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NON-PRESCRIPTION NSAIDS
IN TREATMENT OF OSTEOARTHRITIS

Goal
This program provides insight essential in recognizing clinical parameters under which non-prescription nonsteroidal anti-inflammatory drugs (NSAIDs) are appropriately recommended avoided in the treatment of osteoarthritis (OA).

Educational Objectives
Upon conclusion of this program, the clinician should be able to:
* Triage the patient in pain; helping to evaluate the severity and duration of the pain complaint to determine whether or not non-prescription analgesics may be appropriate therapeutic interventions;
* Counsel patients suffering OA pain regarding appropriate product choices among non-prescription analgesic regimens;
* Discuss advantages and disadvantages among the non-prescription analgesics, including appropriateness for OA pain, contraindications, drug interactions, and impact of a variety of common comorbid illnesses;
* List the NSAIDs and other non-prescription analgesic products currently available without prescription; Provide information on proper non-prescription dosage and long- or short-term therapeutic regimens and dosage forms.

INTRODUCTION: Treating Osteoarthritis – What Now?
     In the wake of rofecoxib’s withdrawal from worldwide markets, along with recent media coverage of celecoxib and possibly valdecoxib as causing similar cardiovascular problems, the role of the COX-II-specific agents and all NSAIDs in treating the pain of osteoarthritis is being reevaluated. Both prescribers and patients must be reminded that these medications have been assigned prescription status for good reason. Prescription medications are designated as such because they bear the potential to cause serious harm, even when used properly. Any prescription medication must be carefully evaluated for the individual patient to properly weigh its potential benefits against its risks.
     While the data on NSAIDs regarding potential cardiovascular events continues to be reported, the future of these medications lies in the hands of regulatory agencies. Until a landmark decision is made on each of the individual agents, their use remains in the hands of prescribers and those who advise prescribers. This program is designed to help the practitioner evaluate and explain treatment options for the individual patient.
     The new information on the NSAIDs simply means at this point that the NSAIDs must be more judiciously prescribed. Logically, any NSAID should be evaluated for its cardiovascular impact on the individual patient, with the idea that more information on long-term side effects may continue to be unveiled in coming weeks or months. Many patients will need to be guided toward other therapeutic options, while others may actually be deemed better-off continuing established NSAID regimens.
     Unless developing news provides more surprises in coming weeks or months, the non-prescription NSAID analgesics will likely continue to be available and accessible to the general public. In the absence of cardiovascular risk factors, these agents may still be the agents of choice when treating simple mild to moderate pain, particularly when inflammation highlights their unique advantage over acetaminophen.
     Osteoarthritis, erroneously referred to as degenerative joint disease, is the prototype disease for which the NSAIDs have become such a therapeutic boon. While other options must be explored in order to treat the disease itself, the pain can usually at least be ameliorated, often with non-prescription products in less-problematic non-prescription doses, for which associated costs and wide availability make non-prescription medications advantageous options. In spite of acetaminophen’s analgesic capabilities, no other class of medication provides more consistent symptomatic relief to the degree provided by NSAIDs in the majority of sufferers.

Impact of Osteoarthritis
      It is the most common articular disorder, with pathology seen asymptomatically even in patients in their twenties and thirties; and evidence of disease can be radiographically demonstrated in almost everyone by the age of 40. Mild to severe symptoms are common among patients 70 and over, and OA is the most common cause of disability among persons over the age of 65. While men and women seem to be affected with fairly equal frequency, elderly black women bear more substantial genetic risks than other groups. By far, the most common complaint of victims, young or old, early- or late-stage disease, severe or mild, is pain. The pain of osteoarthritis (OA) has come to be recognized as the most significant cause of disability among the adult population worldwide; and treatment of OA pain is a serious responsibility for the healthcare practitioner.

