Amir Minerbi1 & Tali Sahar2,3 1 Institute for Pain Medicine, Rambam Health Campus, Haifa, Israel 2 Pain Relief Unit, Department of Anesthesia, Hadassah Medical Center, Jerusalem, Israel 3 Department of Family Medicine, Hebrew University of Jerusalem, Jerusalem, Israel Few treatment modalities for pain evoke as much emotion as does cannabis. Fewer are as ancient: humans have utilized cannabis as a source of fiber (ropes, fabrics and paper) and food, as well as for medicinal and ritual purposes throughout the millennia and over vast areas of the globe [1]. Medical use of cannabis declined through the first half of the twentieth century due to the introduction of new pharmaceutical agents and the adoption of restrictive and prohibition policies worldwide. Following the discovery of the active metabolites Δ9‐tetrahydrocannabinol (THC) and cannabidiol (CBD), as well as the cannabinoid receptors and the endocannabinoid system, interest in the potential therapeutic utility of cannabis has been increasing. This chapter will review the indications and evidence for the use of cannabinoids for pain in light of the complexity of their clinical use. The human body hosts a vast and intricate innate cannabinoid system, comprising both receptors and ligands, as well as enzymes that synthesize and degrade the ligands. This system, known as the endocannabinoid system (ECS), forms a vast network throughout the body, with an important role in many aspects of human physiology. Acting as a modulatory, homoeostatic system, the ECS is involved in cognitive, behavioral, immunologic and metabolic functions [2, 3] in multiple organ systems. ECSs have been identified in various organisms, ranging from invertebrates to mammals, highlighting its putative evolutionary importance [4]. Two cannabinoid receptors have been identified: CB1 and CB2. Both are G‐protein coupled receptors, found predominantly on cell membranes, which vary in their physiologic effects and their distribution on target organs. Ligand binding to CB1 initiates an intracellular signaling cascade while also exerting a modulatory effect on membrane excitability. In the nervous system, CB1 is expressed preferentially on presynaptic terminals, where they modulate synaptic activity. Given their widespread expression, activation of CB1 receptors affects multiple physiologic processes, including memory, appetite, analgesia, anxiety, convulsions, cell proliferation and more. CB2 is abundantly expressed by immune cells, and to a lesser degree in peripheral tissues and in the central nervous system (CNS), where it is thought to play a role in nociception and addiction. The physiologic effects of CB2 are less well understood. In addition to the highly selective cannabinoid receptors CB1 and CB2, other receptors show affinity for endocannabinoid ligands. These include the transient receptor potential cation channel subfamily V member 1 (TRPV1), considered by some as the third cannabinoid receptor CB3. The two most‐studied endocannabinoid ligands are N‐arachidonoyl‐ethanolamine (AEA, also known as anandamide) and 2‐arachidonoylglycerol (2‐AG). Other less‐well studied CB1‐interacting peptides have recently been reported. While both AEA and 2‐AG are produced on demand, they differ in their synthesis, transport and degradation. They also differ in their affinity for cannabinoid receptors: AEA shows high affinity for CB1, of which it is a partial agonist, and negligible effect on CB2. In contrast, 2‐AG is a full agonist of both CB1 and CB2, showing moderate‐low affinity for both. Endocannabinoids also differ in their degradation pathways. While AEA is hydrolyzed by fatty acid amide hydrolase (FAAH), 2‐AG is degraded by monoacylglycerol lipase (MAGL) [3]. The vast distribution of the endocannabinoid system and its role in multiple physiologic systems makes it an attractive target for therapeutic interventions, while also explaining the abundance of side effects associated with its manipulation. The taxonomy of cannabis is controversial. Decades of interbreeding of the two species (Cannabis indica and Cannabis sativa) – have led to intermixing such that they can no longer be considered distinct species or strains [5–7]. Thus, the common attribution of stimulating effects to Cannabis sativa and sedative effects to Cannabis indica is no longer accurate [8]. Cannabis plants produce hundreds of active metabolites, many of which may have biologic effects and are classified as cannabinoids, terpenoids and flavonoids. Plant‐derived cannabinoids (phytocannabinoids) are lipophilic molecules, which act on endogenous cannabinoid receptors [9]. The two major cannabinoids, THC and CBD, play an essential role in the beneficial and adverse effects of cannabis. Minor cannabinoids and terpenoids may interact in a synergistic way to modulate the clinical effects of cannabis. This phenomenon, termed the “entourage effect” [10], may explain some of the differential response to various cannabis cultivars. The entourage effect may also account for the differences in the clinical effects of phytocannabinoids compared to synthetic cannabinoids. Pharmaceutical cannabinoids in clinical use include THC either alone or in combination with CBD, and may be synthetic or plant‐derived [11] (Tables 20.1 and 20.2). Interest in cannabis for medical purposes, and specifically for pain, has increased considerably in recent years, a trend that can be attributed