Arthritis

Two Types of Pain & The Potential Effects of CBD While pain can be described according to its qualities, such as sharp or dull, hot or cold, tingling, numb, etc. for treatment purposes pain is often divided into two categories, according to its cause: 1. Inflammatory Pain Inflammation is a function of the immune system and is your body’s initial response to irritation or damage to the body’s tissues — like when the area around a scratch turns red and puffy. The inflammatory process may occur in response to infection or physical injury (bumps, bruises, fractures) as well as to metabolic, degenerative, and autoimmune conditions. When you suffer an acute injury, such as an ankle sprain, the inflammation is quite noticeable. But when inflammation occurs internally at lower levels in chronic conditions like irritable bowel syndrome, heart disease, or diabetes the signs can go unnoticed — potentially leading to substantial tissue damage. There are two types of inflammatory pain: A) Acute Inflammatory Pain Acute inflammation is the first stage of inflammation. It comes on fast and ideally should go away quickly once the tissue is repaired. Inflammation lasting less than three weeks is considered acute. This type of inflammatory pain involves swelling, inflammation, and migration of white blood cells into the affected area. During this phase, pro-inflammatory molecules called cytokines are released, triggering a cascade of responses that result in swelling, redness, and heat in the injured area. These same cytokines also activate pain receptors, which send pain signals to your brain. B) Chronic Inflammatory Pain This form of pain sets in when inflammation doesn’t resolve after a few weeks’ time. When this happens pain sensors often become hyper-reactive, leading to a heightened sensitivity to lower levels of pain — meaning the pain signal is triggered much sooner than it would normally. Chronic inflammatory pain can result from autoimmune conditions, cardiovascular disease, type 2 diabetes, gastrointestinal disorders, and others . Stopping chronic inflammation is an important step in alleviating chronic pain and a major target in pharmaceutical drug development. CBD has been shown to directly increase levels of anti-inflammatory cytokines (messenger molecules) and decrease levels of pro-inflammatory cytokines — thereby reducing inflammation . 2. Neuropathic pain This type of pain arises when there’s damage to peripheral nerves, i.e. nerves outside of the spinal cord and brain. Peripheral nerve damage can result in persistent impairment of nerve function even after the nerve recovers from the original injury . Causes for nerve damage may include: Trauma or injury Exposure to neurotoxic substances Metabolic disorder (such as diabetes or cardiovascular disease) Autoimmune disease (such as rheumatoid arthritis). Similar to chronic inflammatory pain, neuropathic pain can cause hypersensitization to pain signals . However, while chronic inflammatory pain usually responds well to anti-inflammatory medications, neuropathic pain does not. Instead, opiate-type drugs (Oxycontin, morphine), anticonvulsants, anesthetics, and antidepressants are often used to manage neuropathic pain . These drugs may have significant side effects that can be intolerable for some patients, including: Dizziness Drowsiness Impaired coordination Impaired vision Loss of memory Impaired speaking ability Increased susceptibility to viral infections . How CBD May Help With Neuropathic Pain The endocannabinoid system controls the transmission of nerve pain at many different places along the pain pathway. A) Reducing Pain Transmission Control occurs at the sensory nerves responsible for transmitting the first pain signals from the damaged tissue, as well as areas within the central nervous system that control the amount of pain that reaches the brain . One of the ways CBD and other cannabinoids reduce pain transmission is by activating glycine receptors in the spinal cord — which has inhibitory effects on pain messages . If less pain signals reach the brain, we experience less pain. B) Protecting Nerve Tissue From Damage CBD also offers protective effects on the nerves, which may prevent or reduce nerve damage. This has been shown in research looking at the protective effects of CBD on chemotherapy-induced nerve damage . C) Lowering Inflammation Additionally, the anti-inflammatory