Risk Factors
Relationship to other disease states

  • Gender. Statistics can be misleading, but women are more likely than men develop symptomatic osteoarthritis. The hand and knee seem more susceptible to OA in women, and men more often develop OA of hip joints. Some such differences can be viewed as largely functions of different activities, since men tend to expose themselves to lifting than women, but gender-specific susceptibilities could be somehow associated with so-far unidentified metabolic or hormonal differences.
  • Age. The incidence of osteoarthritis increases dramatically with advancing age. Though many people endure no symptoms even in advanced age, most people eventually at least bear radiographic evidence of the disease, and most of us eventually develop symptoms. Women tend to become symptomatic and present with more severe disease earlier in life. That may only be significant because because there are more women in older age groups. By the age of 65, some 50% of the general population show radiographic evidence of OA in at least one joint.
  • Obesity. While various metabolic processes may be involved in incidence and progression of OA over time, greater body weight simply exerts more pressure on weight-bearing joints, particularly when the weight-bearing joints are stressed by specific activities, making them more susceptible to trauma as well as to OA. It follows that losing weight often helps overweight patients to delay progression of the disease and to help control pain and swelling.
  • Repetitive use and trauma. Osteoarthritis is most common in joints exposed to greater stress from either weight-bearing or repetitive use of joints. For this reason, the knee is particularly vulnerable; and people whose activities stress the knee are logically more susceptible to OA of the knee. This also helps explain the frequency of OA found among patient populations that stress specific joints, like the spine and hips in people who bend or lift frequent or heavy loads, ankles in dancers, and wrists and knuckles in patients who type a great deal. This “wear and tear” theory tends to be inconsistent in various situations, often showing people with advanced disease but relatively free of pain when affected joints are regular exercised. Inactivity of diseased joints tends to increase pain and stiffness, while less-frequent exercise may actually increase symptoms as well.
  • Developmental and/or Congenital Defects and Musculoskeletal Misalignments. Patients with deformities, regardless of origin, tend to stress affected or adjacent joints. The person with one leg longer than the other, spinal curvature, or other structural/functional challenges also bears higher incidence, earlier, and more-severe OA of affected joints, especially since many such deformities affect patients early in life. As with obesity, the effect of what are normal stresses to affected joints is magnified by the underlying condition. 
  • Severe trauma to a joint. Fractures, sprains, and strains that involve joints tend to predispose those joints to OA.
  • Heredity. OA tends to be hereditary, with OA of the knuckles tending especially to run in families. Siblings of people with OA of the knee bear twice the normal risk of developing OA of those without the familial connection, strongly suggesting genetic involvement.

Symptomatology
     Symptoms of OA tend to be insidious. Onset is typically gradual over long periods of time, and symptoms tend to worsen with advancing age, levels of activity, comormid conditions, and genetic factors. Many people with advanced disease show only minor symptoms or even none at all; while others with only minor OA demonstrated radiographically suffer severe symptoms. Symptoms are typically limited to affected joints and may be exacerbated by activity, especially weight-bearing activities in the case of weight-bearing joints; but symptoms may occasionally be fairly constant and bear little association with such activity. Symptoms may be exacerbated by changes in weather or climate, especially cold or wet weather. Typical symptoms affect only involved joints and include: M,Q,R,S

  • Swelling is usually seen once the disease process is well-underway. Contrary to the concept that inflammation is not a feature of OA, inflammation is nonetheless a feature of more advanced disease. A normal physiological response to tissue damage as an essential component of the healing process, inflammation in OA is typically as damaging as it is beneficial.
  • Stiffness of affected joints, especially in the morning upon arising, is usually worst for around 30 minutes after arising, then subsides to some degree with mild activity even in advanced disease.
  • Tenderness of affected joints tends to make the patient reluctant to use the joints, protecting them from use when possible and compensating in order to avoid painful use. A grating sensation of “bone-on-bone” is often reported by patients, and the sensation can occasionally be an accurate assessment in cases of advanced disease, with extensive loss of lubrication, destruction of synovial tissues, hyperproliferation of bone, and deterioration from disuse of supporting structures.
  • Range of motion is diminished in affected joints and normally progressive. Pain and tenderness are generally exacerbated by movement of the joint, especially toward the limits of range of motion. This symptom, too, is usually ameliorated to some degree by mild activity to flex tender joints.
  • Joint pain of OA is typically chronic and progressive, often leaving the patient in substantial pain even with significant medical management. OA pain is usually exacerbated by even normal activity of affected joints, and some relief is usually provided by rest.
  • Radiating pain OA from spinal involvement may lead to shooting pains down the arms or legs, depending on the vertebrae affected.


    * Practical differences between pain, tenderness, stiffness, and limited range of motion may be difficult to discern.

Pathophysiology
Normal Synovial Joint Physiology

Osteoarthritis is an arthropathy characterized by:R,S

  • Altered hyaline cartilage, 
  • Loss of articular cartilage, 
  • Increased osteophyte numbers and activity, 
  • Resultant bone hypertrophy, and 
  • Bone spurs.

