Osteoarthritis and Gout
Sarah F. Uroza
Lauren K. McCluggage
Carol Gullo Mest
Osteoarthritis (OA), formerly known as degenerative joint disease, is the most common joint problem in the United States. Based on U.S. data from 2005, OA affects approximately 14% of adults older than age 25 and one third of adults older than age 65. Although prevalent, OA is often undiagnosed because clinical signs and symptoms are typically attributed to the normal aging process. In population-based studies in which asymptomatic patients were screened, the incidence of radiographic-defined OA was consistently higher than the incidence of symptomatic OA in the hands, knees, and hips.
OA is a progressive disease that can result in chronic pain, restricted range of motion, and muscle weakness, especially if a weight-bearing joint is affected. The joints commonly affected by OA include the knees, hips, cervical and lumbar spine, distal interphalangeal (DIP) joints, and the carpometacarpal joint at the base of the thumb.
CAUSES
There are two forms of OA. Primary, or idiopathic, OA arises from physiologic changes that occur with normal aging. Secondary OA usually results from traumatic injuries or inherited conditions and may present as hemochromatosis, chondrodystrophy, or inflammatory OA.
There are several modifiable and nonmodifiable risk factors that contribute to the development of OA. Of all the risk factors, obesity is the greatest in the development of OA of the knees and hips, especially in women. This is due to mechanical stress on weight-bearing joints. There may also be a metabolic effect of excess fat on articular cartilage that may account for some of the significance of obesity as a systemic risk factor. Other modifiable risk factors include prior joint injury and occupations that require excessive mechanical stress or heavy lifting. For patients with a past knee injury, the lifetime risk of knee OA is 57% compared to 45% in patients with no previous injury.
The nonmodifiable risk factors include gender, age, race, and genetics. Women have a higher overall risk for developing OA, but men tend to have disease onset at an earlier age. Increasing age is a risk factor until age 75, at which point the risk equilibrates. OA of the DIP and carpometacarpal joints is more common in White women; OA of the knees occurs more frequently in African American women. Genetics may determine approximately one fourth of knee OA cases and one half of hip and hand OA cases.
PATHOPHYSIOLOGY
OA must be differentiated from other forms of arthritis because the physiologic changes specific to the condition dictate disease management. Although most forms of arthritis, including OA, result in degeneration of articular cartilage, the subsequent formation of new bone is a change specific to OA.
The physiologic changes associated with OA begin with deterioration of the articular cartilage, which reduces joint friction during movement by diffusing mechanical stress to the underlying bone. Normal articular cartilage is smooth and is supported by subchondral bone. The subchondral bone serves as a flexible base to absorb mechanical force.
Articular cartilage consists of chondrocytes, connective tissue cells that are embedded in an extracellular matrix. The matrix is made up of collagen, water, and proteoglycans
(macromolecules). The proteoglycans provide elasticity and flexibility to the matrix, which allows the articular cartilage to resist direct pressure. In OA, there is a reduction in proteoglycans in the extracellular matrix, leading to a decrease in resiliency to mechanical stress. In time, the articular cartilage becomes friable. The underlying subchondral bone responds to this change through a process termed remodeling. Remodeling involves the production of new bone that is thicker than the original bone. If remodeling occurs at the joint margins, an osteophyte (bone spur) may develop. The adjacent cortical bone becomes fortified with new bone, resulting in an irregular narrowing of the joint space. Sclerosing and cyst formation may ensue.
(macromolecules). The proteoglycans provide elasticity and flexibility to the matrix, which allows the articular cartilage to resist direct pressure. In OA, there is a reduction in proteoglycans in the extracellular matrix, leading to a decrease in resiliency to mechanical stress. In time, the articular cartilage becomes friable. The underlying subchondral bone responds to this change through a process termed remodeling. Remodeling involves the production of new bone that is thicker than the original bone. If remodeling occurs at the joint margins, an osteophyte (bone spur) may develop. The adjacent cortical bone becomes fortified with new bone, resulting in an irregular narrowing of the joint space. Sclerosing and cyst formation may ensue.
