Influence of Δ9-tetrahydrocannabinol (THC) on Oxycodone Induced Ventilatory Depression in Healthy Volunteers (COXY)

Rationale:

Opioid misuse and abuse are common problems in the Western world. The rate of unintentional drug overdose is rapidly increasing, not only in the Unites States but also in the Netherlands. Additionally, it is well known that opioids are often used (and abused) in combination with other legal or illicit substances, for example cannabis, including medicinal (i.e. doctor prescribed) cannabis. A major opioid-induced adverse effect is respiratory depression and there are no data that show how oxycodone interacts with cannabis on the ventilatory control system. An appreciable effect is possible given the sedative effects of cannabis. Moreover, investigators previously showed that combining even a low dose of oxycodone (20 mg) with ethanol increased the likelihood of an apneic event (van der Schrier et al. Anesthesiology 2017; 102: 115-122). Because of this side effect and also due to the rising number of addicted chronic opioid users, there is an increasing imminent societal, political and medical interest in advancing research on opioids, opioid-drug interaction and alternatives for the treatment of various chronic illnesses and chronic pain.

Hypothesis: The investigators hypothesize that cannabis will amplify the ventilatory depressant effect of oxycodone (primary end-point).

Objective: The objective of the study is to quantify the interactive effect of Δ9-tetrahydrocannabinol (THC) and oxycodone on ventilatory control.

Study design: Double blind, randomized cross-over, placebo-controlled design.

Study population: Healthy human volunteers between the age of 18 and 45 years old.

Intervention:

Visit A: placebo capsule at t = 0 min + Bedrocan (22.4 mg THC) at t = 90 and 270 min; Visit B: oxycodone 20 mg at t = 0 min + Bedrocan (22.4 mg THC) at t = 90 and 270 min.

Main study parameters/endpoints:

Primary endpoint: The effect of inhaled THC on ventilation at an end-tidal PCO2 = 55 mmHg without and with concomitant intake of 20 mg oxycodone immediate release (IR) capsule in healthy volunteers 120 min after oxycodone intake.

Secondary endpoints: (1) Outcome of Bowdle and Bond & Lader questionnaires; (2) Level of sedation; (3) Pain Pressure Threshold; (4) slope of the hypercapnic ventilatory response; (5) plasma concentrations of THC, 11-OH-THC and oxycodone; a secondary analysis will be performed on the pharmacokinetic and pharmacodynamic data (PKPD modeling).

Study Overview

• Status: Recruiting
• Conditions: Cannabis Use; Opioid Use; Respiratory Depression
• Intervention / Treatment: Drug: Medicinal cannabis in combination with oxycodon; Drug: Medicinal cannabis in combination with placebo oxycodon

Detailed Description

General study design The design of the study is randomized, placebo-controlled crossover. Each subject will be studied twice, on one occasion he or she will receive THC and a placebo opioid capsule, and on the other occasion THC and an oxycodone capsule. The visits to the lab will be randomized, the washout period between the two occasions is at least 10 days. Subjects will be evaluated by a physician at screening and only healthy volunteers, aged 18-45 years, with a body mass index < 30 kg.m-2, are eligible to participate in the study.

Upon arrival in the laboratory (K5-120), the investigators will perform a urinary drug test and breath alcohol test. When these tests are positive, the subject is excluded from further participation. A venous and an arterial line will be placed. The venous line is used for fluid administration (NaCl/Glucose 50-100 ml/h), the arterial line is for blood sample drawing.

Next, the first hypercapnic ventilatory responses (HCVR) will be obtained (t = -30 min). This is the pre-drug baseline measurement. At t = 0, the subjects will receive 20 mg oxycodone immediate release or placebo. Next, the investigators will obtain HCVRs at 1-hour intervals until 6 hours after oxycodone/placebo intake. At t = 1.5 h and at t = 4.5 h the subject will inhale 100 mg Bedrocan. Breathing will be measured using the "dynamic end-tidal forcing" (DEF) system. At specific time points the investigators will draw 10 mL blood for measurement of drug concentrations. After 8 hours of measurement, we will assess whether the HCVR is still depressed. If so, the investigators will take another measurement at t = 9 h and reassess the HCVR. If still depressed, a last response will be obtained at t = 10 h. If necessary, the subject will stay overnight in the hospital. This will be decided by the physician-investigator. For example, the subject may still be sedated.

