By Charles Bankhead, Staff Writer, MedPage Today; Reviewed by Robert Jasmer, MD, Associate Clinical Professor of Medicine, University of California, San Francisco (October 24, 2007) LA JOLLA, CA -- Smoking marijuana may relieve pain, but only within a narrow therapeutic window, and higher doses can actually intensify pain, investigators here have found.

Healthy volunteers who smoked marijuana containing 8% tetrahydrocannibinol (THC) had a significantly increased pain response to capsaicin-induced hyperalgesia, Mark S. Wallace, M.D., of the University of California, San Diego, and colleagues, reported in the November issue of Anesthesiology.

In contrast, pain response was significantly weaker with a 4% THC dose, they said. And a 2% THC concentration afforded no pain relief.

Although possibly hypothesis generating, the findings will do little to resolve controversy surrounding medical applications of marijuana, they acknowledged.

"No conclusions on the analgesic efficacy of smoked cannabis on clinical pain states can be made from this study, as the relationship between analgesic effects in experimental pain and clinical pain states is unknown," the authors stated.

Expression of the major cannabinoid receptor CB1 in the brain, spinal cord, and related neural pathways has led to speculation that cannabinoids may modulate nociceptive transmission. Preclinical and limited clinical studies have supported the concept. However, potential mechanisms of action and therapeutic efficacy have remained elusive.

"Using models of experimentally induced pain in human volunteers, however, permits simplified stimulus conditions, crossover designs, and comparisons between human and animal models to define in parallel the physiology and pharmacology of pain states," the authors wrote.

Dr. Wallace and colleagues enrolled 15 healthy adult volunteers for a randomized, double-blind, placebo-controlled crossover study. Each participant provided a blood sample to confirm absence of plasma THC before starting the trial.

The protocol stipulated that each volunteer would participate in four dose-randomized sessions at least one week apart. During each session, participants smoked a placebo or low (2% THC), medium (4% THC), or high (8% THC) dose marijuana cigarettes. Participants who could not tolerate the highest dose were excluded from analysis.

Blood was drawn at each session before drug administration to assess plasma THC and it metabolites. Another specimen was obtained five minutes after drug administration to quantify cannabis exposure. Additionally, participants had neurosensory and neurocognitive evaluations and subjectively rated their "highness."

After completion of testing, capsaicin (10 µL, 10 mg/mL) was injected. Pain scores and vital signs were assessed at injection and then every 2.5 minutes for 10 minutes.

A final blood sample was drawn 40 minutes after the cannabis dose to assess THC and metabolite levels, and the neurocognitive and neurosensory tests were repeated. The participants also rated their level of highness again.

Pain was assessed by three different measures and by the McGill Pain Questionnaire Short Form. None of the THC doses produced measurable analgesia five minutes after administration.

Nor was there any difference in pain perception at any time between 2% THC and placebo.

However, at 45 minutes after cannabis exposure, the 4% THC dose resulted in decreased pain sensation that was greater than would be expected as a function of elapsed time from capsaicin injection (P=0.011 to P=0.027). The 8% THC dose led to an increase in pain score of 7.1 to 8.7 points versus placebo (P=0.009 to P=0.002).

The results were similar for all three pain measures. Cannabis had no effect on pain quality, as assessed by the McGill instrument.

Plasma levels of THC and its metabolites correlated significantly with decrease in pain but not with the increased pain observed with the highest dose.

"This suggests that there might be another compound within the cannabis leaf that we did not measure that may be leading to the increased pain at the high dose," the authors stated. "It is known that the cannabis leaf contains over 400 compounds of which 60 are called the cannabinoids."

The investigators also observed a disconnect between the onset of analgesia and the participants' subjective rating of "highness," which peaked early and persisted through the end of the session. The difference may reflect early central nervous system penetration or dissociation between analgesia and side effects.

The authors disclosed no conflicts of interest. The study was supported by the University of California Center for Medicinal Cannabis Research in La Jolla.

http://www.medpagetoday.com/PainManagement/PainManagement/tb/7089