Welcome back, this is the final article of the 3 Part series on The Use of Medical Cannabis for Neuropathic Pain.
While many clinical studies have examined cannabis use, the research has been hampered by FDA regulations effectively prohibiting preclinical and clinical research on the botanical product that is now sold commercially in many states. All research has been conducted through National Institute on Drug Abuse (NIDA), using only cannabis grown at a lab they contract with (DEA monitored) in Mississippi. Understandably, these strains have been unchanged since the 1970s and there is no plan to commercialize them.
Translational research, the study of compounds in animals first to learn how best to use them before testing them in man is a gold standard in drug development. Paradoxically, qualified patients in medical cannabis states can buy an assortment of cannabis products, but FDA and DEA regulations have made it impossible for those products to be tested in animals and humans. In addition, the commercially available medical cannabis products are very different from the unformulated botanical products from NIDA used in the limited animal and human testing. For most conditions, we do not know if THC or CBD or yet another minor cannabinoid is the most effective agent within the cannabis (leading many commercial products to a 1:1 ratio). And we are not able to study formulations to determine how best to “dose”. For example, pain patients often use topical forms (e.g., transdermal patches and creams) and prefer edibles and pills to control their chronic symptoms and only use “vape” or tincture for breakthrough pain. This has led to a lack of scientific rigor that makes it hard to effectively translate benefit to policy makers, health care providers and state health officials.
FDA Approved Drugs (Pharmaceutical Cannabis) Use Synthetic Cannabinoids, Not Botanical Cannabis
The FDA has not yet approved botanical marijuana as a safe and effective drug for any indication. The agency has, however, approved two drugs containing dronabinol, a synthetic version of the THC that is present in the marijuana plant. Marinol, or dronabinol is the pill form of a synthesized version of Delta-9 THC that was first approved in 1985 to treat AIDS patients with appetite loss and cancer patients with nausea. More recently, dronabinol in liquid form (Syndros) was approved by the FDA, with hopes that the liquid form may be easier for the body to absorb than the pill form.
The FDA has also approved one other drug containing a synthetic THC-like compound that is not actually present in marijuana. Cesamet (nabilone) was originally approved by the FDA for use in the treatment of nausea and vomiting in patients undergoing cancer treatment. It would appear that for nausea and vomiting and appetite loss in cancer and AIDS patients, THC-like compounds have been shown to be effective.
These approved cannabinoids drugs have now been classified as Schedule III drugs, meaning the FDA essentially considers it to be safe and have a low risk for abuse. Regular botanical marijuana, on the other hand, remains rated by the FDA at the highest risk for abuse and safety, as a Schedule I drug (alongside heroin and MDMA), which severely limits the ability to study it in animals and humans.
Medical Cannabis sold in the U.S. is derived solely from Botanical Product
Although the FDA has not yet approved any drug product containing or derived from botanical marijuana, the basis for all products that are used as state-regulated medical cannabis is botanical marijuana. The only botanical product that has ever been studied in animals or humans in the US was cannabis flower grown at the University of Mississippi and provided by the National Institute on Drug Abuse (NIDA) and it was smoked or “vaped”. Because this cannabis has no plans for commercialization in the US, there is no translational clinical research happening in the US.
The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research
To help health care providers and government officials digest the data published to date, the National Academies of Sciences, Engineering, and Medicine recently released (Jan 12, 2017) their review “The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research”.
This anticipated document reviewed scientific evidence related to the health effects and potential therapeutic benefits of cannabis. They evaluated the published evidence from clinical trials in various medical conditions and rated the evidence as substantial, moderate or limited for each. The authors are also quick to remind us that their conclusions are not about whether cannabis works for an indication, but whether the data from clinical trials has provided evidence.
There is conclusive or substantial evidence cannabis is effective for the treatment of chronic pain in adults!
The report only made this determination for only 3 conditions, so this is very important in how chronic pain can be treated and studied going forward.
This indication had more data (studies conducted) than any other, with 28 randomized trials involving a total of 2,454 patients with chronic pain. In these trials, the medical condition being studied, or underlying the chronic pain was most often related to a neuropathy (17 trials); other conditions included cancer pain, multiple sclerosis, rheumatoid arthritis, musculoskeletal issues, and chemotherapy-induced pain
The majority of studies on pain in the report were conducted outside the US and evaluated nabiximols (trade name Sativex) a specific extract of Cannabis in a THC: CBD ratio of 1:1 delivered as a mouth spray. Sativex is approved in some European countries for neuropathic pain, spasticity, overactive bladder, and other symptoms of multiple sclerosis. The product used in the US studies was NIDA provided cannabis flower.
Thus, while the use of cannabis for the treatment of pain is supported by well-controlled clinical trials as reviewed above, very little is known about the efficacy, dose, routes of administration, or side effects of commonly used and commercially available cannabis products in the United States. Trials that evaluated synthetic cannabinoids suggested that plant-derived cannabinoids (which is the only product available commercially in the US) increase the odds for improvement of pain, which supports what patients tell us about the “entourage effect” of the minor cannabinoids or terpenes in botanical cannabis that add efficacy. Smoked preparations with a higher content of THC (up to 7-8%, which is the highest NIDA product available) also seemed to be more effective, but those preparations also included CBD as well.
A sample of trials of patients with Neuropathic Pain.