      Osteoarthritis (OA) can be thought of as “. . .failure of the diarthrodial (or movable synovial-lined joint).”S A joint is a junction of two bones that holds the bone ends together and allows for smooth movement (articulation) of the bone ends against each other. The joint capsule and its lining of fibrous or connective tissues hold the joint and its essential components in place while facilitating frictionless movement.L Synovial membranes cover opposing bone ends of a joint, along with the synovial fluid that fills the spaces between those membranes. The synovial cavity is bathed in synovial fluid produced by and enclosed by the synovial membrane.M
     The synovial fluid lubricates the internal surfaces of the joint capsule (the boundary lubrication) and nourishes the articular cartilage capping the ends of the bones, its volume dependent on the size of the joint, and fluid viscosity decreasing normally as the demands of activity and load-bearing on the joint increase. Synovial fluid provides lubrication via hyaluronic acid and lubricin, and it also contains phagocytic cells that remove cellular debris produced by normal wear and tear on the tissues of the joint capsule.L,M Lubricant is forced out of spaces within cartilaginous matrix onto the surfaces when compressed by weight-bearing and returning to expanded spaces when compression is released.
     Stability of the joint is maintained by a fibrous joint capsule attached to both bones and collateral ligaments at the sides of most joints. Intra-articular ligaments and other ligaments outside the joint cavity also add support to help maintain integrity of the joint. L The joint capsule is made up of the fibrous capsule and an inner lining of the synovial membrane that secretes the synovial fluid for lubrication. Various disorders involving synovial tissues like inflammation (synovitis) affect the composition of synovial fluid. Excessive fluid production, for instance, dilutes synovial fluid, increasing water content and decreasing viscosity, signs of altered production of hyaluronic acid. M
     Articular cartilage, subchondral bone underlying the cartilage, the soft tissue of the joint capsule; and its supporting ligaments all combine to act as a natural shock-absorption system, the elasticity and resilience of articular cartilage facilitating ready recovery from compression. L The actual amount of cartilage in a given joint, though, is significantly less, relative to the amounts of soft tissue and bone involved in the joint; so these other elements may actually contribute more shock absorption than the cartilage. M Thus, any condition affecting the health and normal function of these tissues can be expected to impair their combined ability to absorb shock, which will logically result in structural damage to tissues improperly cushioned against normal shock and weight-bearing, most notably the articular hyaline cartilage. L,M
     The extracellular matrix of cartilate is built of type II collagen fibers and the ground substance, which is in turn composed of proteoglycans, and water (with provides 80% of the weight of cartilage), forming a glasslike material embedded with chondrocytes. M Proteoglycans are protein molecules with side chains of glycosaminoglycans (GAGs – molecular chains of sugars, primarily chondroitin sulfate and karatan sulfate in the case of cartilage).L Proteoglycan monomers link to hyaluronic acid to form large aggregates with negative charges, thus repelling each other and attracting water molecules -- forces that combine to provide the stiffness and resistance to compression characteristic of cartilage. M
     GAGs are also major components of synovial fluid, conferring a major portion of the lubricant properties of synovial fluid. L Compression of articular cartilage forces water out of the matrix and into the synovial fluid; then recovery draws the water back into the cartilaginous matrix, with the assistance of the negatively-charged GAGs. M
     Vascularization, nervous innervation, and lymphatic irrigation are conspicuously absent in cartilage; so chondrocytes, the cells responsible for maintenance of the matrix, thus rely on diffusion through the extracellular matrix from the underlying bone or the synovial fluid for nutrition and removal of waste products. L

