Opinions on Cannabis for Neuropathic Pain

I just saw the Clinical Psychiatry News article “Evidence poor on medical marijuana for neuropathic pain,” by Andrew D. Bowen. It was published May 2019, Vol. 47, No. 5 and I couldn’t find it on line yet.

I should also hasten to add that there are a couple of other important articles on management of pain in this issue of Clinical Psychiatry News. One of them expresses a similar opinion about the lack of clear evidence pointing to a clear best choice for a medication for neuropathic pain, “No clear winner emerges for treating for chronic pain” also by Andrew D. Bosen, who interviewed a neurologist, Dr. Raymond Price, associate professor of neurology at the University of Pennsylvania, Philadelphia about his review of the evidence for treatment of neuropathic pain.

In addition, on a more hopeful note, there is good evidence for the effectiveness of cognitive behavioral therapy (CBT) for chronic pain, “In chronic pain, catastrophizing tied to disrupted circuitry,” by Kari Oakes, who interviewed Drs. Robert R. Edwards, PhD, psychologist at Brigham and Women’s Hospital/Harvard Medical School (Boston) Pain Management Center, and Vitaly Napadow, PhD. Connectivity between certain areas of the brain can lead to the perception that pain is a part of who we are. This can even interfere with the effectiveness of pain medications.

Dr. Ellie Grossman, MD, MPH said at the annual meeting of the American College of Physicians that there’s “a lot of the Wild West” in medical marijuana research regarding its use in neuropathic pain. I got the impression she was being as diplomatic as she could when she described the level of evidence as being marked by a lot of “squishiness.”

It’s a frankly cautious comment compared with the more positive opinions expressed just a month ago in Clinical Psychiatry News. Dr. Grossman is quoted, “The upshot here is that there may be some evidence for neuropathic pain, but the evidence is generally of poor quality and kind of mixed.” Dr. Grossman is an instructor at Harvard Medical School and Primary Care Lead for Behavior Health Integration, Cambridge Health Alliance, Somerville, Massachusetts.

In fact, as the author points out, the research in this area is marked by inconsistencies in the medical marijuana formulations, small numbers of patients enrolled in studies, and equivocal results from meta-analyses.

The title of the article says it all and it’s really no surprise. I have little to add except the following very short opinion based on a very superficial scan of PubMed.

First, I happened to find a couple of papers from the mid-1970s about cannabis and pain in cancer patients. They were written by Russell Noyes, MD and Art Canter, Ph.D. and colleagues. Dr. Noyes has retired for the second time from the Psychiatry Dept at University of Iowa and Dr. Canter was enjoying his retirement until his death in October, 2018; he was in his late 90s.

Even in 1975, there was very little reason for enthusiasm about the analgesic effect of cannabis in cancer patients. Admittedly, the number of subjects were low in each study but the side effects of cannabis were severe in a few cases.

The summary from the first Noyes et al paper is essentially that, why analgesic effect was demonstrable at high dose levels, so was “…substantial sedation and mental clouding…”

In the second paper by Noyes et al, the concluding remarks are telling— “Finally, particular difficulty was experienced in evaluating the pain of patients after receiving THC. In many instances they appeared exceptionally peaceful while, at the same time, reporting little pain relief. In other instances, they claimed that, though the pain was unchanged, it bothered them less.”

There seems to be nothing new under the sun in this setting although most of the studies involved patient with chronic non-cancer pain. One study found some benefit and modest tolerability—see the caveat below (Ware et al 2015).

“In conclusion, this study suggests that the AEs of medical cannabis are modest and comparable quantitatively and qualitatively with prescription cannabinoids. The results suggest that cannabis at average doses of 2.5 g/d in current cannabis users may be safe as part of a carefully monitored pain management program when conventional treatments have been considered medically inappropriate or inadequate. However, safety concerns in naive users cannot be addressed. Moreover, long-term effects on pulmonary functions and neurocognitive functions beyond 1 year cannot be determined. Further studies with systematic follow-up are required to characterize safety issues among new cannabis users and should be extended to allow estimation of longer-term risks.”

