Pharmacologic management of common musculoskeletal disorders in women

PHARMACOLOGIC MANAGEMENT OF COMMON MUSCULOSKELETAL DISORDERS IN WOMEN Jan M. Kriebs, CNM, MSN and Karen B. Burgin, CNM, MA ABSTRACT The range of musculoskeletal disorders encountered in primary care settings is broad, extending from simple injuries to complex chronic diseases. Assessment, management, referral, and pharmacologic intervention for many of these conditions may fall to certified nurse-midwives who increasingly are assuming primary care responsibilities. © 1997 by the American College of Nurse-Midwives. The range of musculoskeletal disorders that present clinically is broad; ranging from injuries best treated with rest and ice to complex and poorly understood medical illnesses. The Journal of Nurse-Midwifery recently published a series on primary care for women that presented a comprehensive discussion of the assessment and management of common musculoskeletal problems (1,2). Assessment, management, referral, and pharmacologic interventions for many of these disorders may fall to the certified nurse-midwife (CNM) in primary care. Articles reviewing primary care practices of nurse-midwives and obstetricians have identified minor skeletal injuries, sciatica, and fibromyalgia as problems seen in office settings (3,4). Although many conditions can be managed by the CNM within the context of independent practice, others require specialized skills or referral for specialty care by physicians or therapists. The Institute of Medicine has defined the primary care role as encompassing "a large majority" of health needs and has acknowledged the responsibility of the primary care provider to collaborate, co-ordinate, and monitor care provided by others (5). This article reviews the pharmacologic management of several of the more common musculoskeletal concerns. Included among these concerns are conditions that are appropriate for CNM management as well as others for which the appropriate CNM role is referral and intercurrent care.

CARPAL TUNNEL SYNDROME

Carpal tunnel syndrome is a common disorder that may occur during pregnancy, as a result of repetitive motions Address correspondence to Karen Burgin, CNM~ MA, 616 Third Street Brooklyn, NY 11215.

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or injury, or as part of a systemic disease, such as diabetes or rheumatoid arthritis. It is caused by entrapment and compression of the median nerve in the carpal tunnel. Burning, pain, tingling, or numbness may be experienced in the central portion of the affected hand and the thumb, first two fingers, and the medial aspect of the ring finger. Symptoms often worsen with increased use of the hands and occasionally at night. One or both hands may be affected (2,6). The most common therapy for carpal tunnel syndrome is the use of wrist splints at night and for extended wear during the day if possible. These splints should be fitted to the patient to achieve a neutral wrist position without slippage or constriction. If the patient does not have assistance in determining the correct fit when purchasing splints, she should be instructed in their appropriate fit and use. Patients should be advised that the chronic use of nonsteroidal analgesics is not effective in managing carpal tunnel syndrome (7). When conservative management does not improve symptoms within 2 - 4 weeks, injections of a corticosteroid, often methylprednisolone, into the carpal tunnel are administered. A local anesthetic may be used in conjunction with this treatment. Referral to an orthopedist for steroid injections is appropriate, as the use of injectable steroids into a confined space requires considerable skill to avoid inadvertent nerve injury (6,8). Patients should be advised that relief of symptoms may be temporary; as few as 8% of patients may experience continued relief after 24 months (9). Hydrocortisone (cortisol) and its synthetic anaIogues are glucocorticoids. Cortisol is synthesized from cholesterol and secreted by the adrenal cortex. Among the many functions of these hormones, antiinflammatory action is the basis for their therapeutic use in joint disorders. Because the steroid injection for carpal tunnel syndrome usually is given only once or at most, infrequently, systemic side effects are a minor concern. Patients should be advised that peptic ulcers may worsen or develop as a result of stomach acid and pepsin stimulation. Some patients also may notice increased fluid retention. More serious side elfects such as adrenal suppression, iatrogenic Cushing syndrome, psychosis, or imbalances of potassium and sodium are extremely unlikely in this therapeutic regimen (10).

207 0091-2182/97/$17.00 • PIi 50091-2182(97)00029-3

A possible alternative to steroid injection is the use of oral prednisone. One report of a low-dose 2-week regimen (20 mg daily for 7 days, then 10 mg daily for 7 days) found that treatment results were beneficial but waned during the next 2 months (11). This trial was small, and the literature does not support oral steroids as an alternative to injections. In the future, short-term oral prednisone therapy may become an alternative that will be offered in primary care offices. The risks of steroid use for oral therapy will not be less than those for injection. Used injudiciously, the risks could include systemic effects as mentioned previously. Consultation with, or referral to, a physician is appropriate if oral steroids are under consideration. When symptoms recur or do not resolve with steroid injections, surgery to release the carpal tunnel is the definitive procedure.

LOW BACK PAIN

Most women will experience low back pain at some point in their lives. Common causes include back strain from trauma, lordosis, and anxiety. Risk factors for more serious causes of pain include age older than 50 at onset, a history of cancer or intravenous drug use, symptoms of systemic diseases, and neurologic deficit (12). Symptoms that suggest a more dangerous condition include a dragging gait, decreased reflexes, persistent pain, and impaired bowel or bladder function. Women with these symptoms should be referred to a specialist immediately. When the CNM can rule out serious causes, office management of mechanically caused intermittent low back pain is appropriate. Most cases should resolve spontaneously within 4 weeks, and failure to respond to conservative therapies within this time frame is an additional reason for prompt referral. As with many other musculoskeletal disorders, nonpharmacologic interventions such as transcutaneous electrical nerve stimulation, acupuncture, stretching exercises, and physical therapy are often part of a therapeutic plan (12). One study reported that an early return

Jan M. Kriebs is in a private midwifery practice. She completed her midwifery education at Yale University in 1983. She has an extensive background in clinical practice, has been a service director, and worked in quality management. She serves as the chair of the American College of Nurse-Midwives Division of Standards and Practice.

Karen B. Burgin received her nurse-midwifery education from the State University of New York, Health Science Center at Brooklyn in 1981 and a master of arts degree in nursing education from Teachers College, Columbia University. She is an associate editor of the Journal of Nurse-Midwifery and is a midwife in clinical practice in Brooklyn, New York.

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to normal activity, rather than either bed rest or exercise programs, produced the most rapid recovery among workers with acute low back pain (13). The most commonly used medications for low back pain are the nonsteroidal anti-inflammatory drugs (NSAIDs) discussed in the section on osteoarthritis. Acetaminophen is preferable for those experiencing gastrointestinal (GI) side effects of NSAIDS or those who are allergic or have a bronchospasm response to aspirin. Acetaminophen is a weak prostaglandin inhibitor without anti-inflammatory effect. The usual dose of acetaminophen is 3 2 5 - 5 0 0 mg taken orally every 6 hours. Even at this dose, liver enzyme values may rise. Side effects of excess doses include confusion or disorientation, excitement, and dizziness. Overuse may lead to liver damage, early symptoms of which include nausea, vomiting, diarrhea, and abdominal pain (14). Other medications that have been suggested for use in uncomplicated low back pain include muscle relaxants and antidepressants. Their use is not well defined, however, nor do they offer advantages compared with nonsteroidal drugs and acetaminophen (12). Additionally, their cost can be prohibitive, and neither generally is recommended for treatment of back pain. When pain is severe but the cause is believed to be mechanical, a brief course of mild to moderate strength opiate analgesics can be beneficial (Table 1). Opiate analgesics change the perception of pain, both raising the pain threshold and affecting the patient's response. Codeine, hydrocodone, and oxycodone, which often are found in combinations with aspirin or acetaminophen, are possible selections. All of the opiates have potential for tolerance and abuse. Sedation, respiratory depression, vomiting, increased intracranial pressure, postural hypotension, constipation, urinary retention, and urticaria are symptoms of toxicity. Constriction of the pupils (miosis) can be used to recognize patients whose chronic use of opiates has led to tolerance of greater doses without pain relief. Both physical and psychologic dependence can occur with prolonged use (15). For these reasons, consultation with a clinician experienced in management of musculoskeletal disorders is advised prior to the prescription of opiates for low back pain. FIBROMYALGIA

Fibromyalgia is a chronic rheumatoid condition with a complex of symptoms, including pain and fatigue~ welldefined tender trigger points, and sleep disturbance. It is more common among women, and its onset is most common during middle-age. Because laboratory tests, radiology, and muscle biopsies remain normal in these patients, fibromyalgia often is a diagnosis of exclusion (16). The differential diagnosis includes chronic fatigue syndrome, degenerative disc disease, rheumatoid arthritis

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TABLE 1 Common Preparations of Oral Opiate Analgesics

Generic (Brand) Preparations

Availability

Codeine sulfate or phosphate Oxycodone Codeine/acetaminophen (Tylenol with Codeine) Codeine/aspirin (Empirin Compound) Oxycodone/acetaminophen (Percocet, Tylox) Oxycodone/aspirin (Percodan)

15, 30, and 60 mg tablets 5 mg tablets 7.5, 15, and 30 mg codeine with 300 mg acetaminophen 15, 30, and 60 mg codeine with 325 mg aspirin 5 mg oxycodone with 325 or 500 mg acetaminophen 4.9 mg oxycodone with 325 mg aspirin

(RA) Parkinson disease, hypothyroidism, and many other conditions. Most commonly, the diagnosis is made through careful history taking and tenderness elicited in at least 11 of 18 trigger points (6,17,18). Although the long-term prognosis with fibromyalgia is one of persistent but not progressive symptoms, patients can be reassured by being told that modest relief can be gained through exercise and medication. Even knowing that their symptoms are "real" can provide some benefit, and patient education is particularly important. Fibromyalgia has been treated successfully with such medications as amitriptyline (Elavil), cyclobenzaprine (Flexeril), and triazolam (Halcion)(16), whereas antidepressants from the selective serotonin reuptake inhibitor group, such as fluoxetine and citalopram, have been evaluated and found to be ineffective (19,20). Nonsteroidal anti-inflammatory drugs, opioids, and corticosteroids also have been found to be of no benefit in the management of this condition (6). Amitriptyline is a tricyclic antidepressant that acts to block reuptake of various neurotransmitters. It produces a significant sedative effect that may be less than acceptable to patients. Other side effects of the tricyclic antidepressants include tremor, insomnia, constipation, urinary hesitancy, confusion, orthostatic hypotension, and weight gain. Initially, 10 mg can be taken at bedtime; this dose may be increased to 4 0 - 5 0 mg. Overdosing can produce severe symptoms such as coma with shock, metabolic acidosis, respiratory depression, delirium, seizures, hyperpyrexia, bowel and bladder paralysis, and cardiac arrhythmia and conduction defects (21). Cyclobenzaprine is classified as a spasmolytic, or muscle relaxant; its chemical structure is similar to that of the tricyclic antidepressants. It acts as a central nervous system (CNS) depressant, although its exact mechanism of action is not known; 10 mg can be taken three times a day. Significant side effects include blurred vision, constipation, urinary frequency, sedation, confusion, and visual hallucinations (22). Triazolam is one of the benzodiazepine sedative hypnotics. Its role in relieving fibromyalgia symptoms may relate to the improved rest achieved when taking triazolam or to its muscle relaxation property. This drug is

susceptible to abuse because it produces euphoria, anxiety relief, and disinhibition. Benzodiazepines also produce impaired motor skills, drowsiness, and amnesia (23); initially, 0.125 mg can be taken at bedtime and, if necessary, increased to 0.5 mg. Nurse-midwifery involvement in the management of fibromyalgia will include consultation and referral to establish an effective treatment program. Because of the complexity of this diagnosis, and the significant effects of the medications involved, it is not one that CNMs commonly will manage independently. OSTEOPOROSIS

Osteoporosis is the single most common metabolic condition affecting bone. It is characterized by loss of bone mass, leading to fractures and deformation of the skeleton. Although commonly associated with estrogen decrease in older women, many other causes and associated risks for osteoporosis exist. Some of the most important are listed in Table 2 (24-26). The prevention and management of osteoporosis indudes educating women about the benefits of exercise. Bone loss in women begins prior to menopause; a woman's total lifetime loss may approach one third to one half of her peak bone mass. Osteoporosis risk is based on both the peak bone mass and rate of bone loss. Moderate weight-bearing exercise of approximately 30 minutes for 3 days a week assists in maintaining bone mineralization (27-29). Along with the various medications discussed in this section, exercise forms an important part of the management plan for osteoporosis. Until recently, pharmacologic therapy for osteoporosis was limited to hormone-replacement therapy (HRT) and the use of vitamin or mineral supplements. Current therapeutic regimens also include the use of calcitonin and the biphosphonates. These regimens have shown great promise for prevention and management of osteoporosis in women who are unable or unwilling to use long-term hormone replacements. Two recent articles in this journal (30,31) describe in detail the use of HRT. The reader is referred to these articles for a complete discussion of HRT management.