In addition to cartilaginous changes, concomitant changes in the synovial fluid must be considered. Synovial fluid, the main lubricant of joints, is produced and excreted from the cartilage. Destruction of the proteoglycans in OA renders the mechanism of synovial release ineffective, thereby further impairing the smooth mechanical operation of the joint. Figure 36.1 demonstrates the mechanism of cartilage destruction.
DIAGNOSTIC CRITERIA
Joints commonly affected by OA include the hip, knee, hand, and cervical and lumbosacral spine. The American College of Rheumatology (ACR) published criteria for the diagnosis of OA of the knee (1986), hip (1991), and hand (1990) (Box 36.1). Often, a thorough history and physical examination provide enough data to diagnose OA. The most common symptom is joint pain; the patient in an early stage of OA usually describes the pain as insidious, intermittent, and mild. As the disease progresses, the patient may describe the pain as more constant and more disabling. Most patients report remittance of pain with rest and exacerbation of pain with joint movement.
 FIGURE 36.1 Destruction of cartilage in osteoarthritis. |
BOX 36.1
Diagnostic Criteria for Osteoarthritis
Diagnostic Criteria for Osteoarthritis
Hand: Pain, aching, or stiffness and three of the following:
Hard tissue enlargement of >2 joints
Hard tissue enlargement of >2 DIP joints
<3 swollen MCP joints
Deformity of >1 selected joint
Hip: Pain and 2 of the following
ESR < 20 mm/h
Radiographic femoral or acetabular osteophytes
Radiographic joint space narrowing
Knee
Clinical diagnosis: Knee pain and three of the following
>50 years old
Stiffness < 30 minutes
Crepitus
Bony tenderness
Bony enlargement
No palpable warmth
Clinical and radiographic diagnosis: Knee pain + osteophytes and one of the following:
>50 years old
Stiffness < 30 minutes
Crepitus
Clinical and laboratory diagnosis: Knee pain and five of the following:
Age > 50 years old
Stiffness < 30 minutes
Crepitus
Bony tenderness
Bony enlargement
No palpable warmth
ESR < 40 mm/h
RF < 1:40
Synovial fluid signs of OA (clear, viscous, or WBC count < 2,000/mm3)
MCP, metacarpophalangeal joint; ESR, erythrocyte sedimentation rate.
Although the symptoms of OA are localized, associated pain may be referred. For example, it is common for OA of the hip to be referred to the medial knee. Another symptom associated with OA is crepitus, a painless “crackling” in the joint. Crepitus most commonly affects the knee, but it may be heard in other joints affected by OA as well. As OA progresses to later stages of articular damage, deformity of the joint may be observed. The deformity usually appears as an enlargement of the joint, which may result from either increased bone
production or synovitis. Other deformities resulting from OA of the knee include varus (bow-legged knees) and valgus (knock-kneed legs).
production or synovitis. Other deformities resulting from OA of the knee include varus (bow-legged knees) and valgus (knock-kneed legs).
OA of the cervical spine may present with pain that radiates to the supraclavicular or upper trapezius areas. Depending on the level of nerve involvement, symptoms may progress to include pain in the distal upper extremities. OA of the lumbar spine may produce symptoms of neurogenic claudication.
On physical examination, decreased range of motion is the most common finding. This finding may be absent in the early stages of the disease but gradually progresses as the condition worsens. In later stages of the disease, joint contractures may occur, resulting in varus and valgus deformities. Patients with severe OA of the hip may present with gait disturbances.
Because OA is a progressive disease, complications such as joint effusion and enlargement may occur. Occasionally, radicular problems may occur secondary to changes in the cervical vertebrae.
Joint enlargement due to the formation of osteophytes may be observed. Osteophyte formation in the DIP joint is called Heberden nodes; in the proximal interphalangeal joint, it is referred to as Bouchard nodes.
Radiologic findings in OA may be used to confirm the suspected diagnosis. Narrow joint spaces with osteophyte formation are common findings.
INITIATING DRUG THERAPY
Before initiating drug therapy, the practitioner should recommend appropriate physical activity or physical therapy. The goals of physical therapy are to reduce pain, improve motion, and maintain functional ability (Box 36.2). In addition, for hip and knee OA, overweight patients should be counseled on the need for weight loss.
