Opioid and Cannabinoid Pharmacokinetic Interactions

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT00308555
• Collaborator: National Institute on Drug Abuse (NIDA) (NIH)
• Enrollment: 24
• Location: 1
• Arm: 1
• Duration (Months): 34
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

We are conducting a study to assess whether smoking marijuana affects the safety of prescribed opioids in patients treated for chronic pain. This study will assess whether smoking cannabis affects the absorption, distribution, metabolism and excretion of widely used opioid analgesics. We propose to do this by investigating the effects of smoked cannabis in subjects prescribed morphine or oxycodone for chronic pain. We will also assess the clinical safety of cannabinoids and these opioids by monitoring the short-term side effects associated with combined therapy.

Condition or Disease	Intervention/Treatment	Phase
Pain	Drug: Cannabis	Phase 1

Detailed Description

Chronic pain conditions remain problematic, especially in patients with cancer. Although opioids are effective analgesics, dose-limiting side effects in the form of sedation, nausea and vomiting, and fear of dependence often limit their use at higher - and possibly more effective - doses. Of particular interest, however, is the potential for greater than additive analgesic effect of cannabinoids and opioids in combination that would allow for opioid analgesic effect to be achieved at lower dosages than are necessary alone, which could overcome problems with both tolerance and side effects for both drug classes. Unfortunately, safety data on the combination in humans does not exist at this time and needs to be obtained. As increasing numbers of patients with chronic pain may turn to cannabis to augment the effects of their opioid analgesics, data on potential pharmacokinetic interactions and clinical safety of the combinations should be evaluated in a controlled clinical research setting.

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Opioid and Cannabinoid Pharmacokinetic Interactions: A Pilot Study
• Study Start Date: May 1, 2006
• Actual Primary Completion Date: Mar 1, 2009
• Actual Study Completion Date: Mar 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Other: Cannabis	Drug: Cannabis

Outcome Measures

Primary Outcome Measures

1. Disposition Kinetics of Morphine and Oxycodone Before and After Cannabis Use [Day 1, Day 5]

   Pharmacokinetics are measured on Day 1, prior to cannabis use, and again on Day 5, following cannabis use on Days 2, 3, and 4.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Ongoing analgesic therapy with either oxycodone hydrochloride (OxyContin) or morphine sulfate (MS Contin) every 12 hours for chronic pain.

2. Eligible subjects will be ≥ 18 years of age with a diagnosis of chronic pain and an estimated survival of greater than six months.

3. Subjects must be on a stable dose of opioid medication for at least 2 weeks before enrollment.

4. Current other analgesic medications will be maintained during the study. The subject must have been on a stable medication regimen for at least 2 weeks.

5. The following laboratory parameters documented within 45 days prior to study entry:

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 X upper limit of normal (ULN)

• Total bilirubin ≤ 2 X ULN

• Creatinine ≤ 2.0 mg/dL (177 µmol/L)

1. All men and women in this study must agree to use adequate birth control during this study. Acceptable barrier birth control methods are a male condom, female condom, diaphragm, or intra-uterine (IUD).

2. All women of reproductive potential (who have not reached menopause or undergone hysterectomy, oophorectomy, or tubal ligation) must have a negative urine b-HCG pregnancy test performed before initiating the protocol-specified medication.

3. Prior history of use of marijuana. Subjects must have smoked marijuana on at least 6 occasions in their lifetime prior to enrollment.

4. Able to understand and follow the instructions of the investigator, including completing the pain intensity rating scales.

5. Karnofsky Performance Score >60.

6. Able and willing to provide informed consent.

Exclusion Criteria:

1. Severe coronary artery disease, uncontrolled hypertension, cardiac ventricular conduction abnormalities, or orthostatic mean blood pressure drop greater than 24 mmHg, severe chronic obstructive pulmonary disease.