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TABLE 2 Risk Factors for Osteoporosis (24-26)

months of therapy. Authors of a report published in 1994 estimated the relative benefits and risks of 25 years of estrogen use for postmenopausal women (34). Their conclusion was that the reductions in cardiovascular disease and hip fracture outweighed the increased risks of breast and endometrial cancer. An individual's history and lifestyle affect her risk of any of these events; nonetheless, knowing that in general the benefits outweigh the risks may be reassuring.

Alcoholism Corticosteroid therapy Cushing disease Diabetes mellitus Eating disorders Estrogen or testosterone deficiency Excessive exercise (to amenorrhea) Family history Genetic disorders High caffeine intake Hyperparathyroidism Hyperthyroidism Inactivity Liver disease Low body mass Low calcium intake Metabolic diseases Medications (eg, heparin, anticonvulsants) Multiple myeloma Protein malnutrition Renal failure Small frame Smoking

Vitamin and Mineral Supplementation

Key points to remember regarding HRT for osteoporosis prevention or management include the following (31): 1. A women whose uterus is intact needs both estrogen and progestin 2. To reduce osteoporosis risk, long-term HRT use is essential; bone mass decreases rapidly when circulating estrogens decrease 3. Contraindications for HRT include estrogen-dependent tumors, thromboembolic problems, and liver disease 4. Women with a history of breast or endometrial cancer need to be cared for by a physician for any hormone therapy 5. Abnormal vaginal bleeding on HRT requires prompt evaluation Although initiation of HRT commonly is recommended to coincide with menopause in order to minimize bone loss, initiation of estrogen therapy at a later date will be beneficial, even though the effect is reduced. The progestin component of combined HRT does not appear to affect bone density significantly (31,32). Table 3 lists the recommended daily dosage of various estrogens commonly prescribed for the prevention of bone loss (32,33). Because therapy with hormones must be long term to prevent bone deterioration, a consideration for many women will be the associated side effects and risks. Careful adjustment of dosage can eliminate withdrawal bleeding and mood changes for most users during the first

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Calcium is an essential mineral stored primarily in the bones. Supplementation of calcium to the recommended intake level has been demonstrated to slow bone loss, particularly in women more than 10 years past menopause. (In the earlier postmenopausal period, loss of circulating estrogens is the dominant factor in bone loss.) The role of calcium in prevention of fractures is less clearly defined (35-38). Calcium supplementation is most effective in conjunction with HRT, however, an independent benefit of calcium supplementation has been demonstrated in some studies (37,39). The National Institutes of Health consensus conference on calcium intake recommends a daily intake of 1,000 mg for childbearing age women and for postmenopausal women using estrogen; 1,500 mg taken daily may limit bone loss when women choose not to take supplemental estrogen (40). The products with the highest accessible fraction of elemental calcium are calcium carbonate (40% elemental calcium) and calcium citrate (24%) (33). One study found calcium citrate to be preferable to calcium carbonate (36), but a variety of supplements have been demonstrated to be effective. Calcium carbonate (eg, Turns) certainly is the most commonly available supplement. Its side effects can include constipation, abdominal discomfort, and rebound acidity. In older women with decreased stomach acidity (achlorhydria), calcium carbonate needs to be taken with food; it is not well absorbed in the absence of normal acid levels. Regardless of the choice of calcium salt, split doses usually are recommended to improve absorption.

TABLE 3 Estrogens Commonly Prescribed for the Prevention of Bone Loss (32, 34) Generic (Brand) Preparations

Dosage

Conjugated equine estrogen (Premarin) Micronized estradiol (Estrace) Estropipate (Ogen, Ortho-Est) Estradiol (Estraderm, Climara) Estrone sulfate Estradiol valerate Percutaneous estrogen creams

0.625 mg/d 0.5 mg/d 1.25 mg/d 50 ~g/d 0.625 mg/d 2 g/d 2 g/d

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Other concerns cited when calcium intake is supplemented include interference with the absorption of iron and other nutrients and absorption of medications such as tetracycline. Finally, hypercalcemia and hypercalciuria are risks for women with a history of kidney stones, concurrent disease processes affecting vitamin D synthesis, or prior renal damage (40). The vitamin D metabolite calcitriol is active in stimulation of calcium and phosphate transport and osteoblast function. Although the degree of benefit from adding vitamin D to calcium or other medications for osteoporosis prevention is not clear, there is evidence that it may assist in increasing bone mass and decreasing the incidence of fractures (41,42). The benefit may be greatest in those who are vitamin deficient, older than age 75, or receiving supplemental calcium (34). Regular exposure to natural sunlight generates adequate stores of vitamin D for most adults; however, a natural seasonal shift in individual levels, related to available sunlight and outdoor activity in the winter months, has been noted. Dairy products in the United States also are fortified to supply vitamin D. Among the factors contributing to a need for supplementation in the elderly are decreased exposure to sunlight, reduced dietary intake, reduced intestinal absorption, and a decreased ability of the skin to synthesize the vitamin. There also may be a relationship with parathyroid gland dysfunction (41). Many commercially available calcium supplements include vitamin D, as do most multivitamins. The standard dose is 4 0 0 - 8 0 0 IU daily. For some women, calcium absorption is low even when vitamin D supplements are provided. Urine calcium below 5 0 - 1 0 0 mg daily in the presence of a normal creatinine clearance suggests a need for high-dose vitamin D supplementation. Dosages as high as 50,000 IU for 7 - 1 0 days have been given. It is necessary to regularly monitor serum and urine calcium for excessive levels when a dose greater than the usual pharmacologic amount is given because excess vitamin D can lead to hypercalcemia and renal stone formation (34,35). Another alternative, particularly when there is concern about seasonal variation in vitamin D levels, is the use of single high-dose supplements, either by injection or taken orally (43). Physician consultation should be obtained when using nonstandard doses.

Calcitonin Calcitonin is a hormone secreted primarily by the thyroid. It was discovered in 1962 and takes its name from its ability to lower plasma calcium levels. Its activity in regulating plasma calcium assists in decreasing excess bone resorption by depressing osteoclast activity. It produces an analgesic effect on bone-related pain also (44). Calcitonin primarily is recommended for women who are unable or unwilling to use HRT and who have ex-

perienced bone loss. Available for several years in the United States as an injectable hormone, it is now available as an intranasal spray. Initially, its only use was in women with advanced osteoporosis; however, more recent research reports demonstrate a reduction in bone loss in the first years after menopause (45-47). One drawback to its use has been the expense, as costs for the injectable form may be as high as $3,000 per year (35). Compliance with long-term use of injections also has been demonstrated to be poor. Side effects of calcitonin include nausea, vomiting, flushing, and irritation at the injection site (48). Recently, the intranasal spray Miacalcin has been approved for use, making this drug a more acceptable longterm therapy. Intranasal calcitonin at 200 IU in a single puff is taken once daily. Patients should be advised to alternate nostrils each day to decrease local irritation (48). The incidence of side effects is decreased with this route of administration. Patients using calcitonin should continue to use calcium and vitamin D supplements.

Biphosphonates The biphosphonates are analogues of an endogenous regulator of bone resorption, pyrophosphate. They act to inhibit osteoclast activity. Earlier biphosphonates (eg, etidronate, clodronate, and pamidronate) also inhibited bone mineralization at the therapeutic dose. For this reason, although these drugs are used in the treatment of some bone diseases, they have not been approved for general use in osteoporosis (49,50). Alendronate (Fosamax) is a third-generation biphosphonate. Recently approved by the U.S. Food and Drug Administration (FDA), it is being marketed widely as an alternate to HRT. Alendronate is recommended for use in the presence of decreased bone density (2 standard deviations below young normal) or a history of osteoporotic fractures (51). More potent than earlier biphosphonates, it inhibits bone resorption without decreasing mineralization, which means that it can be given on an ongoing basis. Studies of alendronate have demonstrated increases in bone density, reduction of fractures, and decreases in skeletal deformation and loss of height with daily use (52,53). The standard dose is 10 mg taken orally in the morning, 30 minutes prior to eating and with a full glass of water. Women using alendronate should be further advised to remain erect after taking the medication to reduce irritation in the esophagus. Taking the medication with food or after eating reduces absorption significantly (50). Adverse effects reported by the manufacturer include a variety of GI complaints, muscle cramping or pain, headache, and dizziness; however, it is noteworthy that similar numbers of women receiving placebo versus alendronate withdrew from clinical trials with similar

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complaints. Patients taking aspirin should be advised that they have a greater risk of upper GI problems, including ulcers. This effect did not occur with NSAIDs. At this time, simultaneous use of estrogen and alendronate is not recommended (54).

OSTEOARTHRITIS Osteoarthritis (OA), one of the most frequent conditions for which a primary care provider is consulted, is the most common disease of joints. As many as 80% of the US population have radiographic evidence of osteoarthritic joint changes by age 65; and 60% of these people will be symptomatic (55). Of all visits to primary care providers, 15-30% have been attributed to difficulty in ambulation, largely due to OA (55). What must be underscored, therefore, is the clinician's professional responsibility to independently review the physiology of normal cartilege as well as the alterations brought about by the disease process (56-60) in order to pharmacologically manage OA both appropriately and effectively. Osteoarthritis is poorly understood, not only as to its causation but also as to the rationale for treatment modalities. Even the name lacks accuracy, as the pathophysiologic process is primarily one of degeneration, not of inflammation. Degenerative joint disease is considered a better term to describe a process that is an essentially noninflammatory disorder of movable joints characterized by deterioration of articular cartilage and by the formation of new bone (osteophytes) at the joint surfaces and margins. The disease is thought to be a reaction of joint tissues to injury, involving an interaction of mechanical and biologic factors (56). Pain, often causing disability, is the primary symptom for which medical consultation is sought and for which treatment is instituted. Pain in OA is known to arise from sources other than cartilage itself, which has no nerve endings. Although the exact origin of osteoarthritic pain is still uncertain, a number of factors are thought to contribute to it, including microfractures in the bone beneath the cartilage, irritation of nerve endings in the periosteum, stress on ligaments due to bone deformity or effusion, venous congestion caused by remodeling of subchondral bone, soft tissue rheumatism, and muscle strain. Synovial inflammation is an additional source of pain (57). Although evidence of this condition can be found early in the disease, it is more often a feature of advanced disease; clinical correlates of synovial inflammation such as joint swelling, effusion, and prolonged morning stiffness are only mild or entirely absent in the early stages (54). As the disease advances, however, progressive erosion of articular cartilage leads to secondary inflammation of the synovial membrane. At this stage, symptoms

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related to the inflammatory process become more prominent (60).

Pharmacologic Management of Osteoarthritis Due to the complex nature and incomplete understanding of this chronic disease, there have been differing opinions among researchers and clinicians as to the most effective treatment modalities. Although the standard pharmacologic therapy has been the use of NSAIDs, some leading authorities have questioned prescribing them routinely for a disease process that is inflammatory in only a minority of cases. The point has been made that if the analgesic effect is the primary goal, the use of simple analgesics may, in fact, be preferable to NSAIDs, for several reasons.

Use of simple analgesics in osteoarthritis. The use of the simple analgesic acetaminophen is being increasingly advocated for the initial treatment of OA. One main reason for this trend is the concern about side effects of NSAIDs, especially in the elderly; acetominophen in standard doses has no adverse effects on the GI tract (61). Other factors favoring use of acetaminophen include the lack of convincing evidence that NSAIDs slow the progression of the disease, the growing awareness that a simple analgesic may be as effective as an NSAID for symptomatic relief, and, in this environment of managed care and cost-cutting, the enormous saving to be realized with the use of acetaminophen instead of the more expensive NSAIDs (62). Studies show a growing trend among physicians to begin the treatment of symptomatic OA with acetaminophen. In a 1991 study, 94% of primary care physicians surveyed responded that they would choose an NSAID for the initial treatment of OA of the hip as opposed to I% who responded that they would choose acetaminophen. Rheumatologists' responses were comparable (62). By contrast, a 1995 survey showed that 23% of U.S. community-based practicing rheumatologists stated that they "always" used acetaminophen as compared with NSAIDs (8.7%) in the initial management of OA of the hip (63). The authors advocate the use of acetaminophen in doses of up to 4,000 mg daily as initial treatment for OA of the hip and knee. They emphasize that liver toxicity is rare, occurring primarily in those who consume excessive amounts of alcohol (64). The small risk of the occurrence of chronic renal disease in daily acetaminophen users is believed to be less than the risk of NSAID use (62). In a randomized double-blind study published in 1991, patients with chronic knee pain due to OA were given the NSAID ibuprofen in doses of either 2,400 mg (an anti-inflammatory dose) or 1,200 mg (an analgesic dose) daily, or 4,000 mg of acetaminophen. Acetaminophen

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was as effective as ibuprofen, whether the latter was given as an anti-inflammatory or analgesic dose (55). A 1993 study compared the use of the NSAID naproxen with acetaminophen in patients with OA of the knee. The conclusion was that neither drug had any positive or negative effect on the disease process itself; both drugs were effective purely for their analgesic effect and, in this regard, acetaminophen proved to be as effective as the NSAID (65).

