Decisions related to the initiation of therapy in the elderly individual with rheumatoid (RA) and osteoarthritis (OA) are complicated by changes in symptoms causing diag- nostic uncertainty, presence of comorbid conditions and
contraindications, drug interactions with existing therapy, and additive adverse effects. Added to this are adjustments that may be necessary as therapeutic goals change in the very elderly individual as they become more frail and as life expectancy is limited. Early aggressive treatment with disease-modifying antirheumatic drugs (DMARDs) is still recommended in the elderly individual, often in combination with symptomatic targeted therapy including acetamino- phen (APAP), NSAIDs, opioid analgesics, and low-dose corticosteroids. The advent of biopharmaceutical technology has offered new agents that target specific mediators in the immune response cascade. Use of these agents is growing in the elderly population as clinicians gain experience in using these agents [23].
Acetaminophen
Acetaminophen is commonly considered the safest and best tolerated agent for controlling the pain of OA. Practice guide- lines of the American Pain Society, the American College of Rheumatology, and American Geriatric Society recommend APAP for mild to moderate arthritis pain. In recent guide- lines for treating persistent pain, the American Geriatric Society recommends APAP over NSAIDs for elderly indi- viduals, suggesting scheduled administration over as-needed doses for individuals with cognitive impairment who are not able to request medication appropriately [24]. The maximum daily APAP dose for individuals with no history of alcohol abuse and normal renal and liver function is routinely recom- mended at 4,000 mg daily. The ceiling dose for elderly indi- viduals may be as low as 2,000 mg and generally should be no more than 3,000 mg/day, especially in patients over 75 years of age. Similar dosing limits (50–75% of normal doses) are recommended for those with hepatic or renal disease, but often an alternative form of therapy is recom- mended in these populations [25, 26]. Concerns related to the hepatic effects of long-term exposure to high doses of APAP have prompted a review of these issues by the Food and Drug Administration (FDA); individual and total daily doses should be limited to the lowest effective dose. APAP is present in many over-the-counter preparations, often unex- pected. Both clinicians and individual patients or caregivers are encouraged to monitor total daily doses from all sources.
Use of APAP is often seen as sparing the individual from the utilization of the more potentially toxic NSAIDs, offering reduced risk and cost savings to the individual with arthritis [27]. Adverse reactions are relatively rare at recommended therapeutic doses, although some individuals may be at risk of gastrointestinal toxicity due to mild inhibition of the cyclooxygenase-1 (COX-1) enzyme, especially at higher doses [27–29].
63 7 Pharmacotherapy Considerations Unique to the Older Patient
Nonsteroidal Anti-inflammatory Drugs
NSAIDs are often thought to offer superior pain control over APAP in individuals with moderate to severe pain, but unfor- tunately are associated with increased risk of adverse effects, especially in elderly people [23, 24]. The existence of comor- bidities such as hypertension, CHF, renal insufficiency, and central nervous system (CNS) dysfunction makes the use of NSAIDs in elderly people problematic. It is additionally dif- ficult to apply evidence-based clinical practice guidelines to treatment in the very old (>85) as data for the long-term use of NSAIDs is lacking in this population [25]. A recent meta- analysis of use for OA knee pain indicated that long-term use of NSAIDs for this condition was not supported and that risk may outweigh benefit for individuals requiring long-term ther- apy [30]. Risks associated with the use of NSAIDs for symp- tom control in the elderly people include increased incidence of upper gastrointestinal bleeding, renal insufficiency, and CNS dysfunction or altered mental status [23, 24]. Higher incidence of gastrointestinal bleeding with NSAID use is associated with age greater than 60 years, prior history of ulcer disease, higher doses and prolonged use, and concurrent use of corticoster- oids or anticoagulants [28]. Individuals taking relatively low doses of NSAIDs (less than the equivalent recommended daily ibuprofen doses of 1,200 mg) have been shown to have double the relative risk for gastrointestinal complications, while those taking doses equivalent to 1,200 mg ibuprofen daily had a fourfold increase and those taking higher doses had a sixfold increase in these adverse effects [31]. Use of gastro-protective therapies [proton pump inhibitors (PPIs), H2 receptor antago- nists, and misoprostol] is often recommended to reduce the risk of gastrointestinal (GI) bleeding [24, 32]. A PPI is most often added to a nonselective NSAID; H2 antagonists do not offer the same risk reduction as PPIs against bleeding risk [28]. High doses of H2 antagonists do significantly reduce NSAID-related gastric ulcers, but tolerance may develop with chronic use. Misoprostol offers equivalent protection to PPI therapy but requires dosing up to four times daily and is asso- ciated with significant GI adverse effects, and thus its use should be avoided [32].
