Anesthetic Premedication With a Cannabis Extract (Cannapremed)

Study Overview
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Brief Summary
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Clinical evidence about the effects of cannabis in a perioperative setting or for the management of acute pain is rather scarce, mostly consisting of case report-based opinions on adverse events during or after general anesthesia after smoking cannabis, experimental pain trials in healthy volunteers, and a few clinical trials using different drugs, dosages and routes of administration. It is difficult to draw strong conclusions from the available evidence, that may seem sometimes even contradictory, mainly due -the investigators believe- to the many sources of variability in the study designs (e.g.: heterogeneity of the study samples, underpowered, unblinding, lack of randomization, timing of the therapeutic intervention, different experimental pain models, inclusion of different kind of surgical pain, etc.). Nevertheless, expert's opinion after a critical review of the literature is that cannabis and cannabinoids may have a beneficial role in the management of acute post-operative pain and nausea, at least for a selected group of patients and through an appropriate therapeutic intervention. Therefore, it seems to us pertinent to carry out an investigation in order to re-evaluate the issue of perioperative cannabis use through a sufficiently powered and controlled clinical trial. Some of cannabis effects such as sedation, bronchodilation, dryness of respiratory secretions, vein dilation, and increase of heart rater without producing hypertension, make of it an attractive option for pre-medication; while its antiemetic properties and its analgesic potential without causing respiratory depression may be profitable for the post-operative period. Cannabis oil seem to be most suitable to our investigation. The co-administration of tetrahydrocannabinol (THC) with cannabidiol (CBD) may translate into additional therapeutic benefits with an attenuation of adverse effects. The investigators expect to obtain less sedation, milder high, lower incidence of anxiety, tachycardia, and hyperalgesia, as compared with THC-only acute pain trials.

Detailed Description
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The selection of patients will be done during the pre-anesthetic assessment the day before surgery. After obtaining informed consent, eligible patients will be randomly allocated to one of the following regimes: Cannabis oil high dose (21.6 mg THC + 20 mg CBD), Cannabis oil low dose (10.8 mg THC + 10 mg CBD), placebo control (no premedication drugs). Treatments will be administered in a double-dummy manner. Identical bottles of Cannabis oil and placebo should be obtained from the manufacturer (Bazelet group). Identical prefilled vials containing sodium Olive oil should be prepared by the hospital pharmacist. To the best of our knowledge, no clinical studies evaluating the effects of Cannabis oil on acute pain or in a perioperative setting have been done to date. Therefore, the investigators estimate a Cannabis oil dose range that seems reasonable to obtain relevant clinical and a manageable occurrence of adverse events, mainly based on the recommendations from the manufacturer, on the available pharmacological data presented in the previous section and on the results of other clinical trials with a similar design using comparable doses of oral THC. Nevertheless, the first 10 patients will be randomly assigned either to the Cannabis oil low dose group or to the placebo control group only. The investigators will proceed with the full four-group randomization only if no serious adverse events are registered among the 10 first recruited patients. At the arrival to the operating room, blood samples for baseline levels of cannabinoids will be drawn at the moment of placing the intravenous line, and the first anxiety assessment should be done by the examiner/anesthetist. The study drugs will be administered at the entrance to the O.R. or at the induction room 15 minutes before the induction of anesthesia (i.e.:). Premedication dose should be calculated to be the equivalent of 10 mg and 20 mg oral THC for the low and high dose groups, respectively (4, 8 puffs). At the same time, the prefilled drops containing Olive oil will be administered as intravenous bolus. The patients will be immediately connected to the standard O.R. monitoring. Induction of general anaesthesia will be done in a standardized fashion with fentanyl 2 µg/Kg, propofol 1-4 mg/Kg (and vecuronium 0.1 mg/Kg if intubation is required). For anaesthetic maintenance, isoflurane 0.7-2% on 1:2 oxygen : nitrous oxide gas mixture, and fentanyl boluses 1 µg/Kg to keep a bispectral index (BIS) between 40 to 60, and a heart rate and mean arterial pressure between 70-130% from pre-induction baselines. Preemptive antiemetics (e.g.: granisetron, ondansetron, metoclopramide, dexamethasone, etc.) should not be given. No additional analgesics should be administered (e.g.: ketorolac or other NSAID's, dipyrone). A loading dose of morphine 0.2 mg/Kg will be given before the end of surgery provided that the patient can maintain spontaneous breathing or pressure support ventilation. Intravenous morphine patient-controlled analgesia (PCA) will be initiated on the arrival to the recovery room with boluses of 1 mg and a lockout time of 6 minutes, without background.

Official Title
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Effects of a Cannabis Extract as Anaesthetic Premedication on Postoperative Pain, Nausea-vomiting and Perioperative Anxiety

Conditions
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Pain, Postoperative, Postoperative Nausea and Vomiting, Anxiety

Intervention / Treatment
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* Drug: Tetrahydrocannabinol
* Drug: Dummy oromucosal


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients scheduled for elective surgeries suitable for postoperative pain treatment with intravenous morphine patient-controlled analgesia. American Society of Anesthesiologist (ASA) risk I or II Exclusion Criteria: ASA III or higher Cannabis use within the last 6 months Pregnancy Emergency surgeries Regional anesthesia Ischemic heart disease Renal failure History of psychosis Cognitive impairment or inability to answer questions

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cannabis oil high dose<br>Single-dose, before anesthetic induction: 21.6 mg tetrahydrocannabinol + 20 mg cannabidiol, Sub-linguistic | Drug: Tetrahydrocannabinol<br>* 1:1 THC to CBD standardized extract from cannabis plant<br>* Other names: Cannabis oil;|
| Experimental: Cannabis oil low dose<br>Single-dose, before anesthetic induction: 10.8 mg tetrahydrocannabinol + 10 mg cannabidiol, Sub-linguistic. | Drug: Tetrahydrocannabinol<br>* 1:1 THC to CBD standardized extract from cannabis plant<br>* Other names: Cannabis oil;|
| Placebo Comparator: Control<br>Single-dose, before anesthetic induction: Dummy oromucosal spray containing alcohol vehicle without Cannabis oil . | Drug: Dummy oromucosal<br>* drops containing only Olive oil vehicle without the active compound (i.e.: without Cannabis oil)<br>* Other names: Cannabis oil placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postoperative pain - VAS | Self-reported visual analog scale (VAS 0 - 100 mm) at rest and on movement. Pre-operative baseline, on arrival to recovery room, after 1 h, before discharge, at 6, 12, and 24 h. | 24 hours | 
| Postoperative pain - PCA | Count of patient-controlled analgesia pushes 1 hour after arrival to the recovery room, before discharge, at 6, and 12. Total dose of morphine received in 24 hours. | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postoperative nausea and vomiting (PONV) score | PONV score (0 - 4) on arrival to recovery room, after 1 hour, before discharge, at 6, 12, and 24 hours. 0. No nausea Nausea sometimes Nausea most of the time Dry retching or vomiting Dry retching or vomiting twice or more | 24 hours | 
| Anxiety - VAS | Self-assessed anxiety visual analog scale (0-100 mm) on arrival to the OR; on arrival to and before discharge from recovery room. | 6 hours | 
| Cannabinoid blood levels | Blood sampling from arterial line inserted on arrival to the OR before the main premedication dose, after 30 min, at 1, 3, 6, 12, and 24 hours. | 24 hours |