During the last decade, interest in cannabis in medicine has been increasing, and several countries, including United States and Canada, have produced their own legislation about marijuana and cannabis-based medicines.In 2017, 38 states and the District of Columbia allowed medical use of cannabis, and 8 states and the District of Columbia have legalized its recreational use.Similarly, Health Canada has granted access to cannabis medical uses since 1999 and by 2013, more than 37,000 patients had been treated with cannabis for different conditions.In Germany, physicians may prescribe cannabinoids with costs covered by health insurances for patients with severe diseases, and no alternative treatment options.During recent years, interest in the use of cannabis in clinical practice has being of growing. Additionally, changes on the legislation of several countries have been made. Because of this, there is a current need for reviewing the evidence in order to keep practitioners with up-to-date knowledge. This review concentrates on its evidence for pain control.The endocannabinoid system is found throughout the human body, usually associated with neuronal tissue, but also expanded through other organs and systems as skin, bone, joints, and hematopoietic defense cells.This lipid signaling system modulates pain, mood, appetite, promotion of sleep, emesis, memory, immunity, cell development, the cardiovascular system, and the ‘‘fight or flight’’ phenomenon.These are interesting targets for many therapeutic options, however, the understanding of the endocannabinoid system is very recent and started with the identification of the cannabinoid receptors CB1 and CB2 during the 1980s and the identification of its ligands.The best characterized endogenous ligands are the 2-arachidonoyl glycerol andarachidonoyl ethanolamide .These are derived from the arachidonic acid and are produced during the inflammation triggered by tissue injury or following a presynaptic neuronal trigger.This ligands downregulate pain and inflammatory response.Exogenous ligands, such as phytocannabinoids and pharmaceutical preparations, can also bind to these receptors.Pain is a subjective experience that is composed by sensory, indoor hydroponics grow tent physiological, motivational, cognitive, and affective factors.
The three main pain systems are nociceptive, neuropathic, and central.Nociceptive pain is due to tissue damage, and is usually described as throbbing, aching, or sharp pain. It is usually related with immune cells secreting cytokines such as histamine, serotonin, prostaglandin, and bradykinin on the lesion and injury signals carried by C and A gamma peripheral nerve fifibers to dorsal root ganglia, up to the thalamus, and then to the cerebral cortex.Nociceptive pain has the importance of warning the individual about danger.Neuropathic pain is caused by damage to the nerves, which trigger inaccurate pain messages to the thalamus and the cortex,and centralized pain results as amplification of peripheral system due to persistent central nervous dysfunction.Pain is a complex process modulated by many subjective factors, which makes it difficult to create simple pharmaceutical targets. Cannabis is rarely the first drug used to treat pain, as patients usually start with nonsteroidal anti-inflammatory drugs , cyclooxygenase inhibitors , and opioids.The two major ascending pathways in mammals that are devoted to pain, the spinothalamic pathway, and the spinoparabrachial pathway are responsible for the discriminatory and the affective aspects of pain, respectively.The descending control of pain can be inhibitory or facilitatory, originates in higher cortical regions, amygdala and hypothalamus, and projects to the lower brain stem and the spinal cord.The cannabinoid receptors 1 and 2 have been extensively studied as antinociceptive receptors, either singly or in combination.The CB1 receptors are located on the peripheral endings and central terminals of the primary afferent neurons, as well as the dorsal root ganglion,however, the clinical utility of cannabinoids acting at the CB1 receptor can be limited due to the development of tolerance and the high rate of central adverse effects.
