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Home , Cannabis in Missouri, Dronabinol, Joint (cannabis)

Is an effective treatment for pain? R.J. Miller1, R.E. Miller2

1Department of Pharmacology, ABSTRACT Introduction Northwestern University, Chicago; Cannabis has been used to treat pain Pain is one of the primary symptoms 2 Department of Internal Medicine, for thousands of years. However, since of joint disease and the major reason Division of Rheumatology, Rush University the early part of the 20th century, laws why patients seek medical advice. Un- Medical Center, Chicago, IL, USA. restricting cannabis use have limited fortunately, at this point in time, we Richard J. Miller, PhD its evaluation using modern scientific do not have a detailed understanding Rachel E. Miller, PhD criteria. Over the last decade, the situa- of how joint pain is generated under Please address correspondence to: tion has started to change because of the Dr Richard J. Miller, pathological conditions. When treating Department of Pharmacology, increased availability of cannabis in the osteoarthritis (OA) pain, non-steroidal Northwestern University, United States for either medical or recre- anti-inflammatory drugs (NSAIDs) are Chicago, IL, USA. ational purposes, making it important to usually the initial drugs of choice in pa- E-mail: [email protected] provide the public with accurate informa- tients with mild to moderate pain (1, 2). Received and accepted on September 9, tion as to the effectiveness of the drug for However, the chronic use of NSAIDS 2017. joint pain among other indications. The is often problematic, particularly with Clin Exp Rheumatol 2017; 35 (Suppl. 107): major psychotropic component of can- elder patients owing to gastrointestinal S59-S67. nabis is ∆9- (THC), and renal side effects. Opiates may be © Copyright Clinical and one of some 120 naturally occurring considered for patients who continue Experimental Rheumatology 2017. phytocannabinoids. (CBD) to have severe pain and who do not re- is another molecule found in herbal can- spond or cannot tolerate NSAIDs, and Key words: cannabis, nabis in large amounts. Although CBD can provide relief in a subset of patients phytocannabinoid, endocannabinoid, does not produce psychotropic effects, (1, 2), but tolerance, dependence and joint pain it has been shown to produce a variety other adverse effects such as consti- of pharmacological effects. Hence, the pation often occur during continuous overall effects of herbal cannabis repre- use. Another serious problem is sent the collective activity of THC, CBD their abuse potential. Thus, even though and a number of minor components. The long term use of opiates may sometimes action of THC is mediated by two major produce pain relief, the current epi- G-protein coupled receptors, cannabi- demic of opiate addiction in the United noid receptor type 1 (CB1) and CB2, States clearly demonstrates the down- and recent work has suggested that other side of using opiates as anodynes over targets may also exist. Arachidonic acid extended periods of time. Although it derived endocannabinoids are the nor- is unlikely that the use of NSAIDS for mal physiological activators of the two the treatment of joint pain will be com- receptors. Natural phyto- pletely replaced in the near future, alter- and synthetic derivatives native treatments that are both effective have produced clear activity in a variety and safe would be extremely welcome. of models of joint pain in animals. These One way these may be developed is effects are the result of both inhibition of through a better understanding of the pain pathway signalling (mostly CB1) physiology and pharmacology of the and anti-inflammatory effects (mostly nerves that produce joint pain allow- CB2). There are also numerous anecdo- ing the rational development of novel tal reports of the effectiveness of smok- agents that selectively regulate their ac- ing cannabis for joint pain. Indeed, it is tivity. However, there are also currently the largest medical request for the use of several possible avenues available that the drug. However, these reports gener- might produce new agents for the treat- Funding: Richard Miller was supported ally do not extend to regulated clinical by the US National Institutes of Health/ ment of joint pain. One of the most ob- National Institute of Arthritis and Musculo- trials for rheumatic diseases. Neverthe- vious of these is cannabis. skeletal and Skin Diseases (NIH/NIAMS) less, the preclinical and human data that Cannabis is anything but a new drug, (R01AR064251). Rachel Miller was do exist indicate that the use of cannabis having been used by humans for medi- supported by NIAMS (K01AR070328). should be taken seriously as a potential cal purposes for thousands of years. Competing interests: none declared. treatment of joint pain. Some of the earliest evidence for

