Suvorexant for Opioid Use Disorder
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Johns Hopkins University
Must be taking: Buprenorphine/naloxone
Must not be taking: Benzodiazepines, Suvorexant
Disqualifiers: Pregnancy, Alcohol use disorder, others
Prior Safety Data
Trial Summary
What is the purpose of this trial?
This is a 4-week, randomized-controlled trial of suvorexant vs placebo in persons with opioid use disorder who have recent fentanyl exposure. Participants will first undergo a 5-day residential phase wherein participants are stabilized on sublingual buprenorphine/naloxone, followed by a 3-week outpatient phase wherein participants are maintained on sublingual buprenorphine/naloxone and transitioned to extended-release buprenorphine).
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently using benzodiazepines or medications for insomnia. You will be stabilized on buprenorphine/naloxone during the trial.
Is suvorexant safe for humans?
Suvorexant, also known as Belsomra, has been studied for its safety and shows low potential for abuse in humans. It is generally considered safe, with no significant withdrawal symptoms observed in animal studies, and it has been used to improve sleep and reduce opioid withdrawal symptoms in clinical settings.12345
How does the drug Suvorexant differ from other treatments for opioid use disorder?
Research Team
AS
Andrew S Huhn, Ph.D.
Principal Investigator
Johns Hopkins University
Eligibility Criteria
This trial is for adults aged 18-65 with opioid use disorder, specifically those who have used fentanyl recently. Participants must be interested in buprenorphine treatment for their condition and able to follow the study's rules. They should not have significant medical conditions that could interfere with the trial, nor plans to move away during the study period.Inclusion Criteria
Meets DSM-5 criteria for opioid use disorder (OUD) with evidence of physical dependence on opioids
Willing to comply with study protocol
Plans to reside in current area for study period
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Exclusion Criteria
I have narcolepsy, restless leg syndrome, or sleep paralysis.
Urine sample testing positive for benzodiazepine at screening and admission to residential treatment
Have circumstances that would interfere with study participation (e.g., impending jail)
See 11 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
1-2 weeks
Residential Phase
Participants are stabilized on sublingual buprenorphine/naloxone and receive suvorexant or placebo
5 days
Residential stay
Outpatient Phase
Participants are maintained on sublingual buprenorphine/naloxone and transitioned to extended-release buprenorphine
3 weeks
Regular outpatient visits
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Treatment Details
Interventions
- Placebo (Other)
- Suvorexant (Orexin Receptor Antagonist)
Trial OverviewThe trial tests if suvorexant helps people with opioid use disorder when added to buprenorphine therapy compared to a placebo. It starts with a 5-day stay where participants stabilize on buprenorphine/naloxone, followed by a 3-week outpatient phase including extended-release buprenorphine.
Participant Groups
2Treatment groups
Experimental Treatment
Placebo Group
Group I: SuvorexantExperimental Treatment1 Intervention
Nightly dosing of suvorexant
Group II: PlaceboPlacebo Group1 Intervention
Nightly dosing of placebo
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Johns Hopkins Bayview Medical CenterBaltimore, MD
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Who Is Running the Clinical Trial?
Johns Hopkins University
Lead Sponsor
Trials
2366
Patients Recruited
15,160,000+
National Institute on Drug Abuse (NIDA)
Collaborator
Trials
2658
Patients Recruited
3,409,000+
References
Preclinical assessment of the abuse potential of the orexin receptor antagonist, suvorexant. [2018]Suvorexant (Belsomra®) is a dual orexin receptor antagonist approved for the treatment of insomnia. Because of its pharmacology within the central nervous system, intended therapeutic indication, and first-in-class status, an assessment of suvorexant abuse liability potential was required prior to marketing approval. The nonclinical abuse liability potential studies for suvorexant included: 1) rat drug-dependence model to assess physical dependence following abrupt cessation; 2) rat drug-discrimination model to examine the potential similarity of the interoceptive or subjective effects of suvorexant to those elicited by zolpidem and morphine; 3) self-administration model to assess the relative reinforcing efficacy of suvorexant in rhesus monkeys conditioned to self-administer methohexital. No significant signs of spontaneous drug withdrawal or 'discontinuation syndrome' were observed in rats following abrupt discontinuation of suvorexant. Suvorexant did not elicit complete cross-generalization to either a zolpidem or morphine training/reference stimuli in rats, and suvorexant was devoid of behavioral evidence of positive reinforcing efficacy in monkeys. These nonclinical findings suggested that suvorexant will have low abuse potential in humans. In the final regulatory risk assessment, suvorexant was placed into Schedule IV, likely due to its first-in-class status, its sedative properties, and the outcome of the clinical abuse potential assessment.