Pathophysiology
     Considering the importance of the extracellular matrix to normal physiology of articular joints, it can be no surprise that any factor tending to change the turnover rate and remodeling process will ultimately lead to loss of matrix components and compromise of cartilage integrity.L While progressive loss of articular cartilage is the most prominent morphological feature of OA, the disease affects the entire synovial joint as an organ. All joint tissues are affected: subchondral bone, synovium, meniscus, ligaments, and supporting neuromuscular apparatus as well as the cartilage.M
     While initially, load-bearing cartilage may actually appear thicker than normal on exam, tissues at the joint surface tend to thin and soften as the disease progresses. Once the integrity of the surface is breached, microfissures – fibrillation, or vertical clefts penetrate into the interior off articular cartilage; and ensuing ulcerations in can extend into supporting bone tissue. Resulting fibrocartilaginous repair efforts are generally far less resilient than undamaged hyaline articular cartilage. Chondrocytes proliferate to combat the cartilage damage and form clusters called clones, but chondrocytes numbers decline as disease progresses, eventually leaving the cartilage hypocellular and ill-equipped to effect repairs.S
     In contrast to previous theories that OA is simply a consequence of the aging process and the unavoidable result of wear and tear on affected joints over time, evolving theories are beginning to recognize other factors. While overuse of affected joints undoubtedly contributes to pain associated with existing disease, it is now generally recognized that OA is probably not simply an inevitability of getting older. In the absence of predisposing factors, there may be no reason to simply expect OA as one ages.L,M
     Likewise, the previous notion that inflammation plays no role in OA is also falling out of favor, as inflammatory evidence becomes apparent among the metabolic changes seen in osteoarthritic processes. In the absence of inflammation, acetaminophen, with its almost negligible anti-inflammatory benefits, tends to remain the first choice among systemic therapeutic pharmacological options. Newer findings of variable degrees of inflammatory involvement, though, support use of anti-inflammatory analgesics as the first-line agents; and the NSAIDs, with their mild anti-inflammatory effects, have long been logical choices. (See Pharmacological Therapies below for more detail.) L,M,S
     Evidence now supports the idea that inflammation is a common finding in osteoarthritic joints. If not involved in initial pathological processes, inflammation is clearly a result of the tissue damage. A normal response to tissue injury, inflammation is a consequence of bearing loads on a joint whose synovial function is compromised by the underlying OA processes. The inflammatory processes summon various appropriate immune components to the area for cleanup of damaged tissue, chemical mediators and cellular migration causing edema of surrounding tissues and pain as a natural deterrent to help minimize further mechanical injury. Inflammatory components undoubtedly contribute to the demise of the joint, as compression on articular surfaces suffering the dual compromise of OA and inflammation actually furthers tissue damage to the synovial cartilage and eventually to the bone ends themselves.
     Inflammation is a normal attempt to remove damaged tissue to facilitate repair efforts, with increased inflammatory response to greater injury, and pain increasing with escalated damage in inflammation. While treating the pain provides some symptomatic relief, it does nothing to slow progression of disease; and even attempts to reduce the inflammatory response probably do little to arrest progression, but simply add a measure of pain relief.
     Metabolic processes involved in OA pathophysiology are complex, and theories continue to evolve with study. Attention tends to center on chondrocytes, the cells responsible for the perpetual process of cartilage remodeling. Much like bone and other connective tissues, cartilaginous matrices are constantly broken down and regenerated by complex series of normal processes in order to maintain its functional and structural integrity; and a number of related hormonal and biochemical abnormalities have so far been identified in association with OA.
     Most such abnormalities seem to ultimately result in up-regulated levels of activity in the processes of cartilage restructuring. Increases in damage, breakdown, and resynthesis leave cellular and matrix fragments as well as biochemical intermediates to be removed, and the synovial fluid becomes the dumping ground for these components, thus affecting its normal function by commensurate degrees. More damage creates more waste material, with more impairment of synovial-fluid function, and thus perpetuation of further damage.
     It is a cycle where damage is escalated by damage, making it difficult to pinpoint when and where the initial problem began and where intervention would be most advantageous. Since the precise nature of involved mechanisms continue to evade research efforts, disease modification must await further clarity. Until the disease processes can be elucidated and corrected, symptomatic treatment is the best that can be offered. Since pain is the most salient symptom, pain relief remains the goal of therapy.
      Malfunction of well-lubricated and resilient load bearing on both synovial surfaces and supporting structures escalates by self-perpetuation, progressively involving greater areas and depths of tissue. Damage logically begins at compromised synovial membranes and progressively invades cartilage surfaces, deeper cartilage matrix, then bone surfaces, and eventually supporting bone, as friction and continued load-bearing injure unprotected tissues.

      As examples, the following biochemical entities are recognized as contributing in the following ways in the maintenance of cartilage: O,S

Activation of proteolytic enzymes involved in cartilage breakdown:

  • Interleukin-1 is a cytokine produced by mononuclear cells, a group to which cells of the synovial lining belong. It is also synthesized by chondrocytes and acts to stimulate synthesis and secretion of latent MMPs (metalloprotienases) and of tissue plasminogen activator. IL-1 suppresses prostaglandin synthesis by the chondrocyte, which impedes matrix repair.
  • Plasminogen is also produced by chondrocytes and may enter the cartilage from the synovial fluid. Plasminogen and stromelysin probably contribute by activation of the latent MMPs.
  • Tumor Necrosis Factor-B

Inhibitors of matrix-degrading enzymes are synthesized by chondrocytes and limit the degradative activity of MMPs and plasminogen activator. If destroyed or present in concentrations insufficient relative to those of active enzymes, stromelysin and plasmin degrade matrix substrates by destruction of the protein core of the PG and activation of latent collagenase.

  • Tissue inhibitor of metalloproteinase (TIMP)
  • Plasminogen activator inhibitor-1 (PAI-1), TIMP or PAI-1

Stimulation of new cartilage production: Polypeptide mediators regulate matrix metabolism by both catabolic and anabolic chondrocytes metabolism, stimulating production of prostaglandins and decrease prostaglandin degradation.

  • Growth Factor B
  • Insulin Growth Factor 1
  • Transforming Growth Factor (TGF)

Collagenolytic enzymes involved in degradation of matrix of human articular cartilage include collagenase-3 (MMP-13) and aggrecanase-1 (ADAMTS4). MMP-13 activity is controlled by transcriptional activation by cytokines and activation of the pro-form at the cell surface.

  • Collagenase 1 (matrix metalloprotienase-1, or MMP-1) is a fibroblast collagenase
  • Collagenase 2 (MMP-8) neutorphil collagenase
  • Collagenase 3 (MMP-13) is a very potent collagenolytic

      OA seems to start with early and presumably reversible rearrangements and alterations in the size of the collagen fibers, causing biochemical matrix defects that alter the forces that bind adjacent fibers. The MMPs cause a major portion of observed damage, whether production is facilitated by IL-1 or mechanical factors. MMPs, plasmin, and cathepsins all contribute to breakdown of articular cartilage in OA, which is opposed by the stabilizing influences of TIMP and PAI-1, and IGF-1 and TGF- work to repair damaged tissue to heal microfractures processes that may heal the lesion or, at least, stabilize the process. A stoichiometric imbalance exists between the levels of active enzyme and the level of TIMP, which may be only modestly increased.

