Non-opioid drug approaches In addition to the non-opioid pharmacologic options reviewed above, evidence suggests efficacy for the following drug classes in the context of treating chronic non-cancer pain: • Antidepressants ° serotonin and/or norepinephrine reuptake inhibitors ° tricyclic antidepressants (TCAs) ° selective serotonin reuptake inhibitors (SSRIs) • Topical lidocaine or capsaicin • Possible cannabinoid-based therapies Serotonin norepinephrine reuptake inhibitors SNRIs such as duloxetine, venlafaxine, and milnacipran are characterized by a mixed action on norepinephrine and serotonin, though their exact mechanism of action for pain reduction is unknown. Side effects (e.g., nausea, dizziness, and somnolence) may limit treatment. Routine monitoring for blood pressure (duloxetine and venlafaxine), heart rate (venlafaxine), and drug interactions (duloxetine) is recommended. SNRIs can be very helpful in patients who have central sensitization. TCAs TCAs inhibit reuptake of norepinephrine and serotonin, but their mechanism of action for pain relief is unknown. 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 can 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. 39 Potential side effects of SSRIs include weight gain, sexual dysfunction, and QTc prolongation, especially with citalopram. Topical lidocaine 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.
Cannabinoid preparations With medical cannabis now legal in 34 states and recreational use legal in 11 states and the District of Columbia (as of May, 2020) 40 , there has been increased interest among patients for the use of cannabis or cannabis derivatives (e.g., cannabidiol [CBD]) for chronic pain relief. The CB1 and CB2 receptors have been shown to mediate the analgesic effects of cannabinoids 41 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, 42 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. 43 A systematic review of both randomized trials (47) and observational studies (57) in patients with chronic non-cancer pain published through July 2017 found moderate evidence that cannabinoids can exert analgesia. 44 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, increased risk of anxiety or depression, and cannabis use disorder. 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. 45 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 and Syndros) are 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. 45,46,47 None of these are indicated for the treatment of pain, although some emerging evidence suggests that THC has analgesic and/or antispasmodic properties that can ameliorate some types of acute or chronic pain (e.g., lumbar pain/spasms). 42 BEFORE MOVING ONTO THE NEXT SECTION, PLEASE COMPLETE CASE STUDY 2 ON THE NEXT PAGE.
Disease-specific guidance
Osteoarthritis Exercise and physical activity
A 2018 Cochrane review of 21 randomized trials including 2,372 patients with hip, knee, or hip and knee osteoarthritis (OA) found that exercise- based interventions reduced pain scores (on a 0-20 scale) by a mean of 1.2 points after about 45 weeks (6% absolute reduction compared to non-exercise treatments; 95% CI: -9% to -4%). 48 Physical functioning improved by 5.6 points on a 0-100 scale but the result was not significant (5.6% absolute reduction; 95% CI: -7.6% to 2%). Exercise interventions were diverse and included tai chi, physical therapy, strength training, and aerobic exercise (e.g., walking, cycling). The importance of clear patient education about the potential benefits of exercise for patients with OA was suggested by results from a review of 12 qualitative studies, conducted as part of the same Cochrane review. The authors noted that patients are often worried that they might hurt themselves by exercising, or that the exercise might worsen their symptoms. Patients wanted providers to give better information about the safety and value of exercise as well as exercise recommendations tailored to individual patient needs and abilities. 48 A 2019 trial randomized 171 adults aged ≥60 years with knee OA to a 12-week home-based exercise intervention plus health education vs. health education only. 49 The exercise intervention involved group training sessions plus at-home strength and flexibility exercises to be done 30-40 minutes/day, three days per week. At 12-week follow-up, mean pain scores on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) dropped 3.06 points in the intervention group vs. 1.46 points in the control group (P=0.007), and stiffness level decreased one level vs. no change (P=0.008). Weight loss Weight loss interventions studied for OA typically focus on joint stress or injury rather than pain. However, in the Intensive Diet and Exercise for Arthritis (IDEA) randomized trial, the investigators assessed pain as a secondary outcome. 30 The study included 545 older adults with knee OA and overweight randomized to one of three approaches: diet plus exercise, diet alone, or exercise alone. At 18 months the diet plus exercise intervention was associated with greater pain reduction than the diet or exercise alone groups. In the diet plus exercise group 38% of patients reported little or no pain compared with 20% and 22% of patients with diet or exercise alone, respectively (P=0.002 for both comparisons). 30 WOMAC function scores improved significantly in the diet plus exercise group compared to the diet group and the exercise alone group. 30
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