STUDY DESCRIPTION RESULT Smoked Medicinal Cannabis for Neuropathic Pain in HIV: A Randomized, Crossover Clinical Trial – Ellis et all,
34 patients Cannabis (smoked, 1%-8% THC) vs. Placebo; all patients cannabis crossover Significant decrease in pain intensity with cannabis over placebo, (p=0.02) Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. – Abrams et al,
27 patients Cannabis (smoked, 3.56% THC) vs. 28 Placebo patients 52% cannabis group vs. 24% placebo reported >30% decrease in pain; significant (p=0.04) No serious adverse events were reported. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain – Wilsey et al,
J Pain. 2008;9(6):506-521
38 patients Cannabis (smoked, 7% THC) vs. Placebo; all patients cannabis crossover Significant decrease in pain severity with cannabis over placebo, (p=0.02) Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. – Nurmikko et al,
63 patients Nabiximols: THC (30mg)/cannabidiol (27.5mg) oromucosal spray vs. 62 Placebo patients Significant decrease in pain intensity with THC:CBD over placebo, (p=0.004) Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. -Berman et al,
48 patients Nabiximois: THC (129.6mg) /cannabidiol (120mg) oromucosal spray vs. Placebo; all patients cannabis crossover Significant decrease in pain severity with THC:CBD (p=0.005) and THC alone (p=0.002) compared to placebo
Excerpted from Hill, KP JAMA. 2015;313(24):2474-2483.
Practical Recommendations for Cannabis Usage
Although CBD and THC act differently in the body, they seem to have many of the same medical benefits. Unfortunately, most of this evidence comes from animals, since very few studies on cannabis have been carried out in human patients. The important result from preclinical animal models for neuropathy patients is that in rats, THC and CBD have been shown to be neuroprotective antioxidants. Many of the medical benefits of cannabis are attributed to the CBD content, particularly the strong anti-inflammatory and anti-seizure properties.
Potential Therapeutic properties of Medical Cannabis for Neuropathic Pain Depend on the Effect Required and Other Factors
- “Opiate-type Pain relief”
- Neuropathic Pain relief
- Patient Specific
Ratios most beneficial for Neuropathic Pain is patient specific
- Minimal THC may be better for THC naïve patients, or patients wanting to avoid THC related side effects
- Increased THC may be beneficial for patients using opiates for pain, or experiencing insomnia related to pain
Low THC: V. High CBD
- Treatment of Neuropathic pain for patients wanting to avoid THC-related side effects
- Treatment of Neuropathic pain in THC naïve patients
1:1 Equal THC/CBD
- Treatment of Neuropathic pain in patients who use opiates to treat pain
High THC:Low CBD
- Severe pain relief & sleep
- For patients who use opiates to treat pain
- Patients may experience insomnia from the use of CBD’s
Given the availability of cannabis products now in much of the nation, more research is needed on the various forms, routes of administration, and combination of cannabinoids that would provide effective relief at the lowest doses.
Other Conditions Treatable With Cannabis
Per The NASEM Review
You might enjoy learning about the amount of evidence that exists for cannabis usage in other conditions. Where a particular type of cannabinoid product was used in the trials that produced the evidence, it is noted.
Conclusive or Substantial evidence that cannabis is effective:
- anti-emetics in the treatment of chemotherapy-induced nausea and vomiting (oral cannabinoids, THC)
- improving patient-reported multiple sclerosis spasticity symptoms (oral cannabinoids, THC)
Moderate Evidence that cannabis effective for:
- Improving short-term sleep outcomes in individuals with sleep disturbance associated with obstructive sleep apnea syndrome, fibromyalgia, chronic pain, and multiple sclerosis (cannabinoids, primarily nabiximol
Limited evidence that cannabis or cannabinoids are effective for:
- Improving symptoms of Tourette syndrome (THC capsules)
- Improving anxiety symptoms, as assessed by a public speaking test, in individuals with social anxiety disorders (CBD)
- Improving symptoms of posttraumatic stress disorder (nabilone; one single, small fair quality trial)
There is limited evidence of a statistical association between cannabinoids and:
- Better outcomes (i.e., mortality, disability) after a traumatic brain injury or intracranial hemorrhage
There is limited evidence that cannabis or cannabinoids are ineffective for:
- Improving symptoms associated with dementia
- Improving intraocular pressure associated with glaucoma
- Reducing depressive symptoms in individuals with chronic pain or multiple sclerosis (nabiximols, dronabinol, and nabilone)
There is insufficient evidence to support or refute the conclusion that cannabis or cannabinoids are an effective treatment for:
- Cancers, including glioma
- Cancer-associated anorexia cachexia syndrome and anorexia nervosa
- Symptoms of irritable bowel syndrome
- Epilepsy (cannabinoids)
- Spasticity in patients with paralysis due to spinal cord injury
- Symptoms associated with amyotrophic lateral sclerosis
- Chorea and certain neuropsychiatric symptoms associated with Huntington’s disease
- Motor system symptoms associated with Parkinson’s disease or the levodopa-induced dyskinesia
- Achieving abstinence in the use of addictive substances
- Mental health outcomes in individuals with schizophrenia or schizophreniform psychosis
In Part 1 of this series on “Medical Cannabis for Neuropathic Pain”, we discuss the use of medical cannabis today by neuropathic pain patients. You can read the first of this series “Medical Cannabis for Neuropathic Pain – Part 1 of 3” by clicking here.
In Part 2 of this series on “Medical Cannabis for Neuropathic Pain”, we discuss the active ingredients of medical cannabis. Animal studies show that the effects (both positive and negative) from medical cannabis are predictable and undeniable. You can read the second article of this series “Medical Cannabis for Neuropathic Pain – Part 2 of 3” by clicking here.
We hope you enjoyed reading this series on the exciting and ever changing world of medical cannabis in the U.S. Research results on strain efficacy and usage continues to emerge from trials around the world, and we will report them when they come in. Until then, stay well and talk to your physician about all possible therapies available in your state.
Should you have any questions and/or comments, I encourage you to contact the Neuropathy Journal, and/or myself by clicking here or by commenting below.