to several factors: 1. Growing science demonstrating the endocannabinoid system and potential for therapeutic effects in human health; 2. The high prevalence of chronic pain and the difficulty of many patients to achieve adequate pain relief [12]; 3. The prevalence of comorbid symptoms associated with chronic pain, including impaired sleep, mood and overall quality of life, all of which could be influenced by cannabis; 4. Favorable media coverage of cannabis for medical use, overestimating its beneficial effects while downplaying possible adverse effects [13]; 5. Economic interests in cannabis, driven by a vast global market, both legal and illegal, estimated at hundreds of billions of dollars [14]. This shift in public opinion has facilitated the legalization of cannabis for medical use, generally followed by decriminalization and subsequent recreational legalization, which has been the pattern in many jurisdictions worldwide. Evidence for the efficacy of cannabis and cannabinoids for pain is a constant source of confusion and frustration [15]. Cannabis is widely perceived by the lay public as an effective analgesic, however, well‐designed studies supporting this opinion are scarce, indicating a marginal effect on pain at best [16]. Nevertheless, some patients seem to derive considerable analgesic benefits. How can these discrepancies be settled? Unlike other pharmaceutical agents, cannabis cannot be considered as a single medication. Cannabis hosts hundreds of molecules, with concentrations varying between strains, areas of cultivation, seasonality and route of administration [17]. Table 20.1 Characteristics of commonly available cannabinoid preparations classified by their route of delivery[40,43,63,68]. (min – minutes; hrs – hours; THC ‐ Δ9‐tetrahydrocannabinol; CBD – cannabidiol) Table 20.2 Cannabinoid agents currently available in many countries Furthermore, while most studies focus on THC and CBD composition, evidence is mounting that other metabolites may be as important. An interesting lesson can be learned from studies conducted on the anti‐tumor effect of cannabis extracts on cancer cells, which differs considerably depending on the composition of active metabolites in these extracts [18]. It thus appears that certain combinations of active components are needed for the anti‐tumor effect to be achieved, an effect that is independent of the concentration of THC or CBD in the extract. Extrapolating these observations to the field of pain medicine, one should consider the myriad possible combinations of cannabis‐derived active ingredients in a therapeutic preparation interacting with variables pertaining to the patients and their disease. This may explain why meta‐analyses on the use of cannabis struggle to demonstrate significant benefits. The complexity of the problem (involving multiple ligands, receptors and target organs) may call for a reductionist approach investigating the effects of combinations of active ingredients on various symptoms. Cannabis is widely used to treat chronic pain either by clinicians’ prescriptions or through self‐treatment. Despite its wide public acceptance as an analgesic agent, evidence supporting the use of cannabis and cannabinoids for pain remains limited. Available studies are often assessed as poor quality due to small subject numbers, short follow‐up time and heterogenous pain conditions. Furthermore, meta‐analyses often include various cannabinoid treatments. In a recent systematic review, published by the IASP Presidential Task Force on Cannabis and Cannabinoid Analgesia, the authors conclude that “the evidence neither supports nor refutes claims of efficacy and safety for cannabinoids, cannabis, or cannabis‐based medicines in the management of pain.” [16]. The number needed to treat of cannabinoids for chronic pain has been estimated at 24 [19]. However, there seems to be a difference in the efficacy of cannabinoids in various pain conditions [20, 21]. Neuropathic pain ‐ Several studies have explored the efficacy and safety of cannabinoids in patients with neuropathic pain. In a recent meta‐analysis, including 1750 patients participating in 16 randomized controlled studies, cannabinoids were marginally superior to placebo, with 30% or higher pain relief achieved in 21% of patients treated with cannabinoids compared with 17% of placebo‐treated patients [11]. The number needed to treat was estimated at 20. Adverse effects were more common among individuals treated with cannabinoids (number needed to harm = 3), probably accounting for the higher withdrawal rate. Other meta‐analyses reached similar results [21]. In conclusion, limited evidence supports the use of herbal cannabis and nabiximols (but not dronabinol or nabilone) as a third‐line treatment for neuropathic pain [16, 22]. Musculoskeletal pain ‐ Few clinical trials on cannabinoids for musculoskeletal pain have been published. Nabilone was not associated with significant pain reduction in patients with low back pain [23] and no clinical trials of herbal cannabis in low back pain or arthritis are available. While some observational studies suggest perceived benefit among patients with low back pain and arthritis [24, 25], several systematic reviews of the use of cannabinoids in rheumatic diseases have concluded that the evidence for efficacy is lacking [15, 24, 26]. Nociplastic pain –As patients with fibromyalgia and other nociplastic pain