The goals of pharmacotherapy for OA are to maintain function, prevent further joint damage, and diminish associated pain. The degree of joint involvement and the severity of the symptoms usually dictate proper interventions for individual patients.
BOX 36.2
Nonpharmacologic Therapies for Osteoarthritis
Nonpharmacologic Therapies for Osteoarthritis
Moist heat to help diminish muscle spasm and relieve stiffness
Weight loss if the patient is overweight
Exercises to strengthen the muscles surrounding the involved joint(s) and a fitness program to maintain flexibility of the involved joint through swimming, walking, cycling, and isometric exercises
Use of assistive devices to help with ambulation and activities of daily living
Acetaminophen
First-line pharmacotherapy for OA is geared toward analgesia, specifically with acetaminophen (Tylenol). Due to acetaminophen’s cost-effectiveness and safety, it is currently the first-line treatment recommended in guidelines by the ACR, the European League Against Rheumatism (EULAR), and others.
Mechanism of Action
Acetaminophen exerts its action within the central nervous system (CNS). It is thought to inhibit central cyclooxygenase (COX), which results in decreased prostaglandin synthesis. Through this prostaglandin inhibition, acetaminophen exerts analgesic and antipyretic effects but does not have anti-inflammatory effects.
Dosage
The recommended dose is 650 mg every 4 to 6 hours or 1,000 mg every 6 to 8 hours around the clock. The key to acetaminophen dosing for OA is to schedule the dose regardless of the patient’s pain. To be most effective, it must be taken regularly.
The recommended dose of up to 4 g/d is safe for patients with normal liver function. Higher doses have been associated with hepatotoxicity. Patients with a history of liver disease or who are chronic alcohol drinkers should not take more than 1,800 to 2,000 mg/d. All patients should be counseled regarding the need to avoid other products that contain acetaminophen.
Time Frame for Response
If taken as scheduled, patients can experience pain relief within 1 week of initiation.
Contraindications
The only absolute contraindication to acetaminophen use is hypersensitivity to acetaminophen. Acetaminophen should be used cautiously in patients with hepatic disease or who drink more than three alcoholic drinks daily.
Adverse Events
Acetaminophen is typically well tolerated with the most common adverse events being dizziness and rash. For patients who take more than the recommended daily dose, acetaminophen can induce hepatic failure as a result of the accumulation of the hepatotoxic metabolite acetylimidoquinone. Also, patients need to be educated about the risk of accidental overdose with combination products that also contain acetaminophen. Renal toxicity has also been observed with chronic overdosages.
Interactions
With chronic doses of greater than 1.3 g daily, acetaminophen can increase the international normalized ratio (INR) of a patient on warfarin. If a patient is on chronic acetaminophen and warfarin, the INR should be monitored more frequently upon initiation and discontinuation of acetaminophen. Isoniazid may increase the risk of hepatotoxicity of acetaminophen.
Nonsteroidal Anti-inflammatory Drugs
Second-line therapy for OA includes nonsteroidal anti-inflammatory drugs (NSAIDs), the most commonly used class of drugs in the world. NSAIDs are further classified according to their chemical structure (Table 36.1). Although these classes have subtle differences, they all basically act by inhibiting COX. These drugs may be prescribed if patients do not respond well to acetaminophen or if an inflammatory process has begun.
Mechanism of Action
There are two mechanisms by which NSAIDs exert their antiinflammatory action. One is by inhibiting the conversion of arachidonic acid to prostaglandin, prostacyclin, and thromboxanes— all of which are mediators of pain and inflammation. The other is by interfering with protein kinase activation (especially when taken at higher doses).