2. History of renal or hepatic failure.

3. Evidence of hepatic, hematological or renal dysfunction based on judgment of physician.

4. Active substance abuse (e.g., alcohol or injection drugs).

5. Use of smoked marijuana within 30 days of enrollment verified with a urine THC level.

6. Neurologic dysfunction or psychiatric disorder severe enough to interfere with assessment of pain or sensory systems.

7. Current use of smoked tobacco products or a confirmed cotinine level.

8. Women who are pregnant or breast-feeding may not take part in this study.

9. Unable to read or speak English.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Community Consortium	San Francisco	California	United States	94110

Sponsors and Collaborators

• University of California, San Francisco
• National Institute on Drug Abuse (NIDA)

Investigators

• Principal Investigator: Donald I Abrams, M.D., University of California, San Francisco

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT00308555
• Other Study ID Numbers: CC # 064; 1R21DA020831-01
• First Posted: Mar 29, 2006
• Last Update Posted: Dec 9, 2016
• Last Verified: Oct 1, 2016

• Keywords provided by University of California, San Francisco: Cannabis; Morphine; Oxycodone; Marijuana; chronic pain

Study Results

Participant Flow

Recruitment Details	315 participants were screened, via phone and e-mail, between January 2007 and February 2009. 24 subjects were enrolled, 13 taking morphine and 11 taking oxycodone.

Arm/Group Title	MS Contin	Oxycontin
Arm/Group Description	Patients using morphine sulfate (MS Contin) every 12 hours for chronic pain were administered vaporized cannabis (3.96% delta 9-THC) equivalent to one 0.9 g cigarette on the following schedule: 20:00 on Day 1, 08:00/14:00/20:00 on Days 2 through 4, and 08:00 on Day 5.	Patients using oxycodone hydrochloride (OxyContin) every 12 hours for chronic pain were administered vaporized cannabis (3.96% delta 9-THC) equivalent to one 0.9 g cigarette on the following schedule: 20:00 on Day 1, 08:00/14:00/20:00 on Days 2 through 4, and 08:00 on Day 5.
Period Title: Overall Study
STARTED	13	11
COMPLETED	10	11
NOT COMPLETED	3	0

Baseline Characteristics

Arm/Group Title	MS Contin	Oxycontin	Total
Arm/Group Description	Patients using morphine sulfate (MS Contin) every 12 hours for chronic pain	Patients using oxycodone hydrochloride (OxyContin)every 12 hours for chronic pain	Total of all reporting groups
Overall Participants	13	11	24
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	13 100%	11 100%	24 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.9 (7.4)	47.1 (11.8)	45.1 (10.0)
Gender (Count of Participants)
Female	6 46.2%	6 54.5%	12 50%
Male	7 53.8%	5 45.5%	12 50%
Region of Enrollment (participants) [Number]
United States	13 100%	11 100%	24 100%
Mean opioid dose, twice daily (mg) [Mean (Full Range) ]
Mean (Full Range) [mg]	62	53	58

Outcome Measures

1. Primary Outcome

Title	Disposition Kinetics of Morphine and Oxycodone Before and After Cannabis Use
Description	Pharmacokinetics are measured on Day 1, prior to cannabis use, and again on Day 5, following cannabis use on Days 2, 3, and 4.
Time Frame	Day 1, Day 5

Outcome Measure Data

Analysis Population Description

The number was determined by the number of participants completing both Day 1 and Day 5 procedures.

Arm/Group Title	MS Contin	Oxycodone
Arm/Group Description	Participants on morphine treatment	Participants on oxycodone treatment
Measure Participants	10	11
Time to maximum concentration (Tmax)	1.64	-1.11
Maximum concentration (Cmax)	0.9	0.99
Area under plasma concentration-time curve (AUC)	0.95	0.94

Adverse Events

Arm/Group Title	MS Contin		Oxycontin
Arm/Group Description	Patients using morphine sulfate (MS Contin) every 12 hours for cancer pain		Patients using oxycodone hydrochloride (OxyContin)every 12 hours for cancer pain
All Cause Mortality
	MS Contin		Oxycontin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	MS Contin		Oxycontin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/11 (0%)
Other (Not Including Serious) Adverse Events
	MS Contin		Oxycontin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/11 (0%)

Limitations/Caveats

Small number of participants, powered to detect a 25% change in AUC(12).Further research is needed to determine how cannabis delivery systems other than vapor affect metabolism of opioids and other drugs.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.