A 2022 study concluded that oral, synthetic cannabis products with high THC-to-CBD ratios and sublingual, extracted cannabis products with comparable THC- to-CBD ratios may be associated with short-term improvements in chronic pain. But the evidence for a benefit of cannabinoids on acute pain, is extremely limited and mixed. A small double-blind, cross-over study in 18 females and experimentally-induced mild acute pain found no significant analgesic effect of oral cannabis extract. 58 Another randomized, double-blind study with 15 healthy volunteers using smoked cannabis found no analgesic effect with low doses of cannabis, a modest effect with moderate doses, and enhanced pain responses with high doses. 59 A 2020 systematic review showed that there was moderate evidence to support cannabinoids in treating chronic, non-cancer pain at 2 weeks. found moderate evidence that cannabinoids can exert analgesia. 61 Cannabis preparations, however, may pose both short- term and long-term risks. Short-term effects include impaired memory, motor coordination, and judgment. Paranoid ideation and psychotic symptoms, while rare, may occur with high doses of THC. Possible long-term effects include impaired brain development in young adults, potential for habituation, and increased risk of anxiety or depression. Abrupt cessation of marijuana in long-term users may cause withdrawal symptoms such as anxiety, irritability, craving, dysphoria, and insomnia. There is an increased risk of chronic bronchitis, respiratory infections, and pneumonia with inhaled products. 62 Nonetheless, the use of cannabis may have an opioid-sparing effect at a population level. The use of medical cannabis has been associated with a 25% reduction in opioid overdose mortality in states that legalized medical use. 63 However, a more recent study Opioids exert their analgesic effects by acting on the mu, kappa, and delta opioid receptors. Individual agents may be classified as agonists or partial agonists of those receptors: 70 ● Agonists (e.g., morphine, codeine, hydromorphone, hydrocodone) stimulate at least one of the opioid receptors and provide continued analgesia with increasing doses. ● Partial agonists (e.g., buprenorphine) have high affinity at mu-receptors, have a ceiling for analgesic effect, and are less likely to cause respiratory depression. Opioids are classified by the Drug Enforcement Agency (DEA) according to their presumed abuse and addiction potential, although the evidence base for making these differentiations continues to evolve. Tramadol, for example, is now known to have as much potential for abuse as opioids in more restrictive classes, although its DEA classification has not changed. 71 Opioids Mechanism of Action
showed that states legalizing medical cannabis actually experienced a 22.7% increase in opioid overdose deaths. 64 FDA-approved cannabinoids include dronabinol (Marinol), indicated for second-line treatment of chemotherapy-induced nausea and vomiting, and anorexia-associated weight loss in patients with HIV. Nabilone (Cesamet) is indicated for chemotherapy- induced nausea and vomiting. Common side effects include dizziness/vertigo and euphoria. Dronabinol may cause nausea/vomiting, abdominal pain, and abnormal thinking. Nabilone may cause ataxia and dry mouth. 62,65,66 None of these are indicated for the treatment of pain. When recommending cannabis for patients with chronic pain, clinicians may inform patients that the analgesic properties are due to both the CBD and THC components, which act on different pain pathways. 67 Ketamine Ketamine has been used as a general anesthetic since the 1960s, but its use in subanesthetic concentrations for analgesia has grown rapidly in recent years, due, in part, to efforts to reduce the risks of chronic opioid use. 68 Ketamine has been successfully used to treat such acute pain conditions as sickle cell crises, renal colic, and trauma. 68 Recently the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists released the first joint recommendations for subanesthetic ketamine (including transdermal ketamine) for acute pain. 68 . Ketamine infusions are used for the treatment of complex regional pain syndrome based on placebo- controlled trials, and topical ketamine may also be beneficial for the cutaneous hypersensitivity associated with this condition. 69 Relative effectiveness The analgesic efficacy of opioids for treating acute pain has been known for centuries and they continue to be reliable agents for moderate-to-severe acute pain, although they are not without risks. But the evidence for opioid efficacy for acute pain cannot be extended to chronic pain with a few exceptions that are discussed below. Neuronal and physiologic adaptations to long-term opioid use can result in reduced analgesic effectiveness, or even, paradoxically, increased pain or sensitivity to pain. 72 Opioid-induced hyperalgesia is different pharmacologically from the phenomenon of opioid tolerance, although both can lead to an increased need for opioids and disentangling the two, clinically, can be difficult. 73 For chronic pain, the evidence that opioids reduce pain and improve function more than placebo is relatively weak. A 2018 systematic review and meta-analysis of 96 trials comparing various opioids vs. placebo or non-opioid analgesics in 26,169 patients with chronic noncancer pain found that opioids may slightly reduce pain and increase physical functioning compared to placebo, but not compared to non-opioids. 12
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