Although they offer no superiority in resolving symptoms of arthritis, use of cyclooxygenase-2 (COX-2)-specific inhibi- tors has been promoted over nonselective agents due to pur- ported reductions in the risk of gastrointestinal effects. Use of COX-2 inhibitors has been shown to have lower risk of gas- trointestinal adverse reactions than the use of standard NSAIDs, except when used concomitantly with aspirin [33].
In individuals with preexisting cardiovascular or renal dis- ease, both selective and nonselective NSAIDs may exacer- bate symptoms of congestive failure and hypertension due to reduced prostaglandin-mediated glomerular filtration and altered sodium and water excretion [23, 26, 28, 33, 34].
Heerdink et al. showed that elderly individuals taking NSAIDs concomitantly with diuretics for CHF had a twofold increase in hospitalizations for worsening failure when compared to matched elderly patients with CHF taking only diuretics [35].
Concomitant use of an NSAID and corticosteroid increases the risks of both GI and renal effects and should be used with caution. Simultaneous use of two NSAIDs will increase the risks of GI and cardiovascular effects and reduces the efficacy of pain control due to competition at the receptor site [26].
Reports of increased risk of thrombotic and cardiovascu- lar events including myocardial infarction associated with the use of certain COX-2 inhibitors resulted in the removal of two agents from the US market and reduced utilization of the remaining agent celecoxib (Celebrex®) [33, 36, 37]. Use of an NSAID, including a COX-2 selective agent, may not be recommended in some elderly individuals due to these car- diovascular and renal effects unless trials of less potentially toxic medications have failed and all risks are considered [33]. The “black box” warning, imposed by the FDA in April 2005 for celecoxib, emphasizes the necessity of caution and monitoring due to increased risk from cardiovascular events and potentially life-threatening GI bleeding.
Some authors suggest use of a nonselective NSAID over a COX-2 selective agent in the elderly population due to con- cerns that the risk of ischemic heart disease or stroke is greater with the COX-2 selective agents [29, 33]. However, this has become less clear as it appears that there may be increased car- diovascular risk with some nonselective agents as well. This issue is currently being studied and as yet a clear answer has not been obtained. Current guidelines suggest that regardless of which type of NSAID is used, they should not be given for any longer than 10 days consecutively. When NSAIDs are used in this population, patients must be regularly monitored for signs of efficacy and toxicity, and therapy adjusted accordingly.
Many NSAIDs are commercially available (Table 7.1) [38].
Most do not have specific dosing recommendations for elderly patients or for individuals with hepatic or renal impairment.
Clinicians are recommended to start and maintain therapy at the lowest effective dose and monitor patients closely for signs and symptoms of GI, cardiovascular, and CNS adverse effects.
Opioid Analgesics
For individuals not achieving adequate pain control from APAP or NSAIDs, opioid analgesics may provide symptom control. Opioid use in the elderly people is not without significant risk. Lower starting doses are recommended to reduce the risk of constipation, falls, daytime sleepiness, and interference in cognition [26].
Some experts suggest that chronic use of low-dose opioid analgesics to control pain associated with rheumatic disease
may be preferable over chronic high doses of NSAIDs [25].
Risk must always be weighed against potential benefit.
Rational choice is based on the pattern and intensity of pain, previous history and response to opioid therapies, patterns of adherence, available routes of administration, patient prefer- ence and convenience, and cost. Use of opioid analgesics for chronic control of rheumatic pain is also complicated by the risks associated with opioid tolerance, requiring escalating doses to provide pain control accompanied by increased risk of iatrogenic effects [25]. The potential for abuse must also be considered when assessing for other risks [26].
