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Posts Tagged ‘NSAIDs’

The British Columbia Drug Usage Review program has focused on the use of non-steroidal anti-inflammatory drugs (NSAIDs) and other target medications for a number of years. The program promotes rational prescribing for all age groups, with special emphasis on the elderly. Questions about the type and frequency of monitoring for adverse effects in this age group raise the spectre of horrendous increases in testing costs to monitor every patient. Clearly this is unnecessary. A short course of an non-steroidal anti-inflammatory drug in a normally healthy individual does not require laboratory monitoring. When chronic non-steroidal anti-inflammatory drug treatment is anticipated, however, baseline evaluation of renal, liver, and hematological parameters is prudent, especially in patients at increased risk.

The following are the current monitoring recommendations from the Drug Usage Review Program, which attempt to balance the high frequency of monitoring suggested by the literature with the need for practical guidelines for family physicians.

• Ask patients to weigh themselves twice a week for the first month of therapy and to report any progressive weight gain.

• Monitor blood pressure frequently, especially in hypertensive individuals.

• Measure blood urea nitrogen, serum creatinine, and electrolytes at initiation, at 3 weeks, and then every 6 months.

• Test liver function at initiation, 3 weeks, and then every 6 months.

• Do a complete blood count and platelet estimation at initiation, at 3 weeks, and then every 6 months if indicated.

Clinicians are faced with a dilemma. While potentially severe reactions to non-steroidal anti-inflammatory drugs have been documented, available evidence indicates that such reactions are uncommon and perhaps rare. Thus, in the vast majority of patients, monitoring may be regarded as unwarranted. Yet, the risks of NSAIDs are real, and early detection of toxicity can improve the outcome. We therefore urge physicians to assess patients treated with non-steroidal anti-inflammatory drugs for risk of toxicity and to monitor them appropriately. ■

Four types of renal problems can occur with non-steroidal anti-inflammatory drugs (NSAIDs). Acute renal dysfunction has been reported; it rarely progresses to tubular necrosis. The mechanism involves prostaglandin inhibition. A low circulatory volume in some patients results in the output of catecholamines and the activation of the renin-angiotensin system, resulting in a compensatory vasoconstriction. In order to maintain renal blood flow in the face of this vasoconstriction, the synthesis of vasodilating renal prostaglandin (PGI₂) is increased. Non-steroidal anti-inflammatory drugs inhibit the synthesis of renal prostaglandins and thus decrease renal perfusion. As one would expect with such a mechanism, it occurs only in patients who are dependent on prostaglandins for the maintenance of renal blood flow, and the onset and reversal of the renal failure is rapid.

Hyperkalemia has been reported. In one indomethacin study, an increase in serum potassium levels of 1 mmol/L or more occurred in 26% of patients. The hyperkalemia is also prostaglandin mediated. Renin release is pardy dependent on prostaglandins. Therefore, when non-steroidal anti-inflammatory drugs decrease renin output, lower aldosterone levels and increased serum potassium result.

Sodium and water retention can lead to edema and to the antagonism of the antihypertensive effects of diuretics, (5-blockers, and angiotensin-converting enzyme inhibitors. Prostaglandin effects on the kidney include vasodilation, leading to increased renal blood flow and increased sodium reabsorption in the proximal tubule; inhibition of sodium reabsorption in the ascending loop of Henle; and a reduction of the effect of antidiuretic hormone (ADH). By decreasing this prostaglandin effect, non-steroidal anti-inflammatory drugs increase the effect of ADH in promoting water retention, which can (rarely) lead to hyponatremia. Edema is therefore common and has been observed in 10% of patients taking ibuprofen.

Interstitial nephritis characterized by proteinuria, and a slow rate of recovery is estimated to occur in one in 5000 to 10 000 patients treated with NSAIDs. The cause is postulated to be an immune or a direct toxic effect.

Population at risk. The groups at risk for acute renal failure from non-steroidal anti-inflammatory drug use are 1) those with diseases involving a low circulatory volume and resultant high renin state who are dependent on renal prostaglandins to maintain renal perfusion and 2) those with diseases not related to a high renin state but that may involve low renal synthesis of prostaglandins. Conditions in the first group include decreased cardiac output, volume depletion by high-dose diuretics, hemorrhage or septic shock, cirrhosis with ascites, and sodium depletion. Conditions in the second group include systemic lupus erythematosus, nephrotic syndrome, chronic glomerulonephritis, renal vascular disease, renal artery stenosis, and gout. There is no evidence that the elderly are more susceptible to renal failure, beyond an increased prevalence of some of these risk factors in the elderly population.

