Efeitos da ocitocina intranasal no tratamento da abstinência de benzodiazepínicos: um ensaio clínico piloto

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

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).

• Sintocina

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.