Although commonly used, the use of propoxyphene, a weak opioid agonist, is not recommended in the elderly
population [39]. Efficacy of the drug against pain is suggested to be no better than that of aspirin or APAP alone, and the risk of accumulating toxic metabolites causing ataxia and dizziness, especially in the elderly patients, creates excessive risk with little benefit. With the wide availability of other opioid analgesics, propoxyphene cannot be recommended for patients with persistent mild to moderate pain [25].
Recommended removal of propoxyphene from the US mar- ket by the FDA in late 2010 in response to increasing con- cerns of toxicity should address concerns of increase risk when this agent is used by elderly people.
Use of sustained-release opioid formulations is recom- mended to provide dosing convenience (fewer doses per day)
Table 7.1 Recommended dosing for selected nonsteroidal anti-inflammatory drugs [38]
Medication (trade name) Typical adult daily dose Maximum geriatric daily dosea Typical doses per day Acetaminophen (APAP, Anacin, Excedrin,
Panadol, Tempra, Tylenol, others)
2–4 g 2–3 g 3–4
Nonselective NSAIDs Carboxylic acid derivatives
Aspirin (acetylsalicylic acid (ASA), Bayer Aspirin, others)
Buffered aspirin (Ascriptin, Bufferin, others) Enteric-coated aspirin (Ecotrin, others)
2.4–6 g 3 g 4
Choline magnesium trisalicylate (Tricosol, Trilisate)
1.5–3 g 2,250 mg 2–3
Diflunisal (Dolobid) 1–1.5 g 500–750 mg for ClCr < 50 ml/min 3
Salsalate (Disalcid) 1.5–3 g Lower dose recommended 2
Propionic acid derivatives
Fenoprofen (Nalfon) 1.2–2.4 g
3,200 mg max/day
a 3
Flurbiprofen (Ansaid) 100–200 mg
300 mg max/day
a 2
Ibuprofen (Advil, Motrin, others) 1.2–3.2 g a 4
Ketoprofen (Orudis) 75–225 mg 75–150 mg 3
Naproxen (Naprosyn, others) 500–1,000 mg 1,500 mg max
a 2
Naproxen sodium (Aleve, Anaprox) 550–1,100 mg a 2
Acetic acid derivatives
Diclofenac (Arthrotec, Voltaren, others) 150–200 mg a 3
Etodolac (Lodine) 400–1,200 mg a 3
Indomethacin (Indocin, Indocin SR, others) 75–200 mg Use not recommended [36] 3–4
Sulindac (Clinoril) 300–400 mg a 1
Tolmetin (Tolectin, Tolectin DS) 800–1,800 mg a 3
Fenamates
Meclofenamate (Meclomen) 50–400 mg a 3–4
Mefenamic acid (Ponstel) 1.0–1.5 g a 4
Enolic acid derivatives
Meloxicam (Mobic) 7.5–15 mg Lower dose recommended 1
Phenylbutazone (Butazolidin) 300–600 mg limit to 1 week only Not recommended [36] 3
Piroxicam (Feldene) 10–20 mg a 1
Naphthylakanones
Nabumetone (Relafen) 1–2 g a 2
Cyclooxygenase-2 selective NSAIDs
Celecoxib (Celebrex) 200–400 mg Lowest dose if wt <50 kg 1–2
aNo specific dosage range suggested for the elderly people; use lowest effective dosage and duration
65 7 Pharmacotherapy Considerations Unique to the Older Patient
and more consistent serum concentrations, but care must be taken when altering the dosage form to make medication administration easier in elderly people who have difficulty swallowing tablets. Some products can be broken, while other formulations must not be altered. Chewing or crushing sus- tained-release formulations is generally not recommended due to risks of rapid absorption of the entire daily dose over a short period of time [25]. Prescribers and caregivers should contact a pharmacist prior to crushing or breaking oral formulations and to discuss the availability of alternative dosage forms.