The hypercapnic ventilatory response To obtain the HCVR curve, the subject will rebreathe a gas mixture from a 6 L rebreathing balloon bag containing 7% carbon dioxide in 93% oxygen. The slope of the response and ventilation at 55 mmHg will be used in the analysis.

Oxycodone intake:

At t = 0, the subject will ingest 1 oxycodone 20 mg immediate release or a placebo capsule with 100 mL water. Both drugs will be obtained from the LUMC pharmacy.

Cannabis inhalation: Bedrocan is vaporized using the CE-marked Volcano Medic vaporizer (Storz & Bickel GmbH & Co, Tuttlingen, Germany), a safe and reliable method of intrapulmonary administration of cannabinoids. The Volcano heats the homogenized plant material to 210 °C to allow for conversion of the THC acid and CBD acid into THC and CBD vapor for inhalation. The complete 100 mg from the glass vial will be entered into the vaporizing chamber of the Volcano Medic. The vapor will be collected in a 6-L plastic balloon that, after inflation, is detached from the vaporizer and subsequently equipped with a mouthpiece for inhalation. It is our experience that the full content of the balloon is inhaled without any problems within 3-5 min.

The Bedrocan cannabis variety contains 22% THC (220 mg per gram) and less than 1%CBD. It is developed in the Netherlands out of a requirement by the Dutch Health Ministry to have a "high THC" variety available to patients. We will administer 100 mg Bedrocan that contains 22.4-mg THC and less than 1-mg CBD, twice. Bedrocan will be obtained via the Bureau voor Medicinale Cannabis (BMO), a governmental organization (VWS) that obtains cannabis from Bedrocan Int. BV in Veenendaal, The Netherlands.

Blood sampling Ten mL blood samples will be obtained on 14 occasions on each visit (total volume = 112 mL per visit) at t = 30 and 60 min after oxycodone intake and at t = 5, 20, 40, 60, 120, 180, 185, 200, 220, 240, 300 and 360 min after the first THC inhalation. From these sample, the following drugs will be measured: oxycodone, THC, THC's metabolite 11-OH-THC and cannabidiol (CBD). CBD is measured as it is expected that some minor quantities of CBD are present in Bedrocan.

Arterial blood will be collected in EDTA tubes. After blood collection the tubes will preferably be put in ice water in aluminum foiled containers, will be centrifuged within one hour for 10 minutes at 2000 G at 4 °C. The handling of samples will be done with the lights switched off. The plasma will be equally divided in 2 tubes (Brown Sarstedt) (primary and back-up sample). Plasma samples will be stored at a temperature of -80 °C and blood samples will be sent to Analytical Biochemical Laboratory (ABL) B.V., Assen, The Netherlands on dry-ice. Pharmacokinetic analysis will be performed using a validated assay. Determination of drug concentrations will be performed using liquid chromatography with tandem-mass spectrometer detection (LC-MS/MS). Analysis of the samples and acceptance criteria are indicated in ABL Standard Operating Procedure (SOP) 0251.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Cornelis Jan CJ van Dam, MSc; Phone Number: +31715299797; Email: c.j.van_dam@lumc.nl

Study Locations

• Netherlands
  • Zuid Holland
    • Leiden, Zuid Holland, Netherlands, 2333 ZA
      • Recruiting
      • Leiden University Medical Center
      • Contact: Cornelis Jan CJ van Dam, MSc; Phone Number: 31(0)715299797; Email: c.j.van_dam@lumc.nl
      • Contact: Monique van Velzen, Phd; Phone Number: +31(0)715262301; Email: m.van_velzen@lumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• aged 18-45 years,
• body mass index < 30 kg.m-2,
• able to understand the written informed consent form,
• able to communicate with the staff,
• able and willing to complete the study procedures,
• signed the informed consent form,
• deemed suitable by the investigators.