Clinical and Experimental Rheumatology 2017 S-59 Cannabis for joint pain / R.J. Miller & R.E. Miller knowledge of the psychoactive prop- valuable source of tough fibrous mate- to the use of cannabis beside its psy- erties of cannabis can be found in the rial, which is the basis of cloth. chotropic actions, including effects on Shen-nung pen-ts’ao ching, the world’s Indeed, another term for cannabis is appetite, pain, metabolism and inflam- oldest pharmacopeia, which describes “hemp” or “Indian hemp.” However, mation, Alzheimer’s disease, multi- Chinese practices from the time of Em- as discussed above, the plant has also ple sclerosis, stroke, traumatic brain peror Shen Nung (c. 2700 B.C.) (3). always been used for its beneficial me- injury, Parkinson’s disease, epilepsy, Later editions clearly describe the use dicinal effects. Pharmacologically ac- and various aspects of cancer (pain, of cannabis for a variety of conditions, tive parts of the plant include the leaves nausea, etc.). The list is endless. This including treating pain and inflamma- and flowering tops and particularly the raises an interesting question. Which tion (3). Indeed, cannabis has been con- resin (, ) that is secreted phytocannabinoids are responsible for tinuously used for the treatment of pain by glands (trichomes) in the stems, all of these therapeutic effects? Is THC in Asian countries from prehistory up flowers and leaves of the plant (5). The responsible for all of them or are there until the present day (3). The drug was drug can be smoked, eaten or extracted contributions of the other molecules as subsequently introduced into Europe using alcohol to produce a tincture. well? or eating cannabis will and the United States in the 19th century As organic chemistry developed in the obviously involve ingesting a large and soon became widely used for its an- early part of the 19th century, progress number of different phytocannabinoids. algesic and other properties (4, 5). began to be made in isolating the mole- Moreover, the exact combination of So what happened? As the reader may cules responsible for the pharmacologi- molecules ingested will depend on the be well aware, the highly restrictive cal effects of natural products. Starting strain of cannabis used, growth condi- legal status of cannabis in the United with morphine in 1805, numerous alka- tions and numerous other factors. It is States and Europe beginning in the ear- loids were isolated from different natu- therefore essential to deconvolute the ly part of the 20th century has made rig- ral sources, which helped to “explain” effects of all of the major phytocan- orous clinical evaluation of its effects pharmacological activities associated nabinoids on a particular endpoint such using modern criteria virtually impossi- with these materials. However, the iden- as pain if we wish to understand the po- ble. This situation has recently started to tity of the substances responsible for the tential effects of the drug. In particular, change. In spite of the fact that Federal pharmacological effects of herbal can- when considering the potential effects laws still list cannabis as a Schedule I nabis remained elusive until well into of cannabis, we should be interested in drug “having no medical utility”, many the 20th century, and it was not until 1964 the actions of both THC and CBD, the individual states have moved to make that ∆9-tetrahydrocannabinol (THC) two major phytocannabinoids, as well the drug legal for “medical” purposes, was shown to be the component of herb- as any beneficial interactions between or even for recreational use in some al cannabis responsible for producing its them, and whether cannabis is superior instances. It is therefore time to assess psychotropic effects (5). Interestingly, to either pure substance used by itself. whether we might expect cannabis to THC does not contain a nitrogen atom be effective for joint pain and, ancient and so is not an alkaloid, distinguish- The texts aside, what clear indications there ing it from many of the natural prod- What is the signal transduction mecha- are from the scientific point of view for ucts isolated from other plant sources. nism through which cannabinoids act? believing that it might be useful. It also explains its lipid like properties Two major observations “explain” the This raises several questions. First of that make it chemically difficult to work effects of THC. Two G-protein cou- all, what is cannabis and what active with. THC is the archetypal member of pled receptors have been identified that molecules does it contain? Second, the family of cannabis derived mole- mediate its cellular effects. These two what is the evidence that any of these cules which are known as cannabinoids receptors, known as cannabinoid recep- components might have beneficial ef- or, considering subsequent develop- tor type 1 (CB1) (8) and CB2 (9), have fects on joint pain? Third, is there any ments in the field of cannabis medicinal closely related amino acid sequences. evidence that these substances do ac- chemistry, phytocannabinoids, indicat- Their transmembrane regions are ap- tually ameliorate joint pain in animals ing that they are natural plant products proximately 70% similar (9), and they and humans? (6). Currently, some 120 cannabinoids have characteristic expression patterns have been