COX is the enzyme that converts arachidonic acid to prostaglandin G2. The COX enzyme is present in two forms, COX-1 and COX-2. Most NSAIDs nonselectively inhibit both COX-1 and COX-2, except for celecoxib, which is more selective for COX-2. COX-1 enzymes are found in the gastrointestinal (GI) tract and kidney and produce protective prostaglandins, which is why most research focuses on preserving the activity of COX-1. COX-2 is produced at nonspecific sites of inflammation as well as in the kidneys. Inhibition of COX-2 produces anti-inflammatory and analgesic effects without affecting the GI tract. COX-2 produces protective prostaglandins in the kidney that are responsible for maintaining
adequate blood perfusion via vasodilation of the afferent arteriole. Therefore, inhibition of either COX-1 or COX-2 can result in decreased renal perfusion and impaired kidney function.
adequate blood perfusion via vasodilation of the afferent arteriole. Therefore, inhibition of either COX-1 or COX-2 can result in decreased renal perfusion and impaired kidney function.
TABLE 36.1 Overview of Selected Nonsteroidal Anti-inflammatory Agents Used to Treat Osteoarthritis and Rheumatoid Arthritis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dosage
Dosing of NSAIDs is variable. The drugs are classified into short-, intermediate-, and long-acting categories. NSAIDs require five half-lives to reach peak therapeutic levels and five half-lives to be fully excreted. Categories with a longer half-life require longer periods to reach therapeutic levels.
Some common agents used to treat OA are diclofenac, ibuprofen, and the COX-2 inhibitor celecoxib. Diclofenac is given at 50 mg twice daily, and ibuprofen is usually given at 400 mg four times daily. The typical dose of celecoxib is 100 mg twice daily or 200 mg once daily. Patients should be encouraged to use the prescribed NSAID consistently for 2 to 3 weeks to determine its effectiveness. Table 36.1 gives information about other agents and dosing considerations.
Time Frame for Response
Patients’ responses to NSAIDs are quite variable. Patients who do not respond to one NSAID may respond to another, even one in the same class. This response variability is also seen in the side effect profile of NSAIDs. The practitioner should be familiar with several of the NSAIDs from each class and should try to individualize therapy based on symptom management and side effects.
Contraindications
NSAIDs are contraindicated in patients allergic to aspirin, in patients with alcohol dependence, or in pregnant patients. Further, since celecoxib contains a sulfa moiety, it is contraindicated in patients with a sulfa allergy. Caution should be used when prescribing NSAIDs to patients with renal or hepatic impairment or the elderly. Due to the increase in cardiovascular adverse events, all NSAIDs carry a black box warning emphasizing that they are contraindicated for perioperative pain treatment in patients undergoing coronary artery bypass graft surgery.
Adverse Events
NSAIDs have gained a reputation as innocuous agents because of their over-the-counter (OTC) availability and widespread use. However, this class of drugs is far from benign, and patient education materials should highlight potential adverse events. The side effect profile of NSAIDs is quite extensive.
Visual changes, weight gain, headache, dizziness, nervousness, photosensitivity, weakness, tinnitus, easy bruising or bleeding, and fluid retention are adverse events that have been associated with use of NSAIDs. Again, cautious use and frequent monitoring, particularly of elderly patients, is of paramount importance for safe NSAID use. The most common adverse events of NSAIDs occur in the GI and renal systems.
Adverse GI events may run the gamut from minor GI irritation to ulcers, GI bleeding, perforation, and gastric outlet obstruction. These GI effects are why NSAIDs remain a second-line approach to OA treatment. Concomitant use of misoprostol (Cytotec) has been shown to decrease the incidence of ulcer disease and GI complications. Misoprostol, a prostaglandin analog, is given at 200 mg four times daily. Its use should be limited to patients at high risk for GI complications (age > 65, comorbid medical conditions, history of peptic ulcer disease or upper GI bleeding, oral glucocorticosteroids, or anticoagulants).
Studies of the treatment of GI effects as a result of NSAIDs have compared the efficacy of proton pump inhibitors and histamine-2 (H2) receptor antagonists. Yeomans et al. (1998) determined that omeprazole (Prilosec), a proton pump inhibitor, healed existing ulcers and prevented further ulcer development more effectively than did ranitidine (Zantac), an H2 receptor antagonist. Similarly, Hawkey et al. (1998) found omeprazole and misoprostol equally successful at treating ulcers and other GI symptoms associated with NSAID use. However, omeprazole was better tolerated and was associated with an improved relapse rate.