Tissue Distribution of Suvorexant in Three Forensic Autopsy Cases. [2018]Suvorexant (Belsomra®) is a relatively new insomnia medication that has been available in USA and Japan since 2014. It is a dual orexin receptor antagonist that promotes sleep by inhibiting the binding of orexin neurons to the OX1R and OX2R receptors. In this report, we describe the detection and quantitation of suvorexant from the postmortem specimens of three separate autopsy cases handled by our department. Suvorexant was identified by fast gas chromatography/mass spectrometry during routine screening, and quantitated by a fully validated liquid chromatography-tandem mass spectroscopy method. Quantitation was achieved by positive electrospray ionization in the selected reaction monitoring mode. Monitored transitions were m/z 451 > 186 for quantitation and m/z 451 > 104 for qualification. To our knowledge, this is the first instance of suvorexant being quantitated from actual autopsy cases. It is likely that this compound will be encountered more often by the forensic toxicology community going forward.
Suvorexant, an FDA-approved dual orexin receptor antagonist, reduces oxycodone self-administration and conditioned reinstatement in male and female rats. [2023]Background: The Department of Health and Human Services reports that prescription pain reliever (e.g., oxycodone) misuse was initiated by 4,400 Americans each day in 2019. Amid the opioid crisis, effective strategies to prevent and treat prescription opioid use disorder (OUD) are pressing. In preclinical models, the orexin system is recruited by drugs of abuse, and blockade of orexin receptors (OX receptors) prevents drug-seeking behavior. The present study sought to determine whether repurposing suvorexant (SUV), a dual OX receptor antagonist marketed for the treatment of insomnia, can treat two features of prescription OUD: exaggerated consumption and relapse. Methods: Male and female Wistar rats were trained to self-administer oxycodone (0.15 mg/kg, i. v., 8 h/day) in the presence of a contextual/discriminative stimulus (SD) and the ability of SUV (0-20 mg/kg, p. o.) to decrease oxycodone self-administration was tested. After self-administration testing, the rats underwent extinction training, after which we tested the ability of SUV (0 and 20 mg/kg, p. o.) to prevent reinstatement of oxycodone seeking elicited by the SD. Results: The rats acquired oxycodone self-administration and intake was correlated with the signs of physical opioid withdrawal. Additionally, females self-administered approximately twice as much oxycodone as males. Although SUV had no overall effect on oxycodone self-administration, scrutiny of the 8-h time-course revealed that 20 mg/kg SUV decreased oxycodone self-administration during the first hour in males and females. The oxycodone SD elicited strong reinstatement of oxycodone-seeking behavior that was significantly more robust in females. Suvorexant blocked oxycodone seeking in males and reduced it in females. Conclusions: These results support the targeting of OX receptors for the treatment for prescription OUD and repurposing SUV as pharmacotherapy for OUD.
Suvorexant ameliorated sleep disturbance, opioid withdrawal, and craving during a buprenorphine taper. [2022]Increased orexin/hypocretin signaling is implicated in opioid withdrawal, sleep disturbances, and drug-seeking behaviors. This study examined whether a dual-orexin receptor antagonist would improve sleep and withdrawal outcomes when compared with placebo during a buprenorphine/naloxone taper. Thirty-eight participants with opioid use disorder were recruited to a clinical research unit and maintained on 8/2 to 16/4 mg of buprenorphine/naloxone treatment for 3 days before being randomized to 20 mg of suvorexant (n = 14), 40 mg of suvorexant (n = 12), or placebo (n = 12); 26 individuals completed the study. After randomization, participants underwent a 4-day buprenorphine/naloxone taper and 4-day post-taper observation period. Total sleep time (TST) was collected nightly with a wireless electroencephalography device and wrist-worn actigraphy; opioid withdrawal symptoms were assessed via the Subjective Opiate Withdrawal Scale (SOWS); and abuse potential was assessed on a 0- to 100-point visual analog scale of "High" every morning. A priori outcomes included two-group (collapsing suvorexant doses versus placebo) and three-group comparisons of area-under-the-curve (AUC) scores for TST, SOWS, and High. In two-group comparisons, participants receiving suvorexant displayed increased TST during the buprenorphine/naloxone taper and decreased SOWS during the post-taper period. In three-group comparisons, participants receiving 20 mg of suvorexant versus placebo displayed increased AUC for TST during the buprenorphine/naloxone taper, but there was no difference in SOWS among groups. There was no evidence of abuse potential in two- or three-group analyses. The results suggest that suvorexant might be a promising treatment for sleep and opioid withdrawal in individuals undergoing a buprenorphine/naloxone taper.