effects of CBD may prevent inflammatory conditions from causing nerve damage — again, leading to less neuropathic pain . D) Supporting Microglia in the Spinal Cord CBD inhibits the activity of cells in the brain and spinal cord called microglia. These immune system-derived cells are tasked with the job of protecting and supporting nerve cells and are known to accumulate in neuropathic pain syndromes. By inhibiting microglia CBD may prevent the neuropathic pain response from escalating . Unlike some conventional pain medications, CBD doesn’t cause drug tolerance, a process in which the same dose becomes less effective over time, prompting the user to take progressively higher doses . Pain and Your Brain – How Pain is Amplified by the Central Nervous System When pain persists and becomes chronic the interpretive mechanisms in your brain can go awry — leading to hypersensitization, amplification of pain messages, and worsening of chronic pain symptoms . Referred to as maladaptive pathological changes — this process can cause physical changes in your brain, evidence of which has been demonstrated on neuroimaging studies showing reduced connectivity between areas of the brain and spinal cord where pain messages are processed . This essentially means the more pain you feel, the easier it is to feel pain again, i.e., the threshold is lowered, so small triggers can lead to inappropriate pain responses. Impaired nervous system communication reduces your body’s ability to interpret and respond to pain appropriately, resulting in increased activity of the inflammatory cascade. This shows up on laboratory tests as elevated levels of pro-inflammatory signaling molecules and decreased levels of pain-inhibiting molecules like IL-10 . These changes are most evident in neuropathic pain syndromes but have also been found to occur in chronic inflammatory conditions. In these types of conditions, pain can persist even after inflammation has been brought under control . Pain and Your Emotional State: How Anxiety & Depression Cause & Compound Chronic Pain Pain, anxiety, and depression are intricately intertwined — they often occur together. While it’s easy to see how chronic inflammatory or neuropathic pain can lead to anxiety and depression, the reverse can also occur. These negative emotional states can cause physiological changes in the brain and body that promote pain. This makes managing pain much more complicated because now there’s also an emotional aspect to consider. Anxiety & Pain: Fanning the Flame Chronic pain sufferers often become anxious about their condition. Once anxiety sets in it activates the stress response resulting in elevated levels of stress chemicals — notably cortisol and pro-inflammatory cytokines. Studies show these stress chemicals may cause pain-processing areas of the brain and spinal cord to become hypersensitive to pain messages — a condition known as anxiety-induced hyperalgesia . This essentially means when we’re stressed we experience more inflammation and feel more pain. Depression & Pain: A Self-Perpetuating Cycle The relationship between depression and chronic pain may be mutually reinforcing. Chronic pain can cause depression by inhibiting secretion of dopamine , a neurotransmitter responsible for feelings of reward and accomplishment — such as when you perform well in school or at work, or successfully complete a marathon (or a 5K). Conversely, depression, i.e. low dopamine, has been found to suppress activity in certain areas of the brain that inhibit pain messages, resulting in heightened pain perception . To boil it down, pain causes depression by lowering dopamine levels — and low dopamine causes pain by suppressing areas of the brain responsible for controlling pain. How CBD May Help With Anxiety & Depression There’s promising evidence that CBD offers benefits for treating complex pain syndromes involving anxiety and depression. A large clinical study of psychiatric patients with anxiety and sleep disorders found that anxiety decreased and sleep quality improved significantly within the first month of CBD supplementation . CBD has also been shown to decrease symptoms of depression in laboratory animal studies . However, there’s still much to learn about the complex cause-effect relationship between pain, anxiety, and depression and CBD may prove helpful for some people, in this regard, but less so for others. CBD & Pain Relief: Benefits at All Levels of the Pain Response CBD may work through mechanisms that address the pain response at all levels of the peripheral and central nervous systems. Through these effects, CBD may provide relief for acute and chronic inflammatory and neuropathic pain . 