The CB2 receptor is the classical peripheral cannabinoid receptor and is present in immune cells and in the reproductive, cardiovascular, gastrointestinal, and respiratory systems.It is also presentin cerebral cortex, hippocampus, striatum, amygdala, thalamic nuclei, cerebellum, and brain stem, in particular inflammatory or pathologic conditions.It has been seen shown that inflammatory effects can be modulated by an increased production of endocannabinoids, or by the upregulation of the cannabinoid receptor activity.Additionally, the endocannabinoid system plays a role in neuronal development affecting the growth and pruning of axons,which could represent an impact on brain development; this should be considered during neuronal development.Cannabinoids have been used in animal models to study inflammatory and neuropathic pain. These studies suggest that CB1 and CB2 agonists reverse allodynia induced by inflammation, even at doses that have not shown analgesic effects.It has been seen that the CB2 receptor is upregulated on the spinal cord in rats under inflammatory conditions, which may suggest that it plays an analgesic effect on peripheral sites, but also at central levels of the spinal cord.The effects of intracerebral administration of cannabinoids have also studied, specifically in the nucleus reticularis, which is known to be an important source of descending modulation of pain.Additionally, the intracerebral injection of a CB1 antagonist on rats reverses the analgesia in rat models.It was also seen that the intraarticular injection of cannabinoids in an animal model of arthritis and activation of the CB1 receptor increases the activity of the prefrontal cortex and inhibits neuronal activity related with pain in the central nucleus of the amygdala.On the other hand, cannabinoids have been shown to suppress C-fiber evoked potentials on neurons of the dorsal horn of rats with neuropathic pain,and also inhibit the activity-dependent facilitation of nociceptive stimuli on the spinal cord.Strangman and Walker suggested that the inhibition of nociceptive facilitation was explained by general inhibitors of the central sensitization, through inhibition of calcium entry.Additionally, increased levels of AEA and 2- AG had been seen on the periacueductal grey and the rostral ventromedial medulla of rats, after 7 days of chronic injury of the sciatic nerve.
However, the effectiveness of cannabinoids in preclinical models of neuropathic pain is contradictory.While some authors suggest that systemic administration of cannabinoids mitigates allodynia,other studies have shown that upregulation and activation of CB1 receptor can be maladaptive and contribute to hypersensitivity.However, it is clear that the endocannabinoid system modulates pain, and these receptors might be interesting targets for future therapeutic options.Cannador® has been studied for postoperative pain at doses of 5, 10 and 15 mg,finding a dose dependent reduction in pain overall, with the 10 mg dose the optimal to provide pain-relief without serious adverse effects.However, in other studies, dronabinol and nabilone were not able to prove benefits on postoperative pain of women with abdominal hysterectomy, with some patients showing an increase on pain scores.In another study, in which intravenous THC was studied during dental extraction, low dose THC proved to be superior providing analgesia compared with placebo, but less than diazepam. High dose THC, however, was better analgesic than placebo or diazepam.Another study on the effect of levonantradol administered intramuscularly vs placebo on postoperative or trauma pain, showed that levonantradol was better providing analgesia that placebo, without a dose dependent curve.However, recently studies have disputed this evidence. In 2020, vaporized cannabis did not show any beneficial effect over placebo over pain caused by sickle cell anemia.A recent meta-analysis comparing cannabis vs analgesics for acute pain did not show any additional benefit from cannabis over common analgesics for acute pain.Chronic pain is defined as pain that persists after the normal healing time, or when it persists after 3 to 6 months.There are many conditions that cause chronic pain; it is estimated that 1 in 5 people experience this problem sometime in their lives, and the figure is expected to grow due to an aging population and increasing rates of survival to cancer, and other chronic conditions.Several studies have evaluated the use of cannabis-derivates to treat chronic pain. The causes of chronic pain in these studies are heterogeneous, and include different combinations of neuropathic pain, cancer, diabetes or HIV-associated neuropathy, and fibromyalgia.The evidence needs to be reviewed separately for each of these conditions.Neuropathic pain is caused by damage to the somatosensory system and is a consequence of direct damage to neuronal tissue.Some of the most common causes are diabetic neuropathy, postherpetic neuralgia, phantom limb pain, trauma, spinal cord injury,trim tray trigeminal neuralgia and HIV infection. Many times, however, the cause of the pain remains unknown.It is difficult to treat, and NSAIDs are not very effective, if at all, and patients require opioids, antidepressants, or antiepileptics.Abrams et al. evaluated the subjective report of 24-hour pain of patients with HIV-induced neuropathy who were randomized to 3.56% THC smoked cannabis vs placebo cannabis cigarettes, limiting the study to those patients who had prior exposure to THC.In this study, 52% of the patients in the intervention arm and 24% of the control showed greater than 30% reduction in pain.The number of adverse effects was low, however it was significantly higher on the cannabis arm including sedation, disorientation, confusion, dizziness, and anxiety.