identified from crude canna- throughout the body. The major recep- The components of cannabis bis, although many of these are minor tor in the nervous system is the CB1 The term cannabis is used rather loose- components (6). Among these phytocan- receptor (10), which is also present in ly to describe preparations of the plant nabinoids are THC, cannabidiol (CBD, other tissues such as the adrenal gland, or its close relatives the major phytocannabinoid apart from adipose tissue, heart, liver, lung, pros- or Cannabis Ruder- THC), , , can- tate, uterus, ovary, testis, bone marrow, alis (6). Originally the plant grew as nabichromene, cannabitriol, and can- thymus, tonsils – but poorly expressed a tall gangling weed within the area nabicyclol (6) (Fig. 1 – generated using in the respiratory centres of the brain- around Northern India and the Hima- PubChem Substance (7)). stem indicating that respiratory depres- layas but has been cultivated by man As indicated, a very large number of sion, one of the major problems associ- from ancient times (6). Cannabis is a beneficial effects have been attributed ated with opiates, would not occur with

S-60 Clinical and Experimental Rheumatology 2017 Cannabis for joint pain / R.J. Miller & R.E. Miller

Fig. 1. Chemical structures of the major phytocannabinoids. cannabinoid based . On the lipase (MGL) degrades 2-AG, arachi- mal endogenous ligand for GPR55 is other hand, the CB2 receptor is rarely donic acid being produced in both in- probably lysophosphatidylinositol rath- expressed in neurons, although there stances. Moreover, a number of drugs er than an endocannabinoid (15). The may be exceptions such as in the dor- that inhibit these enzymes have been cognate ligand for GPR18 on the other sal root ganglia (DRG, see below) (11). produced, providing a mechanism for hand is reported to be the CB2 is widely expressed in the immune increasing the levels of either endocan- derivative N-arachidonylglycine. Inter- system, but can also be found in bone, nabinoid in vivo (12, 13). It is interest- estingly, both GPR18 and 55 may also the gastrointestinal system, and in acti- ing from the pharmacological point of recognise the phytocannabinoid canna- vated microglia in the central nervous view that both phytocannabinoids like bidiol (CBD) (15), which has no ago- system under some circumstances (11). THC and the major endocannabinoids nist activity at CB1 or CB2 receptors. The natural activators of CB1 and CB2 act as partial agonists at the cannabi- GPR55 has been shown to be antago- receptors are a family of arachidonic noid receptors (14). nised by CBD in several studies (15). acid derived molecules known as en- In addition to the “classical” cannabi- GPR18 expression has been mostly as- docannabinoids. Here again, there are noid receptors, there are now several sociated with immune cells. GPR55 is many of these, but the major members other receptors that have been sug- expressed in numerous brain regions as of the family are anandamide (arachi- gested as possible mediators of some of well as in the DRG where it is restricted donylethanolamide, AEA) and 2-ara- the effects of phytocannabinoids. These to larger diameter neurons, hippocam- chidonylglycerol (2-AG) (6) (Fig. include the recently deorphanised GP- pus, frontal cortex, cerebellum, stria- 2 – generated using PubChem Sub- CRs: GPR18, GPR55 and GPR119 tum and hypothalamus. There is also stance (7)). Biosynthetic and degrada- (15). GPR18 and GPR55 receptors do evidence of GPR55 expression in the tive pathways for these molecules have not share extensive sequence homolo- immune system, and it is expressed in been clearly identified: fatty acid amide gies with CB1 and CB2, which would microglia and bone. However, the role hydrolase (FAAH) normally degrades presumably result in selectivity for a of GPR55 in pain remains unknown, as anandamide, and monoacylglycerol different set of ligands. Indeed, the nor- GPR55 knock-out mice have recently

Clinical and Experimental Rheumatology 2017 S-61 Cannabis for joint pain / R.J. Miller & R.E. Miller

agonists have been taken up as illegally synthesised street drugs (19). The use of these extremely potent substances has often resulted in the incapacitation or even death of individual consum- ers. In spite of this unfortunate turn of events, one should be aware that some of these substances, used at appropriate doses and under the appropriate condi- tions might turn out to have useful ther- apeutic effects for several indications including pain. In addition to , other drugs are available that are based on the endocannabinoid Fig. 2. Chemical structures of the major endocannabinoids. system. Synthetic endocannabinoids have been produced that exhibit potent been shown to behave similarly to con- Synthetic cannabinoids activity in vivo and selective FAAH trol mice in a variety of inflammatory In the same way that an increased un- and MGL inhibitors have been devel- and models (16). derstanding of the medicinal chemistry oped that can be used to raise levels of There are also several possible sites and pharmacology of morphine led