Nonsteroidal anti-inflammatory drugs. The mainstay of treatment for OA continues to be the NSAIDs, for which 60 million prescriptions for 20 different formulations are written annually in the United States alone (66). Nonsteroidal anti-inflammatory drugs used in low doses are effective analgesics due to their inhibition of prostaglandin sensitization of peripheral pain receptors. It is also postulated that there may be an inhibition of pain stimuli at a subcortical site (62). In higher doses, they exert anti-inflammatory effects, primarily through inhibition of the enzyme cyclo-oxygenase, thereby interrupting the sequence of events that lead to the production of terminal prostaglandins (58). Nonsteroidal antiinflammatory drugs also play a role in altering the immune response by their inhibitory effects on neutrophils, decreasing the release of mediators from granulocytes, basophils, and mast cells. They are thus thought to reduce the enzyme activity that leads to cartilage destruction (67,68). Nonsteroidal anti-inflammatory drugs exert an antipyretic effect by blocking both the pyrogen-induced production of prostaglandins and the CNS response to the cytokine interleukin-1, which causes the hypothalamus to raise the body's temperature. The temperature control of the hypothalamus is reset by these inhibitory mechanisms, and the body can then dissipate heat by vasodilatation (62). Nonsteroidal anti-inflammatory drugs also have an adverse affect on platelet aggregation. Although this effect is reversible with the newer NSAIDs, it is irreversible with aspirin; the effect will last for the 8 days required for new platelets to form. It is from this mechanism that aspirin derives its therapeutic anticoagulant action, as well as its risks for individuals such as pregnant women, hemophiliacs, or preoperative patients (62). There is controversy in academic and clinical research circles regarding the question of a direct biochemical benefit of the NSAIDs on the disease process versus claims that NSAIDs may actually have a destructive effect on cartilage (61,65,69,70). One of the major problems with OA research is that much of it has been conducted in vitro and on various species of animals. Confusion arises when certain NSAIDs seem to exert protective effects whereas others have destructive effects, and still others have no effects at all. Furthermore, when OA is

artificially induced in animal subjects, the animals frequently die from GI side effects long before significant changes in cartilage have developed. Even when changes are observed, it is questionable whether findings from one species can be extrapolated to another (55). Thus, authorities advise caution in the interpretation and application of these studies (61,69,71,72). Clinical studies on humans with OA often have methodologic flaws (61). The slow, chronic course of the disease in itself creates problems for researchers. To date, no clinical study conclusively documents the ability of NSAIDs to protect articular cartilage or to slow the progress of OA. To determine the possibility of such effects, long-term studies enrolling patients with early disease would have to be conducted (57,58).

Pharmacologic Considerations of Nonsteroidal Anti-Inflammatory Drugs Aspirin, the prototype of the other NSAIDs, is chemically related to all of them, nabumetone excepted, in that they are weak organic acids that usually circulate bound to plasma proteins. Aspirin is the acetylated form of salicylic acid; nonacetylated salicylates also have been employed for the same purposes as aspirin, with the added benefit of not affecting platelet aggregation (57) but with less potency than aspirin (62). It was the search for compounds without the adverse effects of aspirin and the salicylates that led to the development and current proliferation of NSAIDs (62). A drug free from side effects, however, has yet to emerge from research. Nonsteroidal anti-inflammatory drugs are grouped into several chemical classes, which may help to account for their differences in efficacy and adverse effects as well as for differences in individual tolerance. It is useful to classify the NSAIDs into compounds with short (less than 6 8 hours) and long (greater than 12 hours) half-lives. Those with long half-lives show much smaller fluctuations between peak and trough concentrations, even on a once-daily dosing regimen. Many of the shorter half-life NSAIDs have been produced in slow or sustained-release formulations that also reduce fluctuations and allow for a once-daily dose. A longer half-life allows the agent more time to achieve stable concentrations in synovial fluid and the synovial membrane, the major sites for the drugs' action (73)(Table 4). The biotransformation of NSAIDs is hepatic, with production of inactive metabolites; in some patients with renal insufficiency, the inactive metabolites may be resynthesized or converted back into their active compounds (58). Salicylates are converted to water-soluble conjugates that are rapidly cleared by the kidney (62). Side effects related to impaired clearance are more common in the elderly, and prudent management calls for the use

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TABLE 4 Common Preparations of Nonsteroidal Anti-inflammatory Drugs (58,66,145) Generic (Brand) Preparation

Dose Range, mgld*

Doses per Day, n

Half-life, h

Diclofenac (Voltaren) Diflunisal (Dolobid) Etodolac (Lodine) Fenoprofen (Nalfon 200) Flurbiprofen (Ansaid) Ibuprofen (Motrin, Advil, Nuprin) Indomethacin (Indocin) Ketoprofen (Orudis, Oruvail) Meclofenamate sodium (Meclomen) Nabumetone (Relafen) Naproxen (Naprosyn) Naproxen sodium (Aflaxen, Anaprox, Aleve) Oxaprozin (Daypro) Phenylbutazone (Butazolidine) Piroxicam (Feldene) Sulindac (Clinoril) Tolmetin (Tolectin)

75-150 500-1,500 600-1,200 1,200-3,200 200-300 1,200-3,200 50-200 150-300 200-400 500-2,000 500-1,500 550-1,650 1,200-1,800 200-800 20 150-400 800-1,600

2 2 I-4 3-4 2-4 3-4 2-3 2 3-4 1-2 2 2-3 1 3-4 1 2 3

1-2 7-15 3.3-11.3 2-3 3-5.7 2 4.5 1-3 2-5 24 12-17 12-17 21-25 40-80 30-86 7.8-16.4 1-5

* Lower end of dose range represents analgesic dose; higher end represents anti-inflammatorydose. Less frequent dosage represents drugs with longer half-lives.

of lower than standard doses, with a cautious increase if side effects are absent and the response is less than optimal (74).

Clinical Considerations Most patients with OA and RA can benefit from aspirin when administered in an anti-inflammatory dosage (4 g daily, in divided doses), the standard to which doses of the newer NSAIDs are compared. It is the concern with adverse GI effects that has caused many practitioners to turn away from aspirin to the newer NSAIDs in the hope that they will be better tolerated. NSAIDs, in general, have a simpler dosing schedule, whereas some of the newer agents, in particular nabumetone (Relafen), cause less gastric irritation; however, side effects still occur and the increased cost is quite substantial (62). It is typical for patients to switch frequently from one NSAID to another due to loss of efficacy or to the occurrence of adverse effects. An NSAID with a dosage schedule of once or twice daily is recommended if compliance is a problem. In the elderly who often suffer from compromised physiological function, it is best to choose one of the least toxic drugs.

Toxicity of Nonsteroidal Anti-lnflammatory Drugs Because prostaglandins contribute to the maintenance of renal hemodynamics, NSAIDs may decrease glomerular filtration and cause renal insufficiency, especially in persons with already impaired renal function or cardiovascular conditions, many of whom are elderly and thus

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prime candidates for OA. The use of NSAIDs in patients with compromised renal function puts the patient at risk of interstitial nephritis (58). Nonsteroidal anti-inflammatory drug-related hepatotoxicity also has been noted, especially in patients who are elderly, take many drugs, have compromised renal function, and undergo prolonged treatment. The worst offender was the drag phenylbutazone (Butazolidine), one of the earliest NSAIDs, which has undergone a sharp decline in its use since the advent of less-toxic NSAIDS. Phenylbutazone is now used primarily for the treatment of gout in a course of treatment limited to no more than 7 days (58). Hematologic side effects, though rare, can include serious or life-threatening conditions such as aplastic anemia, hemolytic anemia, agranulocytosis, neutropenia, and thrombocytopenia. Again, phenylbutazone was found to be a serious offender, and any benefit of its use in OA is not considered worth the risk (58). Other toxic effects seen with NSAIDs include skin eruptions and hypersensitivity reactions. It is particularly important to be alert to the distinct possibility of allergy to aspirin and all other NSAIDs in persons with nasal polyps, asthma, and vasomotor rhinitis; serious anaphylaxis may occur. Central nervous system effects, most prominent with indomethacin, include headaches, altered moods, confusion, insomnia, depression, drowsiness, and paranoia (58) (Table 5). Although it is not common to see OA manifested in pregnancy, the clinician may be faced with the decision of whether or not to prescribe NSAIDs for the pregnant woman. Although most NSAIDs are classified as U.S.

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FDA pregnancy risk Category B (ie, reproductive studies on animals have not revealed evidence of teratogenic effects or fetal harm) such results cannot always be extrapolated to humans. Thus, authorities advise against the use of NSAIDs during pregnancy, especially because patency of the ductus arteriosus is dependent on prostaglandins and NSAIDs might cause premature closure

(58). Table 6 presents a toxicity ranking of commonly used NSAIDs from a 1993 study; note that the ranking is not all-inclusive (73).

Nonsteroidal Anti-lnflammatory Drugs and Increased Risk of Serious Gastrointestinal Side Effects A large case-control study of elderly people hospitalized for peptic ulcer disease points out the serious nature of potential GI side effects of NSAIDs, except for aspirin. The risk of peptic ulcer disease was shown to be 4. I in NSAID users as opposed to nonusers. More than 50% of the study group experienced at least one major GI complication (perforation, obstruction, hemorrhage, or surgery). Risks varied according to the drug; ibuprofen

having the lowest risk and meclofenamate having the highest (75). A similar but larger study of patients with either OA or RA found a 5.2 hazard ratio of those taking NSAIDs to those not taking them, a risk that was greater in patients with RA (76). Studies like these have prompted research into ways of preventing the more serious GI complications. The drug misoprostol (Cytotec), a synthetic analogue of prostaglandin El, has been discovered to protect GI mucosa by inhibiting gastric acid secretion and promoting better mucus production and enhanced mucosal blood flow (62,77). Studies have documented both the healing of gastric and duodenal ulcers (78) and a significant reduction in NSAID-induced GI complications in elderly patients (77). Misoprostol was shown to be significantly more effective in protecting GI mucosa than drugs such as cimetidine, antacids, and sucralfate (77). The two major drawbacks to the use of misoprostol are the incidence of diarrhea, which often leads to noncompliance (79), and the substantial expense of the drug. In one 1995 study, it was suggested that, in this managed care environment, the use of misoprostol should be reserved for the small subgroup of patients with a history of peptic ulcer or GI bleeding, especially the

TABLE 5

Adverse Reactions to Nonsteroidal Anti-inflammatory Drugs Organ System Gastrointestinal

Hepatic Renal

Hematologic

Cutaneous

Respiratory Central nervous system

Reaction Indigestion Erosions Esophageal reflux Peptic ulcer Hemorrhage Perforation Bowel ulcerations Hepatocellular cholestasis Transient rise in serum creatinine Acute renal failure Interstitial nephritis Hyperkalemia Hyponatremia Thrombocytopenia Neutropenia Aplasia Hemolytic anemia Photosensitivity Erythema multiforme Urticaria Toxic epidermal necrolysis Bronchospasm Pneumonitis Headache Dizziness Personality change Aseptic meningitis

Incidence Common (>20%)

Rare (<5%) Rare

Rare

Uncommon (5-20%)

Rare Uncommon

Data from BrooksPM. Drug modification of inflammation: nonsteroidalanti-inflammatorydrugs. In: MaddsonPT, Isenberg DA, Woo P, Glass D, editors. OxfordTextbookof Rheumatology.Oxford(UK):OxfordUniversityPress, 1993.

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TABLE 6 Relative Toxicity of Commonly Used Nonsteroidal Anti-inflammatory Drugs Least toxic Salsalate (Disalcid, Mono-Gesic, Salflex, Salsitab) Ibuprofen (Advil, Motrin, Nuprin) Naproxen (Naprosyn) Sulindac (Clinoril) Piroxicam (Feldene) Fenoprofen (Nalfon 200) Ketoprofen (Orudis, Oruvail) Meclofenamate (Meclomen) Tolmetin (Tolectin) Indomethacin (Indocin) Most toxic

elderly or those with cardiac disease. For others, an NSAID known to be less toxic to the GI mucosa should be prescribed (80). Nabumetone is the first of a new alkanone class of drugs that was first used extensively in Europe before being approved for use in the United States. Nabumetone has been shown to be as effective as more established NSAIDs, with fewer serious GI events such as ul-

cers or significant decreases in hemoglobin. There is, however, an increased incidence of diarrhea relative to the other drugs studied (81,82). Every primary care provider must be aware that NSAIDs interact with many other drugs, sometimes in ways which could result in serious health consequences. Table 7 presents some known drug interactions (83).