Ellis et al. also explored the treatment of HIV neuropathy with smoked cannabis using the Descriptor Differential Scale as a primary measure; patients were exposed to both arms and were able to titrate the dose between 1 and 8%.Participants titrated to 8% while using the THC-free-cannabis but remained at 2 and 4% with the THC-cannabis , however, the use of analgesics did not decrease during the THC-cannabis phase.On another study, different concentrations of THC smoked cannabis were used as treatment for post-traumatic or post-surgical neuropathic pain,patients reported difference in average daily pain, additionally to improved perceptions of time to sleep while being on the highest doses.However, the study did not report improvement in mood, quality of life or mobility.Wilsey et al. compared smoked cannabis for neuropathic pain by randomizing patients between THC 0%, 3.5%, and 7% with previous cannabis exposure was required for inclusion.Both THC treatments decreased pain intensity compared to placebo, but there was no difference of the effect between both.Additionally, cannabinoid blood levels did not correlate with analgesia.Even though these results sound promising, studies have limitations and results are inconsistent. Therefore, there is no high-quality evidence that supports the use of cannabis on neuropathic pain.Furthermore, recently published systematic analysis by Stockings et al showed limited benefit for cannabinoids in chronic neuropathic pain.Additionally, some adverse effects may limit even more the use of cannabis in clinical practice.The Special Interest Group on Neuropathic Pain proposed the evidence of the use of cannabis is weak, nevertheless, the Canadian Pain Society recommended cannabis as a third line of treatment when the previous lines have been used with limited effectiveness.MS is the leading non-traumatic cause of neurologic disability in young adults.People with MS can experience pain, muscle spasms, headaches, fatigue and depression, depending where the plaques are located.In 2017, a survey revealed that 47% of respondents had considered using cannabis to treat symptoms caused by MS, 26% have actually use it, 20% have spoken to the clinician about cannabis and 16% were currently using cannabis.Cannabis has been studied for other symptoms, like spasticity or fatigue, but this review focuses on MS-related pain, which affects two thirds of people with MS and can present itself as headache , neuropathic pain on arms or legs , back pain , painful spams or trigeminal neuralgia .
One trial assessed the role of THC:CBD as an oromucosal spray for the treatment of central pain in MS.Patients were randomized to THC:CBD on one arm and to placebo on the other, showing that THC:CBD as superior for reducing pain and improving sleep.The CAMS study, which enrolled 630 patients with muscle spasticity to receive THC cannabis extract and the MUSEC trial, which enrolled patients with MS from 22 UK centers and was focused on stiffness,measured effectiveness of cannabinoids on pain as secondary outcomes, finding both a reduction in pain when compared with placebo.Another trial studied Nabilone as an adjunctive treatment to gabapentin for neuropathic pain induced by MS, finding that the reduction of pain was greater in patients that used nabilone than in patients who were treated with placebo.No trials were found evaluating the role of smoked cannabinoids for the treatment of MS-related pain. Two systematic reviews were included; on one of them, 15 of 18 trials found at least modest pain relief, on the other one, cannabis preparations were also found effective in reducing pain scores for the treatment of MS-related pain, however the authors did not state implications for clinical practice.Therefore, there is modest evidence of the role that cannabis-based medicines can play on MS-related pain; however, research should be enhanced as evidence suggest there are benefits for these patients.