Wallace MS, Marcotte TD, Umlauf A, Gouaux B, Atkinson JH. Efficacy of inhaled cannabis on painful diabetic neuropathy. J Pain. 2015;16(7):616-627.
Randomized, double-blind, placebo-controlled crossover trial
Sixteen patients with painful diabetic neuropathy
Participants were exposed to 4 single-dosing sessions of placebo or low- [1% tetrahydrocannabinol (THC)], medium- (4% THC), or high-dose (7% THC) vaporized cannabis. A 2-week washout period was implemented between doses to minimize a carryover effect.
Primary Outcome Measures
Neuropathic pain was assessed using a visual analog scale. The primary analysis compared differences in neuropathic pain over time (5, 15, 30, 45, and 60 minutes and then every 30 minutes for an additional 3 hours) between the doses. Evoked pain was also elicited using a foam brush and pinprick with a hair filament on the dorsum of the more painful foot. Cognitive testing was performed and subjects were asked to provide a subjective “highness” score.
Study Parameters Assessed
Subjects were asked to rate their spontaneous (neuropathic) pain as well as pain evoked by the foam brush and hair filament on a 0 to 10 visual analog scale. Psychomotor speed, attention and cognitive sequencing were measured using the Trail Making Test. Attention, working memory, and information processing speed were measured using the Paced Auditory Serial Attention Test (PASAT). Subjective “highness” was assessed by asking participants to rate their feeling of being “high” on a 0 to 10 scale.
A dose-dependent reduction in diabetic peripheral neuropathy pain was seen in patients whose pain was previously refractory to treatment. There was a significant difference in pain scores between doses (P<0.001), with the highest dose (7% THC) being most effective for reducing the neuropathic pain as well as the experimental pain. The high dose, however, was also associated with impaired performance in 2 of the 3 neuropsychological tests. Euphoria and somnolence were scored as “adverse effects.” Compared to placebo, only the high-dose group reported more somnolence. Both the 4% and 7% THC doses produced statistically more euphoria than the placebo.
According to the investigators who conducted this trial, 366 million people worldwide suffer from diabetic peripheral neuropathy. They suggest that 50% of the exploding number of diabetics will develop neuropathy, with about 15% suffering pain. Clearly this is a worldwide problem of enormous magnitude, and the treatments to date are less than ideal. Hence, these findings, albeit from a very small clinical trial, provide the first suggestion that cannabis may be a useful treatment modality for this highly prevalent condition.
Cannabinoids have long been known to be effective in a rat model of neuropathic pain.1-2 That preclinical evidence has led to a number of clinical trials of cannabis in various human neuropathy syndromes. This is the 5th clinical trial funded by the University of California Center for Medicinal Cannabis Research (CMCR) assessing the effectiveness of cannabis in a neuropathic syndrome. The only legal source of cannabis for investigation in the United States continues to be the National Institute on Drug Abuse (NIDA). NIDA has a congressional mandate to only study substances of abuse as substances of abuse and not as therapeutic agents. At the end of the 20th century, the state of California had a budget surplus and designated 3 million dollars a year for 3 years to establish the CMCR that could fund studies investigating the medical benefit of cannabis, using material obtained from NIDA. Three of the CMCR trials investigated the effectiveness of inhaled (smoked or vaporized) cannabis in HIV-related peripheral neuropathy, 1 in neuropathic pain associated with spinal cord injury, and this study in diabetic neuropathy.3-6
Neuropathic pain is a vexing clinical problem. Nonsteroidal anti-inflammatory drugs are often tried but are generally ineffective. As many patients with neuropathy have chronic underlying non–life-threatening illnesses, there is a concern about treating with opiate analgesics. Opiates have also not been shown to be particularly effective. Gabapentin is often prescribed for control of neuropathic pain. In one gabapentin trial, the number of diabetic neuropathy patients who needed to be treated for one person to benefit [ie, the so-called “number needed to treat” (NNT)] was 4.0.7 Other drugs used for neuropathic pain have similar NNTs: tricyclic antidepressants (NNT=3.6), serotonin-norepinephrine reuptake inhibitors (NNT= 3.1-6.0, depending on the drug), and calcium channel agonists (NNT= 4.3-7.5, depending on dose and drug).8 Interestingly, the NNTs in the 3 CMCR trials of cannabis in HIV-related peripheral neuropathy all clustered in the 3.5 to 4.0 range. This not only suggests impressive consistency of the findings across studies, but also suggests cannabis is similar to current treatments in effectiveness. Recent meta-analyses have reviewed all the clinical trials completed to date investigating cannabis as a treatment for painful neuropathy.9-10
One area that remains unexplored, unfortunately, is the effect of cannabis in patients with chemotherapy-induced peripheral neuropathy (CIPN). As we near 14 million cancer survivors in the United States, it is important to note that a number of these patients are disabled to some extent by peripheral neuropathy that resulted from their cytotoxic chemotherapy. Preclinical evidence from animal models suggests that cannabis may be particularly useful in chemotherapy-induced peripheral neuropathy. The 3 most frequent classes of drugs leading to CIPN are vinca alkaloids, platinum agents, and taxanes. In rodent models, cannabinoids were effective in not only treating neuropathy, but also in preventing its development.11-13 Clearly, a clinical trial needs to be done. To date, 1 small placebo-controlled cross-over study has investigated the whole plant extract nabiximols (Sativex) as a treatment for CIPN.14 Although there was a trend for improvement in those using the sublingual sprayed nabiximols versus placebo, statistical significance was not reached. Five of the 16 participants overall were deemed responders, and this, combined with the trend for improvement, suggests a larger trial should be conducted.
