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LAS VEGAS -- Can concurrent cannabinoid and opioid use enhance analgesic effects, or should their combined use be avoided? Presenters at the 2019 PAINWeek conference took on this question, agreeing that many of the effects associated with cannabinoids remain unknown.

"I feel like I'm speaking to the choir here -- this is something we're all dealing with already," said Chris Herndon, PharmD, of Southern Illinois University in Carbondale, Illinois, at a talk entitled "Cannabis and Opioid Together: Syn or Synergy?"

The proportion of patients in primary care clinics that are on chronic opioid therapy and using cannabis has been reported to be anywhere from 16% to 25%, Herndon said. As such, the potential harms and benefits are certainly something that "need to be discussed."

There are as many as 400 constituents of the cannabis plant, 66 of which are of the cannabinoid structure, including tetrahydrocannabinol (THC) and cannabidiol (CBD).

They each have a number of different pharmacological modalities, many of which support the idea of using these drugs to treat pain, including calcium channel antagonism, downstream effects on lysergic glutamatergic, and potential N-methyl-D-aspartate receptor (NMDA) activity, Herndon said.

He cited that found adding medical cannabis to opioid therapy among fibromyalgia patients was associated with significant improvements in pain, measured through the visual analog scale, fibromyalgia pain severity scales, and disability measures.

However, cannabis may affect pain tolerance in a bell or j-shaped curve, in which stimulating pain receptors at certain levels can actually produce a hyperalgesic effect, countered Bradlee Rea, PharmD, of Kaweah Delta Health Care in Visalia, California.

"THC may actually reduce a patient's tolerance or ability to tolerate pain," Rea said.

Herndon argued that at the right ratio, CBD and THC together have been shown to reduce pain. For example, that tested four different cannabis varieties in patients with fibromyalgia found much greater improvements in pain with Bediol -- which contains 13.4 mg THC and 17.8 mg CBD -- than with Bedrocan, which contains mostly THC (22.4 mg THC and <1 mg CBD).

But the problem is that in practice, medical marijuana can be a "potpourri surprise," Rea said, and the majority of studies examining analgesic effects of cannabidiol are not standardized in terms of strain, species, or dosing.

"We have agonists, we have antagonists, we have inverse agonists," Rea said. "How do we figure out what is going on when we have so many different products in the flower of cannabis? How do we know what product is doing what without more data looking at least in vitro at some of these constituents found in marijuana?"

Rea added that cannabidiol could be functioning by changing how patients perceive their pain, reducing pain catastrophizing, or decreasing the amount of other medications they use.

Herndon said in a clinical environment that is increasingly encouraging opioid alternatives, this could be one advantage to cannabinoids. In a , nearly three-quarters of patients who completed a survey said they were able to completely terminate their opioid use after they started using cannabis for chronic pain, he noted. Another found just over one-third of patients authorized to use medical cannabis in Canada were able to substitute cannabis for prescription opioids.

"There are those who would get up and argue with me, and say they're just substituting one drug for another, or potentially they were using prescribed opioids for non-therapeutic intent," Herndon said. "But I think showing the change in non-opioid analgesics like some of these studies do supports my premise."

However, cannabis is not without its own side effects, including associations with increased anxiety, depression of the central nervous system, and decreased testosterone production. But all of those have also been linked with opioid use, Rea said.

Patients with underlying depression and anxiety may be even more vulnerable to some comorbidities associated with both drugs, Rea said. For example, in examining patients on concomitant medical cannabis and opioids, patients with depression and anxiety were significantly more likely to show signs of misuse for both drugs.

"Chronic pain isn't just chronic pain -- it can be coupled with stress, anxiety, sleep disturbances, and PTSD [post-traumatic stress disorder]," Rea said. "All of these do have an effect on how people perceive their pain. It's important to look at the whole picture and treat the whole picture versus just treating the chronic pain."

Currently, 22 states permit the use of medical marijuana, each with different regulations and products. In New York, Colorado, and Illinois, for example, clinicians can now prescribe . Ultimately, there are many factors that go into the decision, which should jointly be made by the provider and patient, Herndon said.

"We're trying to balance what's working for the patient, and trying to provide compassionate care with what little we know about this substance, and the different constituents, and how it might impact the drugs they're already on," Herndon said. "Then also making sure you protect yourself as a prescriber because you're providing care for these patients."

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