Non-steroidal anti-inflammatory drug-related sodium retention and edema are more common in patients with incipient heart failure, renal disease, or other high renin states, but can occur in healthy patients. The occurrence of interstitial nephritis with NSAIDs is unpredictable, and all patients are at risk. The prostaglandin-related effects can occur with any non-steroidal anti-inflammatory drug.

It has been suggested that sulindac is “renal-sparing” because it is metabolized into an inactive form in the kidneys; and initial studies reported a lack of inhibition of renal prostaglandin synthesis. Subsequent studies have reported decreased glomerular filtration rate and urinary prostaglandins with sulindac, a case of renal failure in an elderly patient with congestive heart failure and hypertension who was using diuretics, and a case of hyperkalemia above 6 mmol/L. It therefore appears that sulindac is only relatively “renal-sparing”.

Interstitial nephritis is most common with fenoprofen. Interstitial nephritis has been reported after 2 weeks to 18 months of non-steroidal anti-inflammatory drug treatment. Eosino-philia is sometimes present.

Monitoring. Acute renal failure, hyperkalemia, and sodium retention related to NSAIDs are all of rapid onset, within days of starting the drugs.’ Acute renal failure and interstitial nephritis are usually rapidly reversible if the NSAID is withdrawn early. If it is not, acute renal failure can progress to tubular necrosis; tubular necrosis and nephritis can progress to renal failure.

Monitoring strategies (Table 3) include 1) in patients at risk, measuring initial baseline serum creatinine, blood pressure, serum potassium, and body weight, and repeating within the first 3 weeks; 2) monitoring all patients regularly (the same monitoring schedule should be followed for patients receiving sulindac); 3) checking for urine protein and cells to aid in early detection of intestinal nephritis; and 4) asking patients to report symptoms of interstitial nephritis and papillary necrosis (back pain, polyuria, edema, hematuria).

Preventive measures. Preventive measures include 1) avoiding non-steroidal anti-inflammatory drugs in patients with risk factors if suitable alternatives exist; 2) otherwise using the lowest effective dose; and 3) using sulindac, a reasonable choice in these patients. But be aware that NSAID-related renal toxicity is still possible.

Blood dyscrasias related to non-steroidal anti-inflammatory drug (NSAID) therapy are clinically important, although rare. In the Danish study, one third of reported deaths associated with NSAIDs had hematologic causes. All blood cell lines can be affected, resulting in red cell aplasia, hemolytic anemia, agranulocytosis, thrombocytopenia, and aplastic anemia. Reduced platelet aggregation also occurs.

The exact incidence of NSAID-related blood dyscrasias is unknown. The most recent investigation was the International Agranulocytosis and Aplastic Anaemia Study (IAAAS), in which the risk of aplastic anemia was estimated to be on the order of six to 10 events per million subjects per year, following an exposure of at least 5 months.

Most of the hematologic effects of NSAIDs (agranulocytosis, red cell aplasia, aplastic anemia, hemolytic anemia, thrombocytopenia) are thought to result from an immune reaction and are, therefore, drug specific. Drugs that bind strongly to proteins, such as non-steroidal anti-inflammatory drugs, can act as haptens and elicit antibody production and other immune responses.

Nonimmune hematologic effects of non-steroidal anti-inflammatory drugs include inhibition of platelet aggregation and hemolysis. Reversible inhibition of platelet cyclooxygenase occurs for all NSAIDs except acetylsalicylic acid (ASA), which irreversibly acetylates the cyclooxygenase for the lifetime of the platelet. Hemolysis can occur owing to the ability of non-steroidal anti-inflammatory drugs to oxidize hemoglobin to methemoglobin or sulfhemoglobin.

