December 13, 2011 — For patients with chronic pain, adding a cannabinoid to opioid therapy may lead to greater pain relief at lower opioid doses, hints a new study.
The study's findings add to a "body of evidence that cannabinoids in association with opioids are synergistic in relieving pain," first author Donald Abrams, MD, professor of clinical medicine, University of California, San Francisco, and chief of the Hematology/Oncology Division, San Francisco General Hospital and Trauma Center, told Medscape Medical News.
The study was published in the December issue of Clinical Pharmacology & Therapeutics.
Less Pain With Cannabinoid
Dr. Abrams and colleagues conducted a pharmacokinetic interaction study in a group of patients who were each receiving, on a long-term basis, a stable dose of either sustained-release morphine (n = 10) or sustained-release oxycodone (n = 11). The mean morphine dose was 62 mg twice a day, and the mean oxycodone dose was 53 mg twice daily.
The study included 21 participants with chronic pain. The origin of pain was musculoskeletal (not otherwise specified) in 7 patients, posttraumatic in 4 patients, arthritic in 2 patients, associated with peripheral neuropathy in 2 patients, and associated with cancer, fibromyalgia, migraine, multiple sclerosis, sickle cell disease, and thoracic outlet syndrome in 1 patient each.
After determining baseline plasma opiate levels, the researchers exposed patients to controlled amounts of vaporized cannabis for 4 consecutive days and then reanalyzed their opiate levels on day 5. They also evaluated the patients' level of pain.
"Interestingly," Dr. Abrams said, there was no significant change in the area under the plasma concentration–time curves for either morphine or oxycodone after exposure to cannabis. For morphine, the level was slightly lower with cannabis.
Despite this, however, the patients experienced a reduction in pain when cannabis was added to the opiate alone. The average pain reduction was 27.2% (95% confidence interval, 8.9% - 45.5%).
Because the level of morphine was slightly lower and the level of oxycodone was virtually unchanged with the addition of cannabis, "one would expect they would have less relief of pain, and what we found that was interesting was that instead of having less pain relief, patients had more pain relief," Dr. Abrams said. "So that was a little surprising."
This is a "pretty exciting" result, Dr. Abrams said, and one that "warrants further investigation. It suggests that people could potentially get away with taking a lower dose of opiate if they mix it with the cannabis," possibly reducing opioid-related adverse effects such as sedation and nausea.
In a telephone interview with Medscape Medical News, Seddon R. Savage, MD, president of the American Pain Society, who was not involved in the study, said that cannabinoid medications are "very promising analgesic medications. The synergistic effect with opioids has been suggested in a number of other studies both in animals and humans."
Dr. Savage noted that the American Pain Society does not currently have a particular position on medical marijuana, "although we are working on one."
She also noted that 2 cannabinoids have been approved by the US Food and Drug Administration and are currently available in medicinal form; they do not have an indication at this time for pain, but they can be used off-label for it.
"Personally," she said, "I think they are underutilized for a variety of reasons." However, they are "not perfect, and there is a broader-spectrum cannabinoid drug in the pipeline that's anticipated to be available in the US in the next few years."
"For a patient having trouble getting neuropathic pain or other pain under control with the usual anticonvulsants and antidepressants in combination with opioids, it is certainly reasonable," Dr. Savage said, "to use a cannabinoid with very careful documentation and monitoring."
"What we need to do now," Dr. Abrams said, "is look at pain as the primary endpoint of a larger trial. Particularly I would be interested in looking at the effect of different strains of cannabis."
He noted that the marijuana used in the current study is mainly delta-9-tetrahydrocannabinol (THC), not cannabidiol (CBD). CBD has been shown to be effective against pain and inflammation without creating the "high" caused by THC.
"What I'd really like to do is compare the THC-rich with the CBD-rich cannabis and see if there is any difference in pain-relieving activity," he said.
Serious Evaluation Needed
In an editorial accompanying the publication, Mark Ware, MD, from the Department of Family Medicine and the Department of Anesthesia at McGill University Faculty of Medicine in Montreal, Quebec, Canada, cautions that the study "has its flaws," notably that, as with many studies investigating medical marijuana, it is small and was not designed as an efficacy trial using randomization or control participants.
However, it does add to emerging evidence that cannabinoids and opioids have clinically significant synergistic effects, he writes. "Given widespread concerns about opioid misuse, and the anecdotal suggestion that patients using medical marijuana may reduce opioid doses, Abrams and colleagues' study further reinforces the need for serious evaluation of the potential role of cannabinoids as opioid-sparing drugs."
Vaporization of the cannabis, used for the first time in this study for patients with chronic pain, may overcome some of the concerns about smoking it, although the long-term effects have still to be studied.
However, it is of some concern that patients reported feeling high after exposure. That inhaling a cannabinoid causes a patient to feel high is not "earth-shattering," Dr. Ware writes. The wider concern is that these are patients with serious painful conditions who are seeking symptom relief, he adds. They are not "kids looking for a buzz."
Although some would argue that the feelings of euphoria and well-being might offset the nausea, itching, constipation, and drowsiness of opioids and relieve the chronic pain, others point to potentially adverse cognitive effects and suggest that patients may not be able to function at the doses used.
"The answer to all this is clear: We need more clinical research teams with the dedication, credibility, and expertise to carry out the work required to address these issues," Dr. Ware concludes.
The study was funded by the National Institute on Drug Abuse, part of the National Institutes of Health. The authors and Dr. Savage have disclosed no relevant financial relationships. Dr. Ware reports that he has received grants and speaker's fees from Valeant and Bayer, companies that market cannabinoids, and has acted as a consultant to Ironwood, Pfizer, Boerhinger, and AstraZeneca, companies that are developing related medicines. He owns no stock in these companies nor has other financial interest in these companies.
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