1. CBD at The Site of Injury CBD has demonstrated potent anti-inflammatory effects, which in preclinical studies have been found to inhibit pain and prevent further tissue destruction. In autoimmune conditions, such as rheumatoid arthritis, type 1 diabetes, and others, inflammation and related tissue destruction occurs on a continual basis and is one of the underlying causes of pain. CBD’s anti-inflammatory activity may play a key role in pain management in these cases as well as in degenerative metabolic and neurological conditions such as type 2 diabetes, atherosclerosis, and Alzheimer’s disease, where inflammation also plays a key role . The endocannabinoid system also plays an important role in maintaining balance in the gastrointestinal system. CBD may prove helpful in managing chronic gastrointestinal pain syndromes, such as Crohn’s disease, irritable bowel syndrome, and ulcerative colitis . 2. CBD in the Spinal Cord on the Way to the Brain CBD shows promise in early studies for its ability to affect pain messages at the spinal cord level. It interacts with receptors for glycine — a calming neurotransmitter that modulates the transmission of pain in the brain and spinal cord . This may indicate a potential role for CBD in preventing or managing chronic pain conditions without causing the sedative effects that typically occur with other pain medications. 3. CBD in the Brain Endocannabinoid receptors (CB1 and CB2 receptors) work in the brain where pain messages are interpreted. Activation of CB2 receptors in particular help promote the release of dopamine — which has pain-inhibiting activity . There’s evidence that CBD works in areas of the brain where memories are stored to suppress harmful or fearful memories that trigger anxiety . This could prevent the stress response to certain memories in conditions like PTSD that contribute to the overall pain picture. CBD may alleviate pain by increasing the activity of serotonin — one of the body’s calming neurotransmitters . There’s some evidence serotonin may have anti-inflammatory and antioxidant effects that help modulate pain as well . Drugs that increase serotonin activity, known as serotonin reuptake inhibitors (SSRIs) are widely used to alleviate depression and anxiety and are also often prescribed for the management of chronic pain . However, SSRIs are fraught with side-effects including: Blurred vision Digestive system disturbances Insomnia Sexual dysfunction Weight gain Preliminary evidence also shows that CBD may affect inflammatory conditions by increasing the activity of adenosine — a neuromodulator in the brain that “turns down” inflammation triggered by hyperactivity in the immune system . 4. CBD in the Gastrointestinal Tract The endocannabinoid system plays an important role in maintaining balance in the gastrointestinal system. CBD may prove helpful in managing chronic gastrointestinal pain syndromes, such as Crohn’s disease, irritable bowel syndrome, and ulcerative colitis . What the Studies Show: CBD for Specific Pain Conditions Human clinical trials are the gold standard for all medical therapies. However, most human research on cannabinoids largely centers on formulations that include higher levels of THC, often at a 1:1 ratio with CBD. That said, CBD research is rapidly catching up to where it needs to be with regard to the uses and benefits for symptoms like pain and inflammation. The following human clinical trials and promising animal studies showcase some of the proven benefits and promising potential of CBD for specific conditions: 1. Chemotherapy-Induced Pain An animal study found CBD may prevent painful hypersensitization of nerve receptors to temperature and pressure, a side-effect from chemotherapy medications . The study found that CBD alleviated pain by binding directly to serotonin receptors in the brain. 2. NSAID-Induced Chronic Pain NSAIDs are a common class of anti-inflammatories like aspirin and ibuprofen. Many kidney transplant patients experience chronic pain due to toxic effects to the kidneys of NSAID — which they need to take following surgery. In a small clinical trial, kidney transplant patients were given doses of 50 mg to 150 mg of CBD twice per day. Results showed partial to complete pain relief in the majority of participants within the first 15 days of the 3-week study . 