Effects of Intranasal Oxytocin in the Treatment of Benzodiazepine Withdrawal: A Pilot RCT
Effects of Intranasal Oxytocin in the Treatment of Benzodiazepine Withdrawal: A Pilot Randomized Parallel Group Placebo-Controlled Trial
The goal of this clinical trial is to learn if oxytocin administered as a nasal spray will reduce withdrawal symptoms in adults during benzodiazepine tapering for 21 days. It will also learn about the safety of oxytocin. The main questions it aims to answer are:
Does oxytocin reduce benzodiazepine withdrawal symptoms and make it easier to succeed tapering? Does oxytocin help reduce sleep difficulties and anxiety or restlessness during benzodiazepine tapering? Does oxytocin help reduce benzodiazepine craving?
We will compare oxytocin nasal spray to a placebo nasal spray containing regular saline to see if oxytocin works accordingly.
Participants will:
Take oxytocin or a placebo nasal spray, three times daily for 21 days during inpatient benzodiazepine tapering.
Fill out an online questionnaire every day and keep a record of their symptoms.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Background Benzodiazepine withdrawal can be challenging, often accompanied by severe anxiety, insomnia, and other withdrawal symptoms. Recent studies suggest that intranasal oxytocin (OT) may have anxiolytic properties and could potentially ease withdrawal symptoms. This study aims to evaluate the efficacy and safety of intranasal OT in the treatment of benzodiazepine withdrawal.
Objectives The primary objective is to evaluate if intranasal OT can reduce withdrawal symptoms in patients during benzodiazepine tapering. Secondary objectives include evaluating the safety and tolerability of intranasal OT and its impact on anxiety levels and sleep quality.
Methods
- Design: This is a randomized, parallel-group, placebo-controlled trial.
- Participants: Adults (aged 18-65) undergoing inpatient benzodiazepine tapering.
- Intervention: Participants were randomly assigned to receive either intranasal OT (16 IU per administration, given three times daily, for a total daily dose of 48 IU) or placebo for 21 days during inpatient benzodiazepine tapering.
- Assessments: Withdrawal symptoms were measured using the Clinical Institute Withdrawal Assessment for Benzodiazepines (CIWA-B) scale. Anxiety and depression symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS), and sleep was measured using the Insomnia Severity Index (ISI), actigraphy, and Somnofy.
Procedure
- Screening: Eligible participants underwent a screening process, including medical history, physical examination, and baseline assessments.
- Randomization: Participants were randomly assigned to the OT or placebo group.
- Treatment Phase: Participants self-administered the nasal spray three times daily for three weeks. Participants filled out daily questionnaires to monitor symptoms and side effects. Urine samples for toxicology were collected twice weekly during the intervention period, and blood samples were collected at screening and at the end of the intervention period.
- Post-Treatment Follow-Up: Participants were assessed at the end of the treatment period and again four and twelve weeks post-treatment to evaluate the persistence of effects.
Expected Outcomes It was hypothesized that participants receiving intranasal OT would experience a significant reduction in withdrawal symptoms compared to the placebo group. Improvements in anxiety levels and sleep quality were also anticipated.
Significance This study could provide preliminary evidence for the use of intranasal OT as a supportive treatment for benzodiazepine withdrawal, potentially improving patient outcomes and comfort during the tapering process.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Trøndelag
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Trondheim, Trøndelag, Norway, 7091
- Blue Cross, Clinic Lade
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Patients aged 18 - 65 years, taking benzodiazepines at a daily dose of 20-80 mg diazepam-equivalent, and requiring inpatient benzodiazepine withdrawal. Included patients must consent to participate in the study.
Exclusion Criteria:
- Female patients will be excluded if they are pregnant or are planning to become so, or if they are breast-feeding. Individuals incapable of completing questionnaires or giving informed consent will be excluded. Patients with concurrent acute medical or psychiatric illness requiring acute care hospitalization, misuse or dependency of alcohol or pregabalin/gabapentin will be excluded.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Placebo Comparator: Placebo
Participants in the placebo arm will receive a saline solution. Saline is an inert substance, meaning it has no therapeutic effect, making it an ideal placebo. The saline solution will be administered in the same manner as the experimental treatment. The treatment is administered intranasally. The treatment is blinded. Neither the participants nor the researchers know who is receiving the placebo and who is receiving the active treatment. Participants in the placebo arm will be monitored the same as those in the treatment arm. Participants will be fully informed about the possibility of receiving a placebo and will provide informed consent. The same outcome measures will be used for both the placebo and treatment arms. |
Saline intranasal placebo comparator |
|
Experimental: Oxytocin
Participants in this arm will receive intranasal oxytocin. The dosage and administration schedule will be consistent with the study protocol. Participants will receive 48 international units (IU) of oxytocin. The oxytocin will be administered intranasally using a nasal spray. Participants will insert the nasal spray container approximately 1 cm into each nostril and spray. They will wait 15 seconds before repeating administration until they have received a total of 4 puffs (2 in each nostril) per session thrice daily. |
Syntocinon contains synthetic oxytocinfor intranasal use, 6.7 microg (4 IU) per dose. We are planning to use 4 insufflations (16 IU) three times daily (i.e. a total daily dose of 48 IU).