Intra-Articular Corticosteroid Therapy Once customary treatment modalities begin to lose effectiveness, the patient with OA may be referred to a specialist for an injection of long-acting intra-articular corticosteroids. Systemic use of corticosteroids, although warranted for RA, is contraindicated in OA because the risks far outweigh the benefits. Clinical efficacy of intra-articular corticosteroid therapy was rigorously documented in three controlled trials of OA of the knee, which showed that compared to placebo, corticosteroid injections were associated with definite but limited improvement, primarily in decreased pain, with little alteration in function. Pain relief lasted up to 3 weeks. Response to placebo, although less, was

TABLE 7

Drug Interactions with Nonsteroidal Anti-inflammatory Drugs Drug~Class

NSAID

Effect

Digoxin

All

Antihypertensive agents /~-blockers Diuretics Adverse clinical event inhibitors Vasodilators Diuretics

Indomethacin; all others*

Oral anticoagulants

Lithium Oral hypoglycemic agents Phenytoin

Valproate sodium Methotrexate Cyclosporine A

Indomethacin; all others* Phenylbutazone Oxyphenbutazone Probably all except acetyl salicylic acid (ASA)* Probably all except ASA* Phenylbutazone Oxyphenbutazone Azapropazone Phenylbutazone Oxyphenbutazone All others* ASA Probably all* Probably all*

In those with already impaired renal function, increased plasma concentration with risk of increased toxicity Reduction of hypotensive effect

Reduction in natriuretic and diuretic effects; exacerbation of chronic heart failure Increased anti-coagulant effect of warfarin; GI tract mucosal damage, inhibition of platelet aggregation, increased risk of GI bleeding Increased serum concentrations; risk of toxicity Inhibits drug metabolism; risk of hypoglycemia Increased plasma concentration Displacement from plasma protein, reducing total concentration for same unbound (active) concentration Increased plasma concentration Increased plasma concentration; risk of severe toxicity Inhibition of prostaglandin synthesis aggravates potential of cyclosporine A to induce renal dysfunction

NSAIDs, nonsteroidalanti-inflammatorydrugs; GI, gastrointestinal;ASA, acetylsalicylicacid. * Indicates probably all NSAIDsexcept for ASAs. Data from Tonkin AL, WingLMH. Interactionsof nonsteroidalanti-inflammatorydrugs. BaillieresClin Rheumato11988,2:455-83.

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also significant, with 35-45% of subjects claiming improvement (55). As with the NSAIDs, controversy exists regarding effects on the joint structures, with some studies pointing to damage and others claiming a protective effect. It was initially conjectured that overuse of an injected joint was likely to occur due to the analgesia obtained with the steroid, and that this could lead to further joint destruction (56). Historical data from two large studies in humans showed a less than 1% incidence of rapid joint destruction (55). Conflicting data emerged from another study that tracked radiographic changes in a small group of patients for a course of more than 10 years. The study found that 78.6% of the steroid-treated knees had undergone degeneration as opposed to 52.4% of the knees without steroid treatment. The authors are careful to point out that even untreated knees underwent deterioration in half the cases, illustrating that other factors of a biochemical, metabolic, and immunologic nature also must play a role (84). In a study providing evidence of cartilage improvement after steroid injection in dogs with experimentally induced OA, the authors point out that corticosteroids have both anabolic and catabolic effects, and that clinicians must determine just how much steroid is the right dose to suppress the destructive enzymes without suppressing proteoglycan production (85). These authors concluded in an earlier study that intra-articular corticosteroid injections in therapeutic doses are unlikely to damage articular cartilage (69).

Clinical Implications A major consideration in the use of intra-articular corticosteroid injections is that systemic absorption occurs from synovial fluid, directly related to the solubility of the crystals and thus, suppression of the hypothalamic-pituitary-adrenal axis can occur, especially with injection of multiple joints at once or injection of the same joint at close intervals. Even single injections of large doses cause transient reversible depression of endogenous corticosteroid production (55). For this reason, as well as the lingering fear of causing long-term suppression of cartilage matrix synthesis, most clinicians limit the number of intra-articular corticosteroid injections to 2 - 4 per year in any one joint; patients who do not improve with this regimen are considered, by many physicians, as candidates for total joint arthroplasty (58). Toxicity with the use of systemic corticosteroids will be mentioned in the discussion of the treatment of RA. Complications from the intra-articular use of steroids consist of rare infection (less than 1%) and occasional flares of inflammation lasting less than 24 hours. The medications used in current practice are triamcinolone acetonide and triamcinolone hexacetonide (Aris-

tospan), which is combined with lidocaine and frequently is used in injections of the knee (58). Some clinicians advocate a period of joint rest after injection in accordance with a study that showed a longer-lasting response in patients placed at rest than in the ambulatory position

(57). Topical Therapy According to a self-help book for arthritis patients, a majority of patients in the authors' survey who used overthe-counter liniments, creams, oils, lotions, or gels found them at least somewhat effective (86). These preparations work either by counterirritation or, in the case of salicylate creams, by local prostaglandin inhibition. There also is a new topical agent, available by prescription only, that is gaining favor among clinicians. Capsaicin cream (Zostrix) has been found to reduce inflammatory mediators in human synovial fluid and to diminish substance P, a neurotransmitter of pain from sensory neurons. These observations correlated with the symptomatic relief obtained by patients with arthritis; findings reached statistical significance in placebo groups (8789). The only adverse effects were a stinging or burning sensation at the site of application, which decreased with continued use over time. Capsaicin cream is considered ideal as monotherapy for patients with one or two painful joints, such as the distal or proximal interphalangeal joints, the carpometacarpal joint, or the knee, especially in those at high risk for NSAID-related adverse effects. It is recommended as an adjunct also when other treatments provide only partial relief. It comes in two strengths, 0.025% and 0.075%. The lower strength is recommended as initial treatment, with a small amount applied three to four times daily, reducing the dosage to twice daily as a maintenance dose (89).

Research Drugs In the search for agents that modify the disease process rather than simply providing palliation, researchers in Europe and the United States have conducted clinical trials with several agents that are administered by intraarticular or intramuscular injection. Although animal studies point to amelioration of cartilage lesions and a decrease in cartilage degeneration, two of the agents, Arteparon and Rumalon (extracted from bovine tissue) have proved to be excessively toxic with a high incidence of anaphylaxis and have been withdrawn from clinical use (58,90). A third agent, hyaluronic acid (Hylan G-F, Synvisc), has been approved for clinical use in several countries, and clinical trials are in progress in the United States. Hyaluronic acid is one of the major glysoaminoglycan components of synovial fluid and cartilage. Its ex-

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act mechanism as a treatment modality is unknown, but trials have shown symptomatic improvement with no adverse systemic effects (58). RHEUMATOID ARTHRITIS

Rheumatoid arthritis is a chronic systemic inflammatory disease, initiated by immune mechanisms, that primarily affects the synovial membrane but progresses to cause deeper destruction of articular cartilage and bone with severe permanent joint deformity. The discovery of the autoantibody immunoglobulin M (IgM) rheumatoid factor (RF) in the blood of patients with RA was the principal reason for its inclusion in the group of autoimmune diseases. Rheumatoid factor can be found in approximately 70% of patients with RA (91,92). The history of RA has consisted of a long and only partially successful search for an understanding of its etiology and for a treatment that will arrest the progress of the disease. Unlike OA, which often plateaus for many years and does not shorten life expectancy, RA is not a benign condition. It leads to marked disability in 50% of its victims within 5 years and in 90% within 30 years of onset. It also carries a significant mortality and shortening of life-expectancy. In its most severe stage, as characterized by dysfunction involving more than 30 joints, RA is associated with a 5-year survival rate of less than 50%. Mortality is related primarily to infections, rheumatic complications such as vasculitis, and GI events such as hemorrhage or perforation (93). In light of all the complexities associated with RA, it would behoove the clinician to independently review the pathophysiology of the disease (91,94,95) as a basis for understanding the standard treatment modalities and their implications for the health of the individual. Some authorities on RA differentiate between type I and type II disease, a classification considered helpful in designing therapeutic approaches. Type I RA has a less serious course, with a prompt response to simple treatment or the occurrence of remission. Type II disease is characterized by aggressive synovitis with inexorable progression, demonstrated by radiographic evidence of joint damage within the first 2 years after diagnosis (96). Criteria for identifying type II disease include symmetrical polyarthritis, positive RF, and lack of response to a test dose of prednisone (97). It is type II disease that has posed the greatest challenge to rheumatologists, inspiring many as yet unsuccessful quests for a definitive cure. As medical research has made new discoveries about the inflammatory and immunologic mechanisms responsible for the pathology of RA, the focus of treatment has shifted from symptomatic relief to an attempt to alter or arrest the disease process itself. Traditional therapy, known as the "pyramid approach", began with aspirin or NSAIDs at the base of the pyramid, followed, when

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the disease worsened, by the "second-line drugs," corticosteroids and an eclectic group of unrelated drugs, the DMARDs (disease-modifying antirheumatic drugs) also called SAARDs (slow-acting antirheumatic drugs). Most of these antirheumatic drugs, all of which carry a risk of significant side effects, were originally intended for the treatment of other disease entities and were used serendipitously to treat RA. Whether they actually can arrest the disease process is still in dispute, although they all have been shown to have anti-inflammatory and immunomodulatory effects, primarily the suppression of macrophages and lymphocyte function and the inhibition of T- and B-cell activity (73). The apex of the pyramid consisted of a group of "third-line drugs", the cytotoxic or immunosuppressive group, to be used as a last resort. Their rheumatologic uses were largely experimental (97). Within the past decade, leading rheumatologists have challenged the pyramid approach, contending that it afforded only symptomatic relief during the critical first 2 years of the disease when an earlier, more aggressive use of disease-modifying drugs in combination with first-line drugs might have retarded or altered the destructive effects of the inflammatory process and thus prevented joint damage (98). In an effort to "remodel the pyramid", a "step-down bridge approach" was designed that employs combinations of fast-acting NSAIDs and sloweracting DMARDs as initial therapy. The program is progressively simplified when the slower-acting drugs begin to take effect, the ultimate goal being a maintenance dose of one of the slower-acting, least toxic DMARDs. The long-term aim of the program is to control inflammation, prevent joint damage, preserve function, and prove safe, inexpensive, and convenient for the patient (98). Subsequent studies have supported this paradigm, documenting that early control of inflammation with various combinations of drugs can, in fact, lead to improvement in long-term functional outcomes in RA (97, 99,100). Such research has been relatively short-term, however, making it clear that clinical investigations must be ongoing and that definitive answers lie in the future (101). Special Considerations of Nonsteroidal AntiInflammatory Drugs Use in Rheumatoid Arthritis

Although the role of NSAIDs as first-line drugs has been undergoing reevaluation, it is likely that they will continue to have a place in any new therapeutic model of RA treatment. In addition to fast-acting symptomatic relief, NSAIDs are employed for their modifying effects on the inflammatory process. The inhibition of neutrophil activation by NSAIDs is well documented; rheumatoid joint inflammation, as discussed previously, results from the activation of neutrophils with release of many inflam-

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matory mediators (102). In a recent study, patients who improved clinically while taking NSAIDs also showed a decrease in circulating activated T cells and B cells as well as decreased erythrocyte sedimentation rate, C-reactive protein, and RF levels. Thus, NSAIDs may be associated with a more profound effect on the rheumatic process than was previously thought (103). This concept of NSAIDs concurs with the opinion of Wilske and Healey (98) that the distinction between anti-inflammatory and disease-modifying drugs may be an artificial one and should be discarded (98). It should be remembered that unlike patients with OA, those with RA will require anti-inflammatory, not just analgesic doses of NSAIDs, possibly on a long-term basis and depending on the treatment regimen (96). Thus, potential toxicity is a serious concern. Because it is well known that patients with RA are at increased risk for GI complications, the former practice was to prescribe nonacetylated salicylates, due to their lesser GI toxicity (96); most recently, misoprostol in combination with nabumetone has become a state-of-the-art therapy. Disease-Modifying Antirheumatic Drugs Efficacy studies conducted on DMARDs investigate certain parameters by which beneficial effects of the drugs can be determined. To make clinical trials comparable, U.S. and European rheumatologic societies have recommended a core set of outcome measures that include painful joint count, swollen joint count, patient's and physician's global assessment of RA activity (measured on a Likert scale), patient's assessment of pain, the Health Assessment Questionnaire of self-reported physical functioning, and blood levels of acute phase reactants (ESR and CRP). For studies lasting more than 1 year, the added criterion of radiographic progression of joint erosions is recommended (104). Ongoing studies have demonstrated that reduction of clinical markers of inflammation (ESR, CRP, RF, and circulating activated T and B cells) correlates with clinical improvement and the arrest of radiologic progression (98,103). Thus, a great deal of interest is generated by study outcomes that suggest that any DMARD alters these last two parameters. Despite numerous comparative studies, no one agent has yet been designated as the treatment of choice. For example, the therapeutic benefit of all of the DMARDs in common use usually is offset by significant toxicity, idiosyncratic reactions, or eventual lack of efficacy. Adverse reactions were shown in one study to be a more common reason for discontinuation than lack of efficacy, and most of the drugs were discontinued within 2 years or less (105). This finding points out a major problem in attempting to conduct the long-term studies necessary to come to conclusions about optimum treatment for a disabling chronic disease.

