although CBT is a well-established and evidence-based treatment for chronic insomnia [37], including in patients previously treated with prescribed sleep medications [38], its effectiveness in the context of OUD remains insufficiently studied.

These findings are consistent with previous literature emphasizing the clinical relevance of sleep disturbances in individuals receiving medications for OUD [16], persistent sleep complaints, reduced duration, and sleep-disordered breathing have been frequently reported [16], and observational studies have described associations between sleep disturbances and symptoms of depression and anxiety [16, 36, 39–41].

The available evidence suggests complex relationships between OUD treatment, psychiatric symptoms, and sleep disturbances. Further longitudinal studies are needed to better characterize this interplay, particularly given the association between persistent sleep disturbances and relapse risk. From a clinical perspective, these findings suggest that sleep disturbances may warrant consideration across different phases of OUD treatment. Such interventions should be individualized according to the patient’s sleep profile and may include sleep hygiene education, CBT for insomnia, management of comorbid sleep-disordered breathing, and, when indicated, pharmacological treatments targeting either chronic insomnia or sleep disturbances associated with depression and anxiety.

Review limitations

This study has several limitations. First, the literature search was restricted to two databases, PubMed and CAIRN Info, which may have limited the scope of included studies. No data from CAIRN Info were included in the analysis, a further limitation of the present review. Additionally, we excluded articles focusing on sleep-disordered breathing. These restrictions may have led to the omission of relevant studies that were less precisely indexed or categorized. Gaps in reporting and lower methodological quality observed in some studies represent important limitations and warrant cautious interpretation of the results. There was substantial heterogeneity in outcome assessment, with sleep evaluated across studies using scales, clinical diagnoses, adverse event reporting, or physiological markers, limiting comparability and synthesis. Studies were included without restrictions on sample size, and several trials had small sample sizes and heterogeneous follow-up durations, increasing the risk of random error. Additionally, although controlled trials were included, no structured risk of bias assessment was performed, representing a further methodological limitation.

Gender and cultural factors represent important potential effect modifiers that may influence the clinical presentation of OUD, associated sleep disturbances, and treatment responses. Differences in substance use patterns, access to care, and cultural attitudes toward mental health and addiction may further contribute to variability in outcomes. However, none of the studies included in this scoping review provided data allowing exploration of these factors. This lack of reporting limits the generalizability of the findings across diverse populations. Future research should systematically incorporate gender-based analyses, as well as cultural and contextual variables, to better understand their impact on treatment strategies and outcomes in OUD [42].

A major limitation also lies in the complex nature of sleep disturbances and insomnia themselves. Insomnia may function as an independent clinical entity, a risk factor for developing SUD, or a symptom induced by opioid use or withdrawal. They may also be symptomatic of underlying psychiatric symptoms such as depression, anxiety or PTSD. The bidirectional relationships among these conditions further complicate interpretation. Insomnia can both precede and persist after recovery from depressive or anxiety disorders. These overlapping and intertwined factors are particularly challenging to disentangle, especially in the clinically fragile population of individuals with OUD. Although improving sleep may represent a promising approach to reduce relapse risk, the available evidence remains limited. None of the included studies directly demonstrated that treatment of insomnia leads to improved OUD-related outcomes, such as treatment retention, opioid use, or relapse rates.

Conclusion

Sleep disturbances are closely interwoven with psychological vulnerability and social instability, which are common in individuals with OUD. They may act as precipitating factors and contribute to the cyclical nature of OUD. Improving the characterization and management of sleep and wake disorders in this population could open new avenues for prevention and treatment. Although sleep disturbances may represent an important treatment target in OUD, the available evidence remains insufficient to determine whether improving sleep leads to better OUD-related outcomes, including relapse prevention. A range of non-pharmacological strategies – including CBT, sleep-hygiene education – and individualized pharmacological treatments have been used in practice, reflecting diverse approaches rather than established standards of care. For clinicians, it is essential to recognize and address the complex interplay between OUD, psychiatric symptoms, and sleep disturbances as part of a comprehensive treatment approach. Further research is needed to better understand these interactions and to guide evidence-based, integrated care strategies.

Abbreviations

CBT

Cognitive behavioral therapy

CT

Controlled trials

ER

Extended-release

MAT

Medication-assisted treatment

mPE

Modified prolonged exposure

NPSI

Neurotransmitter-precursor-supplement intervention

NTX

Naltrexone

OUD

Opioid use disorder

PICO

P - Population (or Patient / Problem), I - Intervention (or Exposure), C - Comparison (or Control / Comparator), O - Outcome

PRISMA-ScR

Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews

RCT

Randomized controlled trial

PTSD

Post-traumatic stress disorder

SUD

Substance use disorders

XR-NTX

Extended-release naltrexone

Author contributions

Conception and design: ER, AM and LL; acquisition and analysis: ER, JR, AP and LL; interpretation of data: ER, JR, AP, AM and LL; draft and draft revision: ER, JR, AM, AP and LL. All authors read and approved the final and submitted manuscript.

Funding

This work did not benefit from any funding.

Data availability

Data are available upon reasonable request.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.