     Nitric oxide (NO) is gaining recognition for its role in the biochemistry of OA, as chondrocytes in OA cartilage undergo increased proliferation and metabolism, producing increased quantities of DNA, RNA collagen,  prostaglandins, and noncollagenous proteins. S

  • NO stimulates chondrocytes synthesis of MMPs.
  • Chondrocytes are a major source of NO, and production is stimulated by shear stress, IL-1, and TNF-1.
  • Treatment of OA in one model with a selective inhibitor of inducible NO synthase markedly reduced the severity of cartilage damage

      Thus, the term degenerative joint disease is further disparage in light of observed elevated chondrocytes activity prior to cartilage loss and PG depletion. The increases in biosynthetic activity increase prostaglandin concentration andis probably responsible for thickening of the cartilage and a homeostasis called “compensated OA.” While this mechanism is touted to help maintain a functional state for years after OA onset, the repaired tissue, is less resilient in the face of mechanical stresses than normal hyaline cartilage. Eventually, PG synthesis is thought to drop to an "end-stage" where almost all cartilage is lost.S Traumatic joint injury to articular cartilage causes swelling, biomechanical changes, apoptosis, changes in biosynthesis of matrix macromolecules, loss of prostaglandins and collagen, and increased gene expression of MMP. Joint tissue injury may somehow increase responsiveness of chondrocytes via stimulation by cytokines, perhaps by enhancing diffusion of cytokines into the matrix or by increasing cytokine production. Chondrocytes in articular cartilage from some joints have been observed to react differently to the presence of cytokines, mechanical forces, and growth factors than to those in other joints, which might help to explain why some joints are more prone to OA than others. For example, glycosaminoglycan loss from ankle cartilage is not increased after mechanical injury of the tissue and exposure to cytokines, but the same stimuli increase response in cartilage of the knee.S In addition to these biochemical factors, chondrocyte metabolism in normal cartilage can be affected directly by mechanical loading, inhibiting synthesis of prostaglandins and protein with static loading, and short-duration loading may enhance biosynthesis. S Treating The Symptoms What Is Pain? Aside from the issues surrounding treatment of the underlying disease of OA, symptomatic treatment centers on the relief of pain. Pain has received a great deal of attention in professional media over the past few years, as treatment has become not only a priority, but a serious responsibility of the healthcare system and the individual practitioner. Since the experience of pain may vary among patients and may or may not be directly associated with severity of OA, assessment and treatment can be difficult.Q,P Patients all too often face the realization that professional efforts to treat their pain (or not to treat their pain in many cases) can fall woefully short of expectations. Most come to understand that they must live with a certain amount of pain, and that level of constant pain may be up to the healthcare provider. Q Professional groups of several types have issued consensus statements or guidelines to assist their members in the effective management of pain. All rely initially on accurate assessment, regardless of the source of pain; and the duration of pain is a primary consideration, as chronic pain of longstanding disease is considered an entity entirely different from acute pain of trauma. As such, effective management must rely on different medical tactics from those found effective for acute pain. Q,P While the health professions have long recognized acute pain as an issue to be treated, only in the last few years has chronic pain been identified as a unique problem that not only demands recognition for quality-of life reasons, but also may have direct impact on long-term outcomes and associated financial impact. Patients enduring severe and intractable pain over long periods tend to have far more illnesses that may or may not be directly related to their pain than those whose chronic pain is recognized and adequately addressed. Patients with chronic pain are five times more likely to utilize health care services with complaints of physical, social, and psychological origin, with almost 60% experiencing coexisting symptoms of depression or anxiety for which they also need treatment.. Q,P Acute Vs. Chronic Pain The pain of trauma, which includes not only injury, but most acute post-surgical pain of limited duration, leads to inflammation and predictable changes within the central nervous system. Pain signals are relayed from proprioceptors to the brain, where they are translated to signals that effect reflex muscle spasm. This tends to protect the injured area, enveloping it in a muscular cast that helps prevent further trauma; and the negative sensations of pain help prevent further injury and facilitate learning how to avoid similar injury in the future. As tissues heal and inflammation resolves, pain signals grow fewer and less emphatic to decrease muscular spasm and painsensation. Q,P Chronic pain often begins as acute pain with an injury, obviously including the same inflammatory, muscular, and central-nervous-system consequences as acute pain, but chronic pain, by definition, persists in the absence of ongoing illness or long after healing processes are completed. The injured area heals; scar tissue is produced; inflammation resolves; but the nervous system continues to send pain signals to somatic muscles, as if new injury were occurring, the nervous system apparently reacting to the memory of the original injury. These perpetual pain stimuli eventually become a constant and disabling neurological message that reminds the patient, often subconsciously, of the injury and the severe pain experienced with the original trauma and through its resolution. Q,P The process is typical of OA. Since cartilage is aneural, pain of OA may not be perceived until severe and irreparable damage is done to the structural tissues of the joint, as the bone itself endures injury, repair, inflammation, hyperproliferation, and pain/inflammation from bone spurs. Pain from OA tends to escalate in intensity over time as the perpetual injury exacerbates, often affecting multiple joints. The patient eventually becomes aware of enduring, severe, and unrelenting pain that may impair ambulatory ability and diminish quality of life. P Situational depression is a typical finding associated with any chronic disease state.R As the patient comes to realize that he has an illness that will likely not be cured during his lifetime, resulting depression may be mild or sufficiently severe as to require treatment itself. It stands to reason that if treatment of a chronic pain syndrome is inadequate, the depression tends to escalate, the patient realizing that every day he must endure a measure of pain that others would consider unbearable. Situational depression is often exacerbated by financial difficulties secondary to failing health, escalating health care utilization, and inability to work. In all too many cases, the combination of severe unrelenting pain and consequent depression add up to suicide. P,R A variety of antidepressant medications have been used with success in situation al depression, but they are often as valuable as adjuctive pain therapy as for their antidepressant properties. The degree to which the two functions may be related is undocumented, but treatment of chronic pain often benefits from medical management of depression. Chronic pain is increasingly recognized as a complex series of neurological changes distinctly different from those associated with acute pain. Autopsy reveals structural changes within the central nervous system that alter neural transmission. Removal of a herniated disk, for example, can lead to persistent radiculopathy and pain from central sensitization and acute painful injury causing hyperalgesia, allodynia and spread of pain. P