3. Neuropathic Pain A small clinical trial of patients with neuropathic pain of various origins compared the effects of a sublingual spray of THC, CBD, or a 1:1 combination of both, for 12 weeks . Though results showed that THC and THC:CBD combination therapies were more effective than CBD at reducing pain, CBD produced fewer side effects — such as drowsiness and dry mouth, while providing modest relief. The CBD used in the study was not a full spectrum extract so did not offer the synergistic benefits of the entourage effect — whereby the presence of other ingredients in hemp (such as THC and other cannabinoids) make the overall effects stronger. As a result, when using purified CBD isolate higher doses might be needed to achieve comparable effects than were used in this study. 4.Pediatric Muscle & Joint Pain Children with painful congenital movement disorders were given either CBD oil, a 20:1 combination of CBD with THC, or a 6:1 combination of CBD with THC for 5 months in a clinical trial. Results showed significant improvements in pain severity and a decrease in pain frequency and duration in all 3 groups . In the 20:1 group, a questionnaire that measured the overall quality of life, including pain levels, showed improved scores on an average dose of 92 mg per day of CBD . 5. Fibromyalgia A challenging condition to treat, fibromyalgia involves chronic muscle and joint pain throughout the body, along with fatigue, sleep disturbances, and cognitive impairment. In a clinical trial, participants were given one of three forms of medical cannabis, one of which contained a high CBD:THC ratio of nearly 20:1 . Results showed that none of the cannabis strains resulted in pain relief that was greater than placebo. However, a closer look at the study raises some questions about the effectiveness of its design. In this study, participants were given vaporized cannabis in four treatment sessions spaced at least two weeks apart. Since inhaled cannabinoids are rapidly absorbed but also rapidly cleared from the bloodstream, the inhalation method produces high peak levels but lower overall bioavailability compared to other delivery forms. So, could a different delivery form or a more frequent dosing schedule that would raise and maintain blood and tissue levels of CBD produce different results for fibromyalgia patients? Possibly, but more research is needed to explore this effect. Best Forms & Dosages of CBD for Pain Relief Dosage recommendations for CBD vary widely. There are many factors to consider when determining the best dose, including: The condition being treated The severity of symptoms Individual response to CBD The form of CBD used (capsules, sprays, vaporizer, etc) The presence of other drugs or medications Underlying medical conditions The weight and size of the person taking CBD The age and gender of the person taking CBD In animal studies, doses can range from 1 to 20 mg/kg body weight. In studies on seizure disorders in children doses reportedly range from 0.5 to 300 mg/kg body weight per day . This is a very large dosage range. In order to determine the best dosage level for your pain relief needs while avoiding uncomfortable side-effects, it’s best to take a cautionary approach when dosing with CBD and gradually increase over a period of two or more weeks . A symptom diary can help you keep track of how well you respond to a particular product or dosage level. 1. Oral CBD Oral delivery forms include CBD oils, capsules, and edibles. CBD incorporated into foods and beverages enter the system more slowly and stay in circulation longer than other forms. Oral CBD is often recommended as a primary delivery method for managing chronic pain conditions but is poorly absorbed compared to other methods . To improve the oral bioavailability of CBD nanotechnology is being used to convert the highly fat-soluble CBD molecules, which are difficult to absorb, into tiny nano-particles that are more easily absorbed in the intestinal tract . 