Acetaminophen is the most commonly used analgesic in the United States, and it remains the first-line treatment for older adults with persistent mild-to-moderate pain. Musculoskeletal pain, such as osteoarthritis and low back pain, should initially be treated with acetaminophen. It is less effective in relieving inflammatory conditions, such as rheumatoid arthritis. The FDA recommends a maximum daily dose of 3 g. Lower doses or avoidance altogether is recommended for individuals with liver disease [65, 66]. Compared with NSAIDs, acetaminophen is associated with less gastrointestinal (GI), renal, or cardiovascular toxicity, and no age-related differences exist in its clearance [67].

Nonselective NSAIDs are widely used to manage musculoskeletal and inflammatory pain conditions. NSAID use was responsible for 23.5% of ADE-related hospital admissions in elderly patients [68]. Prolonged NSAID therapy is associated with an increased risk of hospitalization, renal toxicity, myocardial infarction, stroke, and death in older adults [69–71]. Specific NSAIDs such as indomethacin, naproxen, oxaprozin, and piroxicam should not be prescribed for older adults (Table 21.1). The risk of GI complications triples in the elderly. The incidence of GI side effects appears to be more time-dependent, rather than associated with the specific drug used, but indomethacin may induce significant adverse effects within a week after initiation of treatment [72]. The combined use of thiazide diuretics and NSAIDs tripled the risk of hospitalization for congestive heart failure in elderly patients [73]. Concomitant administration of NSAIDs and aspirin increases the risk of GI bleeding [74]. Even cyclooxygenase-2 (COX-2) selective inhibitors increase the risk for GI adverse effects in older adults. Therefore coadministration of a proton pump inhibitor or another gastroprotective agent (e.g., misoprostol) is recommended when COX-2 inhibitors are taken for an extended period [74]. Topical agents primarily forgo the systemic adverse effects seen with their oral counterparts. Topical diclofenac demonstrated a superior effect on pain and function over placebo in several trials. Moreover, it proved to be as efficient as oral diclofenac , ibuprofen, and naproxen, but exhibited fewer GI complications. Topical diclofenac preferentially distributes to synovial fluid, leading to therapeutic concentrations in the target tissues [75].

Patients with moderate-to-severe pain, pain-related functional impairment, or diminished quality of life due to pain should be considered for opioid therapy according to the 2009 AGS guidelines [74]. Several studies have established the benefits of opioids in managing neuropathic, somatic, and visceral pain. Potent opioids are significantly more effective at providing pain relief than NSAIDs or TCAs [76]. They exhibit no ceiling effect and can produce profound analgesia by stepwise dose escalation. When long-acting opioids are prescribed, breakthrough pain should be anticipated and addressed. Most opioids, apart from morphine, hydromorphone, oxymorphone, and tapentadol, are primarily metabolized by CYP450 enzymes and have potential drug–drug interactions. Major metabolites of morphine and tapentadol undergo renal excretion; thus, care should be used when prescribing these drugs for older adults with compromised renal function. Chronic opioid use may be associated with fewer potential life-threatening adverse effects compared with long-term NSAID use but opioids have their distinct set of potential risks. Common opioid adverse effects include nausea, vomiting, sedation, respiratory depression, hyperalgesia, hypogonadism, pruritus, immune suppression, and cardiac dysrhythmias. Patients with a history of substance-use disorder may be prone to opioid diversion and abuse. The Opioid Risk Tool and the revised version of the Screener and Opioid Assessment for Patients with Pain are available for risk stratification for these patients [77, 78]. On the other hand, some experts suggest that underuse may be a larger problem among the elderly [74]. Older patients may use their opioid medication sporadically because of cost and fear of addiction. Meperidine should be avoided in patients with current or recent use of monoamine oxidase inhibitors (MAOIs) due to the potential of developing serotonin syndrome (symptoms: agitation, hyperthermia, diarrhea, tachycardia, sweating, tremors, and impaired consciousness). Tramadol is a centrally acting, synthetic μ-receptor agonist that also inhibits reuptake of serotonin and norepinephrine . It is used for managing acute and chronic, neuropathic and nonneuropathic pain conditions. The most common side effects of tramadol are sweating, nausea, constipation, pruritus, and dizziness. Concomitant administration with MAOIs, TCAs, or selective serotonin reuptake inhibitors (SSRIs) may result in serotonin syndrome.

The potential risks of developing hyponatremia and syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH) limit the use of older anticonvulsants, such as carbamazepine and oxcarbazepine. Due to their more benign side-effect profiles and wider therapeutic windows, gabapentin and pregabalin are often used to manage neuropathic pain in older adults. Regardless, patients should be monitored for ataxia, dizziness, somnolence, weight gain, and edema. Drug–drug interactions do not limit the use of gabapentinoids as they do not inhibit any major CYP450 enzymes, although naproxen and morphine may increase systemic gabapentin levels. Pregabalin or gabapentin doses should be reduced or dosing intervals increased in patients with renal dysfunction. Pregabalin is effective for treating fibromyalgia, postherpetic neuralgia, diabetic peripheral neuropathy, and central neuropathic pain [79].

TCAs are effective in treating neuropathic pain, but there are several safety considerations for using them in the elderly. Contraindications include concomitant use of MAOIs, uncontrolled narrow-angle glaucoma, hepatic disease, or heart block. TCAs may also be inappropriate for older adults with cardiovascular disease, seizure disorder, or an increased risk of falling. Tertiary TCAs such as amitriptyline, imipramine, and doxepin should be avoided in older adults due to anticholinergic effects and cognitive impairment. Secondary amines such as nortriptyline and desipramine have a more favorable side effect profile [80]. Duloxetine, a serotonin norepinephrine reuptake inhibitor (SNRI), is indicated for diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain. Duloxetine can have important drug–drug interactions with CYP1A2 inhibitors (e.g., fluoroquinolones, cimetidine), with CYP2D6 inhibitors (e.g., quinidine, ritonavir), and with CYP2D6 substrates (e.g., metoprolol, propafenone, tramadol, codeine, dextromethorphan, and ondansetron) [80]. Concomitant administration of duloxetine and NSAIDs increases bleeding risk. Duloxetine is contraindicated in end-stage renal disease, chronic liver disease, and uncontrolled narrow-angle glaucoma. It should be discontinued before initiating treatment with MAOIs. It should be used cautiously in patients with hypertension , seizure disorder, and increased fasting blood glucose. Serotonin-norepinephrine reuptake inhibitors (SNRIs) or SSRIs should be considered in patients with comorbid depression and pain [81].

Skeletal muscle relaxants include carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, and orphenadrine. These drugs may relieve skeletal muscle pain, but their effects are nonspecific and not related to muscle relaxation. The 2015 Beers list does not recommend the use of most muscle relaxants due to their anticholinergic adverse effects, sedation, and increased fall risk in older persons. Baclofen, a γ-aminobutyric acid (GABA)-type B agonist, is particularly effective in the management of paroxysmal neuropathic pain. It has been used in patients with severe spasticity as a result of central nervous system injury, demyelinating conditions and other neuromuscular disorders [82]. Discontinuation after prolonged use requires gradual tapering because of the potential for delirium and seizures [77, 78].