disorders often experience symptoms in multiple body systems, many show interest in cannabinoids. Few clinical trials have explored the efficacy of cannabinoids in fibromyalgia. A Cochrane review was published in 2016, including two studies comparing nabilone (a synthetic THC) with amitriptyline for 4–6 weeks [27]. These studies provided low‐quality evidence suggesting a slightly greater reduction in pain in the nabilone treated participants but at the cost of a higher frequency of adverse events. Several observational studies have indicated that cannabis use might be associated with lower pain intensity and improved sleep in fibromyalgia [28–30]. As individuals with fibromyalgia are often hypersensitive to the side effects of medications, they may also be more prone to developing adverse effects when using cannabinoids [30]. Cancer pain ‐ Cannabis is often prescribed for oncological symptom management, although its effects on pain are not established. Recent meta‐analyses demonstrated no added value for cannabinoids in pain reduction among patients with advanced cancer both for cannabinoids used alone and for cannabinoids added to opioids [16, 31, 32]. The addition of cannabinoids did increase the risk of adverse events, most notably somnolence and dizziness. The effects of cannabinoids on tumors are beyond the scope of this chapter. However, one should bear in mind that cannabinoids have been shown to possess anti‐tumor effects (in‐vitro and in‐vivo)[18], but also to compromise the efficacy of certain anti‐cancer treatments [33]. Headaches – Evidence for the clinical efficacy and safety of cannabinoids in primary headaches is lacking. In the absence of randomized controlled trials, current evidence relies on observational reports, case series and anecdotal reports [9]. In one retrospective study, patients reported a 50% reduction in their pain in 50% of the cases when using cannabis, but typically with the need for increasing doses over time [34]. To conclude, there is inadequate evidence on efficacy of cannabis in the management of headache. Moreover, headache is a common side effect of cannabinoids [16, 35]. Acute pain ‐ Several systematic reviews have concluded that cannabinoids were not superior to placebo in acute pain [20, 21, 36]. Accompanying symptoms – individuals affected by chronic pain experience an increased prevalence of comorbid symptoms, including sleep problems, affective disorders, post‐traumatic stress disorder (PTSD) and overall compromised quality of life. Cannabis and cannabinoids have been proposed to offer a beneficial effect on sleep, anxiety, PTSD and well‐being in some patients [19, 28, 37]. In conclusion, when a strict evidence‐based approach is taken, cannabinoids can be recommended as a third‐line treatment for patients with neuropathic pain. There is currently no tangible evidence to support their use in other pain indications. Proper patient selection is a key to safe and efficient use of cannabinoids [20, 38], along with the intelligent choice of appropriate cannabinoid preparations, open and accurate communication[40]
Chapter 20
Cannabis and cannabinoid for pain
Introduction
A brief history of human cannabis use
The endocannabinoid system
Endocannabinoid receptors
Endocannabinoid ligands
Plant‐derived cannabinoids and pharmaceutical cannabinoids
Increasing interest in cannabis for medical use
The complexity of cannabinoids as a medication
Route of delivery
Oral
Inhaled
Trans‐mucosal
Absorption
Enteral absorption followed by 1st & 2nd pass liver metabolism accounts for 20‐30% absorption and high inter‐individual variation.
Direct absorption to systemic circulation at rates of 10‐60%
Direct absorption over mucous membranes
Onset of action
60‐180 min; unpredictable
5‐10 min
15‐45 min
Duration of action
6‐8 hrs
2‐4 hrs
6‐8 hrs
Factors affecting the absorbed dose
Dietary consumption of fats and alcohol
Type of vaporizer
Technique and duration of inhalation
Advantages
Simple, odorless
Rapid onset of action
Convenient
Disadvantages
Gastrointestinal side effect
Unpredictable absorption
Requires dexterity
May contain toxins (vaporizing<smoking)
Exposure to combustion bi‐products (smoking)
Respiratory symptoms
Concerns of vaping‐associated lung disease
Requires dexterity
Agent
Source
On label indications
Dose supplied
Start dose
Maximum dose
Nabilone
(Cesamet)
Synthetic analog of THC
Chemotherapy induced nausea and vomiting
0.5 mg, 1 mg
0.5 mg once or twice daily
6 mg/day
Dronabinol
(Marinol)
Synthetic THC
Chemotherapy induced nausea and vomiting
Anorexia in AIDS
2.5 mg, 5 mg, 10 mg
capsules
2.5 mg once or twice daily
20 mg/day
Nabiximols
(Sativex)
Extract of cannabis as oromucosal spray with THC and CBD
Neuropathic pain in MS
Adjunctive analgesic in cancer pain
Each spray contains 2.7 mg THC, 2.5 mg CBD
1 spray once or twice daily
12 sprays/day
Epidiolex
Cannabidiol
Extract of CBD from cannabis plant
Anticonvulsant
Lennox‐ Gastaut or Dravet syndrome
100mg/ml
2.5 mg/kg twice daily
10 mg/kg twice daily
Medical cannabis programs in several nations
Cannabis plant
Non‐specific, patient choice but most commonly used for pain in most surveys
Multiple strains and preparations for smoked, oral and topical use
Start low and go slow, watch for side effects
Product dependent
Indications for cannabinoids in the management of pain
Maximizing the safety and efficacy of cannabinoids
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