2. Vaporized CBD Faster acting methods, such as CBD vape oils and vape pens are useful for sudden or recent onset of pain or flare-ups of chronic pain. However, vaporization can be counterproductive for pain management in some instances in that it can irritate the lungs and increase inflammation in the body. 3. Topical CBD Opinions vary with regard to topical CBD products. Topical CBD includes salves, ointments, and patches. Some experts say the best use of topicals is for spot treatment on a muscle or joint injuries, such as a sprained ankle or pulled hamstring . Others assert that topical CBD, which is slowly absorbed into the bloodstream, can be used as a systemic delivery form. These experts predict that topical CBD may prove particularly effective for maintaining consistent blood levels of CBD in chronic pain patients, particularly for those who are unable to tolerate oral CBD or other delivery forms because of digestive or other issues . 4. CBD Suppositories CBD suppositories provide yet another option for patients for whom oral consumption is not recommended, such as those with gastrointestinal conditions who may have difficulty absorbing oral CBD, or for very young or elderly patients . Summing it All Up: Using CBD For Pain Pain is a complex process that involves finely coordinated communication between the body and the brain. Pain sensors are first activated in response to a trigger, like damage to the tissue, and send messages which travel to the brain and spinal cord. Once in the brain, pain signals are interpreted, causing us to feel what we think of as pain. From what we know about pain mechanisms and the endocannabinoid system’s role in pain management CBD may play a considerable role. To sum it up briefly: CBD acts on the endocannabinoid system, which functions primarily to maintain homeostasis or balance, within the body, including acting as one of the body’s inherent pain management systems. CBD acts at numerous levels within the pain processing pathways, from the tissue level where pain is generated to the spinal cord and brain, where pain is interpreted and managed. Studies show that CBD may offer considerable pain-relieving benefits for a wide variety of pain syndromes. Dosing with CBD for pain is highly individual. It is recommended to start low and slowly increase dosage levels to find the optimal dose for your particular needs. Although more research is needed to confirm the effects of CBD for different types of pain, the research thus far is very promising. References Dahlhamer, J., Lucas, J., Zelaya, C., Nahin, R., Mackey, S., DeBar, L., . . . Helmick, C. (2018). Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults – United States, 2016. MMWR Morb Mortal Wkly Rep, 67(36), 1001-1006. doi:10.15585/mmwr.mm6736a2 Bruni, N., Della Pepa, C., Oliaro-Bosso, S., Pessione, E., Gastaldi, D., & Dosio, F. (2018). Cannabinoid Delivery Systems for Pain and Inflammation Treatment. Molecules, 23(10). doi:10.3390/molecules23102478 Xu, Q., & Yaksh, T. L. (2011). A brief comparison of the pathophysiology of inflammatory versus neuropathic pain. Curr Opin Anaesthesiol, 24(4), 400-407. doi:10.1097/ACO.0b013e32834871df Kidd, B. A., Wroblewska, A., Boland, M. R., Agudo, J., Merad, M., Tatonetti, N. P., … & Dudley, J. T. (2016). Mapping the effects of drugs on the immune system. Nature biotechnology, 34(1), 47. Xiong, W., Cui, T., Cheng, K., Yang, F., Chen, S. R., Willenbring, D., . . . Zhang, L. (2012). Cannabinoids suppress inflammatory and neuropathic pain by targeting alpha3 glycine receptors. J Exp Med, 209(6), 1121-1134. doi:10.1084/jem.20120242 Meacham, K., Shepherd, A., Mohapatra, D. P., & Haroutounian, S. (2017). Neuropathic Pain: Central vs. Peripheral Mechanisms. Curr Pain Headache Rep, 21(6), 28. doi:10.1007/s11916-017-0629-5 Rifbjerg-Madsen, S., Christensen, A. W., Christensen, R., Hetland, M. L., Bliddal, H., Kristensen, L. E., . . . Amris, K. (2017). Pain and pain mechanisms in patients with inflammatory arthritis: A Danish nationwide cross-sectional DANBIO registry survey. PLoS One, 12(7), e0180014. doi:10.1371/journal.pone.0180014 De Gregorio, D., McLaughlin, R. J., Posa, L., Ochoa-Sanchez, R., Enns, J., Lopez-Canul, M., . . . Gobbi, G. (2019). Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain. Pain, 160(1), 136-150. doi:10.1097/j.pain.0000000000001386 Adela Hilda Onuțu, D. S. D. a. C. P. (2018). Serotonin Reuptake Inhibitors and Their Role in Chronic Pain Management. Retrieved from https://www.intechopen.com/books/serotonin/serotonin-reuptake-inhibitors-and-their-role-in-chronic-pain-management Ward, S. J., McAllister, S. D., Kawamura, R., Murase, R., Neelakantan, H., & Walker, E. A. (2014). Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT(1A) receptors without diminishing nervous system function or chemotherapy efficacy. Br J Pharmacol, 171(3), 636-645. doi:10.1111/bph.12439 Cunetti, L., Manzo, L., Peyraube, R., Arnaiz, J., Curi, L., & Orihuela, S. (2018). Chronic Pain Treatment With Cannabidiol in Kidney Transplant Patients in Uruguay. Transplant Proc, 50(2), 461-464. doi:10.1016/j.transproceed.2017.12.042 Notcutt, W., Price, M., Miller, R., Newport, S., Phillips, C., Simmons, S., & Sansom, C. (2004). Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 ‘N of 1’ studies. Anaesthesia, 59(5), 440-452. doi:10.1111/j.1365-2044.2004.03674.x Libzon, S., Schleider, L. B., Saban, N., Levit, L., Tamari, Y., Linder, I., . . . Blumkin, L. (2018). Medical Cannabis for Pediatric Moderate to Severe Complex Motor Disorders. J Child Neurol, 33(9), 565-571. doi:10.1177/0883073818773028 Naftali, T., Mechulam, R., Marii, A., Gabay, G., Stein, A., Bronshtain, M., . . . Konikoff, F. M. (2017). Low-Dose Cannabidiol Is Safe but Not Effective in the Treatment for Crohn’s Disease, a Randomized Controlled Trial. Dig Dis Sci, 62(6), 1615-1620. doi:10.1007/s10620-017-4540-z MacCallum, C. A., & Russo, E. B. (2018). Practical considerations in medical cannabis administration and dosing. Eur J Intern Med, 49, 12-19. doi:10.1016/j.ejim.2018.01.004 Lodzki, M., Godin, B., Rakou, L., Mechoulam, R., Gallily, R., & Touitou, E. (2003). Cannabidiol-transdermal delivery and anti-inflammatory effect in a murine model. J Control Release, 93(3), 377-387. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/14644587 Singh, H., Bhushan, S., Arora, R., Buttar, H. S., Arora, S., & Singh, B. (2017). Alternative treatment strategies for neuropathic pain: Role of Indian medicinal plants and compounds of plant origin-A review. Biomedicine & Pharmacotherapy, 92, 634-650. Walia, K. S., Khan, E. A., Ko, D. H., Raza, S. S., & Khan, Y. N. (2004). Side effects of antiepileptics—a review. Pain Practice, 4(3), 194-203. Lee, G., Grovey, B., Furnish, T., & Wallace, M. (2018). Medical cannabis for neuropathic pain. Current pain and headache reports, 22(1), 8. Xiong, W., Cui, T., Cheng, K., Yang, F., Chen, S. R., Willenbring, D., … & Zhang, L. (2012). Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors. Journal of Experimental Medicine, 209(6), 1121-1134. King, K. M., Myers, A. M., Soroka‐Monzo, A. J., Tuma, R. F., Tallarida, R. J., Walker, E. A., & Ward, S. J. (2017). Single and combined effects of Δ9‐tetrahydrocannabinol and cannabidiol in a mouse model of chemotherapy‐induced neuropathic pain. British journal of pharmacology, 174(17), 2832-2841. Philpott, H. T., O’brien, M., & McDougall, J. J. (2017). Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. Pain, 158(12), 2442. Toth, C. C., Jedrzejewski, N. M., Ellis, C. L., & Frey, W. H. (2010). Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain. Molecular pain, 6(1), 16. Rivat, C., Becker, C., Blugeot, A., Zeau, B., Mauborgne, A., Pohl, M., & Benoliel, J. J. (2010). Chronic stress induces transient spinal neuroinflammation, triggering sensory hypersensitivity and long-lasting anxiety-induced hyperalgesia. Pain, 150(2), 358-368. Taylor, A. M., Castonguay, A., Taylor, A. J., Murphy, N. P., Ghogha, A., Cook, C., … & Cahill, C. M. (2015). Microglia disrupt mesolimbic reward circuitry in chronic pain. Journal of Neuroscience, 35(22), 8442-8450. Scanlon, G. C., Jain, F. A., Hunter, A. M., Cook, I. A., & Leuchter, A. F. (2017). Neurophysiologic correlates of headache pain in subjects with major depressive disorder. Clinical EEG and neuroscience, 48(3), 159-167. Shannon, S., Lewis, N., Lee, H., & Hughes, S. (2019). Cannabidiol in anxiety and sleep: a large case series. The Permanente journal, 23. Shbiro, L., Hen-Shoval, D., Hazut, N., Rapps, K., Dar, S., Zalsman, G., … & Shoval, G. (2019). Effects of cannabidiol in males and females in two different rat models of depression. Physiology & behavior, 201, 59-63. Lee, J. L., Bertoglio, L. J., Guimarães, F. S., & Stevenson, C. W. (2017). Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety‐related and substance abuse disorders. British journal of pharmacology, 174(19), 3242-3256. van de Donk, T., Niesters, M., Kowal, M. A., Olofsen, E., Dahan, A., & van Velzen, M. (2019). An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia. Pain, 160(4), 860.