• Indomethacin, immediate release 25 to 50mg every 8 to 12 hours, or controlled release 75mg once or twice daily • Sulindac, 150 to 200mg every 12 hours
Topical NSAIDs, such as diclofenac gel or patches, can be considered in these patients to reduce the risk of adverse reactions. 111,130 Pregnant patients should avoid NSAIDs if possible in order to avoid the risk of adverse pregnancy outcomes. There is limited information on the use of NSAIDs in lactation, but ibuprofen appears to be the preferred agent in these patients since it is only excreted into the breast milk in very small amounts and has the most information available on its safety. 111,132 Selective COX-2 Inhibitors A focus of drug development in the early 1990s was to create a product that selectively inhibits COX-2, targeting prostaglandin production without affecting the various cellular processes that rely on COX-1. This led to the development of several products, most of which have been removed from the market due to an increased risk of adverse cardiovascular events. There is one product that remains available in the US – celecoxib. 131 It is typically given in doses of 200mg daily or 100mg every 12 hours. 111,130 Celecoxib has similar efficacy to NSAIDs in terms of analgesia and anti-inflammatory effects. It is associated with a reduction in gastric toxicity compared to NSAIDs, and little to no effects on inhibiting platelet function, allowing for increased use in patients with bleeding disorders and those at risk for gastrointestinal bleeding. However, like NSAIDs, celecoxib is associated with an increased risk of adverse cardiovascular events, including stroke, myocardial infarction, heart failure, and death. This increased risk is seen in patients with and without pre-existing cardiovascular disease. This risk can be minimized by using the lowest effective dose for the shortest duration possible. In addition, celecoxib can cause acute renal failure, though it appears to be associated with 40% fewer renal events when compared with ibuprofen. The risk of acute kidney injury is increased in patients with chronic kidney disease, those who are volume- depleted due to as aggressive diuresis or heart failure, and those with severe hypercalcemia. 111,131 Antiepileptic Medications Gabapentin and pregabalin are anticonvulsants that are approved by the FDA for the treatment of neuropathic pain. Gabapentin and pregabalin both work by binding to the voltage-gated calcium channels in the central nervous system; their true mechanism in pain control is not clear and likely multifactorial. Gabapentin was primarily studied for the treatment of postherpetic neuralgia and diabetic neuropathy; evidence of efficacy in other types of neuropathic pain is limited. When used for neuropathic pain, it is typically initiated at a dose of 300mg at night; older adults and those who are sensitive to sedation should consider starting at 100mg. The daily dose range of 1200 to 2400mg per day is typically most effective for neuropathy, with doses divided into three daily doses. An adequate trial of gabapentin can take two months or longer. Patients with renal impairment require dosage adjustment. 111,129
A systematic review in 2019 found that among 45 randomized trials, pregabalin was found to be more effective than placebo in treating diabetic neuropathy, postherpetic neuralgia, and mixed neuropathic pain; daily doses of 300 to 600mg were most effective. Pregabalin is also the only medication FDA approved for the treatment of neuropathic pain associated with spinal cord injury. It is recommended to initiate pregabalin at a daily dose of 150mg per day, divided into two to three daily doses. It can be increased to 300 to 600mg per day over the course of two to four weeks if needed. Patients with renal impairment require dosage adjustment. Pregabalin may provide more rapid analgesia than gabapentin, due to the use of lower doses and shorter titration schedules. 111,129 The most common side effects associated with gabapentin and pregabalin are dizziness and sedation, which are dose-dependent. These effects can be reduced with lower starting doses and slow titration. In addition, respiratory depression has been reported in older adults and patients who received gabapentin along with opioids or other sedatives. One study reported that co-prescribing pregabalin with opioids was associated with a dose-related increase in the risk of opioid-related mortality; similar results have been reported when combining gabapentin with opioids. There are also increasing reports of abuse potential with gabapentin and pregabalin; they should be used with caution in patients with substance use disorders. 111,129 Muscle Relaxants Muscle relaxants describe a diverse category of medications with similar effects of analgesia and skeletal muscle relaxation or muscle spasm relief. Muscle relaxants have been shown to provide short-term pain relief in patients with low back pain when compared with a placebo, though their utility in long-term pain treatment is unclear. 134 However, some patients may benefit from the addition of a muscle relaxant, such as those with low back pain who have pain disrupting their sleep and may benefit from their sedating effects, and those at risk of opioid misuse. 111,133 Skeletal muscle relaxants are recommended as second-line therapy in patients with low back pain whose symptoms are not managed with acetaminophen or NSAIDs alone. If used, cyclobenzaprine and tizanidine are preferred agents because they have more data available to support their use and they have less abuse potential than other agents such as carisoprodol. The lowest effective dose and frequency should be utilized, and these medications are often given on an ‘as needed’ basis. Muscle relaxants include agents such as: 111,133,134 • Cyclobenzaprine 5 to 10mg three times daily as needed, with one dose at bedtime to help with sleep • Carisoprodol 250 to 350mg three times daily for a maximum of 2 to 3 weeks
• Meloxicam, 7.5 to 15mg once daily • Piroxicam, 10 to 20mg once daily
A variety of side effects are associated with NSAIDs; the risk of developing side effects is increased with high, frequent dosing or longer durations. Gastrointestinal effects, such as dyspepsia, peptic ulcer disease, and bleeding, are more likely in patients over 60, those with a prior history of a gastrointestinal event, those taking high doses of NSAIDs, or those taking glucocorticoids, antiplatelet drugs, or anticoagulants. Gastrointestinal effects may be reduced by taking the drug with food, milk, or antacids. Adverse effects on the kidneys can include worsening of underlying hypertension, electrolyte and fluid abnormalities, and an increased risk of acute renal failure and renal cell cancer. Patients with existing glomerular disease, hypercalcemia, renal insufficiency, or volume depletion conditions are at an increased risk of developing acute renal failure. 111,130 Both chronic and short-term use of NSAIDs is associated with an increased risk of myocardial infarction or stroke. In addition, NSAIDs can exacerbate heart failure through sodium and water retention and increases in blood pressure. This risk can be minimized by using the lowest effective dose for the shortest duration possible. Hepatic enzymes can be elevated by NSAIDs, but liver failure is rare. Other rare side effects include anaphylaxis, pulmonary effects such as bronchospasm or pulmonary infiltrates, neutropenia, tinnitus, and life-threatening rashes such as Stevens-Johnson syndrome. 111,130 NSAIDs have antiplatelet effects that can be beneficial in some patients, such as using aspirin for cardiac prophylaxis in patients with coronary heart disease. However, these effects can create issues in patients with preexisting platelet deficits or when considering surgery. For most NSAIDs, platelet function normalizes within 3 days of discontinuation, suggesting that NSAIDs should generally be discontinued at least 3 days prior to surgery. The antiplatelet effects of NSAIDs can be exacerbated when combined with other antiplatelet agents or anticoagulants, increasing the risk of bleeding. Therefore, NSAIDs should be avoided if possible in patients taking blood thinning agents. Certain antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) also appear to have antiplatelet effects, so combination with NSAIDs can increase the risk of gastrointestinal bleeding. 111,130 Oral NSAIDs should be avoided in patients with GI bleeding, platelet dysfunction, uncontrolled hypertension, hyponatremia, cirrhosis, and creatinine clearance of less than 60mL/min. NSAIDs should be used cautiously in older adults, due to the increased risk of adverse effects. Lower doses and limited durations are preferable to mitigate these risks.
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