  • Nerve injury may result in multiple changes within the central nervous system that perpetuate the pain experience.
  • Increased numbers of action potentials cause hypersensitivity to pain.
  • Redistribution of synapses for mechanoreceptors causes allodynia. Allodynia is pain caused by stimuli usually not painful, like simple touch or vibration. This results from a redistribution of central terminals, establishing new synapses of mechanoreceptors, with cells of the dorsal horn that normally receive nociceptive input. With this redistribution, mechanoreceptors stimulated by mere touch or vibration will activate pain pathways, just as nociceptive neurons respond to pain.
  • An increase in the size of receptive fields within the dorsal horn spreads pain perception, involving areas not normally innervated by the injured nerve.
  • Hyperalgesia, or lowered pain threshold, is experienced as a magnified response to painful stimuli previously perceived as less painful. Second-order neurons of the dorsal horn become more sensitive to peripheral stimuli, increasing numbers of action potentials and spontaneous discharges in response to painful stimuli. P
  • Central plasticity, like phantom limb pain, for example, where treating postamputation pain as if the painful limb were still intact (with nerve blocks) and generating pain signals has been shown to be an effective method of reducing continued chronic pain.
  • Exercise and psychotherapy may be effective in chronic pain as efforts to retrain the nervous system and reestablish more-normal neural connections.

      Osteoarthritis is one of the most common causes of pain in aging populations and is frequently amenable to appropriate treatment with non-prescription agents.
      Treatment Options – In the absence of a cure, or even disease-modifying agents used in rheumatoid arthritis and other autoimmune diseases, medical therapy focuses primarily on amelioration of symptoms.

  • Lifestyle Modifications 
  • Chondroitin/Glucosamine combinations
  • Acetaminophen
  • NSAIDs