Another option for patients experiencing GI adverse events with nonselective NSAIDs is celecoxib. In a study conducted by Chan et al. (2010), patients randomized to celecoxib had a lower incidence of upper or lower GI events compared with patients treated with diclofenac plus omeprazole.
Patients with renal disease, congestive heart failure (CHF), cirrhosis, and volume depletion may experience renal aberrations, particularly related to renal blood flow. These adverse events underscore the need for frequent monitoring of patients on long-term NSAID therapy.
Controversy surrounds the issue of increased risk of cardiovascular events, including thrombotic events, myocardial infarction, and stroke due to NSAID use. This increased risk led to the market removal of two COX-2 selective agents, rofecoxib and valdecoxib. All NSAIDs have a black box warning regarding this increased risk and warn that patients with cardiovascular disease risk factors may be at an increased risk. In multiple analyses, naproxen seems to have little to no increased cardiovascular risk, whereas diclofenac consistently demonstrates an increased risk.
Interactions
NSAIDs have the potential to increase bleeding so they need to be used cautiously with other anticoagulants, specifically warfarin. Also, due to the risk of hypertension, NSAIDs may counteract the effect of antihypertensives. If possible, patients with hypertension should not be on NSAIDs. The combination of NSAIDs and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may result in decreased renal function and should be avoided. For patients who take aspirin daily, ibuprofen must be taken 30 minutes to 2 hours after or 8 hours before the aspirin in order for the aspirin to be cardioprotective. If taken concurrently with lithium, NSAIDs may increase the drug concentrations of lithium and caution is advised.
Nonacetylated Salicylates
Nonacetylated salicylates (Box 36.3) are especially beneficial in patients who are sensitive to the GI irritation caused by long-term aspirin use. Diflunisal (Dolobid), the most commonly used nonacetylated salicylate, is an effective COX-1 inhibitor with anti-inflammatory and analgesic properties, but its antipyretic activities are weak. In terms of symptom relief, the
nonacetylated salicylates are probably as effective as aspirin in treating inflammatory disorders.
nonacetylated salicylates are probably as effective as aspirin in treating inflammatory disorders.
BOX 36.3
Nonacetylated Salicylates
Nonacetylated Salicylates
Diflunisal
Sodium salicylate
Choline salicylate
Magnesium salicylate
Choline magnesium trisalicylate
Salsalate
Analgesics
When the pain associated with OA progresses and is no longer responsive to acetaminophen or NSAIDs, analgesics are the next option. Analgesics can also be used in patients who cannot tolerate acetaminophen or NSAIDs or in whom they are contraindicated. Analgesics only decrease pain and have no effect on inflammation. These drugs should be prescribed for a limited time because of potential dependence and withdrawal symptoms. Analgesics used for OA other than tramadol and tapentadol, detailed below, include codeine in combination with acetaminophen.
Tramadol
Mechanism of Action
Tramadol exerts multiple effects to induce pain relief. It is a mu opioid receptor agonist similar to other opioids such as morphine. By binding to the mu opioid receptor, ascending pain pathways are inhibited, resulting in decreased pain sensation. In addition, tramadol also inhibits the reuptake of serotonin and norepinephrine. These neurotransmitters are also involved in the ascending pain pathway.
Dosage
Tramadol is available as an immediate-release tablet (Ultram), extended-release tablet (Ultram ER), and in combination with acetaminophen (Ultracet). For the immediate-release tablet, patients can take 50 to 100 mg every 4 to 6 hours as needed for pain with a maximum daily dose of 400 mg. For patients taking the extended-release tablet, the starting dose is 100 mg daily with an increase every 5 days to the maximum of 300 mg/d. All forms of tramadol need to be dose adjusted for renal and hepatic dysfunction.
Time Frame for Response
Patients may feel a decrease in pain as soon as 1 hour after taking an immediate-release tramadol dose with a maximum effect at 2 hours. The extended-release tablet takes about 12 hours for the maximum effect to be seen.
Contraindications
Patients with an opioid dependency should not take tramadol since it has opioid effects. Also, patients with acute intoxication with alcohol, hypnotics, central-acting analgesics, opioids, or psychotropic drugs should not be given tramadol. Tramadol has the ability to lower the seizure threshold. Therefore, tramadol should not be used in patients with a history of seizures and needs to be used cautiously with other medications that may lower the seizure threshold.