endocannabinoids in vivo (20). of cannabinoid action which are not to the development of numerous use- One should also remember that al- GPCRs. Transient receptor potential ful synthetic and semisynthetic opiate though cannabis is a Schedule I drug, (TRP) channels are a widely expressed drugs, there have been similar develop- strangely this is not the case for pure group of ligand activated ion channels. ments in the field of cannabinoid phar- THC, known as , which is Some members of the TRP family play macology. As a result, there is now a marketed under the name Marinol. This a central role in sensory physiology act- complete range of small molecules that is a Schedule III drug and can therefore ing as chemical receptor/transducers can act as agonists, partial agonists, an- be prescribed for a number of disorders expressed by sensory neurons or cells tagonists, inverse agonists and biased (5). It is most commonly employed to that act in close proximity to them. The agonists at the two cannabinoid recep- treat nausea in connection with chemo- role of TRP channels in the detection of tors (18). Many of these molecules are therapy. In addition, , a close painful stimuli is well established. One actually much more potent than the semisynthetic derivative of THC, is characteristic that is shared by many phytocannabinoids and act as full ago- also available for the same purposes TRPs is their ability to be activated or nists at CB1 and CB2 receptors (18). (5). Nabilone is marketed under the “sensitised” by lipids, particularly prod- Although most of the initial attempts name Cesamet. In many countries, Na- ucts of the phosphatidylinositol 4,5-bi- to make cannabinoid like drugs did not biximols, which is sold under the name sphosphate (PIP2) signalling pathway. stray too far from the structure of the Sativex, is also available. This is an Consistent with their lipid like charac- phytocannabinoids, more recent devel- oral spray containing approximately teristics, it has also been demonstrated opments have produced a number of equal amounts of THC and CBD and that several endocannabinoids can acti- structural types that bear no apparent therefore better mimics the effects of vate several TRPs including TRPV1-4, chemical similarity to THC but have actually taking herbal cannabis, which TRPM8 and TRPA1 (17). In addition, nevertheless been shown to strongly ac- contains both of these molecules. Na- several phytocannabinoids share this tivate CB1 and/or CB2 receptors (18). biximols in most countries is sold for ability, leading to the suggestion that Interestingly many of these molecules a number of purposes including the TRPs act as “ionotropic” cannabinoid resulted from development programs treatment of neuropathic pain, particu- receptors (6). Finally, THC has also that took place in large pharmaceuti- larly in the context of multiple sclerosis been shown to activate peroxisome cal companies such as Pfizer, Eli Lilly (phase 3 clinical trials in the US are on- proliferator-activated receptor gamma and Sterling-Winthrop in an attempt to going) (5). A limited, but ever increas- (PPARγ), resulting in vasorelaxation, produce non-opiate drugs for pain. In- ing amount of data, has been obtained reduction of tumour growth rate, and deed, many of these substances proved assessing the effectiveness of different other actions preclinically (6). to have potent effects in a types of cannabinoid molecules for the In summary, although the actions of variety of pain models. However, the control of pain in both pre clinical and cannabinoids have traditionally been fact that they also produced powerful clinical situations. thought to be mediated by CB1 and psychotropic effects limited their ul- CB2 receptors, it is becoming clear timate attractiveness as drug develop- Preclinical studies that other signal transduction mecha- ment targets. Currently these advances on cannabinoids and pain nisms may be involved in some of their have taken a somewhat ominous turn. Based on the ancient literature, in- actions. Many of the most potent cannabinoid formal reports and the results of drug

S-62 Clinical and Experimental Rheumatology 2017 Cannabis for joint pain / R.J. Miller & R.E. Miller development programs, one might an- human osteoarthritic synovium, raising be effective is the treatment of joint ticipate that cannabinoids would have the possibility that activation of CB2 pain. However, thus far, peripherally a beneficial effect on pain of different receptors might also directly regulate restricted CB1 agonists have failed in types. Given the current problems with the excitability of nociceptors (11). clinical trials of pain due to cardiovas- drug abuse encountered by people us- Indeed, this possibility has been con- cular and metabolic side effects (27). ing opiates for long term pain relief, firmed in one study of OA related pain Of course, cannabis doesn’t only con- there is a pressing need for non opi- in rats (23). tain THC but a large number of other ate analgesics, and the effects of can- One potential problem, however, is that related phytocannabinoids as well. nabinoids