Although the management of patients requiring DMARDs may not come under the scope of practice of the primary care provider, an understanding of these drugs and their effects will provide the practitioner with a broader perspective when arthritic patients seek care for other health problems. Therefore, a discussion of DMARDs in common use will be presented. Gold Therapy Although newer drugs have gained favor since the 1920s when gold salts were first used to treat RA (61) a substantial number of patients have reportedly experienced a clinical response to gold therapy (93). A small but often-quoted 1974 study demonstrated that the administration of gold injections arrested radiologic progression of the disease in several patients, and they sufficiently slowed the mean progression rate for the treatment group (106). The parenteral forms, aurothiomalate (Myochrysine) and aurothioglucose (Solganol), are 50% gold by weight and water-soluble. Patients receive a weekly intramuscular dose of increasing strength, up to a cumulative dose of 1,000 mg over a 20-week period. Response usually is not observed for 3 - 4 months (93). Regular weekly clinical monitoring (cell blood count [CBC] and urinalysis) is mandatory for early recognition of the potential complications of cutaneous, hematologic, and renal toxicities. Fatal thrombocytopenia and pneumonitis have been associated with injectable gold and, in toxicity studies, it has been ranked consistently as highly toxic (107,108). Gold also is available in the oral preparation auranofin (Ridaura), which is less effective than parenteral gold but may be recommended for mild cases of RA (93). Given in a dose of 3 - 9 mg per day, it is associated with GI toxicity in the form of diarrhea in 50% of users; another third develop skin rashes or stomatitis. Although less toxic than parenteral gold, auranofin has been associated with bone marrow depression and exfoliative dermatitis. The possibility of such life-threatening complications makes weekly clinical monitoring essential; 50% of all patients taking auranofin discontinue its use within 2 years. Antimalarial Therapy The anti-malarial drugs chloroquine and hydroxychloroquine (Plaquenil) have been used extensively since 1943 for their immunosuppressive and anti-inflammatory effects. Hydroxychloroquine, considered by some to be the least toxic DMARD (107), is given orally in a dose of 200-400 mg per day; it evokes a positive response in 40-60% of patients by 3 - 6 months of therapy. The major toxic effect is retinopathy in 0.5% of patients, usually seen with high dosages. An ophthalmologic examination

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is recommended prior to initiation of therapy and every 6 months during the course of treatment; retinal damage and visual impairment may be irreversible. Infrequent adverse effects include dermatitis, nausea, epigastric pain, insomnia, myopathy, headache, reversible blurred vision unrelated to retinopathy, hemolytic anemia, and rare leukopenia. Hydroxychloroquine is being used in early mild disease and sometimes continued as a background treatment with other DMARDs (96).

Sulfasalazine Sulfasalazine (Azulfidine), an anti-inflammatory agent most commonly used for inflammatory bowel disease, has been shown to reduce the intensity of rheumatoid synovitis. Its mechanism of action is thought to be related to its immunosuppressive properties, which have been observed in vitro and in animal models. Although most studies give no clear evidence of long-term functional improvement, one 1989 study using the drug in patients with early disease showed that after 48 weeks, 32% of sulfasalazine-treated patients had no joint erosions as determined radiographically, compared to 12% of a group given hydroxychloroquine (109). The drug is given orally in divided doses of 0.5-3 g per day. Fifty percent of patients experience toxic effects, resulting in discontinuation in half of this number. Gastrointestinal toxicity occurs in 20%; reversible infertility due to oligospermia occurs in 70% of males. Rare life-threatening effects have been seen; these include liver and renal toxicity, neutropenia in 6%, and fatal bone marrow depression. Cell blood count, liver function tests, and urinalysis must be done on a regular basis.

PeniciUamine Penicillamine (Cuprimine, Depen), a metabolite of penicillin, is similar to gold in its anti-inflammatory properties as well as in its efficacy and toxicity. Its exact mechanism of action is unknown; however, it has been shown to lower immunoglobulin M RF and to depress T-cell activity in vitro. It is recommended for patients in whom gold has proven ineffective and who have active, erosive disease. A typical dosage is 250 mg daily, taken orally, with gradual increases to a maximum of 1,000 mg per day. Significant toxicity limits the drug's usefulness; skin and mucous membrane effects and reversible proteinuria are the most common adverse reactions, but many others have been noted. The effects of greatest concern are potentially fatal aplastic anemia and a variety of autoimmune diseases, which include myasthenia gravis, lupus erythematosus, Goodpasture's syndrome (a condition characterized by pulmonary hemorrhage and severe glomerulonephritis), hemolytic anemia, and thyroiditis. These conditions require permanent discontinuation of

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the drug. In most clinical trials, 30-50% of patients discontinued the drug within the first 6 - 1 2 months of therapy. Clinical monitoring of the CBC, with particular attention to platelets, and urinalysis are mandatory every 2 weeks for the first 6 months, after which intervals can be lengthened (61,96).

Cytotoxic Drugs In the past two decades, rheumatology practice has incorporated the use of the cytotoxic drugs methotrexate, azathioprine, chlorambucil, and cyclophosphamide, all of which interfere with cell biosynthesis and, thus, have immunosuppressive effects. Of these four, methotrexate has been found most promising. The adverse effects of chlorambucil and cyclophosphamide, on the contrary, have been found to outweigh the expected therapeutic value of the two drugs. Methotrexate. Methotrexate (Rheumatrex), a folic acid antagonist, was once used exclusively as a cancer chemotherapeutic agent; however, the drug has been demonstrated to have anti-inflammatory and immunologic activity, inhibiting T and B lymphocytes and the cytokine interleukin-1 as well as suppressing the production of rheumatoid factor (110). Methotrexate is being used increasingly because studies have determined that along with the antimalarials, it has the best benefit-to-risk ratio of all the DMARDs (108). In a large, long-term study in which the median time for discontinuation for intramuscular gold, auranofin, hydroxychloroquine, or penicillamine was 2 years or less, the time for discontinuation of methotrexate was 4.25 years. Fewer drop-outs occurred with methotrexate for either adverse effects or lack of efficacy than with the other drugs (105). Although the package insert for Rheumatrex recommends its use for "recalcitrant, disabling disease" that is "not adequately responsive to other forms of treatment," there are growing numbers of rheumatologists who advocate the use of methotrexate early in the treatment program (110). Two separate groups of research clinicians recommend methotrexate as the first DMARD after a short course of NSAIDs or corticosteroids in patients who have clinical markers of aggressive disease (97,100). Joint inflammation has been found to be reduced and function improved in 80% of patients in the first 12 weeks of treatment, and improvement maintained for up to 2 years in 50% of patients. Methotrexate, along with injectable gold and sulfasalazine, has been proven capable of retarding radiographic progression of joint erosions (111). Methotrexate is given in small weekly oral doses ("lowdose pulse therapy") with a maximum dose of 5.0-7.5 mg per week, much less than the standard oncology dose. Routine reliance on low doses may be the reason

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for the lower rate of discontinuation due to serious toxicity, although toxic potential remains a reality. Even at low doses, mucosal ulcers and nausea are common side effects (61). Serious toxic effects include severe septic complications, both fungal and bacterial; a life-threatening interstitial pneumonitis has been reported in 3-5% of patients (111). Unfortunately, significant risk factors for pulmonary toxicity remain difficult to identify. Occurrence of pneumonitis requires withdrawal of the drug and intensive supportive treatment, but the associated mortality rate is high (102). The question of long-term liver toxicity is still in dispute. Biopsy studies reveal dose-dependent increased liver fibrosis, but frank cirrhosis has not been documented with low-dose regimens (112). In the past, patients on methotrexate regimens were subjected to routine liver biopsies; these procedures are now reserved for patients with other risk factors for hepatic disease, notably alcoholism. Liver function tests are recommended initially and every 4 - 8 weeks for those undergoing longterm maintenance therapy (95). As high as a 30% incidence of abnormal liver enzymes has been seen; this finding usually does not indicate significant or irreversible disease, and requires withdrawal of the drug in less than 10% of patients (113). Concomitant treatment with NSAIDs increases the frequency of abnormal liver function tests; those with preexisting impaired renal function are at higher risk. Some authorities, therefore, warn against the use of salicylates, sulfonamides, or NSAIDs during methotrexate therapy (112). Recommended measures to decrease possible toxicity are the use of folic acid supplements (113) and the administration of a dose of leucovorin 24 hours after each weekly dose of methotrexate (61). Miscellaneous adverse effects include alopecia and skin rash in 15%, necessitating withdrawal; proteinuria in 4%; dizziness and altered mood in 1% (more likely in the elderly); and the hematologic effects of macrocytosis (frequent and benign), neutropenia, and pancytopenia (rare and serious). Methotrexate has well-known teratogenicity and embryotoxicity, which mitigates against its use in women likely to become pregnant (113). Methotrexate has the lowest oncogenic potential of all the cytotoxic drugs, an effect believed to be due to its augmentation of natural killer cells, which are important in the process of immunologic surveillance (I 14). Azathioprine. Azathioprine (Imuran) is a purine analogue that interferes with DNA synthesis and is approved for treatment of RA. It is usually chosen when patients have not responded to more conventional therapies (96). It is at least as effective as gold and penicillamine and has raised hopes that it may limit the development of erosive changes (113); another benefit is that it allows patients to do well on a reduced dosage of cor-

ticosteroids. The recommended dosage is 2.5 mg/kg daily of body weight, taken orally. As with other DMARDs, monthly clinical monitoring of liver function and CBC is essential. Close to 40% of patients experience GI symptoms, which may be controllable with other drugs but sometimes force withdrawal. Up to 30% of patients discontinue the drug in the first 6 months due to adverse effects; however, those who tolerate azathioprine for the first six months have been observed to tolerate it well from 3 - 1 0 years in one study (115). Rare life-threatening side effects include thrombocytopenia and bone marrow aplasia. Acute hypersensitivity reactions may occur rapidly and mandate withdrawal. Studies conflict regarding the incidence of neoplasia, with some reports suggesting an increase in bladder cancer, adrenocortical cancer, acute leukemia, and cervical atypia (114). A much-quoted study of 91 patients found no association with lymphoreticular tumors, and in the six patients who developed malignancies, four were heavy smokers who died of lung cancer (115). The possibility of opportunistic infections due to immunosuppression must always be kept in mind (99), however. Chlorambucil. The alkylating agent chlorambucil (Leukeran), a derivative of nitrogen mustard, exhibits immunosuppressive and anti-inflammatory activity, arousing interest in the drug as a treatment for severe, refractory RA; use was most widespread in France. Given in a mean daily dose of 4 mg, it was proved effective in clinical trials, with one trial showing significant improvement in 72% of patients; remissions were also reported (116). However, a high incidence of serious toxicity has been reported; major adverse effects have included: cumularive, sometimes irreversible, bone marrow suppression, particularly detrimental to lymphocytes and thrombocytes; infections due to altered immune and inflammatory response; GI toxicity; permanent infertility in males and at least a 30% risk in females; and increased incidence of teratogenicity (117). Chromosomal damage was the focus of a British study; all study patients had abnormal lymphocyte sister chromatid exchanges, an indication of the potential oncogenic effects of chlorambucil (118). Empirical studies confirmed this finding with a significantly increased incidence of malignancies, particularly cutaneous and hematologic, leading to the conclusion that the use of chlorambucil in RA cannot, in most circumstances, be justified (116,119). Cyclophosphamide. Cyclophosphamide (Cytoxan), another alkylating agent, acts to disrupt the cell's DNA and depletes B lymphocytes. It also has potent anti-inflammatory properties, which along with its immunosuppressive effects, led to its use in the treatment of RA, in a dose of 1.5-2.5 mg/kg/d. It was found more effective

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than corticosteroids in the treatment of rheumatoid vasculitis (113); but, like chlorambucil, its serious toxicity and oncogenicity have resulted in the opinion of most authorities that the risks outweigh the benefits. The risks of malignancy are in the area of a tenfold increase (115); a recent study documented a significantly increased risk of skin and bladder cancers, which persisted even 17 years after discontinuation of the drug (120). The nonmalignant risks are similar to those of chlorambucil, with the addition of a greater incidence of hair loss, hepatotoxicity, and pulmonary fibrosis (116,119).