CYP450-Mediated metabolism of suvorexant and investigation of metabolites in forensic case specimens. [2021]Suvorexant (Belsomra®) is a sedative hypnotic that was approved for use in 2015. It has a novel mechanism of action and was the first dual orexin receptor antagonist (DORA) to be approved for the treatment of sleep disorders. Sedative hypnotics often feature prominently in forensic investigations such as impaired driving and drug-facilitated sexual assault (DFSA) cases. As such, suvorexant is a drug of interest and its identification in forensic toxicology investigations is of significance. However, limited studies have been published to date and the disposition or importance of its metabolites has been largely uninvestigated. In this report, we investigate the enzymes responsible for metabolism and explore the prevalence of metabolites in blood from a series of thirteen forensic investigations. Recombinant cytochrome P450 enzymes (rCYPs) were used to generate phase I metabolites for suvorexant in vitro, and metabolites were identified using liquid chromatography-quadrupole/time-of-flight-mass spectrometry (LC-Q/TOF-MS). Four rCYP isoenzymes (3A4, 2C19, 2D6, and 2C9) were found to contribute to suvorexant metabolism. The only metabolite identified in blood or plasma arose from hydroxylation of the benzyl triazole moiety (M9). This metabolite was identified in seventeen blood and plasma specimens from twelve medicolegal death investigations and one impaired driving investigation. In the absence of a commercially available reference material, the metabolite was confirmed using rCYP-generated in vitro controls using high resolution mass spectrometry.
A placebo controlled clinical trial of buprenorphine as a treatment for opioid dependence. [2019]Large-scale placebo controlled clinical trials assessing the efficacy of medications for the treatment of drug dependence have generally been limited to alcohol, cocaine and nicotine dependent populations. The purpose of the present study was to assess the early (1-2 week) clinical effectiveness of buprenorphine versus placebo in an opioid dependent population. The study used a parallel-group design with a behavioral choice component to compare buprenorphine (a mu-opioid partial agonist) to placebo for the treatment of opioid dependence. Opioid dependent volunteer patients participated in a 14-day study to assess the effectiveness and patient acceptance of this new pharmacotherapy for the treatment of opioid dependence. Patients were randomly assigned to placebo (n = 60) or 2 mg (n = 60) or 8 mg (n = 30) daily sublingual buprenorphine. All doses were administered double-blind. On days 6-13 all patients could request a dose change, knowing that their new dose would be randomly chosen from the remaining 2 alternatives. Compared to placebo, patients given buprenorphine (independent of dose) showed greater time on initial dose, requested fewer dose changes, used less illicit opioids (assessed by urinalysis), and rated dose adequacy higher. These results demonstrate that a placebo controlled study with a behavioral choice component is an effective means of assessing the potential efficacy and acceptability of new pharmacotherapies for opioid dependence.
Effects of beta-funaltrexamine in normal and morphine-dependent rhesus monkeys: observational studies. [2013]The behavioral effects of the opioid receptor alkylating agent beta-funaltrexamine (beta-FNA) were assessed in normal (drug-naive) and morphine-dependent rhesus monkeys. In normal monkeys, beta-FNA (10 mg/kg s.c.) produced muscle relaxation and stupor, which could be reversed by the opioid antagonist Win 44,441. Given as a 48-hr pretreatment, beta-FNA antagonized the behavioral effects of acute morphine, but not those of two kappa agonists, ethylketazocine and Mr 2033 (UM 1072). In morphine-dependent monkeys, beta-FNA (10 mg/kg, s.c. and 0.003 mg i.c.v.) precipitated severe abstinence which lasted for 3 days. beta-FNA was more than 13,000 times more potent in precipitating withdrawal after i.c.v. than s.c. administration, whereas naltrexone and Win 44,441 were equipotent by these routes. Deprivation-induced abstinence (14 hr) and withdrawal of similar severity precipitated by naltrexone, Win 44,441 or naloxonazine were suppressed completely by 17.5 mg/kg of morphine. In contrast, 320 mg/kg of morphine failed to suppress completely a withdrawal syndrome of the same severity elicited by s.c. or i.c.v. beta-FNA. These data are consistent with the view that beta-FNA has reversible opioid agonist and insurmountable mu selective antagonist activity in the rhesus monkey.
