Cannabinoids for Pain Management

Key Points

• The endocannabinoid system is a complex biologic system composed of endogenous CBR and their respective agonists. It is involved in the regulation of multiple physiologic and cognitive processes in the human body to maintain homeostasis.

• Endocannabinoids are endogenous fatty acid neurotransmitters that are responsible for intercellular signaling. Seven endocannabinoids have been identified to date, but the most studied are AEA and 2-AG.

• CBR are cell membrane GPCR. The most well-known CBR are cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R).

• CBR exist in various locations in the body such as the brain, spinal cord, pituitary gland, thyroid gland, adrenal gland, and digestive system, but their distribution, signaling pathways, and functions are still being elucidated. Please see Table 56.1 for details.

  TABLE56.1

  Cannabinoid Receptors and Their Roles

  	CB1R	CB2R
  Location	Predominantly in the central nervous system (CNS: brain - hippocampus, basal ganglia, cerebellum, olfactory bulb, amygdala, hypothalamus, and cerebral cortex, spinal cord, dorsal root ganglion); some in the peripheral nervous system (PNS), liver, reproductive system, cardiovascular system, and gastrointestinal system	Predominantly in the peripheral tissues, immune cells, hematopoietic cells, bone, liver, keratinocytes, PNS, and some in the CNS
  Chromosome location of cannabinoid receptor gene	Chromosome 6	Chromosome 1
  Physiologic actions	Psychoactivity, pain & memory processing, and motor control	Regulation of analgesia in response to inflammation, peripheral analgesia, intestinal inflammatory response, and neuroimmune interactions
  Involvement in disease processes	Anxiety, depression, addiction, schizophrenia, stroke, multiple sclerosis, neurodegeneration, and epilepsy	Alzheimer’s, multiple sclerosis, autoimmune diseases, hepatitis, endometritis, pancreatitis, and inflammatory bowel disease

• Phytocannabinoids are natural substances capable of either directly interacting with CBR or sharing chemical similarities with endocannabinoids or both. More than 100 active phytocannabinoids have been identified within the cannabis sativa plant alone.

• Synthetic cannabinoids are chemical molecules that have been designed to possess active pharmacologic properties through activation of CBR. Only two synthetic THC have established clinical applications: nabilone and dronabinol. Nabilone is approved for treating CINV, and dronabinol is indicated for the treatment of AIDS-induced anorexia and CINV.

• Several analgesic mechanisms have been proposed for cannabinoids’ analgesic effect on acute, chronic inflammatory, and neuropathic pain. Similar to opioids, cannabinoids act on both the CNS and the PNS. CBR are involved in the transduction, transmission, modulation, and perception of pain in both the ascending and descending nociception pathways.

• A large diversity of cannabis-derived products exist in the market for recreational and medicinal uses. Common ROA include inhalation or smoking via a joint, spliff, pipe, blunt, water-pipe/bong, vaporizing (inhalation), dabbing, e-cigarettes, oral sprays, edibles, drinkables, tinctures (alcohol-based liquid cannabis extracts), other oromucosal/sublingual (e.g. strips and lozenges), transdermal topicals (cannabis-infused lotions, balms, oils), intravenous (syringe), and rectal (suppositories).

• Short-term and long-term use of cannabis may result in significant adverse events affecting the cardiovascular system, the respiratory system, the neurologic system, and the gastroenterology system.

• At the time of the submission of this chapter, 33 states in the United States, District of Columbia, Guam, Puerto Rico, and U.S. Virgin Islands have approved comprehensive, publicly available medical marijuana/cannabis programs.

• The recommendations around the dosing of cannabis-related products continue to evolve. There is no established dosing schedule for dried cannabis, smoked/vaporized marijuana, and CBD oil. The common guiding principle of titrating cannabinoids is to “start low and go slow,” aiming for the maximum potential therapeutic effect while minimizing AE.

Introduction

Cannabis is a plant genus in the family of Cannabacae, and its medical use dates to ancient China (around 2,700 BC). Its use for medical purposes was first recorded in the worlds’ oldest pharmacopeia, the Pen-Ts’ao Ching. Cannabis was indicated for diseases such as rheumatic pain, intestinal constipation, and others. Though awareness about its medicinal properties spread soon to India, Middle East, Africa, Europe, and the Americas, it was not until the 18th century when Willian B. O’Shaughnessy, an Irish physician, first introduced cannabis and its use for rheumatism, convulsions, and muscular spasms in the Western medicine. Cannabinoids have the potential to treat several medical conditions, including refractory epilepsy, cancer chemotherapy induced nausea and vomiting (CINV), and loss of appetite and weight loss in people with HIV/AIDS. In addition, there is a growing body of evidence for the analgesic effect of cannabinoids for acute and chronic pain. – Cannabinoids also are a potential option to reduce the dose of opioids prescribed for chronic pain. Today, cannabis and its related products have gained a broader acceptance in the popular culture with widespread recreational and medicinal use.

Definitions/Terminology

The cannabis genus encompasses many species, but the most well-known are cannabis sativa, cannabis indica, and cannabis ruderalis . The cannabis plant contains about 540 chemical substances, and the word “cannabis” refers to all products derived from the plant cannabis sativa . The word “marijuana” refers to parts of or products from the plant cannabis sativa that contain substantial amounts of Δ9-tetrahydrocannabinol (THC), the substance primarily responsible for cannabis’s physiologic effects through its actions on cannabinoid receptors (CBR). The term “medical marijuana” refers to using the whole, unprocessed marijuana plant or its basic extracts to treat medical conditions.

Cannabinoids are a group of over 100 different chemicals found in the cannabis plant that are used for recreational or medicinal purposes. In addition to THC, cannabidiol (CBD) and cannabinol (CBN) are other cannabinoids found in cannabis that stimulate CBR. The cannabis plants also contain over 120 volatile compounds that are called terpenes and sesquiterpenes that are responsible for their characteristic aroma. Synthetic cannabinoids are products manufactured to stimulate CBR.

Endocannabinoid System

The endocannabinoid system is a complex biologic system composed of endogenous CBR and their respective agonists. It is involved in the regulation of multiple physiologic and cognitive processes in the human body to maintain homeostasis.

Cannabinoid