have been examined with drugs like THC that work by activat- There is a widely held view that natu- great interest. Generally speaking, can- ing CB1 receptors in the central nerv- ral cannabis may have advantages over nabinoid agonists have been repeatedly ous system are likely to produce psy- pure THC in a number of cases owing shown to produce antinociceptive ef- chotropic effects. However, it is now to the “added value” of the beneficial fects in numerous animal pain models. believed that many of the potentially effects produced by these other mol- Moreover, considerable evidence also beneficial effects of cannabinoids such ecules. It is certainly clear that the psy- exists demonstrating that mobilisation as pain relief, amelioration of certain chotropic are relat- of the endocannabinoid signalling path- intestinal and cardiovascular disorders, ed to activation of CB1 in the brain. As way represents an important factor in and inhibition of cell proliferation and other major phytocannabinoids such as the body’s response to pain. The distri- spread of many cancers can be pro- CBD don’t produce such effects, it is bution of cannabinoid receptors is con- duced by selectively activating CB1 argued that their therapeutic benefits sistent with this idea. CB1 receptors are and/or CB2 receptors expressed out- would be free of what is considered expressed by neurons in many parts of side the central nervous system (24). by many to be an undesirable side ef- the neuraxis, and CB1 mediated modu- This raises the possibility that develop- fect. It has even been suggested that lation of neural pathways in the cortex, ing peripherally restricted molecules CBD may antagonise the psychotropic amygdala, rostroventral medulla, peri- that selectively activate cannabinoid effects of THC (28), and so prepara- aqueductal gray and the spinal cord can receptors located outside the blood- tions that contain both of them, such inhibit nociceptive processing. Injec- brain barrier may be useful for some as herbal cannabis or preparations like tion of CB1 agonists into many of these purposes. Attention has focused par- , might actually be better brain regions or intrathecally elicits an ticularly on the possibility of develop- than either agent alone. There has been antinociceptive response (21). Moreo- ing such medicines for pain relief. The quite a lot of effort put into investigat- ver, analgesia evoked by electrical relative roles of central and peripheral ing the pharmacology and mechanism stimulation of brain regions such as the CB1 receptors in the antinociceptive of action of CBD, including its effects periaqueductal grey is blocked by CB1 effects of a mixed CB1/2 agonist were in pain models. While there is now antagonists, indicating a role for endo- therefore assessed in mice in which the considerable evidence that CBD does cannabinoid signalling in this response CB1 receptor had been selectively de- produce interesting effects on pain and (22). In the peripheral nervous system, leted from nociceptors expressing the other disease syndromes, it has been

CB1 receptors are also expressed in sodium channel NaV1.8 (25). Under difficult to pin down its precise mecha- many DRG neurons, including nocic- such circumstances mice showed an nism of action, which makes the entire eptors (21). enhanced response to both inflamma- enterprise somewhat unsatisfactory. Consistent with these data, several pa- tory stimuli and in the spared nerve Indeed, a recent review of the effects pers demonstrate the ability of system- injury model of neuropathic pain. of CBD listed 65 potential molecular ic CB1 agonists or inhibitors of FAAH Moreover, the analgesic effects of sys- targets for this molecule (29). Accord- and MGL to elicit antinociceptive ef- temically administered mixed CB1/2 ing to one line of reasoning, although fects in different rodent models of pain agonist were reduced, although not CBD doesn’t seem to bind to CB1/2 (21). Interestingly, CB2 agonists also entirely absent. These results indicate receptors as a conventional orthosteric have many positive effects in rodent that there is an important role for the agonist it has been shown to antagonise pain models, presumably due to their peripheral endocannabinoid system in the effects of the synthetic CB1/CB2 anti inflammatory effects, including the regulation of pain and of peripheral agonists CP55940 and WIN55212 at their ability to reduce the activation of CB1 receptors in the antinociceptive both the mouse CB1 and at the human microglia in the central nervous sys- actions of cannabinoids. In keeping CB2 receptors and has therefore been tem. As THC activates both of these re- with this conclusion, several studies proposed as having some type of allos- ceptors, one would predict that smoked have tested the effectiveness of periph- teric activity at these targets (30). CBD herbal cannabis might reduce pain erally restricted may also have effects at other GPCRs. through both of these mechanisms. It agonists or FAAH/MGL inhibitors in For example, it has been reported to act should be noted that there are a couple pain models and have found them to be on the two novel cannabinoid recep- of older reports suggesting that CB2 effective (26, 27), suggesting that drugs tors GPR18 and GPR55 (15). CBD has receptors are also expressed in DRG that target CB1 receptors expressed in been reported to act as a GPR55 antag- neurons, including nerves innervating joint tissue rather than centrally might onist, as well as a weak partial agonist