NSAIDs      

     The NSAIDs are the most extensively utilized group of medications worldwide, with some 1.2% of the American population taking them on a daily basis, and accounting for almost 4% of all prescriptions filled in this country.1,2 The availability of the selective COX-2 inhibitors has acted to further increase usage of the category, and these agents are becoming increasingly important in pain management protocols independent of their anti-inflammatory properties. Choice of pain medication must carefully weigh advantages and disadvantages of the agent balanced with evaluation of the individual patient’s needs, conditions, and medication regimen.     
     With increasing utilization comes an increased responsibility on the part of the pharmacist to understand the potential problems associated with NSAID therapy. Much attention has been paid to the gastric effects of prostaglandin inhibition; but as more of our elderly become exposed to NSAIDs, their tendency to impair renal function must be emphasized. Though incidence of renal complications is comparatively low at around 1%, the sheer number of NSAID patients and their demographics make this a vital consideration. Incidence is highest among patients with risk factors like existing impaired renal function, congestive heart failure, and hypertension, which are obviously more common in older patients.3,4 Risks for the hypertensive or CHF patient are further increased by concurrent therapy with ACE inhibitors, diuretics, and beta-blockers. The potential for NSAIDs to interact with these drug classes must be recognized by the pharmacist.
     Unfortunately, the very thing that makes NSAIDs work on pain and inflammation – inhibition of prostaglandin synthesis – is also what causes problems in the kidney. Production of prostaglandins, is of course, dependent upon the cyclooxygenase enzymes, COX-1 and COX-2. COX-2, found mainly in inflammatory cells, is induced by proinflammatory cytokines and growth factors and is responsible for production of proinflammatory and hyperalgesic prostaglandins and other inflammatory mediators.5
     COX-1 is found in most cells and tissues, producing prostaglandins in the kidney mainly from the ascending loop of Henle, the renal medulla, and the cortex.1 It catalyzes production of prostacline PGI2 and prostaglandin PGE2, both essential for their role in gastric protection; and PGE2 also helps to preserve kidney function. While the selective COX-2 inhibitors would be expected to be less prone to such renal effects than earlier non-selective agents, this has yet to be proven.1,2 COX-2 has been shown to function in renin production,1 which may negate most anticipated advantages of the COX-2 inhibitors with regard to renal side effects.
     Prostaglandins have a number of important functions in the kidney, including hemodyanamic regulation of renal blood flow and glomerular filtration rate (GFR), production and release of renin, reabsorption of water, and excretion of potassium and sodium. Blockage of prostaglandin production, then, can cause a variety of abnormalities in renal function, including fluid and electrolyte disorders, acute renal dysfunction, nephrotic syndrome, interstitial nephritis, renal papillary necrosis, and even end-stage renal disease, especially with high doses and extended therapy.2,6
     Renal dysfunction can occur at any time during the course of NSAID therapy, with the first dose or within the first week of therapy; but it is of particular concern with long-term use. For example, parenteral ketorolac therapy for up to 5 days is associated with an incidence of acute renal failure (ARF) no different from that seen with opioid analgesics; but extending therapy beyond 5 days doubles the risk of ARF with parenteral ketorolac.7 While NSAID-induced renal impairment is generally reversible upon discontinuation, it can also become a chronic condition in spite of discontinuation of therapy.1
     Some 25% of cardiac output reaches the glomerular vasculature, which has extensive endothelial surfaces. This is necessary not only for sufficient GFR, but also for adequate renal perfusion to supply tubular cells with oxygen.8 One prominent function of prostaglandins it to maintain renal vasodilation,1 autoregulating GFR in spite of dysregulating insults like hypovolemia.8 Suppression of this prostaglandin function, while of minimal significance in the patient with normal kidney function, decreases renal perfusion and glomerular filtration rate in patients with hypertensive renal disease or hypovolemia, regardless of origin.2 This acute renal insufficiency can lead to renal ischemia, tubular anoxia, necrosis, and fibrosis with long-term exposure.I The decreased GFR causes NSAIDs, other renally-eliminated toxins, and their metabolites to concentrate in tubular fluid to exacerbate the impairment of function.2,9
     The most common renal syndrome associated with NSAID therapy is sodium retention and edema. The renal prostaglandins promote natiuresis by direct inhibition of tubular sodium, potassium, and chloride reabsorption; and they diminish tubular response to vasopressin.4 The ensuing electrolyte disturbances lead to water retention, edema, and even organ congestion, which of course further impairs function of not only the kidney, but other congested organs. This certainly exacerbates existing CHF and hypertensive states and compromises efforts to control such conditions. Disruption of the normal intrarenal and extrarenal vasodilatory effects acts to increase renal and splanchnic peripheral resistance.4
     Prostaglandin suppression can also further contribute to hyperkalemia (with obvious implications for digoxin therapy) and disrupt blood pressure control by affecting the renin-angiotensin-aldosterone system. The renal prostaglandins have been proven potent stimuli to release renin, which also eventually stimulates adrenal delivery of aldosterone, which in turn helps to regulate sodium/potassium/fluid homeostasis by stimulating potassium secretion and sodium reabsorption. While this inhibition might theoretically act to reduce blood pressure, the other deleterious effects seem to predominate, overshadowing any benefit.4
     This also highlights the effect of NSAIDs on ACE inhibitor therapy. The ACE inhibitors not only reduce levels of endogenous vasoconstrictors, but increase bradykinin levels and its mediation of natiuretic and vasodilating prostaglandin production both in renal and peripheral vasculature. Blocking production of these prostaglandins with NSAIDs can significantly impair the clinical effectiveness of the ACE inhibitor.4
     NSAIDs tend to cause net effects generally counterproductive to diuretic therapy (retention of sodium, potassium, and water), to create a relative contraindication. Since the therapeutic benefits diuretics are largely prostaglandin-dependent, though, suppression of their natiuretic and renin activity by prostaglandin inhibition can severely hamper the goals diuretic therapy.G The issue is of particular concern in patients with CHF treated with daily diuretics. Regardless of NSAID choice, these patients are twice as likely to be hospitalized due to exacerbation of CHF as those who don’t take NSAIDs. The greatest risk is seen in the first few days of therapy, and over half of such hospitalizations occur within 30 days of initiating NSAID therapy.10
     Antihypertensive effects of beta-blockers can be similarly impaired, since they tend to reduce peripheral resistance by increasing circulating vasodilatory prostaglandins and reducing plasma renin activity. This effect is not always seen, though, supposedly because reductions in prostaglandin production may cause adrenergic receptors to become more sensitive to available prostaglandin levels in many patients.