The use of fixed-dose combinations of an opioid analgesic and APAP (e.g., hydrocodone + APAP) is convenient to patients and prescribers and is common. Care must be main- tained when using these combination products as doses are escalated to optimize pain control. It is easy to overlook the dose of APAP delivered daily with increasingly aggressive treatment; the maximum daily dose of 3,000 mg of APAP for elderly individuals can easily be reached or exceeded.
Multiple dosage combinations are available, offering the ability to increase the opioid component dosage while remain- ing within recommended limits for the APAP component.
Corticosteroids
In elderly individuals, symptom control may hold priority over long-term strategies to slow progression in individuals with limited expected lifetime, and the risks of adverse drug reactions from DMARD therapy outweigh the expected benefit. Thus, low-dose corticosteroids (e.g., prednisone doses <10 mg and more typically £5 mg) have been recom- mended as an option early in treatment. This option may reduce the risk of more rapid deterioration in the elderly patient due to deconditioning, loss of physiologic reserve, and limitations due to other comorbidities [23, 40].
Using the lowest corticosteroid dose and shortest effective therapy is recommended for symptoms of RA while waiting for response after initiating DMARD therapy [23]. Use of corticos- teroids in elderly individuals is complicated by the high risk of adverse effects, especially at daily doses greater than physio- logic levels (prednisone >7.5 mg daily). The risks commonly associated with corticosteroid use and especially with use in the elderly population include GI effects (dyspepsia and erosive gastritis), metabolic effects (diabetes and osteoporosis), cardio- vascular effects (hypertension, sodium and fluid retention/swell- ing, worsening CHF, myocardial infarction, stroke, and other ischemic events), CNS effects (mood disturbances, depression, subtle cognitive changes, delirium, worsening dementia, cata- racts, and glaucoma), and dermal changes (thinned skin and fat redistribution) which may lead to increased risk of pressure ulcers in elderly, debilitated patients [23, 28].
The increased risk of osteoporosis associated with corticos- teroid therapy especially in elderly postmenopausal women
may outweigh potential benefits. Concomitant use of calcium supplements (1,500 mg/day), vitamin D (400–800 IU/day), and bisphosphonate therapy (etidronate, alendronate, risedronate, and others) is often recommended and employed to combat the effects of corticosteroids on bone loss [28]. Long-term use, especially in the elderly population, requires care to anticipate, monitor, prevent, or correct decreases in bone mineral density.
DMARD Therapies
DMARDs are considered a cornerstone of current therapy and are often used in combination with APAP, NSAIDs, and low- dose corticosteroids to control symptoms while waiting for full response. Agents within this group include methotrexate, leflunomide, the antimalarials chloroquine and hydroxychloro- quine, sulfasalazine, cyclosporine, and azathioprine. Although increased toxicity with reduced benefit has been reported in elderly people compared to younger individuals treated with DMARDs, these agents may still prove to be beneficial to the elderly individual [23]. Some experts have suggested that early discontinuation in these elderly individuals may simply reflect the typical discontinuation patterns seen with DMARD therapy in most patients treated for prolonged periods due to the high risk of adverse effects [23, 41, 42].
Methotrexate
Clearance of methotrexate is closely linked to creatinine clearance and predictably, serum half-life is prolonged in the typical elderly individual, most of who have decreased crea- tinine clearance [43]. Pharmacokinetic and pharmacody- namic interactions are relatively common with methotrexate.
Medications that affect renal clearance (e.g., NSAIDs and salicylates) may additionally reduce clearance of methotrex- ate when used concomitantly [44]. CNS effects and hepatic and bone marrow toxicities occur more often in elderly people. Drugs known to displace methotrexate from serum protein-binding sites, thus increasing the amount of free drug to exert effect and adverse effects, include phenytoin, salicy- lates, sulfonamides, and tetracycline [28]. Methotrexate combined with cotrimoxazole, commonly used to treat uri- nary tract infections, can cause life-threatening bone marrow depression due to additive folic acid antagonism [44].
Supplementation with folic acid is well documented to reduce adverse effects on hepatic and hematologic function and the incidence of GI symptoms [28, 44].