Clinical and Experimental Rheumatology 2017 S-63 Cannabis for joint pain / R.J. Miller & R.E. Miller of GPR18 (15). Moreover, CBD acts as undergoing total knee arthroplasty for ingly, in both small DRG neurons and a full 5-HT1A agonist, 5-HT2A weak both advanced osteoarthritis and rheu- the synovium, TRPV1 was always partial agonist, and non-competitive matoid arthritis (33). The endocannabi- coexpressed with CB2. Local admin- 5HT3A antagonist (6). The ability of noids AEA and 2-AG were also detect- istration of GW405833 to control ani- CBD to activate the A1A adenosine re- ed in the synovial fluid of these patients mals inhibited the electrical response ceptor has also been proposed (29). In at levels that were much higher than in of joint nociceptors to a painful knee addition, the many potential effects of normal control patients, providing fur- twist. On the other hand, the same CBD extend well beyond the sphere of ther evidence for a functional endocan- drug sensitised nociceptors in MIA GPCRs (29). nabinoid system in osteoarthritic joints treated rats. According to the authors, Although CBD has been shown to (33). Spinal cord levels of AEA, 2-AG this “paradoxical” effect appeared to have a large number of effects, gener- and their synthesising enzymes were be due to the fact that in MIA animals ally speaking these occur at relatively also increased in the rat monosodium the primary effect of the drug was to high concentrations. CBD administra- iodoacetate (MIA) model of OA (34). directly activate TRPV1 channels on tion has been shown to have beneficial Endocannabinoids have been shown to nociceptors leading to an enhanced effects in some pain models (e.g. pa- limit the excitability of spinal neurons release of CGRP. In contrast to these clitaxel chemotherapy associated pain and DRG nociceptors in osteoarthritic results, systemic administration of the (31)) but it isn’t really clear whether animal models (34-37), suggesting CB2 agonists A-796260 and JWH133 CBD actually reaches high enough that endocannabinoid signalling may were reported to produce analgesia concentrations in vivo to produce such function as a feedback system for the in MIA rats (37, 39). Of course, fol- effects through any of the numerous limitation of pain in patients with joint lowing systemic administration, these molecular mechanisms suggested in disease. Interestingly, overexpression drugs would also have access to sites the literature (29). Hence, although it of CB2 receptor attenuated mechanical outside the knee such as the central does appear that CBD can be of benefit allodynia associated with MIA induced nervous system, which could represent for treating pain under some circum- OA in mice (38), further suggesting a their major site of action under these stances, the molecular/cellular basis role for endocannabinoid signalling in circumstances. Examination of the role for such effects are still far from clear. this model. of endocannabinoids in OA was further Local peripheral administration of a investigated through local administra- The cannabinoid system CB1 agonist arachidonyl-2-chloroeth- tion of the FAAH inhibitor ULRB597 in animal models of joint pain ylamide (ACEA) reduced the firing which would produce increases in The above discussion indicates that of mechanosensitive knee afferents in anandamide. This had the effect of in- there are clear indications that can- both control rats and those with MIA hibiting the activity of joint afferents in nabinoids can reduce pain in several associated knee pathology, consistent MIA treated or Dunkin-Hartley guinea animal models using a variety of sig- with a direct inhibitory action on CB1 pigs, but the drug had no effect on nor- nal transduction mechanisms, but are expressing joint nociceptors under mal controls (36). As such, effects were they effective in models of joint pain these circumstances (35). The effects of blocked by a CB1 but not a CB2 ago- in particular? Although the number of ACEA were inhibited by antagonists of nist, supporting the idea that activation studies relating to the function of the both CB1 receptors and TRPV1 chan- of joint CB1 receptors may be a useful cannabinoid system in arthritic joints nels. In contrast, the CB1 receptor an- strategy for inhibiting OA associated is somewhat limited, they do suggest tagonist AM251 significantly increased joint pain. Also in the MIA rat model, that cannabis might well be effective mechanosensitivity in OA afflicted a potent and selective MGL inhibitor in treating arthritic pain either through joints but not in controls, indicating a (MJN110) was able to acutely reverse direct effects on nociceptive neurons or role for endocannabinoid activation of both