Chronic pain: Cannabinoids help??

 The Agency for Healthcare Research and Quality (AHRQ) just published a living systematic review on cannabis and other cannabinoid treatments for chronic pain (see https://effectivehealthcare.ahrq.gov/products/plant-based-chronic-pain-treatment/living-review#toc_js_2 for the webpage and https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/plant-based-chronic-pain-review-q2.pdf for the document.). This is considered a “living” systematic review since it will be updated regularly with new published literature. So, I am including the 1st link which gets to the general webpage and has links to all of the recent (and future) analyses, and the 2nd link is to the most current PDF (February 2021 update). A 3rd update/progress report is scheduled for late May 2021

 

This review adds 6 additional RCTs to the prior report of 14 RCTs of cannabis-related products and 3 observational studies, for a total of 23 studies including both 7 RCTs on products that contained a combination of THC (tetrahydrocannabinol) and CBD (cannabidiol), 3 on the effects of plant-derived THC alone, and 8 evaluating synthetic forms of THC. There also is a new study on the effect of topical CBD alone and another that evaluated CBDV (cannabidivarin)

 

Key Question 1 (KQ1): in adults with chronic pain, what are the benefits of the cannabinoids for treatment of chronic pain? 

KQ2: in adults with chronic pain, what are the harms of cannabinoids for treatment of chronic pain? 

 

-- 7 studies (6 from prior review, one new one with just 16 patients ), risk of bias was high in 29%, moderate in 57%, low in 14%; 882 patients, mean of 126 per study; mean age 56; female 67%; 1.6% nonwhite; neuropathic pain in 6, and rheumatoid arthritis in 1; durations 4-15 weeks

-- combination of THC and CBD vs placebo; all of the studies used an oromucosal spray with 2.7mg of THC and 2.5mg of CBD per 100 mcl

-- median daily dose of 8.4 sprays for those on cannabis and 12.7 sprays for those on placebo [ie, 50% more sprays with placebo, which by itself suggests that the cannabis worked better than placebo]

-- 3 studies on THC alone: risk of bias moderate in 67%, low in 33%; 362 patients (mean 121); mean age 52;  female 79%; non-white 1.6%; neuropathic pain in 1, visceral pain in 1, fibromyalgia in 1; study durations 7 to 12 weeks

 

-- results for pain reduction:

    -- 2 trials reported significantly more patients achieved response (> 30% reduction in pain) with THC/CBD

    -- 3 trials reported significantly lower pain severity

    -- 2 trials reported small but not statistically significant reduction in pain

-- results for sleep:

    -- 4 trials reported significant improvement in sleep (though function or disability and quality of life were not clearly improved)

-- adverse effects:

    -- 2 trials reported more adverse effects with a combination of THC/CBD: dizziness, nausea, and sedation

 

-- Plant derived Delta-9-THC by itself:

    -- Initial report of 2 RCTs (344 patients with chronic pain), total final dose after titration to 15 to 24 mg in one study and 25 mg in the other. All trials lasted 7 to 15 weeks.

        --One additional trial of patients with fibromyalgia was added to the group, an RCT of 17 patients with fibromyalgia. Lower risk of bias, 8-week study, sublingual THC oil. This study did involve a combination THC/CBD, but the amount of CBD was considered inadequate for a response. This was not a great report, with several problems including the fact that 25% of the patients had been on opiates, and there was no comment on additional medications (including opiates) during the study

-- results for plant-derived THC by itself (total of the 3 studies):

    -- difference overall not statistically significant, though one study did have a large absolute difference favoring THC (numbers not reported)

    -- the fibromyalgia study did find significant improvements with THC vs placebo; improvement, per the Fibromyalgia Impact Questionnaire, was with THC for pain interference, though in physical functioning there was a very small difference

    -- pain severity: small difference, not statistically significant

    -- more dizziness, nausea, sedation with the THC

 

-- Synthetic Delta-9-THC, 6 RCTs in the initial report with 416 people, and 2 more in this 2nd progress report:

    -- initial report: 2 reports evaluated dronabinol (titrated to maximum dose of 15 -20mg) and 4 evaluated nabilone (maximum dose 0.5-2mg) for chronic pain, studies lasting from 5 to 14 weeks. Trials had low to moderate risk of bias

        -- the designs of these studies were quite different, one added nabilone vs placebo to gabapentin to those not achieving pain relief, 3 others were crossover design comparing to diphenhydramine, ibuprofen, and dihydrocodeine

        -- compared to placebo, one trial found synthetic THC was significantly better in pain response (>30% improvement, large difference), the others did not report this outcome.

        -- for improvement in pain severity, dronabinol was nonsignificantly better, while nabilone achieved statistical significance (moderate difference in effect).

        -- adverse effects: 3 RCTs had people withdrawing from the study in the medication group because of adverse reactions, and one noted serious adverse effects. Dizziness and sedation were the most common adverse effects

    -- 2nd report, 2 more trials with a total of 51 people, moderate to high risk of bias, duration less than 6 months.