Experimental Drug Therapies Cyclosporine. Cyclosporine A (Sandimmune, Neoral), a standard treatment for preventing rejection of organ transplants, is a specific immunomodulatory drug that suppresses T-cell production of cytokines. This property attracted much attention as increasing emphasis was placed on RA as a T-cell-mediated autoimmune disease (121). A small 1979 study first used cyclosporine A in patients with psoriatic arthritis; the favorable outcomes sparked further interest in the drug and international clinical trials ensued (122). Cyclosporine A is still considered experimental in the United States for the treatment of RA; although its use was initially reserved for patients with recalcitrant late disease, there are physicians who feel that it holds promise for early type II disease, which is known to have a poor prognosis despite DMARD use (69). Recent studies have shown significant reduction in joint erosions correlated with significant clinical improvement as well as a decrease in C-reactive protein levels (122,123). A group of patients with only partial improvement on standard DMARDs improved markedly with the addition of cyclosporine, and on its withdrawal their condition relapsed. Once the drug was reintroduced, the patients regained their improved status (124). A follow-up study combining methotrexate with cyclosporine achieved comparably successful outcomes

(125). The side effect of greatest concern is nephrotoxicity, evidenced in the majority of patients by rising serum creatinine levels and lowered renal creatinine clearance. Most studies have found that use of low doses (less than 5 m g / k g / d , ideally 3.0-3.5 rag) will maintain the serum creatinine level at no greater than 30% over baseline; this is considered a safe level, indicating the probability of no p e r m a n e n t renal structural d a m a g e (122,123,125). Renal biopsies on patients who used the drug for 3 - 5 years showed no irreversible structural changes. (121). Cyclosporine A is contraindicated in patients with impaired renal function, and frequent moni-

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toring of serum creatinine levels is mandatory (126). It is thought that concurrent use of NSAIDs may predispose the patient to nephrotoxicity: NSAID inhibition of prostaglandin synthesis in the kidney may aggravate the potential of cyclosporine A to induce renal dysfunction (126, 123). Other adverse affects include hypertension, sometimes requiring medication for control; excessive hair growth (hypertrichosis), headache, GI disturbances, hand tremors, and paresthesias and flushing, some of which may be controllable by dosage reduction (121). The drug is absolutely contraindicated in hematopoietic and skin cancers, uncontrolled hypertension, immunodeficiency, and hepatic or renal dysfunction. Relative contraindications include controlled hypertension, older age, pregnancy and lactation, use of alkylating agents, premalignant conditions, and active infection (123). Patients should be cautioned to avoid those drugs which can alter blood concentrations of cyclosporine, specifically phenytoin, cimetidine, danazol, ketoconazole, fluconazole, trimethoprim, erythromycin, verapamil, and diltiazem. NSAIDs, grapefruit, and grapefruit juice are best avoided as well, they are known to raise cyclosporine concentrations (123).

Tenidap. Tenidap is a drug of the oxindole class of compounds, unrelated to NSAIDs, corticosteroids, or any DMARD in current use (127). Because it has properties in common with both NSAIDs and DMARDs and generally is well tolerated, it has excited interest both in the United States and abroad; results of phase III clinical trials are being awaited with much optimism. The drug exhibits the cyclo-oxygenase-inhibitory properties of NSAIDs combined with the cytokine-modulating effects of DMARDs; its ability to reduce interleukin-6 and Creactive proteins levels reflects its cytokine-inhibiting ability and strongly suggests that it has disease-modifying potential (128-131). Comparative studies have shown tenidap to be more effective in all efficacy parameters than the NSAIDs diclofenac and piroxicam when used alone (129,130) and clinically equivalent to a combination of the DMARD hydroxychloroquine with the NSAID piroxicam (130). Tenidap also is being investigated for use in OA due to the discovery that it enhances chondrocyte proteoglycan synthesis and reduces (in vitro) levels of destructive enzymes (131). The most common adverse effect is minor GI symptomatology, similar to that seen with most NSAIDs and not considered a serious problem (129). Of somewhat greater concern has been the finding that a small percentage of patients develop reversible proteinuria. One study found that 20% of patients taking the standard dose of 120 mg daily developed proteinuria at ~ 5 0 0 mg/day (131). The proteinuria was thought to be due to partial inhibition of proximal tubular reuptake and not

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a more serious glomerular effect (127). Conclusions as to the implications for renal function await the publication of a large clinical trial now in progress (131). THE ROLE OF CORTICOSTEROIDS IN RHEUMATOID ARTHRITIS

The proper place for corticosteroids in the treatment of RA has been controversial for almost 50 years. Enthusiasm for their use has been dampened by the realization of the devastating side effects, which were a consequence of the suppression of the hypothalamic-pituitary-adrenal axis (132-134). However, the knowledge that corticosteroids can provide dramatic symptomatic relief has resulted in continued use, often in combination with other antirheumatic drugs (135). Low doses are preferred in the hope of achieving maximum benefit while avoiding untoward effects. Various dosage regimens are used: short-term high dosages, long-term low dosages, parenteral "pulse therapy," and scheduled tapering of dosage. A 1983 study noted clinical symptomatic improvement in patients receiving 5 mg daily of prednisone and marked deterioration in the group given a placebo (136). A 1995 study reinvestigated prednisone effects with lower doses; patients on parenteral gold were given either placebo or prednisone in a tapered-dosage schedule for 18 weeks. Although the prednisone reduced disease activity, there was significant rebound deterioration and no significant differences in x-ray progression of joint erosions (137). A recent long-term study, measuring radiographic progression of joint erosions in the hands, found that prednisolone given for 2 years substantially reduced the rate of radiologically detected progression of the disease. Clinical improvements noted in the first year, however, did not persist into the second year (135). A group of authors published two studies of intravenous pulse therapy (a I g intravenous dose daily for three consecutive days) with methylprednisolone or placebo in patients, all of whom were also taking a DMARD. Their intent was to study long-term effects on the disease process; they also felt that pulse therapy would avoid most adverse effects. Although an immediate decrease in signs of inflammation was noted, this had disappeared in 4 - 8 weeks, and neither study showed any significant differences. Most notable was the finding that after 8-12 months both groups had the same degree of progression of joint erosions (138,139). Studies investigating adverse effects of current corticosteroid regimens have not entirely put old fears to rest. Although it was hoped that low-dose regimens might avoid some of the typical side effects, this has not proven to be the case. A 1994 study showed a dose-dependent relationship between prednisone use and fractures, se-

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rious infections, GI bleeding or ulcers, and cataracts (140). The current consensus on the cause of fractures is that corticosteroid use brings about decreased bone mineralization and increased bone resorption, as well as blocking GI calcium absorption and increasing renal calcium excretion and parathyroid hormone secretion. This process results in osteoporosis. Earlier studies had questioned the osteoporotic causation, postulating that perhaps the disease itself increases the fracture risk (141). A 1993 study of prednisone use for 5 years or more found that even with low doses, the fracture rate rose by 33% (142). The GI risk is small but significant, and prednisone has been found to be an important comorbidity agent when used with NSAIDs (140). A 17-year study of mortality in RA linked prednisone-associated GI complications with increased mortality. This study also associates prednisone with death in patients with rheumatoid vasculitis (142). A more recent study, however, questions the association of prednisone with increased mortality, postulating that the use of prednisone may be a marker of disease severity, which in itself accounts for the increased mortality (143). Treatment guidelines have emerged from these and similar studies; although not all authorities agree on every aspect of corticosteroid use, some degree of consistency has resulted. All agree that there is no justification for high doses; newer DMARDs, such as methotrexate, give a comparable degree of anti-inflammatory disease control with less morbidity (136). The use of systemic corticosteroids is not justified by symptomatic benefit alone, as in most studies the effect is not sustained and the results are no better than those of conventional treatment; the benefits must outweigh the risks (133). Corticosteroids should not be used as primary therapy or for patients whose disease can be controlled with NSAIDs (134). Long-term administration is to be avoided if at all possible (142); and, tapering from low-dose regimens needs to be individualized in very small increments. Every-other-day regimens result in severe symptoms on off-days and thus are not recommended (134). Despite the two studies that found no real benefit in intravenous pulse therapy, there are physicians who still advocate it to relieve symptoms while avoiding excessive toxicity. Low doses of 250 mg of depot methylprednisolone given intravenously have been shown to have only mild toxicity and transient bone demineralization effects, thus lowering the risk of osteoporotic fractures (144). Some authorities prefer low-dose prednisone to NSAIDs in the elderly, in patients with moderate renal insufficiency, and in those at high risk for GI bleeding. Corticosteroids also are considered the safest anti-inflammatory drug for use in pregnancy and lactation, due to minimal transfer into fetal circulation or milk and because

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TABLE 8 U.S. Food and Drug Administration Pregnancy Risk Categories of Antirheumatic Drugs

Drug

Pregnancy Risk Category

Oral corticosteroids Sulfasalazine Cyclosporine Hydroxychloroquine Parenteral and oral gold Azathioprine Cyclophosphamide Chlorambucil Penicillamine Methotrexate

B B C C C D D D D X

Data from Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 4th ed. Baltimore: Williams & Wilkins, 1994.

t h e r e is n o (Table 8).

documented

teratogenicity

(136,145)

SUMMARY In s u m m a r i z i n g t h e principles of m a n a g i n g musculoskeletal p r o b l e m s in w o m e n , it m u s t b e r e m e m b e r e d t h a t m a n y a r e c h r o n i c c o n d i t i o n s that m a y s p a n four o r five d e c a d e s . Clinicians would, t h e r e f o r e , be wise to b e g i n t r e a t m e n t with t h e simplest t h e r a p i e s a n d e m p l o y the m o r e c o m p l e x only w h e n p r o g r e s s i o n of t h e d i s e a s e dem a n d s it. It also m u s t be r e m e m b e r e d that a p p r o p r i a t e m e d i c a l a n d surgical referrals n e e d to b e a n integral p a r t of all clinical p r o t o c o l s , especially w h e n a d v a n c e d d i s e a s e is e n c o u n t e r e d within t h e p r i m a r y c a r e setting. Finally, all p h a r m a c o l o g i c m o d a l i t i e s should, f r o m t h e initiation of t r e a t m e n t , be a c c o m p a n i e d by n o n p h a r m a c o l o g i c interventions, including exercise, physical t h e r a p y , weight control, nutritious diet, a n d g e n e r a l g o o d health habits.

REFERENCES 1. Maldonado A, Barger M. Primary care for women: comprehensive assessment of common musculoskeletal disorders. J Nurse Midwife 1995;40:202-15. 2. Benetti MC, Marchese T. Primary care for women: management of common musculoskeletal disorders. J Nurse Midwife 1996;41:173-87. 3. Scupholme A, Carr KC. CNMs and primary care. Quickening 1993;24(6):14. 4. Hendrix SL, Piereson SD, McNeeley SG. Primary and preventative care in a university obstetrics and gynecology group practice. Am J Obstet Gynecol 1995;172:1719-25. 5. Institute of Medicine. Defining primary care: an interim report. Washington (DC): National Academy Press, 1994. 6. Hellman DB. Arthritis and muscoloskeletal disorders. In: Tierney LM, McPhee SJ, Papadakis MA, editors. Current medical diagnosis and treatment. 35th ed. Stamford (CT): Appleton & Lange, 1996. 7. Katz JN. Regional musculoskeletal disorders. In: Carlson KJ, Eisenstat SA, editors. Primary care of women. St. Louis: Mosby, 1995.