Exclusion Criteria:

• Presence or history of any medical or psychiatric disease (incl. a history of substance abuse, anxiety, or the presence of a painful syndrome such as fibromyalgia);
• Use of any medication in the three months prior to the study (incl. paracetamol or other pain killers), except for oral contraceptives (females);
• Use of more than 21 alcohol units per week;
• Use of cannabis in the 4 weeks prior to the study;
• A positive urinary drug test or a breath alcohol test at screening or on the morning of the experiment;
• Pregnancy, lactating or a positive pregnancy test on the morning of the experiment;
• Participation in another drug trial in the 60 days prior to dosing.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 20mg Oxycodon (capsule) + 100 mg Bedrocan (vaporized); As stated above	Drug: Medicinal cannabis in combination with oxycodon; The intervention will be administering the combination of medicinal cannabis in combination with oxycodon
PLACEBO_COMPARATOR: Placebo oxycodon (capsule) + 100 mg Bedrocan (vaporized); As stated above	Drug: Medicinal cannabis in combination with placebo oxycodon; The intervention will be administering the combination of medicinal cannabis in combination with placebo oxycodon

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The effect of inhaled THC on ventilation (Liters per minute) at an end-tidal PCO2 = 55 mmHG without and with concomitant intake of 20 mg oxycodone immediate release (IR) capsule in healthy volunteers 120 min after oxycodone intake.	As stated above	120 minutes after oxycodone intake

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bowdle questionnaire score;	Three factors of psychedelic effects can be derived from the Bowdle questionnaire: drug high, internal perception, and external perception. Internal perception reflects inner feelings that do not correspond with the reality and is derived from questions regarding the hearing of unrealistic voices or sounds and having unrealistic thoughts and paranoid or anxious feelings. The external perception indicates a misperception of an external stimulus or change in the awareness of the subject's surroundings and is derived from questions regarding the change of body parts, the change of surroundings, the altered passing of time, the difficulty of controlling thoughts, and the change in color and sound intensity.	Time 0, 30, 90, 150, 210, 270, 330, 390 and 450 minutes after oxycodon or placebo administration.
Pain Pressure Threshold (mN);	We will use the FPN 100 N Algometer (FDN 100, Wagner Instruments Inc., Greenwich, CT, USA; Rolke et al., 2005) to deliver pressure pain on a skin area of 1 cm2 between thumb and index finger. The FDN 100 has a force capacity (± accuracy) of 100 ± 2 N (10 ± 0.2 kgf) and graduation of 1 N (100 gf), respectively. A gradually increasing pressure is manually applied and the subjects are asked to indicate when the procedure becomes painful (pressure pain threshold, PPTh).	Time 0, 25, 55, 90, 105, 125, 145, 205, 265, 270, 285, 305, 325, 385 and 445 minutes after oxycodon or placebo administration.
slope of the hypercapnic ventilatory response;	Slope	Time 0, 60, 120, 180, 240, 300, 360 and 420 minutes after oxycodon or placebo administration.
plasma concentrations of THC, 11-OH-THC and oxycodone; a secondary analysis will be performed on the pharmacokinetic and pharmacodynamic data (PKPD modeling).	Plasma concentration	Time 0, 30, 60, 95, 110, 130, 150, 210, 270, 275, 290, 310, 330, 390 and 450 minutes after oxycodon or placebo administration.
Bond & Lader questionnaire score	The Bond and Lader scales are calculated from sixteen 100 mm visual analog scales.	Time 0, 30, 90, 150, 210, 270, 330, 390 and 450 minutes after oxycodon or placebo administration.

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Investigators: Principal Investigator: Monique van Velzen, PhD, LUMC

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 9, 2021
• Primary Completion (ANTICIPATED): December 1, 2022
• Study Completion (ANTICIPATED): June 1, 2023

Study Registration Dates

• First Submitted: November 30, 2021
• First Submitted That Met QC Criteria: February 10, 2022
• First Posted (ACTUAL): February 11, 2022

Study Record Updates

• Last Update Posted (ACTUAL): February 11, 2022
• Last Update Submitted That Met QC Criteria: February 10, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Respiratory Tract Diseases; Mood Disorders; Respiration Disorders; Depression; Depressive Disorder; Respiratory Insufficiency
• Other Study ID Numbers: P21.030; 2021-000083-29 (EUDRACT_NUMBER); NL76443.058.21 (OTHER: CCMO Netherlands)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No