Clinical Context

Diabetic peripheral neuropathy is increasing in prevalence, affecting approximately half of patients with diabetes, with roughly 15% being painful. Control of pain is insufficient in many patients using either of the 2 medications currently approved by the US Food and Drug Administration.

The major cannabinoid receptor, CB1, is expressed in regions involved in pain perception, including the dorsal root ganglion, dorsal horn of the spinal cord, periaqueductal gray and raphe nucleus, and forebrain. Animal models also suggest upregulation of cannabinoid receptors in nerve injury and pain relief with cannabinoids. The hypothesis tested by this randomized, short-term, placebo-controlled crossover trial by Wallace and colleagues was that cannabis would result in a dose-dependent reduction in spontaneous and evoked pain with a concomitant dose-dependent effect on cognitive function in patients with diabetic neuropathy.

Study Synopsis and Perspective

Inhaled cannabis can blunt the pain of diabetic neuropathy without seriously impairing cognitive function, a new study shows.

"The higher the dose, the more the pain relief," first author Mark S. Wallace, MD, told Medscape Medical News. "There was, however, a dose-dependent increase in euphoria."

The study is the first randomized controlled trial of inhaled cannabis for diabetic neuropathy pain, said Dr Wallace, chair of the Division of Pain Management at the University of California, San Diego. It was published in the July issue of The Journal of Pain.

Painful diabetic neuropathy appears to be increasingly common, and currently approved medications do not provide adequate relief to most patients with this condition, Dr Wallace and his colleagues write.

A cannabinoid receptor is expressed in several regions of the nervous system. Recent studies on inhaled cannabis and neuropathic pain were promising, but none of them focused on diabetic neuropathy, the researchers note.

To fill that gap, they recruited 16 patients with diabetes mellitus types 1 or 2 with stable glycemia. All had experienced painful diabetic neuropathy for at least 6 months, including both spontaneous and evoked pain in the feet, which the patients rated at least 4 on an 11-point scale.

The researchers used a Volcano system vaporizer (Storz and Bickel), to heat the cannabis to 200 °C, vaporizing the active ingredients by hot air so the participants could inhale them.

Vaporization has advantages over other routes of administration, they said. It avoids the hazardous pyrroles and some of the carbon monoxide in burned marijuana leaves. Also, peak effects occur more quickly and doses are more easily titrated than with ingested cannabis.

The cannabis was provided by the Research Triangle Institute under contract with the National Institute on Drug Abuse. It was certified to contain delta-9-tetrahydrocannabinol (THC) concentrations of 0%, 1%, 4%, or 7% by weight. So the 400 mg of plant material per administration contained 0, 4, 16, or 28 mg of THC.

The researchers randomly assigned the patients to inhale one of these various dosages and then crossed them over to each of the other doses, with 2 weeks between sessions.

Participants rated their spontaneous pain and also the pain they experienced in response to a gentle stroke from a 1-inch foam brush as well as a pinprick with a 5.18 von Frey hair filament on the dorsum of the more painful foot. They rated their pain at 5, 15, 30, 45, and 60 minutes and every 30 minutes thereafter for 4 hours after inhaling the cannabis.

Analgesic effects lasted all 4 hours. The average spontaneous pain intensity score in the placebo dose (0% THC) was 0.44 points higher than the pain score in the low dose, and this finding was statistically significant (P =.031). It was 0.42 points higher than the score for the medium dose (P =.04) and 1.2 points higher than for the high dose (P <.001).

After adjustment for previous dose level, which also affected pain, only the difference between the high dose and other doses remained significant.

The dosage effects on pain evoked by the foam brush and von Frey pinprick were similar.

Table 1. Change in Pain Scores After 60 Minutes

THC = delta-9-tetrahydrocannabinol.

The researchers evaluated the participants' psychomotor speed, attention, and cognitive sequencing capacities using the Trail Making Test in which the participants had to quickly connect a series of dots and arrange circles in a designated order.

They also measured attention, working memory, and information-processing speeds using the Paced Auditory Serial Attention Test (PASAT), in which the participants had to add a series of numbers.

The overall differences between doses in changes from baseline were not statistically significant. However, after adjusting for visit order and baseline scaled score, the researchers found that the patients taking the medium and high doses lost some speed on a portion of the Trail Making Test and scores on the PASAT.

Although none of the cognitive scores decreased into the "impaired" range, the researchers warned that the effects were strong enough that they could affect driving.

All of the participants said they felt euphoria or somnolence. They rated their highness on a 10-point scale, and the researchers estimated that their average score increased by 1 point for every decrease of 0.32 points in pain.

Although getting high is the best-known reason for smoking cannabis, patients with pain worry that their cognitive abilities will be impaired, and they sometimes experience some paranoia, said Dr Wallace.

"I have been prescribing medicinal marijuana for the last few years, and what I'm finding with this medicinal use is they don't like the high feeling," he said. "If they do get that effect, they only use it at night because it helps them sleep."

One avenue for future research is to test cannabis with less THC and more cannabidiol than the samples used in this study, said Dr Wallace. THC causes most of the psychoactive effects, he said. "There are some patients who say cannabidiol doesn't give them pain relief. Some say it gives them really good relief."

It is also possible that THC, cannabidiol, and hundreds of other cannabinoids have a synergistic effect on pain relief, he said.

In addition to testing other formulations, he said, he would like to repeat this trial with more patients and to study cannabis in this formulation as a long-term treatment.

This study provides good support for that kind of larger trial, said Mark Ware, MD, MSc, an associate professor of anesthesia and family medicine at McGill University in Montreal, Quebec, Canada. "It's a valuable data point," he told Medscape Medical News.

One of the study's contributions is to provide more information about a dose response, Dr Ware said. "It raises the question whether using lower doses may be able to get analgesic effects without causing excessive euphoria."

A longer-term study would also help detect any effects on diabetes other than pain control, he said. For example, cannabis can increase appetite. "If someone has difficulty controlling their intake of sugar, we would want to be sure they did not exacerbate this problem."

Such information is particularly important because approximately 15% of people with chronic pain are already self-treating themselves with marijuana, said Dr Ware.

However, many challenges lie ahead for understanding how cannabis might help in diabetic neuropathy and other pain. One is that it is difficult to obtain standardized dosages. "The distribution of medicinal marijuana is very erratic," said Dr Wallace. "In California, the dispensaries have very poor quality control so we don't know exactly what the patients are getting."

Another challenge is that cannabis can be administered in so many forms, and it is hard to know which is ideal without studying all of them.

Research is difficult as well in the United States because marijuana is classified as a Schedule 1 drug, making it difficult to obtain and dispense to participants.

Dr Wallace spent 2 years obtaining approval from 6 state and federal agencies before he could begin the study, he said.

Dr Wallace disclosed that he has served on the advisory boards for Inergetics and Zynerba. Dr Ware disclosed that his institution received a grant from CanniMed.

J Pain. 2015;16:616-627. Abstract

Clinical Implications

• A small, short-duration, randomized crossover trial showed that inhaled cannabis had a dose-dependent reduction in painful diabetic neuropathy in treatment-refractory patients.
• In this crossover study, there were modest but significant reductions in cognitive test performance on the PASAT and Trail Making Test Part B. Learning, memory, and other cognitive functions have been affected in other clinical trials of cannabis.
• Implications for the Healthcare Team: Members of the healthcare team should be aware that all patients in this study experienced euphoria ("highness") or sleepiness with THC.

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