See the abstracts below. They tend to echo Dr. Grossman’s impressions. I wonder whether the quality of the research in this area will ever be strengthened.

References:

NOYES, R., et al. (1975). “Analgesic Effect of Delta‐9‐Tetrahydrocannabinol.” The Journal of Clinical Pharmacology 15(2‐3): 139-143.

Noyes, R., et al. (1975). “The analgesic properties of delta‐9‐tetrahydrocannabinol and codeine.” Clinical Pharmacology & Therapeutics 18(1): 84-89.

            The administration of single oral doses of delta‐9‐tetrahydrocannabinol (THC) to patients with cancer pain demonstrated a mild analgesic effect. At a dose of 20 mg, however, THC induced side effects that would prohibit its therapeutic use including somnolence, dizziness, ataxia, and blurred vision. Alarming adverse reactions were also observed at this dose. THC, 10 mg, was well tolerated and, despite its sedative effect, may have analgesic potential.

Ware, M. A., et al. (2015). “Cannabis for the Management of Pain: Assessment of Safety Study (COMPASS).” The Journal of Pain 16(12): 1233-1242.

            Cannabis is widely used as a self-management strategy by patients with a wide range of symptoms and diseases including chronic non-cancer pain. The safety of cannabis use for medical purposes has not been systematically evaluated. We conducted a prospective cohort study to describe safety issues among individuals with chronic non-cancer pain. A standardized herbal cannabis product (12.5% tetrahydrocannabinol) was dispensed to eligible individuals for a 1-year period; controls were individuals with chronic pain from the same clinics who were not cannabis users. The primary outcome consisted of serious adverse events and non-serious adverse events. Secondary safety outcomes included pulmonary and neurocognitive function and standard hematology, biochemistry, renal, liver, and endocrine function. Secondary efficacy parameters included pain and other symptoms, mood, and quality of life. Two hundred and fifteen individuals with chronic pain were recruited to the cannabis group (141 current users and 58 ex-users) and 216 controls (chronic pain but no current cannabis use) from 7 clinics across Canada. The median daily cannabis dose was 2.5 g/d. There was no difference in risk of serious adverse events (adjusted incidence rate ratio = 1.08, 95% confidence interval = .57–2.04) between groups. Medical cannabis users were at increased risk of non-serious adverse events (adjusted incidence rate ratio = 1.73, 95% confidence interval = 1.41–2.13); most were mild to moderate. There were no differences in secondary safety assessments. Quality-controlled herbal cannabis, when used by patients with experience of cannabis use as part of a monitored treatment program over 1 year, appears to have a reasonable safety profile. Longer-term monitoring for functional outcomes is needed. Study registration The study was registered with http://www.controlled-trials.com (ISRCTN19449752). Perspective This study evaluated the safety of cannabis use by patients with chronic pain over 1 year. The study found that there was a higher rate of adverse events among cannabis users compared with controls but not for serious adverse events at an average dose of 2.5 g herbal cannabis per day.

Andreae, M. H., et al. (2015). “Inhaled Cannabis for Chronic Neuropathic Pain: A Meta-analysis of Individual Patient Data.” The Journal of Pain 16(12): 1221-1232.