Leflunomide
Leflunomide is a newer DMARD approved by the FDA in the late 1990s. It is sometimes used in place of or in combination
with methotrexate in individuals with incomplete response [23]. Little information is available concerning pharmacoki- netic differences and specific toxicities of leflunomide in the elderly people [44]. Adverse effects are similar to those of sulfasalazine and methotrexate, including GI complaints (diarrhea, nausea, and abdominal pain) and increases in hepatic transaminases. Other effects include increased blood pressure, alopecia, rash, headache, and anorexia. Rare serious effects include life-threatening dermal reactions and bone marrow suppression [44]. These potential adverse effects may be difficult to identify or differentiate from common elderly maladies and complaints; these symptoms may mimic the adverse effect profiles seen with many medications used in the elderly population. Current data suggest that leflunomide administration does not require significant dosage adjustment in elderly individuals, although some authors suggest avoiding the initial loading dose suggested by the manufacturer to reduce the risk of adverse effects or alternating typical daily dosages (20 mg/day) on alternate days [28]. This product is associated with causing hepatic adverse effects and should not be used in individuals known to consume alcohol regu- larly or those with liver disease.
Sulfasalazine
Sulfasalazine may be used as an option in older individuals with mild to moderate forms of RA in situations where meth- otrexate therapy may be considered too potentially toxic to the individual [23]. Elimination half-life is prolonged in elderly individuals, especially in slow acetylators. Increased serum concentrations may increase the risk of concentration- dependent adverse effects such as GI upset and CNS effects.
Few drug interactions are reported with sulfasalazine, although digoxin serum concentrations may be reduced with concomitant use [44]. Some elderly individuals may have difficulty swallowing these large tablets. The enteric-coated, sustained-release formulations of this medication must be taken whole and not broken or crushed; otherwise increased GI symptoms will occur.
Chloroquine and Hydroxychloroquine
Although not as effective as other DMARDs, the use of the antimalarials chloroquine and hydroxychloroquine may be beneficial in elderly individuals with milder forms of RA due to reduced need of monitoring for life-threatening adverse effects [23, 28]. Ophthalmic adverse effects, although not com- mon early in therapy, are well documented and may lead to progressive and irreversible vision loss and blindness, suggesting the need for fundoscopic examinations at 6-month intervals [44]. Some individuals may have difficulty differentiating
these adverse effects from typical age-related alterations in vision including age-related macular degeneration [44]. Risk factors for the development of retinal toxicity include age
>65 years, renal disease, hepatic disease, and higher daily doses of hydroxychloroquine [45].
Although no specific pharmacokinetic and pharmacody- namic studies have been done in the elderly population, these agents may interact with agents commonly used in this popu- lation. Concomitant use of these agents may increase free digoxin concentrations by displacement of digoxin from binding sites and reduced renal clearance. Hydroxychloroquine concentrations may be increased when used with cimetidine [44]. The adverse effect profiles for these agents include complaints common to many therapies used in the elderly population and include GI symptoms (nausea, diarrhea, and abdominal discomfort), dermatologic effects (rash and pigmen- tation changes), CNS effects (tinnitus and headache), and rare serious complications such as cardiomyopathy, heart block, and dyskinesias [44].
Azathioprine
Use of azathioprine is often reserved for individuals not responding to other DMARD therapy. Caution is necessary for individuals with existing hepatic disease and renal impairment.
Frequent monitoring is necessary in all patients, but especially the elderly due to the risk of GI intolerance, bone marrow suppression, and elevations in hepatic transaminases [23].
Cyclosporine
Use of cyclosporine is often reserved for individuals not responding to other DMARD therapy. This agent is known for its adverse effect profile and extensive list of drug inter- actions. Use is contraindicated in renal failure and care should be taken when used in individuals with malignancy.
Cyclosporine use is associated with increased blood pres- sure, elevated creatinine and hepatic transaminases, and alterations in potassium, all conditions that would be trou- blesome in the elderly individual. Other adverse effects include hirsutism, GI upset, and tremor [23].
Biologic/Immune Response Therapies
Anti-TNF Alpha Agents
Agents such as infliximab [chimeric antitumor necrosis factor (TNF) alpha mAB], etanercept (soluble TNF-receptor construct), and adalimumab (human anti-TNF alpha mAB)