Non-Pharmacological and Natural Treatments for Nerve Pain, Part 3

 

Does cannabis relieve nerve pain? The third part of this article series will provide an introduction to world of cannabinoids and the scientific implications for neuropathy pain management!

This is the third part of the blog series on non-pharmacological and natural treatments for nerve pain. The first article discussed diet and exercise, and the second article explored which supplements have evidence of efficacy. A collaborative scientific article I co-authored, serves as the primary reference source for this blog series. If you are unable to view the official published article via digital library access, please click here for the Word/Google Docs version of the article. 

This specific article includes mostly bonus information, not published in our journal article. This blog contains health education information but is not intended to diagnose or treat any medical condition. I'm acting in the capacity of a medical writer, not as a treating medical doctor. 

Cannabis medicine is a controversial topic. This article only provides an introduction and does not delve deep into the many nuances of cannabis for chronic pain management. The safest effective use and long-term health effects of cannabis for chronic pain are largely unknown at this time.

--Danielle Zelnik, MD, ABPMR, ABOIM (blog author, review article co-author)
  IMHealth.blog
  drzelnikmd.com

Cannabis Has Come A Long Way...5,000 years later

A super-condensed history & perspective

Knowledge of the medicinal properties of cannabis sativa plant originated thousands of years ago in ancient China [1]. Identification and isolation of plant-derived chemical compounds, called phytocannabinoids, began at the end of the 19th century with cannabinol (CBN) [2]. Science later caught up with the isolation of cannabidiol (CBD) and the plant's main active chemical constituent, Δ(9)-tetrahydrocannabinol (THC) [2, 3]. 

In modern times, cannabis gained popularity as a mind-altering recreational drug, commonly referred to as marijuana (as well as other slang names). Scientific discoveries identified THC as the main phytocannabinoid responsible for the plant's psychological effects and recognized CBD, a non-psychoactive phytocannabinoid, for its anti-inflammatory, anti-convulsant, and anti-tumor properties (among many others). Identification of over 80 phytocannabinoids opened the door further into the mysteries of this ancient plant. Serious public interest followed, and American society's attitude toward the cannabis plant changed dramatically over the past twenty years. 

Medicinal cannabis use has become popular among those with chronic nerve pain in recent years. Currently legal in some form in 42 US states, cannabis can no longer be ignored by medical pain management providers. We, as providers, struggle to properly advise our patients on safe use of non-pharmaceutical cannabis and cannabis-derived products. These challenge arise due to lack of clear safety and quality standards for formulations, dosing, and long-term treatment. 

Due to legal and regulatory issues, clinical trials involving bioactive ingredients derived from or inspired by the cannabis plant lagged for years behind animal and basic science studies. Fortunately, a group of cannabinoid medications have been extensively studied and approved for a variety of medical conditions, such as chemotherapy induced nausea and vomiting. 

Our Body Produces It's Own Cannabinoids

Further, the body's biological responses from its own homemade (endogenous) cannabinoid and cannabinoid-like molecules continue to be uncovered. The body's endocannabinoid system and extended pathways, referred to as the endocannabinoidome, provide the key to understanding how cannabinoids can modulate pain in the body [4]. Understanding these pathways furthers the development of new pharmaceutical drugs to treat pain refractory to our current prescription pain medications. 

Meet the Body's Endocannabinoids

The endocanabinoid system contains receptors, ligands, and the enzymes that construct or break down the molecules [4]. The endocannabinoid system regulates more than just pain; however, its other functions will not be covered in this article.

First, some definitions:

Receptors=Docking stations on cells where the body’s own molecules land and bind causing a chemical reaction in the body. Pharmaceutical drugs are designed to imitate our body's own molecules, which fit with and bind to these receptors.

• Endocannabinoidome Receptors [4,5]
• Many receptors interact within this complex system; the ones named below are highlighted for their role in pain regulation.
• The main receptors in the endocannabinoid system are referred to as CB1R and CB2R.
• CB1 receptors are the most common endocannabinoid receptors in the nervous system.
• CB2 receptors are abundant in the immune system.
• TRP receptors (for example, TRPV1) initiate nervous system responses to heat, cold, and a variety of stimuli that produce strong sensations in the body, often interpreted as uncomfortable or painful.

Ligands=The body’s molecules which bind to receptors. Each receptor has a customized shape that will allow only certain ligands to bind.

• Endocannabinoid Ligands [4,5,6]
• The body’s two main endocannabinoid ligands that have an affinity to and bind with endocannabinoidome receptors are N-arachidonoylethanolamine (referred to as anandamide or AEA) and 2-arachidonoylglycerol (2-AG).
• These ligands are made on demand from available fatty acids in the body.
• AEA and 2-AG can bind to other receptors within the system, besides the ones highlighted above.