Synthesis and characterization of a dual kappa-delta opioid receptor agonist analgesic blocking cocaine reward behavior. [2019]3-Iodobenzoyl naltrexamine (IBNtxA) is a potent analgesic belonging to the pharmacologically diverse 6β-amidoepoxymorphinan group of opioids. We present the synthesis and pharmacological evaluation of five analogs of IBNtxA. The scaffold of IBNtxA was modified by removing the 14-hydroxy group, incorporating a 7,8 double bond and various N-17 alkyl substituents. The structural modifications resulted in analogs with picomolar affinities for opioid receptors. The lead compound (MP1104) was found to exhibit approximately 15-fold greater antinociceptive potency (ED50 = 0.33 mg/kg) compared with morphine, mediated through the activation of kappa- and delta-opioid receptors. Despite its kappa agonism, this lead derivative did not cause place aversion or preference in mice in a place-conditioning assay, even at doses 3 times the analgesic ED50. However, pretreatment with the lead compound prevented the reward behavior associated with cocaine in a conditioned place preference assay. Together, these results suggest the promise of dual acting kappa- and delta-opioid receptor agonists as analgesics and treatments for cocaine addiction.
[Therapeutic use of metadoxine in chronic alcoholism. Double blind study of patients in a department of general medicine]. [2015]Sixty patients, recognized as chronic alcoholics on the grounds of the case history and with a score above 11 of the Munich Alcoholism Test (MALT) have been treated with metadoxine or placebo for thirty days according to a double blind randomized design. In the group treated with active drug there has been a significant reduction higher than in the controls of the scores relating to the abstinence symptomatology, in particular regarding the neuropsychic residual symptomatology (anxiety, depression, insomnia) after the first week of treatment, a reduced requirement of benzodiazepines and/or neuroleptics, and a significant decrement higher than in the controls of the score of MALT at the end of treatment. Furthermore, metadoxine seems to make easy the maintenance of abstinence, at least at short term.
Effects of buprenorphine maintenance dose on mu-opioid receptor availability, plasma concentrations, and antagonist blockade in heroin-dependent volunteers. [2022]The clinical effectiveness of opioid maintenance for heroin dependence is believed to result from a medication's ability to decrease mu-opioid receptor (muOR) availability thereby replacing agonist effects, alleviating withdrawal symptoms and attenuating heroin effects. We empirically tested this hypothesis in five heroin-dependent volunteers who were successively maintained on 32, 16, 2, and 0 mg daily buprenorphine (BUP) tablet doses. We predicted and confirmed that higher BUP doses would decrease in vivo muOR availability (measured with PET and [(11)C]carfentanil), increase plasma levels of BUP and its metabolite nor-BUP, and decrease withdrawal symptoms and hydromorphone (HYD) responses. Relative to placebo, BUP significantly decreased mean (+/-SEM) whole-brain muOR availability 41+/-8, 80+/-2, and 84+/-2% at 2, 16, and 32 mg, respectively. Regions of interest (ROIs) (prefrontal cortex, anterior cingulate, thalamus, amygdala, nucleus accumbens, caudate) showed similar dose-dependent effects. Changes in muOR availability varied across ROIs (prefrontal cortex, 47% vs amygdala, 27%) at BUP 2 mg, but were more homogeneous across ROIs at BUP 32 mg (94-98%; except thalamus, 88%). Relative to placebo (0 ng/ml), peak plasma levels of BUP and nor-BUP were comparable and dose-dependent (0.5-1, 5-6, and 13-14 ng/ml at 2, 16, and 32 mg, respectively). muOR availability decreases were negatively correlated with BUP plasma level and positively correlated with questionnaire-based opioid withdrawal symptoms and attenuation of HYD symptoms. These findings suggest that high-dose BUP maintenance produces near-maximal muOR occupation, muOR availability correlates well with plasma levels, and BUP-related opioid symptoms and antagonist blockade exhibit concentration-effect relationships.