weight-bearing asymmetry and through a reduction in painful joint in- CB1 receptors under pathological cir- mechanical allodynia of the hind paw flammation. cumstances. These results clearly sug- via both CB1 and CB2 (40). Given the fact that CB1 and CB2 re- gest that in MIA induced OA there is There are few preclinical studies on the ceptors and a variety of “non classical” activation of CB1 receptors expressed effects of CBD in joint disease. Mal- cannabinoid receptors are expressed in by the knee that in turn decrease the ex- fait et al. demonstrated that i.p. or oral different joint tissues including neu- citability of afferent nociceptors. delivery of CBD after onset of symp- rons, chondrocytes, synovium and The effects of CB2 agonists in OA are toms in the collagen-induced arthri- bone (32), it is not surprising that can- less clear cut. Schuelert et al. exam- tis mouse model (rheumatoid arthritis nabinoids would exhibit activity in joint ined the effects of GW405833, a CB2 model) blocked progression of arthritis disease. We should note that this is not agonist, in the rat MIA model (23). via an immunosuppressive pathway just the case in animal models. The These authors confirmed the older re- (41). Interestingly, a bell-shaped dose main components of the endocannabi- ports that DRG neurons express CB2 dependency was observed, which has noid signalling system, including CB1 receptors even under normal condi- been observed for other cannabinoids and CB2 receptors, have been found in tions. They also demonstrated CB2 as well. Hammell et al. examined the synovial biopsies taken from patients expression in the synovium. Interest- effects of transdermally administered

S-64 Clinical and Experimental Rheumatology 2017 Cannabis for joint pain / R.J. Miller & R.E. Miller

CBD in a model of inflammatory joint active cannabinoids may be a useful these informal reports that do not dif- disease (complete Freund’s adjuvant) therapy for diseases such as osteoporo- ferentiate between benefits to overall in rats (42). CBD gel significantly re- sis in which bone resorption is a central quality of life from specific indications duced joint swelling, limb posture feature. such as pain. scores as a rating of spontaneous pain, Overall, there is strong support for the Indeed, informal reports are not the immune cell infiltration and thickening idea that the endocannabinoid system same as controlled clinical trials. When of the synovial membrane in a dose- operates to limit pain in joint disease these are considered, the evidence is dependent manner. CBD also produced and that activation of this system with much less clear cut. Although significant a reduction in CGRP expression in the the appropriate cannabinoids is effec- preclinical data have highlighted the po- dorsal horn, a reduction in the number tive in limiting joint pain at both central tential therapeutic benefits of smoked of activated microglia and a reduction and peripheral sites. cannabis for pain relief in patients suf- of TNF-α production by DRG neurons. fering from osteoarthritis, rheumatoid Unfortunately, in spite of the fact that Effects of cannabinoids arthritis, , and cancer, no the drug produced such clear cut ef- on human joint disease randomised controlled trials (RCTs) for fects, no further studies were performed Considering what is now known about smoked herbal cannabis have been car- to assess its mechanism of action. Stud- the distribution of the endocannabinoid ried out for these conditions. ies have also been carried out using system and the generally positive re- The situation is complicated. For exam- O-1602, a semisynthetic analogue of sults from preclinical studies, it would ple, there are numerous ways that peo- CBD, in an acute inflammatory model be reasonable to expect that the use of ple can take herbal cannabis – smoking, of joint pain induced in rats using intra- cannabis would have a beneficial effect vaping or ingesting brownies or candies. articular kaolin/carrageenan (43). The on pain, including joint pain in human Secondly, not all strains of cannabis are drug produced a clear reduction in me- subjects. Whether this is actually the the same and may differ substantially in chanically evoked discharges of joint case is of considerable importance giv- terms of their overall content of THC nociceptors. This effect was not inhib- en the increasing availability of medi- and CBD or even other naturally oc- ited by CB1 or CB2 antagonists, con- cal or recreational cannabis in the USA curring cannabinoids. Then there is sistent with the well established obser- and elsewhere. Although much of the also data on individual products such as vation that CBD does not activate these present interest is centered on the use of Dronabinol, Nabilone and Nabiximols receptors. On the other hand, the effects herbal cannabis, this is also a good time to be considered. In order to begin get- of O-1602 were inhibited by a blocker to reconsider the use of currently avail- ting to grips with the problem the US of GPR55, suggesting that activation of able cannabis related products such as National Academy