        -- Pain severity decreased with nabilone (Moderate difference)

        -- one of the studies included 50 people with fibromyalgia, finding significant improvement in the Fibromyalgia Impact Questionnaire in those on nabilone (-12.07, p<0.02)

        -- higher incidence of withdrawals because of adverse med effects in one of the 2 trials. Increased sedation in both

 

-- Cannabidiol (CBD) and cannabidivarin (CBDV)

    -- a single study for each, both in the 2nd report

        --CBD: a single small study of 29 people using topical CBD oil in patients with neuropathic pain, high risk of bias (many details not reported), randomized to CBD cream (250 mg/3 ounces) vs placebo, using up to 4 times a day (total dose not reported)

            -- significant decrease in pain intensity with CBD, but a small difference

        --CBVD: a single study of 32 people given CBDV, including patients with HIV-related chronic pain, randomized to oral CBVD oil (50 mg per mL) dosed at 8 mL daily or placebo oil for 4 weeks

            -- no difference in pain severity and fewer patients achieved a >30% reduction in pain with the CBDV (i.e. a large difference, favoring placebo)

            -- no difference in anxiety, depression, or insomnia, though more patients did report an adverse effect from the CBDV

 

KQ3: in adults with chronic pain, what are the benefits of kratom or other plant-based substances for treatment of chronic pain?

KQ4: in adults with chronic pain, what the harms of kratom or other plant-based substances for treatment of chronic pain?

-- No evidence was identified

-- there have been concerns expressed about kratom, see http://gmodestmedblogs.blogspot.com/2018/02/crystal-meth-and-kratom-opioid.html and http://gmodestmedblogs.blogspot.com/2016/01/2-blogs-in-1-kratom-and-repeated-opioid.html

 

Commentary:

-- it is great to have ongoing, “living” systematic reviews such as this one, incorporating new studies as they come out. This was invaluable especially in the early hepatitis C treatment days when the AASLD (American Association for the Study of Liver Diseases) along with the Infectious Diseases Society of America incorporated new studies into a single document, highlighting the most recent studies [this would be great with Covid 19, though a daunting task since there are around 2500 new articles being printed weekly, and many pre-print, pre-peer review]

-- the compilation on cannabinoids above does suggest a few concerns:

    -- there have not been many studies done overall. And, this is really concerning given the huge prevalence of chronic pain in our society, the high level of personal disability from the pain, the inadequacy of many of our current therapies in treating chronic pain, the profound desire by many chronic pain sufferers to find anything that will relieve their pain, and the availability as well as the promotion of cannabinoids as a potential therapy in social media and (it seems, per patient requests) quite pervasively. There is clearly a large lacuna in our knowledge, as well as our ability to treat people maximally

    -- the studies that do exist, as above, our overall not very good. There’s lots of missing information (e.g. the use of other meds for pain relief, including opiates in some studies), differences in outcomes assessed and the quality of that assessment, and generally the integrity of the study themselves (many have pretty high risk of bias)

    -- and, the studies were quite short-term, limiting our understanding of the benefits as well as adverse effects to these cannabinoids

-- in general, the benefits of cannabinoids in those studies showing benefit was not large (though that is also true for many of our current drugs as well)

-- the not-so-great studies on nabilone did find at least moderate improvements in pain, and it would be great to have a rigorous study looking at this (those of CBVD and dronabinol were disappointing)

-- the single trial on CBD alone was very small, had very high risk of bias, and found a very small difference in pain and effect. Again, a rigorous trial would be useful, especially given the apparent frequency of CBD usage in the community

-- and, of course, there were pretty consistent adverse effects in the use of cannabinoids, with several RCTs reporting patients dropping out of the studies because of these adverse effects

    -- one concern is the placebo effect with cannabinoids: since there seem to be significant differences in adverse effects between the meds and placebo, those having adverse effects may feel that they are getting the active drug and might bias their responses to the drug (ie, perhaps have a stronger "placebo" effect to the drug than to the actual placebo)

 

so, it seems to me that there are enough studies suggesting that there might well be benefit from cannabinoids (perhaps some more than others) that there really should be large, well-designed RCTs to assess their real value. Especially so in light of the above comments: chronic pain is a really common issue, it results in huge disability for those afflicted, we have very poor ability to adequately treat chronic pain, there often should be a multidimensional approach (nonpharmacologic as well as pharmacologic treatments), and certain cannabinoids may be part of that even if they are not fully effective as a single agent.  But we just need more data......


see http://gmodestmedblogs.blogspot.com/2020/10/sciatica-early-pt-helps-longterm.html , which refers to other blogs on nonpharmacologic effective therapies (such as mindfulness, stress reduction, CBT, yoga)


geoff

 

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For access to the dropbox, go to link: https://www.dropbox.com/sh/0bmvtita8mzms11/XDTwHySFFg

Then go to "clinic", then to "clinical stuff" for articles, or go to https://www.dropbox.com/sh/nyle22q1fn6lkpk/AAB9B2hBj5Kw4gtrJAkI-UF8a?dl=0 for the powerpoint presentations

 

to get access to all of the blogs (2 options):

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or: go to https://www.bucommunitymedicine.org/ , a website from the Community Medicine section at Boston Medical Center.  This site does have a very searchable and accessible list of my blogs (though there have been a few that did not upload over the last year or two). but overall it is much easier to view blogs and displays more at a time.

 

 

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