How do these molecules regulate nerve pain?

Injured nerves produce and release AEA and 2-AG, which bind with various receptors in the brain and at the nervous system's periphery, initiating a number of chemical reactions that reduce inflammation, pain signals, and pain sensitivity at multiple levels of the nervous system [7,8]. AEA activates CB1R, which has been proposed to be central in modulating pain signals. 2-AG has been suggested to reduce pain signals traveling back down from the brain (termed descending inhibition) [8]. CB2R also plays a role in reducing peripheral hypersensitivity (termed, allodynia) in animal models of nerve pain; however, its effects are less known than those of CB1R [9]. 

Future targets for drug therapy could include those that inhibit the enzyme that breaks down AEA and similar active endocannabinoid ligands or enhances the transport of these ligands to their target sites [7]. Non-drug therapy could consist of activating the system through tactile or electrical stimulation, such as targeting specific acupressure or acupuncture-like points on the body's surface. 

Aside from reducing nerve pain, there is evidence that widespread activation and proliferation of the endocannabinoid system does not always produce good effects in the body. Increased CB1R activity has been associated with liver and cardiac disease, among other pathological states [5,6]. The endocannabinoid system closely links to addiction and reward centers in the brain, and certain low dose exposures to cannabinoids may even enhance tumor growth [6]. 

These complex and often contradictory interactions within the endocannabinoidome confounds even experts, but continued study will likely yield the next generation of chronic pain treatments.

In the case of cannabis...does it relieve nerve pain?

The short answer is YES, cannabis appears to relieve nerve pain. Basic science studies show that the cannabis extract, THC (and to a lesser degree, CBD) reduces nerve pain signaling. THC binds CB1R and TRPV1 to produce effects linked to nerve pain relief [4,7]. CBD does not typically bind CB1R or CB2R, but, instead interacts with other receptors, such as those from the TRP class [4,7]. THC and CBD appear to desensitize nerve endings via their interactions with TRP [4]. CBD is not psychoactive, and does not appear to produce a strong pain relief effect when used alone.  However, CBD has potent anti-inflammatory and antioxidant properties that can indirectly aid in pain reduction or lessening other effects of nerve injury. It also likely inhibits the breakdown of AEA.

Keep in mind that the cannabis plant contains a multitude of phytocannabinoids, besides just THC and CBD. The whole plant also contains terpenes, which could have important pain relief effects on their own or in combination with the other biologically active plant compounds.

Also, while there is evidence cannabis relieves nerve pain, it remains to be proven whether this information bears any clinical significance in the actual management of nerve pain (that is: real life scenarios). See the section below for more insight into this.

Whole Plant Cannabis, THC, & CBD

Medicinal cannabis and its main chemical components, THC and CBD, are currently available via dispensaries in either whole plant form or as extracts. THC produces pain-relief effects in a narrow dosing window before limiting side effects start to occur [8]. Unfortunately, the side effects of the THC significantly limit its potential for therapeutic use in pain management. Potential THC side effects of cognitive impairment and psychosis, not to mention drug dependence, raise concerns regarding the safety and tolerability of high-dose THC preparations for treatment of refractory nerve pain [5]. CBD is thought to modulate the side effects of THC, making it more tolerable. An example of this is the drug for multiple sclerosis spasticity and pain, Sativex (nabiximols), which contains THC and CBD in a ratio of 1:1 [6].

Studies of Cannabis for Nerve Pain

There are a small number of clinical studies investigating different formulations of cannabis for chronic nerve pain, including various THC concentrations in smoked whole plant, isolated THC+CBD, plant-derived THC, and synthetic THC. These studies suggest that patients can benefit from cannabis for neuropathic pain relief, however; use is still accompanied by expected dose-dependent side effects [10, 11, 12]. The variety of formulations used in the studies present a challenge for comparing and analyzing data among studies. 

A 2015 systematic review and meta-analysis of patient clinical trials looked at 28 chronic pain studies with the majority testing plant-derived cannabinoids and predominantly studying neuropathic pain. Only 8 studies were used for the final analysis figure showing moderate quality evidence for pain reduction of 30% compared to placebo. Of note, all 8 pain studies analyzed, except one, used the drug nabiximols [11]. 

The 2018 systematic review of patient clinical trials yielded 16 low quality clinical trials of 1750 participants showing moderate quality evidence (in 10 of the studies) that cannabis-based medicines increased the number of participants achieving at least 30% pain relief over placebo [12]. 

