Examples of TCAs studied for the management of chronic pain include amitriptyline, desipramine, and nortriptyline. Side effects, such as anticholinergic effects (e.g., dry mouth, constipation, dizziness) and QTc prolongation limit the use of TCAs in elderly patients. The majority of side effects occur at the typically higher doses used to treat depression. SSRIs SSRIs, such as citalopram, fluoxetine, and paroxetine, block the reuptake of serotonin in the brain, making more serotonin available in the synapse. The mechanism of SSRIs for pain remains unknown. Compared to SNRIs and TCAs, there is relatively little evidence to support the use of SSRIs in treating chronic pain conditions. 28 Potential side effects of SSRIs include weight gain, sexual dysfunction, and QTc prolongation, especially with citalopram. Anticonvulsants, gabapentin, pregabalin, oxcarbazepine, and carbamazepine, are often prescribed for neuropathic pain and are thought to exert their analgesic effect by inhibiting neuronal calcium channels. Potential side effects include sedation, dizziness, and peripheral edema. Pregabalin and gabapentin have low abuse potential in the general population, are currently classified as Schedule V by the DEA, and prescriptions for these drugs are tracked by some state Prescription Drug Monitoring Programs (PDMPs). Anticonvulsants can be very helpful in patients who have central sensitization and neuropathic pain. Anticonvulsants such as Topical lidocaine and capsaicin Topical lidocaine inhibits the conduction of nociceptive nerve impulses. Irritation at the application site is the most common side effect. The most common products for chronic pain management are lidocaine 5% patches, available by prescription, and lidocaine 4% patches available OTC. Capsaicin is an active component of chili peppers and has moderate analgesic properties at 8% concentrations for neuropathic pain, specifically postherpetic neuralgia and diabetic neuropathic pain of the feet. 53 The most common side effect is a mild-to-severe burning sensation at the application site. Cannabinoid preparations With medical cannabis now legal in 36 states and recreational use legal in at least 10 states and the District of Columbia (as of 2020) 54 , there has been increased interest among patients for the use of cannabis or cannabis derivatives (e.g., cannabidiol [CBD]) for pain relief. The CB1 and CB2 receptors have been shown to mediate the analgesic effects of cannabinoids 55 and some evidence suggests a potential benefit for chronic pain.
A 2017 National Academies of Science report, for example, concluded that “conclusive or substantial evidence” supports a beneficial role for cannabis or cannabinoids for treating chronic pain, 56 and a 2018 Cochrane review of the existing literature evaluating cannabinoids (cannabis, CBD, or combinations) suggests that these agents are moderately effective for neuropathic pain with adverse effects that are less than, or comparable to, existing non-opioid analgesics. 57 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 The authors of a 2017 review on cannabis and pain conclude that cannabis may have a narrow therapeutic window as a pharmacotherapy for chronic pain but that much more research is needed to inform physician recommendations to patients regarding the analgesic efficacy of cannabis. 60 A systematic review of both randomized trials (47) and observational studies (57) in patients with chronic noncancer pain published through July 2017 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 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
Opioids
Mechanism of Action 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
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