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Benzodiazepine withdrawal symptoms
Time Frame: 21 days
|
Benzodiazepine withdrawal symptoms severity is measured with CIWA-B score, a 20-item scale where each item can be assigned a score from 0 to 4, i.e. the total score can range from 0 and 80 points. CIWA-B score will be measured daily from baseline (i.e. the day before the intervention starts) to day 21. |
21 days
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Benzodiazepine craving
Time Frame: 21 days
|
To test whether there is a difference between oxytocin and placebo on craving. Craving is measured daily with a Norwegian translation of the Brief Substance Craving Scale, adapted to benzodiazepines. Three items covering the intensity, frequency, and duration of craving during the past 24 hours are each scored from 0 to 4, giving a total score from 0 to 12. Higher scores indicate stronger craving, that is, a worse outcome. A fourth item records the number of craving episodes during the past 24 hours and is reported separately. The change in scores from baseline to day 21 is compared between the two study groups. |
21 days
|
|
Benzodiazepine anxiety and depression symptoms
Time Frame: 21 days
|
To test whether there is a difference between oxytocin and placebo on rebound anxiety and depression symptoms. Symptoms are measured with the Hospital Anxiety and Depression Scale (HADS), a 14-item scale where each item is scored from 0 to 3, giving subscale scores from 0 to 21 for anxiety and for depression and a total score from 0 to 42. Higher scores indicate more severe symptoms, that is, a worse outcome. HADS is measured weekly from baseline to day 21, and the change in scores from baseline to day 21 is compared between the two groups. |
21 days
|
|
Benzodiazepine sleep distress
Time Frame: 21 days
|
To test whether there is a difference between oxytocin and placebo on sleep. Sleep difficulties are measured with the Insomnia Severity Index (ISI), a 7-item scale where each item is scored from 0 to 4, giving a total score from 0 to 28. Higher scores indicate more severe insomnia, that is, a worse outcome. Sleep variables are also assessed by actigraphy and Somnofy. Scores are compared between the two study groups from baseline to day 21 during the intervention. |
21 days
|
|
Benzodiazepine tapering "freezes"
Time Frame: 21 days
|
To test whether there is a difference between oxytocin and placebo in the number of "freezes" in diazepam tapering. A "freeze" (not reducing the diazepam dose as scheduled during tapering) will be noted for each subject and compared between the two study groups. |
21 days
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Follow-up: Relapse
Time Frame: 15 weeks
|
To test whether there is a difference between oxytocin and placebo in time to first benzodiazepine intake (up to 12 weeks after discharge). Comparing time (number of days) to first self-reported benzodiazepine intake after discharge (week 3) between the two study groups, by registration on the follow-up visits at week 7 and week 15. |
15 weeks
|
|
Follow-up: Benzodiazepine withdrawal symptoms
Time Frame: 15 weeks
|
Difference between the oxytocin and placebo group in withdrawal symptoms measured with the Clinical Institute Withdrawal Assessment Scale for Benzodiazepines (CIWA-B) at week 7 and week 15 after discharge. CIWA-B is a 20-item scale where each item is scored from 0 to 4, giving a total score from 0 to 80. Higher scores indicate more severe withdrawal symptoms, that is, a worse outcome. |
15 weeks
|
|
Follow-up: Benzodiazepine craving
Time Frame: 15 weeks
|
To test whether there is a difference between oxytocin and placebo on craving at week 7 and week 15 after discharge. Craving is measured with a Norwegian translation of the Brief Substance Craving Scale, adapted to benzodiazepines. Three items covering the intensity, frequency, and duration of craving during the past 24 hours are each scored from 0 to 4, giving a total score from 0 to 12. Higher scores indicate stronger craving, that is, a worse outcome. A fourth item records the number of craving episodes during the past 24 hours and is reported separately. Scores are compared between the two study groups. |
15 weeks
|
|
Follow-up: Benzodiazepine anxiety and depression symptoms
Time Frame: 15 weeks
|
To test whether there is a difference between oxytocin and placebo on rebound anxiety and depression symptoms at week 7 and week 15 after discharge. Symptoms are measured with the Hospital Anxiety and Depression Scale (HADS), a 14-item scale where each item is scored from 0 to 3, giving subscale scores from 0 to 21 for anxiety and for depression and a total score from 0 to 42. Higher scores indicate more severe symptoms, that is, a worse outcome. Scores are compared between the two study groups. |
15 weeks
|
|
Follow-up: Benzodiazepine sleep distress
Time Frame: 15 weeks
|
To test whether there is a difference between oxytocin and placebo on sleep distress at week 7 and week 15 after discharge. Sleep difficulties are measured with the Insomnia Severity Index (ISI), a 7-item scale where each item is scored from 0 to 4, giving a total score from 0 to 28. Higher scores indicate more severe insomnia, that is, a worse outcome. Scores are compared between the two study groups. |
15 weeks
|
Collaborators and Investigators
Sponsor
Investigators
- Study Chair: Tone Aurora Pleym, MD, PhD-candidate, NTNU, Blue Cross, Clinic Lade, St. Olavs hospital
- Principal Investigator: Olav Spigset, MD, PhD, Department of Clinical Pharmacology, St. Olavs Hospital, and Norwegian University of Science and Technology (NTNU)
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- 32672
- 2019 (U.S. NIH Grant/Contract)
- 2024-516262-11-00 (Ctis)
- 2019-002280-10 (EudraCT Number)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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