            Chronic neuropathic pain, the most frequent condition affecting the peripheral nervous system, remains underdiagnosed and difficult to treat. Inhaled cannabis may alleviate chronic neuropathic pain. Our objective was to synthesize the evidence on the use of inhaled cannabis for chronic neuropathic pain. We performed a systematic review and a meta-analysis of individual patient data. We registered our protocol with PROSPERO CRD42011001182. We searched in Cochrane Central, PubMed, EMBASE, and AMED. We considered all randomized controlled trials investigating chronic painful neuropathy and comparing inhaled cannabis with placebo. We pooled treatment effects following a hierarchical random-effects Bayesian responder model for the population-averaged subject-specific effect. Our evidence synthesis of individual patient data from 178 participants with 405 observed responses in 5 randomized controlled trials following patients for days to weeks provides evidence that inhaled cannabis results in short-term reductions in chronic neuropathic pain for 1 in every 5 to 6 patients treated (number needed to treat = 5.6 with a Bayesian 95% credible interval ranging between 3.4 and 14). Our inferences were insensitive to model assumptions, priors, and parameter choices. We caution that the small number of studies and participants, the short follow-up, shortcomings in allocation concealment, and considerable attrition limit the conclusions that can be drawn from the review. The Bayes factor is 332, corresponding to a posterior probability of effect of 99.7%. Perspective This novel Bayesian meta-analysis of individual patient data from 5 randomized trials suggests that inhaled cannabis may provide short-term relief for 1 in 5 to 6 patients with neuropathic pain. Pragmatic trials are needed to evaluate the long-term benefits and risks of this treatment.

Ashrafioun, L., et al. (2015). “Characteristics of substance use disorder treatment patients using medical cannabis for pain.” Addictive Behaviors 42: 185-188.

            Background This study was designed to assess the prevalence and correlates of self-reported medical cannabis use for pain in a substance use disorder (SUD) treatment program. Method Participants (n=433) aged 18years and older were recruited from February 2012 to July 2014 at a large residential SUD treatment program. They completed a battery of questionnaires to assess demographics, usual pain level in the past three months (using the 11-point Numeric Rating Scale for pain), depression (using the Beck Depression Inventory), previous types of pain treatments, and lifetime and past-year use of substances (using the Addiction Severity Index). Using both adjusted and unadjusted logistic regression models, we compared those who reported medical cannabis use for pain with those who did not report it. Results Overall, 15% of the sample (n=63) reported using medical cannabis for pain in the past year. After adjusting for age, medical cannabis use for pain was significantly associated with past-year use of alcohol, cocaine, heroin, other opioids, and sedatives, but was not associated with usual pain level or depression. It was also associated with past year treatment of pain using prescription pain relievers without prescriptions. Conclusions These results indicate that medical cannabis use for pain is relatively common and is associated with more extensive substance use among SUD patients. Future work is needed to develop and evaluate strategies to assess and treat individuals who report medical cannabis for pain in SUD treatment settings.

Hefner, K., et al. (2015). “Concomitant cannabis abuse/dependence in patients treated with opioids for non‐cancer pain.” The American Journal on Addictions 24(6): 538-545.

            Background and Objectives Cannabis use is common among patients taking prescription opioids, although rates of concomitant cannabis use disorder (CUD) have been largely unexamined. CUD may increase safety risks in those taking opioid pain medications but it is unknown whether cannabis and opioids function as substitutes (cannabis use is associated with less prescription opioid use), or rather as complements (cannabis is associated with increased use of prescription opioids). Methods We examined rates of CUD in a national sample of Veterans Health Administration (VHA) patients (n = 1,316,464) with non‐cancer pain diagnoses receiving opioid medications in fiscal year 2012. Using bivariate analysis to identify potentially confounding variables associated with CUD (eg, psychotropic medication, other substance use disorders) in this population, we then utilized logistic regression to examine rates of cannabis use disorder among individuals receiving different numbers of opioid prescriptions (0, 1–2, 3–10, 11–19, 20+). Results Descriptive analysis, largely confirmed by logistic regression, demonstrated that greater numbers of prescription opioid fills were associated with greater likelihood of CUD. This relationship was reduced somewhat for those receiving the most opioid prescriptions (20+) in the logistic regression, which controlled for potentially confounding variables. Discussion and Conclusions These results warrant increased attention to CUDs among patients receiving numerous opioid prescriptions. Increasing legalization of cannabis is likely to further increase use and abuse of cannabis in patients prescribed opioids. Scientific Significance These findings suggest that clinicians should be alert to concomitant CUD and prescription opioid use, as these substances appear to complement each other. (Am J Addict 2015;24:538–545)

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