Unfortunately, there is no long-term outcome data regarding benefits or side effects of cannabis use and further investigation is needed. 

An Endocannabinoid-Like Supplement For Pain 

Palmitoylethanolamide (PEA) is an endogenous fatty acid similar to the body's own endocannabinoid, AEA. PEA does not bind CB1R or CB2R but interacts with other receptors to modulate indirectly modulate pain [7, 13]. Thus, PEA demonstrates anti-inflammatory and pain relieving properties. PEA is classified in Europe as a “food for special medical purposes” and is available in micronized and ultra-micronized preparations. High-quality PEA supplements are difficult to locate within the United States and could present a challenge if clinician and patient decide to pursue a therapeutic trial. A 2016 PEA metanalysis for treating chronic pain pooled data from 12 trials, including a subset of 56 patients with PPN [14]. A dose of ultra-micronized oral PEA of 1,200 mg daily was used in the neuropathic pain studies. Serious adverse effects related to PEA were not reported in any of the studies. Despite finding of significant pain reduction in both PEA and control groups, pain reduction in the PEA group was significantly greater than controls, and that effect increased with continued treatment over time [14].

Conclusion

Cannabinoids demonstrate evidence that they can relieve nerve pain. Controversies and legalities aside, endocannabinoid and phytocannabinoid research needs to continue in order for any major breakthrough to occur in understanding and effectively treating chronic nerve pain.  

References

1. Hill KP, Palastro MD, Johnson B, Ditre JW. Cannabis and Pain: A Clinical Review. Cannabis Cannabinoid Res. 2017;2(1):96-104. Published 2017 May 1. doi:10.1089/can.2017.0017

2. Kalant H. Medicinal use of cannabis: history and current status. Pain Res Manag. 2001 Summer;6(2):80-91. doi: 10.1155/2001/469629. PMID: 11854770.

3. Gaoni Y, Mecoulam R. Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish. J. Am. Chem. Soc. 1964; 86 (8): 1646–1647. doi:10.1021/ja01062a046

4. Di Marzo V, Piscitelli F. The Endocannabinoid System and its Modulation by Phytocannabinoids. Neurotherapeutics. 2015;12(4):692-698. doi:10.1007/s13311-015-0374-6

5. Pertwee RG. Cannabinoid pharmacology: the first 66 years. Br J Pharmacol. 2006;147 Suppl 1(Suppl 1):S163-S171. doi:10.1038/sj.bjp.0706406

6. Zou S, Kumar U. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. Int J Mol Sci. 2018;19(3):833. Published 2018 Mar 13. doi:10.3390/ijms19030833

7. Manzanares J, Julian M, Carrascosa A. Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes. Curr Neuropharmacol. 2006;4(3):239-257. doi:10.2174/157015906778019527

8. Donvito G, Nass SR, Wilkerson JL, et al. The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain. Neuropsychopharmacology. 2018;43(1):52-79. doi:10.1038/npp.2017.204

9. Aly E, Khajah MA, Masocha W. β-Caryophyllene, a CB2-Receptor-Selective Phytocannabinoid, Suppresses Mechanical Allodynia in a Mouse Model of Antiretroviral-Induced Neuropathic Pain. Molecules. 2019;25(1):106. Published 2019 Dec 27. doi:10.3390/molecules25010106

10. Hill KP, Palastro MD, Johnson B, Ditre JW. Cannabis and Pain: A Clinical Review. Cannabis Cannabinoid Res. 2017;2(1):96-104. Published 2017 May 1. doi:10.1089/can.2017.0017

11. Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, Keurentjes JC, Lang S, Misso K, Ryder S, Schmidlkofer S, Westwood M, Kleijnen J. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015 Jun 23-30;313(24):2456-73. doi: 10.1001/jama.2015.6358.

12. Mücke M, Phillips T, Radbruch L, Petzke F, Häuser W. Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2018;3(3):CD012182. Published 2018 Mar 7. doi:10.1002/14651858.CD012182.pub2

13. De Petrocellis L, Davis JB, Di Marzo V. Palmitoylethanolamide enhances anandamide stimulation of human vanilloid VR1 receptors. FEBS Lett. 2001 Oct 12;506(3):253-6. doi: 10.1016/s0014-5793(01)02934-9. PMID: 11602256.

14. Paladini A, Fusco M, Cenacchi T, Schievano C, Piroli A, Varrassi G. Palmitoylethanolamide, a Special Food for Medical Purposes, in the Treatment of Chronic Pain: A Pooled Data Meta-analysis. Pain Physician. 2016 Feb;19(2):11-24. PMID: 26815246.