In the current study, the pain-relieving effect of the high-dose cannabis was significantly better than placebo at the 30-, 45- and 60-minute time points. That is good news and bad news. It suggests that the onset of action is rapid. At later time points, however, pain decreases were not different than what was seen in the placebo recipients. This suggests that the benefit of the vaporized cannabis was short-lived. This would dictate using a frequent dosing regimen for sustained analgesia or perhaps considering an oral delivery system that might have a longer time to effect onset but a more prolonged benefit.
The investigators involved in the CMCR diabetic neuropathy study are all based at the University of California San Diego site where there is significant interest in studying the neuropsychiatric effects of cannabis. Hence there was quite a bit of testing that demonstrated that patients get high inhaling cannabis. One could question, however, the classification of euphoria and somnolence as “adverse effects.” Is it our Puritanical heritage that makes us define euphoria as “adverse”? Certainly for people suffering from chronic refractory pain, a little euphoria may go a long way. Of interest, if one carefully looks at the data, 56% of the placebo group reported euphoria. That’s not a bad placebo! Although the cannabis placebo from NIDA reportedly has all of the cannabinoids extracted, it still likely contains terpenoids and flavonoids and they, perhaps, could be making the placebo group happy. There was a linear dose response with euphoria noted in 67% of the 1% THC group, 87% of the 4% THC group and 100% of the 7% THC group. Somnolence as an adverse effect is also questionable in a group of patients with chronic pain, for whom sleep quality can be a challenge.
This study adds to the growing body of evidence that cannabis is effective in the treatment of neuropathic syndromes. It is unfortunate that the sample size was so small, considering the abundance of diabetics available for a larger study. The dose response was encouraging and could have been even more robust had not 60% of the placebo group reported a reduction in pain. Again, the placebo cannabis still contained terpenoids and flavonoids, which may have some of their own analgesic effects. Future studies of cannabis in neuropathy should also attempt to assess the role of cannabidiol (CBD) in pain relief. CBD is gaining popularity in cannabis therapeutics as it is analgesic and anti-inflammatory without being psychoactive.15 Many patients are querying whether they can use CBD-rich cannabis for their neuropathy instead of THC. The study waiting to be done would compare a THC-rich strain, to a CBD-rich strain to a strain with both THC and CBD in an attempt to answer this important question. The body of evidence suggesting cannabis is beneficial for peripheral neuropathy continues to grow. Meanwhile, we as healthcare providers, have a duty to bring this evidence to our patients who are suffering. Cannabis is listed as a Schedule I substance and is only available as a medicine in select states. By definition, schedule I drugs are substances without medical use. It appears the time has come to acknowledge there is medicinal use of the plant. Perhaps, someday soon, science will guide a change in policy.
- Herzberg U, Eliav E, Bennett GJ, Kopin IJ. The analgesic effects of R(+)-WIN 55,212-2 mesylate, a high affinity cannabinoid agonist, in a rat model of neuropathic pain. Neurosci Lett. 1997;221(2-3):157-160.
- Rahn EJ, Hohmann AG. Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside. Neurotherapeutics. 2009;6(4):713-737.
- Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 2007;68(7):515-521.
- Wilsey B, Marcotte T, Tsodikov A, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain. 2008;9(6):506-521.
- Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology. 2009;34(3):672-680.
- Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, Donaghe H. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain. 2013;14(2):136-148.
- Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA. 1998;280(21):1831-1836.
- Jefferies K. Treatment of neuropathic pain. Semin Neurol. 2010;30(4):425-432.
- Deshpande A, Mailis-Gagnon A, Zoheiry N, Lakha SF. Efficacy and adverse effects of medical marijuana for chronic noncancer pain: Systematic review of randomized controlled trials. Can Fam Physician. 2015;61(8):e372-381.
- Andreae MH, Carter GM, Shaparin N, et al. Inhaled cannabis for chronic neuropathic pain: an individual patient data meta-analysis. J Pain. 2015 Sep 8. pii: S1526-5900(15)00812-3. [Epub ahead of print]
- Rahn EJ, Makriyannis A, Hohmann AG. Activation of cannabinoid CB1 and CB2 receptors suppresses neuropathic nociception evoked by the chemotherapeutic agent vincristine in rats. Br J Pharmacol. 2007;152(5):765-777.
- Khasabova IA, Khasabov S, Paz J, Harding-Rose C, Simone DA, Seybold VS. Cannabinoid type-1 receptor reduces pain and neurotoxicity produced by chemotherapy. J Neurosci. 2012;32(20):7091-7101.
- Ward SJ, McAllister SD, Kawamura R, Murase R, Neelakantan H, Walker EA. Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT(1A) receptors without diminishing nervous system function or chemotherapy efficacy. Br J Pharmacol. 2014;171(3):636-645.
- Lynch ME, Cesar-Rittenberg P, Hohmann AG. A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. J Pain Symptom Manage. 2014;47(1):166-173.
- Mechoulam R, Parker LA, Gallily R. Cannabidiol: an overview of some pharmacological aspects. J Clin Pharmacol. 2002;42(11 Suppl):11S-19S.