Anesthetic Premedication With a Cannabis Extract (Cannapremed)

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: nabiximols high dose (21.6 mg THC + 20 mg CBD), nabiximols low dose (10.8 mg THC + 10 mg CBD), active placebo (prefilled syringe with 1 mg midazolam + 1 g acetaminophen I.V.), placebo control (no premedication drugs).

Treatments will be administered in a double-dummy manner. Identical bottles of Sativex® and placebo should be obtained from the manufacturer (GW Pharmaceuticals). Identical prefilled vials containing either the active placebo (1 mg midazolam + 1 g acetaminophen) or sodium chloride 0.9% should be prepared by the hospital pharmacist. To the best of our knowledge, no clinical studies evaluating the effects of nabiximols on acute pain or in a perioperative setting have been done to date. Therefore, the investigators estimate a Sativex® 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 nabiximols 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 syringe containing either 1 mg midazolam + 1 g acetaminophen or sodium chloride 0.9% 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.