Adverse Events
Unlike NSAIDs, tramadol does not produce serious GI adverse events nor does it aggravate existing hypertension, CHF, or renal disease. The most common side effects of tramadol include nausea, dizziness, drowsiness, and sweating. Due to the opioid receptor agonism, tramadol has the potential to exert similar adverse events as other opioids, such as constipation, dependency, euphoria, and respiratory depression.
Interactions
Tramadol is metabolized by CYP2D6, and any medication that inhibits or induces this enzyme will interact with tramadol. Also, because it inhibits serotonin reuptake, tramadol has the potential to induce serotonin syndrome when used in combination with other serotonergic agents, such as selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, or linezolid.
Tapentadol
Mechanism of Action
Similar to opioids, tapentadol is an agonist for the mu opiate receptor. In addition, tapentadol also inhibits the reuptake of norepinephrine.
Dosage
For patients starting tapentadol (Nucynta), the recommended dose for the first day of therapy is 50 to 100 mg every 4 to 6 hours as needed with the option of giving the second dose as soon as 1 hour after the first dose, if needed. After the first day of therapy, the recommended dose is 50 to 100 mg every 4 to 6 hours as needed with a maximum daily dose of 600 mg. The dosing interval should be increased to every 8 hours or longer in patients with moderate hepatic impairment. Tapentadol is not recommended in patients with severe hepatic or renal impairment (clearance less than 30 mL/min).
Tapentadol is also available in an extended-release formulation. For opioid-naïve patients, the recommended starting dose is 50 mg by mouth twice daily. The dose can be increased by 50 mg per dose every 3 days to a maximum daily dose of 500 mg.
Time Frame for Response
Patients are likely to experience pain relief within 1 to 2 hours of taking the dose. The ER formulation peaks after 3 to 6 hours of ingestion.
Contraindications
Due to the opioid receptor agonism, tapentadol is contraindicated in patients with impaired pulmonary function who are not in a monitored setting. Also, patients with paralytic ileus should avoid use due to the risk of opioid-induced constipation. Last, since tapentadol inhibits norepinephrine reuptake, it cannot be used within 14 days of a MAO inhibitor.
Adverse Events
The adverse event profile of tapentadol is similar to that of other opioids and tramadol. The most common adverse events are dizziness, somnolence, constipation, nausea, and vomiting. There is a risk of respiratory depression and CNS depression.
Interactions
Tapentadol needs to be used cautiously with other CNS depressants due to additive effects. As mentioned above, tapentadol and MAO inhibitors cannot be used within 14 days of each other. Using tapentadol with serotonergic agents increases the risk of serotonin syndrome.
Ethanol may increase the tapentadol concentrations if patients are taking the extended-release product. Therefore, patients taking extended-release tapentadol need to refrain from alcohol and any medication containing ethanol.
Duloxetine
Mechanism of Action
Duloxetine is a serotonin and norepinephrine reuptake inhibitor. By enhancing serotonin and norepinephrine, duloxetine works in the CNS to reduce pain transmission. Duloxetine is a relatively balanced serotonin and norepinephrine reuptake inhibitor.
Dosage
The FDA-approved dosing for chronic musculoskeletal pain is 30 mg by mouth daily for 7 days and then increase to 60 mg by mouth daily, which is the listed maximum dose for this indication. However, the trials that resulted in duloxetine’s approval for this indication increased the dose to 120 mg by mouth daily in patients not having an adequate response to the 60 mg dose.
Time Frame for Response
The benefit of duloxetine was seen as early as 4 weeks in the clinical trials. Time points sooner than this were not assessed, so it is not known if its effect starts sooner.
Contraindications
Due to the risk for serotonin syndrome, duloxetine should not be started while a patient is on a monoamine oxidase inhibitor (MAOI) or within 14 days of stopping an MAOI. Also, starting duloxetine while a patient is receiving linezolid and intravenous methylene blue may increase the risk of serotonin syndrome and is contraindicated.