Conclusion

     A comprehensive discussion of other drug interactions and contraindications with each of the NSAIDs is beyond the scope of this article, but here are a few basic ideas to help the pharmacist keep NSIAD patients out of renal or hypertensive trouble. While renal effects are relatively uncommon, the sheer number of people taking these products and the potential consequences of this type of adverse reaction merit special attention to those at risk.

  • The older the patient, the more susceptible he is to NSAID-induced renal insufficiency.
  • The older the patient, the more likely he is to suffer comorbid conditions that predispose to NSAID-induced renal insufficiency: Congestive heart failure, hypertension, diabetes, ascites, electrolyte imbalances, or existing renal impairment of any origin.
  • While the therapeutic benefits of ACE inhibitors diuretics and beta-blockers can be severely compromised by NSAIDs, patients on regular diuretic therapy for CHF are at particular risk for exacerbating CHF.
  • Any other medications or conditions significantly affected by fluid and electrolyte dysregulation warrant special consideration: Digoxin and lithium therapy are two examples.
  • Counseling should include warnings to watch for unusual weight gain, shortness of breath, edema of the lower extremities, or decreased urinary output. The hypertensive patient should be warned that a change in hypertensive medication or dosage may be necessary after starting an NSAID.

Non-Prescription Options
     Advantages

  • Ready Availability without a prescription
  • Cost
  • Lower doses and fewer/less-severe side effect profiles     

     Disadvantages
     Ramifications of Lower OTC Doses
     It must be recognized that the FDA has designated the myriad non-prescription products as such for two basic reasons.

  • First, these products have been shown to be reasonably effective in treating their basic indications under conditions delineated in product labeling.
  • Second, these products are regarded as having limited potential for causing harm in most adult patients under most conditions of reasonably responsible use. Thus, patients may tend to view non-prescription products with less credibility, a problem that must be addressed via patient education when making recommendations in order to avoid higher-than-recommended doses or inappropriate use for any number of reasons.

Guidelines for Non-Prescription Recommendations
     Assess:

  • Contraindications
  • Patient Age
  • Diagnosis/Primary Complaint
  • Comorbid Illnesses e.
  • Drug Interactions

     Emphasize reduction by ibuprofen of cardiovascular benefits of daily aspirin therapy. Discuss basis of aspirin therapy in CVD/TED by ibuprofen – reduction seen with ibuprofen, but not with naproxen. Naproxen sodium might be limited in patients with restrictions on daily sodium intake.

Narrowing the Field
     The non-prescription NSAIDs are distinctly different medications. While basic pharmacology is very similar, long-time availability and extensive observation of millions of doses given over the years underscore the differences among these few agents. A few interactions can provide the basis for optimum individual recommendations.

References
 
COX-2 inhibitors. http://www.powerpak.com/CE/cox2/lesson.htm.
Panther L, Eland J. Effects of Long Term NSAIDs. http://pedspain.nursing.uiowa.edu/CEU/NSAID_longterm.htm.
Cantini C, Ungar A, Vallotti B, DiSerio C, Altobelli A, Castellani S, Masotti G. Ageing kidney and autacoids. Exp Clin Cardiol 1998;3(2):90-95. Yang C. Nonsteroidal anti-inflammatory drugs and blood pressure. http://www.hsph.harvard.edu/Organizations/DDIL/NSAID_BP.htm.
Selective COX-2 Inhibitors. The Drug Monitor. http://home.eznet.net/-webtent/coxi.html. Whelton A. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications. Am J Med 1999 May 31; 106:5B 13s-24s.
Feldman H, Kinman J, Berlin J, et al. Parenteral Ketorolac: The Risk for Acute Renal Failure. Ann Intern Med 1997 February 1; 126:193.
Acute renal failure (ARF). http://www.vetmed.wsu.edu/boeing/smal_animal_medicine/arf.htm.
Toxic nephropathy. http://www.vetmed.wsu.edu/boeing/smal_animal_medicine/toxic.htm.
Cariati S. NSAIDs, Diuretics Can Be Lethal If Taken Together. Medical Tribune: Family Practice Edition. 39(13):6-7, 1998.

  
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