224

8. Linsky ME, Segal R. Median nerve injury from local steroid injection in carpal tunnel syndrome. Neurosurgery 1990;26:512-5. 9. Girlanda P, Dattola R, Venuto C, Mangiapane R, Nicolosi C, Messina C. Local steroid treatment in idiopathic carpal tunnel syndrome: short- and long-term efficacy. J Neurol 1993;240:187-90. 10. Goldfien A. Adrenocorticosteroids and adrenocortical antagonists. In: Katzung BG, editors. Basic and clinical pharmacology. 6th ed. Norwalk (CT): Appleton & Lange, 1995. 11. Herskovitz S, Berger AR, Lipton RB. Low-dose, short-term oral prednisone in the treatment of carpal tunnel syndrome. Neurology 1995;45:1923-5. 12. Wipf JE, Deyo RA. Low back pain. Med Clin North Am 1995;79:231-45. 13. Malmivaara A, Hakkinen U, Aro T, et al. The treatment of low back pain: bed rest, exercises or ordinary activity? N Engl J Med 1995;332:351-5. 14. Payan DG, Katzung BG. Nonsteroidal anti-inflammatory drugs; nonopioid analgesics; drugs used in gout. In: Katzung BG, editor. Basic and clinical pharmacology. 6th ed. Norwalk (CT): Appleton & Lange, 1995. 15. Way WJ, Way EL, Fields HL. Opiate analgesics and antagonists. In: Katzung BG, editor. Basic and clinical pharmacology. 6th ed. Norwalk (CT): Appleton & Lange, 1995. 16. Unger J. Question and answer: fibromyalgia. J Am Acad Nurse Pract 1996;8:27-9. 17. Williams FH, Kaul MP. Fibromyalgia and myofascial pain. In: Lemcke DP, Pattison J, Marshall LA, Cowley DS. Primary care of women. Norwalk (CT): Appleton & Lange, 1995. 18. Geel SE. The fibromyalgia syndrome: musculoskeletal pathophysiology. Semin Arthritis Rheum 1994;23:347-53. 19. Wolfe F, Cathey MA, Hawley DJ. A double-blind placebo controlled trial of fluoxetine in fibromyalgia. Scand J Rheumatol 1994;23:255-9. 20. Norregaard J, Volkmann H, Danneskiold-Samsoe B. A randomized controlled trial of citalopram in the treatment of fibromyalgia. Pain 1995;61:445-9. 21. Hollister LE. Antidepressant agents. In: Katzung BG, editor. Basic and clinical pharmacology. 6th ed. Norwalk (CT): Appleton & Lange, 1995. 22. MillerRD. Skeletal muscle relaxants. In: Katzung BG. editor. Basic and clinical pharmacology. 6th ed. Norwalk (CT): Appleton & Lange, 1995. 23. Trevor AJ, Way WL. Sedative-hypnotic drugs. In: Katzung BG, editor. Basic and clinical pharmacology. 6th ed. Norwalk (CT): Appleton & Lange, 1995. 24. Kaltenborn KC. Perspectives on osteoporosis. Clin Obstet Gynecol 1992;35:901-12. 25. Lufkin EG. Therapeutic alternatives for postmenopausal osteoporosis. Compr Ther 1992;18(12):14-7. 26. Murray C, O'Brien K. Osteoporosis workup: evaluating bone loss and risk of fractures. Geriatrics 1995;50(9):41-55. 27. Rousseau ME. Midlife health. In: Varney H, editor. Varney's Midwifery. 3rd ed. Sudbury (MA); Jones and Bartlett, 1996. 28. Preisinger E, Alacamlioglu Y, Pils K, Saradeth T, Schneider B. Therapeutic exercise in the prevention of bone loss. Am J Phys Med Rehab 1995;74:120-3. 29. Nelson ME, Fiaterone MA, Morganti CM, et al. Effects of highintensity strength training on multiple risk factors for osteoporotic fractures. JAMA 1994;272:1909-14. 30. Lichtman R. Perimenopausal and postmenopausal hormone replacement therapy: part 1. An update of the literature on benefits and risks. J Nurse Midwife 1996;41:3-28. 31. Lichtman R. Perimenopausal and postmenopausal hormone replacement therapy: part 2. Hormonal regimens and complementary and alternative therapies. J Nurse Midwife 1996;41:195-210.

Journal of Nurse-Midwifery • Vol. 42, No. 3, May/June 1997

32. Lindsay R. Hormone replacement therapy for prevention and treatment of osteoporosis. Am J Med 1993;95 Suppl 5A:37s-9s. 33. Gamble CL. Osteoporosis: drug and nondrug therapies for the patient at risk. Geriatrics 1995;50:39-43. 34. Gorsky RD, Kaplan JP, Peterson HB, Thacker SB. Relative risks and benefits of long-term estrogen replacement therapy: a decision analysis. Obstet Gynecol 1994;83:161-6. 35. Khosla S, Riggs BL. Treatment options for osteoporosis. Mayo Clin Proc 1995;70:978-82. 36. Dawson-Hughes B, DallalGE, KrallEA, Sadowski L, Sahyoun N, Tannenbaum S. A controlled trial of calcium supplementation on bone density in postmenopausal women. N Engl J Med 1990;323:878-83. 37. Reid IR, Ames RW, Evans MC, Gamble GD, Sharpe SJ. Effect of calcium supplementation on bone loss in postmenopausal women. N Engl J Med 1993;328:460-4. 38. Haines CJ, Chung TKH, Leung PC, Hsu SYC, Leung DHY. Calcium supplementation and bone mineral density in postmenopausal women using estrogen replacement therapy. Bone 1995; 16:529-31. 39. AloiaJF, Vaswani A, Yeh JK, Ross PL, Flaster E, Dilmanian FA. Calcium supplementation with and without hormone replacement therapy to prevent postmenopausal bone loss. Ann Intern Med 1994; 120:97-103. 40. National Institutes of Health Consensus Development Panel on Optimum Calcium Intake. Optimal calcium intake. JAMA 1994;272:1942-8. 41. Compston JE. The role of vitamin D and calcium supplementation in the prevention of osteoporotic fractures in the elderly, Clin Endocrinol 1995;43:393-405. 42. Dawson-Hughes B, Dallal G, Krall EA, et al. Effect of vitamin D supplementation on wintertime and overallbone loss in healthy postmenopausal women. Ann Intern Med 1991~115:505-12. 43. Weisman Y, Schen RJ, Eisenberg Z, et al. Single high-dose vitamin D3 prophylaxis in the elderly. J Am Geriatr Soc 1986; 34:5158. 44. McDermott MT, Kidd GS. The role of calcitonin in the development and treatment of osteoporosis. Endocr Rev 1987;8:377-90. 45. Reginster J-Y. Calcitonin for prevention and treatment of osteoporosis. Am J Med 1993;950 Suppl 5A:44s-7s. 46. Overgaard K. Effect of intranasal calcitonin therapy on bone mass and bone turnover in early postmenopausal women: a dose response study. Calcif Tissue Int 1994;55:82-6. 47. Reginster J-Y, Deroisy R, Lecart MP, et al. A double-blind, placebo-controlled, dose-findingtrial of intermittent nasal calcitonin for prevention of postmenopausal lumbar spine bone loss. Am J Med 1996;98:452-8. 48. Kessenich CR. Update on pharmacological therapies of osteoporosis. Nurse Pract 1996;21(8):19-24. 49. Riggs BL, Melton LJ. The prevention and treatment of osteoporosis. N Engl J Med 1992;327:620-7. 50. Kupecz D. Alendronate for the treatment of osteoporosis. Nurse Pract 1996;21(1):86-9. 51. Bikle DD. Agents that affect bone homeostasis. In: Katzung BG, editor. Basic and clinical pharmacology. 6th ed. Norwalk (CT): Appleton & Lange, 1995. 52. Liberman UA, Weiss SR, Broll J, Minne HW, Quan H, Bell NH. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995;333:1437-43. 53. Chestnut CH, McClungMR, Ensrud KE, Bell NH, Genant HK, Harris ST. Alendronate treatment of the postmenopausal woman: Effect of multipledosages on bone mass and bone remodeling. Am J Med 1995;99:144-52. 54. Manufacturer's prescribing information for Fosamax (Alendronate Sodium Tablets), Merck and Company, 1995.

55. Bradley JD, Brandt KD, Kalze BP, Kalasinski LA, Ryan SI. Comparison of an anti-inflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. N Engl J Med 1991;325:87-91. 56. Hough AJ. Osteoarthritis. In: McCarty DJ, Koopman WJ, editors. Arthritis and allied conditions. 12th ed. Philadelphia: Lea & Febiger, 1993. 57. Brandt KD. Management of osteoarthritis. In: KelleyWN, Harris ED, Ruddy S, Sledge CB, editors. Textbook of rheumatology. 4th ed. Philadelphia: WB Saunders, 1993. 58. Gramas DA, Lane NE. Osteoarthritis. In: Weisman MH, Weinblatt ME, editors. Treatment of the rheumatic diseases. Philadelphia: WB Saunders, 1995. 59. Brandt KD, Mankin HJ. Pathogenesis of osteoarthritis. In: Kelly WN, Harris ED, Ruddy S, Sledge CB, editors. Textbook of rheumatology. 4th ed. Philadelphia: WB Saunders, 1993. 60. GaffneyK, Ledingham J, Perry JD. Intra-articular triamcinolone hexacetomide in knee osteoarthritis: factors influencingthe clinical response. Ann Rheum Dis 1995;54:379-81. 61. Payan DG, Katzung, BG. Nonsteroidal anti-inflammatory drugs: nonopiod analgesics. Drugs used in gout. In: Katzung BG, editor. Basic and clinical pharmacology. 6th ed. Norwalk (CT): Appleton & Lange, 1995. 62. Brandt KD. Should osteoarthritis be treated with nonsteroidal anti-inflammatory drugs? Rheum Dis Clin North Am 1993;19:679712. 63. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis: part I. Osteoarthritis of the hip. Arthritis Rheum 1995;38:1535-40. 64. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis: part II. Osteoarthritis of the knee, Arthritis Rheum 1995;38:1541-6. 65. Williams HJ, Ward JR, Egger MJ, et al. Comparison of naproxen and acetaminophen in a two-year study of treatment of osteoarthritis of the knee. Arthritis Rheum 1993;36:1196-1206. 66. Polisson R. Non-steroidal anti-inflammatory drugs: practical and theoretical considerations in their selection. Am J Med 1996; 100 Suppl 2A:31S-65S. 67. Abramson SB, Cherksey B, Gude D, et al. Nonsteroidal antiinflammatory drugs exert differentialeffects on neutrophil function and plasma membrane viscosity: studies in human neutrophils and liposomes. Inflammation 1990;14:11-30. 68. Hochberg MC. NSAIDs: mechanisms and pathways of action. Hospital Pract 1989;24:185-195. 69. Pelletier JP, Marter-Pelletier J. The therapeutic effects of NSAID and corticosteroids in osteoarthritis: to be or not to be. J Rheumatol 1989;16:19-27. 70. Rashad S, Revell P, Hemingway A, et al. Effects of non-steroidal anti-inflammatory drugs on the course of osteoarthritis. Lancet 1989;8662:519-22. 71. Dieppe P, Cushnaghan J, Jasani MK, McCrae F, Watt I. A two-year, placebo-controlled trial of non-steroidal anti-inflammatory therapy in osteoarthritis of the knee joint. Br J Rheumatol 1993;32:595-600. 72. Blower PR. The unique pharmacologic profile of nabumetone. J Rheumatol 1992;36 Suppl 19:13-9, 73. FriesJF, WilliamsCA, Raney DR, Block DA. The relative toxicity of alternative therapies for rheumatoid arthritis: implications for the therapeutic progression. Semin Arthritis Rheum 1993;23 Suppl 2:68-73. 74. Brooks PM. Drug modification of inflammation: non-steroidal anti-inflammatorydrugs. In: Maddson PT, Isenberg DA, Woo P, Glass D, editors. Oxford textbook of rheumatology. Oxford (UK): Oxford UniversityPress, 1993. 75. Griffin MR, Piper JM, Daugherty JR, Snowden M, Ray WA. Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons. Ann Intern Med 1991;114:257-63.