of Sciences commis- such receptors might also represent a Dronabinol, Nabilone and Nabiximols. sioned a report on all the data on can- route for inhibiting joint pain. One thing that is already abundantly nabis use since 1999. The report was is- It should also be pointed out that the clear is that patients like to self medi- sued in Jan 2017 (5). The committee did benefits of cannabinoids for treating cate themselves using herbal cannabis come out with some specific recommen- OA may extend beyond their effects in for joint pain. Indeed, it is the most dations encapsulated in the following pain and inflammation. In particular, commonly requested use of the drug statement, “In adults with chemother- several papers have now demonstrated (48). Many individuals report that they apy-induced nausea and vomiting, oral that chondrocytes express cannabinoid do benefit from its use. For example, cannabinoids are effective . receptors, including human osteoar- a recent survey of users in Arizona re- In adults with chronic pain, patients thritic chondrocytes (44), and activa- ported a very high frequency of satis- who were treated with cannabis or can- tion of these receptors has a protective faction with the results-77% of fibro- nabinoids are more likely to experience effect on cartilage, particularly CB2 myalgia patients, 63% of patients with a clinically significant reduction in pain (45). Chondrocytes express both CB1 arthritis, and 51% of patients suffering symptoms. In adults with multiple scle- and CB2 receptors and synthetic can- from neuropathic pain reported experi- rosis (MS)-related spasticity, short-term nabinoid agonists such as WIN-55,212- encing “a lot or almost complete overall use of oral cannabinoids improves pa- 2 and HU-210 produce a variety of ef- pain relief” (4). Most patients suffering tient reported spasticity symptoms. For fects on these cells (46). For example, from these conditions (94% of patients these conditions, the effects of cannabi- cannabinoid agonists reduced both ba- with fibromyalgia, 81% of arthritic pa- noids are modest; for all other condi- sal and IL-1 stimulated gene and pro- tients, and 61% of patients with neu- tions evaluated, there is inadequate in- tein expression of MMP-3, MMP-13 ropathy) also found that they were able formation to assess their effects.” The and ADAMTS-4 and inhibited IL-1 to lower their use of other medications report did not consider joint pain as a stimulated proteoglycan and collagen such as . Of course, one also has separate modality, but it is clear that the degradation. Bone may also be anoth- to consider the beneficial effects of can- “chronic pain” population likely con- er target for cannabinoid action. CB1 nabis on conditions such as insomnia, tained numerous patients suffering from knock-out mice are more susceptible anxiety, and depression, which are fre- these complaints. to developing age-related osteoporosis quently comorbid with pain in patients Individual RCTs examining the effects (47), suggesting that some non-psycho- with joint disease, may have influenced of cannabinoids on neuropathic pain

Clinical and Experimental Rheumatology 2017 S-65 Cannabis for joint pain / R.J. Miller & R.E. Miller have produced some positive results. dence is really not available supporting mies of Sciences, and Medicine. 2017, Wash- Individual cannabinoids (Dronabinol, this claim at this point in time. On the ington, D.C.: The National Academies Press. 6. Phytocannabinoids. Progress in the Chem- Nabilone, Nabiximols) have been test- other hand, there are numerous surveys istry of Organic Natural Products 2017: ed as adjunct analgesics in conditions suggesting that patients themselves are Springer International Publishing. such as multiple sclerosis, avulsion in- convinced that they do benefit from us- 7. KIM S, THIESSEN PA, BOLTON EE et al.: juries to the brachial plexus, and painful ing it. Moreover, cannabis does seem PubChem Substance and Compound databas- es. Nucleic Acids Res 2016; 44: D1202-13. (49). Although the to be helpful in other chronic pain syn- 8. MATSUDA LA, LOLAIT SJ, BROWNSTEIN MJ, data from such studies suffer from defi- dromes (neuropathic pain, cancer pain YOUNG AC, BONNER TI: Structure of a can- ciencies (low numbers, bias etc), meta- etc.). Furthermore, preclinical data has nabinoid receptor and functional expression of the cloned cDNA. Nature 1990; 346: 561-4. analyses of these trials have reported clearly demonstrated that the different 9. MUNRO S, THOMAS KL, ABU-SHAAR M: Mo- small positive effects, particularly for elements of the endocannabinoid sig- lecular characterization of a peripheral recep- Nabiximols, which because it contains nalling system are expressed in the ap- tor for cannabinoids. Nature 1993; 365: 61-5. both THC and CBD most resembles the propriate tissues in humans and animals 10. HOWLETT AC, ABOOD ME: CB1 and CB2 Receptor Pharmacology. Adv Pharmacol chemical composition of smoked can- and that cannabinoids do produce ben- 2017; 80: 169-206. nabis (50). eficial effects in animal models of joint 11. 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