Journal of Nurse-Midwifery • Vo|. 42, No. 3, May/June 1997

225

76. Fries JF, Williams CA, Block DA, Michel BA. Nonsteroidal anti-inflammatory drug-associated gastropathy: incidence and risk factor models. Am J Med 1991;91:213-22. 77. Silverstein FE, Graham DY, Senior JR, Davies HW, Struthers BJ, Bittman RM, Geis GS. Misoprostol reduces serious G-I complications in patients with rheumatoid arthritis receiving nonsteroidal anti~ inflammatory drugs: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123:241-9. 78. Roth S, Agrawal N, Mahowald M, et al. Misoprostol heals gastroduodenal injury in patients with rheumatoid arthritis receiving aspirin. Arch Intern Med 1989;149:775-9. 79. Gabriel SE, Campion ME, O'Fallon WM. Patient preferences for nonsteroidal anti-inflammatory drug related gastrointestinal complications and their prophylaxis. J Rheumatol 1993;20:358-61. 80. Levine JS. Misoprostol and nonsteroidal anti-inflammatory drugs: a tale of effects, outcomes and costs [editorial; comment]. Ann Intern Med 1995;123:309-10. 81. Lister BJ, Poland M~ DeLapp RE. Efficacy of nabumetone vs diclofenac, naproxen, ibuprofen and piroxicam in osteoarthritis and rheumatoid arthritis. Am J Med 1993;95 Suppl 2A:2S-9S. 82. Eversmeyer W, Poland M, DeLapp RE, Jensen CP. Safety experience with nabumetone vs diclofenac, naproxen, ibuprofen and piroxicam in osteoarthritis and rheumatoid arthritis. Am J Med 1993;95 Suppl 2A:10S-8S. 83. Tonkin AL, Wing LMH. Interactions of nonsteroidal anti-inflammatory drugs. Baillieres Clin Rheumatol 1988;2:455-83. 84. Wada J, Koshiro T, Morii T, Sugimoto K. Natural course of osteoarthritis of the knee treated with or without intra-articular corticosteroid injections. Bull Hosp J Dis Orthop Inst 1993;53:45-8. 85. Pelletier JP, Mineau F, Raynauld JP, et al. Intra-articular injections with methylprednisone acetate reduce osteoarthritic lesions in parallel with chondrocyte stromelysin synthesis in experimental osteoarthritis. Arthritis Rheum 1994;37:414-23. 86. Sobel D, Klein AC. Arthritis: what works. New York: St. Martin's Press, 1989. 87. Weisman MH, Hagaman C, Yaksh T, Lotz M. Preliminary findings on the role of neuropeptide suppression by topical agents in the management of rheumatoid arthritis. Semin Arthritis Rheum 1994~23 suppl 3:18-24. 88. Altman RD, Aven A~ Holmburg CE. Capsaicin cream 0.25% as monotherapy for osteoarthritis: a double-blindstudy. Semin Arthritis Rheum 1994;23 Suppl 3:25-33. 89. Deal CL. The use of topical capsaicin in managing arthritis pain: a clinician's perspective. Semin Arthritis Rheum 1994; 23 Suppl 3:48-52. 90. Schnitzer TJ. Osteoarthritis treatment update: minimizingpain while limiting patient risk. Postgraduate Med 1993;93:89-90. 91. Maini RN, Feldmann M. Immunopathogenesis of rheumatoid arthritis. In: Maddison PJ, Isenberg D, Woo P, Glass D, editors. Oxford textbook of rheumatology. Oxford (UK): Oxford University Press, 1993. 92. Berkow R, Fletcher AJ, editors. The Merck manual of diagnosis and treatment. 16th ed. Rahway (NJ): Merck Research Laboratories, 1992. 93. Mitchell DM, Spitz PW, Young DY, et al. Survival, prognosis and causes of death in rheumatoid arthritis. Arthritis Rheum 1986;29:706-14. 94. Panayi GS. Pathogenesis of rheumatoid arthritis. In: Wolfe F, Pincus T, editors. Rheumatoid arthritis: pathogenesis, assessment, outcome and treatment. New York: Marcel Decker Inc., 1994. 95. Blackburn WD. Management of osteoarthritis and rheumatoid arthritis: prospects and possibilities. Am J Med 1996;100 Suppl 2A:24S-30S. 96. Borgini MJ, Paulus HE. Rheumatoid arthritis. In: Weisman MH, Weinblatt ME, editors. Treatment of the rheumatic diseases. Philadelphia: WB Saunders, 1995.

226

97. Wilske KR. Inverting the therapeutic pyramid: observations and recommendations on new directions in rheumatoid therapy based on the author's experience. Semin Arthritis Rheum 1993;23 Suppl 2:11-8. 98. Wilske KR, Healey LA. Remodeling the pyramid: a concept whose time has come. J Rheumatol 1989; 16:565-567. 99. Epstein WV. Efficacy of standard slow-acting anti-rheumatic drugs. Semin Arthritis Rheum 1994;6 suppl 2:32-8. 100. Fries JF, Williams CA, Morfeld D, Singh G, Sibley J. Reduction in long-term disability in patients with rheumatoid arthritis by diseasemodifying anti-rheumatic drug-based treatment strategies. Arthritis Rheum 1996;39:616-22. 101. Conaghan PG, Brooks P. Disease-modifying anti-rheumatic drugs, including methotrexate, gold, antimalarials and D-penicillamine. Curr Opin Rheumatol 1995;7:167-73. 102. Wolfe F, Pincus T, Callahan LF. Rationale for reassessment of paradigms. In: Wolfe F, Pincus T, editors. Rheumatoid arthritis: pathogenesis, assessment, outcome and treatment. New York: Marcel Decker Inc, 1994. 103. Cush JJ, Jasin HE, Johnson R, Lipsky PE. Relationship between clinical efficacy and laboratory correlates of inflammatory and immunologic activity in rheumatoid arthritis patients treated with nonsteroidal anti-inflammatorydrugs. Arthritis Rheum 1990;33:623-33. 104. Paulus HE, Bulpitt KJ. Outcome measures. Rheum Dis Clin North Am 1995;21:605-18. 105. Wolfe F, Hawley DJ, Cartley MA. Termination of slow-acting anti-rheumatic drug therapy in rheumatoid arthritis: a 14-year evaluation of 1017 consecutive starts. J Rheumatol 1990; 17:994-1002. 106. Sigler JW~ Bluhm GB, Duncan H, et al. Gold salts in the treatment of rheumatoid arthritis: a double-blind study. Ann Intern Med 1974;80:21-6. 107. Felson DT, Anderson JJ, Meenan RF. The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis: results of 2 meta-analyses. Arthritis Rheum 1990; 93:1449-61. 108. Felson DT, Anderson JJ, Meenan RF. Use of short-term efficacy-toxicity tradeoffs to select second-line drugs in rheumatoid arthritis: a meta-analysis of published clinical trials. Arthritis Rheum 1992;35:1117-25. 109. van der Heijde DM, van Riel PL, Nuver-Zwart IH, Gribnau FW, van de Putte LB. Effects of hydroxychloroquine and sulphasalazine on progression of joint damage in rheumatoid arthritis. Lancet 1989;8646:1036-8. 110. Rose CD, Doughty RA. Pharmacological management of juvenile rheumatoid arthritis. Drugs 1992;43:849-63. 111. van Riel PL, van der Heijde DM, Nuver-Zwart IH, van de Putte LB. Radiographic progression in rheumatoid arthritis: results of 3 comparative trials. J Rheumatol 1995; 22:1797-9. 112. Wollheim FA. Rheumatoid arthritis: clinical picture. In: Maddison PF, Isenberg D, Woo P, Glass D, editors. Oxford textbook of rheumatology. Oxford (UK): Oxford University Press, 1993. 113. Denman AM, Brooks PM. Antirheumatic therapy. In: Maddison PJ, Isenberg DA, Woo P, Glass D, editors. Oxford textbook of rheumatology. Oxford (UK): Oxford University Press, 1993. 114. Nashal DJ. Mechanisms of action and clinical applications of cytotoxic drugs in rheumatic disorders. Med Clin North Am 1985;69:817-40. 115. Speerstra F, Boerbooms AM, van de Putte LB, et al. Sideeffects of azathioprine treatment in rheumatoid arthritis: analysis of 10 years of experience. Ann Rheum Dis 1982;41 suppl 1:37-9. 116. Cannon GW, Jackson CG, Samuelson CO Jr, et al. Chlorambucil therapy in rheumatoid arthritis: clinical experience in 28 patients and literature review. Semin Arthritis Rheum 1985; 15:106-18. 117. Clements PJ, Davis J. Cytotoxic drugs: their clinical application to the rheumatic diseases. Semin Arthritis Rheum 1986;15:23154.

Journal of Nurse-Midwifery • Vol. 42, No. 3, May/June 1997

118. Palmer RG, Dore CJ, Denman AM. Chlorambucil-induced chromosome damage to human lymphocytes is dose-dependent and cumulative. Lancet 1984;8371:246-9. 119. Patapanian H, Graham S, Sambrook PN, et al. The oncogenicity of chlorambucil in rheumatoid arthritis. Br J Rheumatol 1988;27:44-7. 120. Radis CD, Kahl LE, Baker GL, et al. Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis: a 20-year follow-up study. Arthritis Rheum 1995;38:1120-7. 121. Forre O. Radiologic evidence of disease modification in rheumatoid arthritis patients treated with cyclosporine: results of a 48-week multicenter study comparing low-dose cyclosporine with placebo. Atthritis Rheum 1994;37:1506-12. 122. Yocum DE, Torley H. Cyclosporine in rheumatoid arthritis. Rheum Dis Clin North Am 1995;21:835-44. 123. Landewe RB, Goei The HS, van Rijthoven AW, et al. Cyclosporine in common clinical practice: an estimation of the benefit/risk ratio in patients with rheumatoid arthritis. J Rheumatol 1994; 21:1631-6. 124. Bensen W, Tugwell P, Roberts RM, et al. Combination therapy of cyclosporine with methotrexate and gold in rheumatoid arthritis (2 pilot studies). J Rheumatol 1994;21:2034-8. 125. Tugwell P, Pincus T, Yocum D~ et al. Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis: the methotrexate-cyclosporine study group. N Engl J Med 1995; 333:13741. 126. Panayi GS, Tugwell P. The use of cyclosporin A in rheumatoid arthritis: conclusions of an international review. Br J Rheumatol 1994;33:967-9. 127. Breedveld F. Tenidap: a novel cytokine-modulating antirheumatic drug for the treatment of rheumatoid arthritis. Scand J Rheumatol 1994; 100:31-44. 128. Wylie G, Appelboom T, Bolten W, et al. A comparative study of tenidap, a cytokine-modulating anti-rheumatic drug, and diclofenac in rheumatoid arthritis: a 24-week analysis of a l-year clinical trial. Br J Rheumatol 1995;34:554-63. 129. Blackburn WD Jr, Prupas HM, Silverfield JC, et al. Tenidap in rheumatoid arthritis. A 24-week double-blind comparison with hydroxychloroquine-plus-piroxicam, and piroxicam alone. Arthritis Rheum 1995; 38:1447-56. 130. 8ipe JD, Bartle LM, Loose LD. Modification of proinflammatory cytokine production by the anti-rheumatic agents tenidap and na-

proxen: a possible correlate with clinical acute phase response. J Immunology 1992; 148:480-4. 131. Nerkel PA, Letourneau EN, Polisson RP. Investigational agents for rheumatoid arthritis. Rheum Dis Clin North Am 1995;21:779-96. 132. Morrison E, Capell H. Corticosteroids in the management of rheumatoid arthritis. Br J Rheumatol 1996;35:2-4. 133. Harris ED Jr. Glucorticoids in rheumatoid arthritis. Hospital Pract 1983; 18:137-41. 134. Weisman MH. Should steroids be used in the management of rheumatoid arthritis? Rheum Dis Clin North Am 1993; 19:189-99. 135. Kirwan JR. The effect of glucocorticoids on joint destruction in rheumatoid arthritis: the Arthritis and Rheumatism Council LowDose Glucocorticoid Study Group. N Engl J Med 1995;333:142-6. 136. Harris ED Jr, Emkey RD, Nichols JE, Newberg A. Low-dose prednisone therapy in rheumatoid arthritis: a double-blind study. J Rheumatol 1983; 10:713-21. 137. van Gestel AM, Laan RF, Haagsma CJ, van de Putte LB, van Riel PL. Oral steroids as bridge therapy in rheumatoid arthritis patients starting with parenteral gold. A randomized double-blind placebo-controlled trial. Br J Rheumatol 1995;34:347-51. 138. Hansen TM, Dickmeiss E, Jans H, et al. Combination of methylprednisolone pulse therapy and remission inducing drugs in rheumatoid arthritis. Ann Rheum Dis 1987;46:290-5. 139. Hansen TM, Kryger P, Elling H, et al. Double-blind placebocontrolled trial of pulse treatment with methylprednisolone combined with disease-modifying drugs in rheumatoid arthritis. Br Med J 1990;301:268-70. 140. Saag KG, Koehnke R, Caldwell JR, et al. Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events. Am J Med 1994;96:115-23. 141. Hooyman JR, Melton LJ Ill, Nelson AM, O'Fallon WM, Riggs BL. Fractures after rheumatoid arthritis: a population-based study. Arthritis Rheum 1984; 27:1353-61. 142. Michel BA, Block DA, Wolfe F, Fries JF. Fractures in rheumatoid arthritis: an evaluation of associated risk factors. J Rheumatol 1993;20:1666-9~ 143. Wolfe F, Mitchell DM, Sibley JT, et al. The mortality of rheumatoid arthritis. Arthritis Rheum 1994; 37:481-94. 144. Cash JM, Wilder RL. Refractory rheumatoid arthritis: therapeutic options. Rheum Dis Clin North Am 1995;21:1-18. 145. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 4th ed. Baltimore: Williams & Wilkins, 1994.

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