Populations at risk. Patients of all ages appear to be at risk for NSAID-related blood dyscrasias. Aplastic anemia associated with phenylbutazone and oxyphenbutazone use has occurred mainly in women older than 60 years. In the IAAAS study, only indomethacin, diclofenac, phenylbutazone, and oxyphenbutazone were significantly associated with aplastic anemia, although there have been reports of an association with acetylsalicylic acid. Agranulocytosis has been associated with the use of indomethacin, phenylbutazone, oxyphenbutazone, sulindac, tolmetin, naproxen and mefenamic acid.

The pharmacologic reactions (platelet aggregation inhibition, hemolysis) could be caused by any member of this class of drugs, in a dose-dependent manner. But nonacetylated salicylates are weak, reversible inhibitors of prostaglandin synthesis and are less likely to inhibit platelet aggregation.

Interestingly, ibuprofen has been used without reported adverse effects in hemophiliacs. Patients with glucose-6-dehydrogenase deficiency who take NSAIDs are at risk of hemolysis. Patients with defective platelet function, gastrointestinal lesions, or a bleeding diathesis are at increased risk of hemorrhage, as are patients receiving anticoagulant therapy. Two deaths from hemorrhage have been reported associated with the combined use of non-steroidal anti-inflammatory drugs and coumarins.

Monitoring. Monitoring strategies (Table 2) include 1) informing the patient of the warning symptoms of agranulocytosis (sore throat, fever, muscle pain, headache) and of thrombocytopenia (ecchymoses, purpura); and 2) monitoring blood cell counts at initiation, at 3 weeks, and regularly over the long term (the risk of allergic reactions is usually highest when a drug is initiated or re-instituted, but can occur after long-term drug therapy).

Preventive measures. Non-steroidal anti-inflammatory drugs should be avoided in patients at risk for hematologic adverse effects: avoid NSAIDs, if possible, in those with platelet dysfunction, gastrointestinal lesions likely to bleed, or other bleeding diathesis and in patients on anticoagulants; use non-steroidal anti-inflammatory drugs with caution in patients with glucose-6-phosphate dehydrogenase deficiency; and avoid phenylbutazone and oxyphenbutazone, or use only for a short time and monitor closely.

Hepatotoxic effects range from asymptomatic elevations of serum transaminases and alkaline phosphatase to acute cytolytic, cholestatic, or mixed hepatitis. Reye’s syndrome may occur in children in association with acetylsalicylic acid (ASA) use and a viral illness.

Elevated liver enzymes are fairly common with non-steroidal anti-inflammatory drug (NSAID) use. In prospective clinical trials, elevated transaminases or alkaline phosphatase were detected in approximately 4% of non-steroidal anti-inflammatory drug users. While the exact incidence of NSAID-induced hepatitis is not known, it appears to be rare. Fatalities from NSAID hepatotoxicity are also rare: in a 17-year Danish study of voluntary reports of drug adverse drug reactions, three of 67 deaths were due to hepatotoxicity related to non-steroidal anti-inflammatory drug use.

Little is known of the mechanism of NSAID-related hepatotoxicity. There is no evidence that prostaglandin synthesis or hypersensitivity is involved.

Because of the low incidence of hepatic reactions, it has been difficult to identify populations at risk. The mild biochemical changes associated with acetylsalicylic acid have commonly been reported in female patients with collagen diseases, such as SLE and rheumatoid arthritis.

In an analysis of Michigan Medicaid data for ibuprofen, indomethacin, and sulindac, incidence was not related to age. Cholestatic liver dysfunction from benoxaprofen, which led to its ultimate withdrawal from the United Kingdom market, was most evident in elderly, especially small women who had renal dysfunction and who received high doses. Acetylsalicylic acid hepatitis and Reye’s syndrome in children also show a relationship with dose.

Hepatotoxicity has been reported occasionally with almost all of the NSAIDs; the relative risk for specific drugs is not known. Increases in serum transaminase and alkaline phosphatase are observed in all forms of hepatotoxicity from all non-steroidal anti-inflammatory drugs and are, therefore, useful parameters to monitor as an early warning sign. In more severe cases, there may be accompanying signs and symptoms of anorexia, nausea, vomiting, abdominal pain, weakness, and jaundice, as well as increases in bilirubin and prothrombin time. The onset of hepatotoxicity is often within the first few weeks of therapy.

Monitoring. Monitoring strategies include 1) taking initial transaminase and alkaline phosphatase levels to provide a baseline, then repeating regularly (some recommend monthly checks for the first year; others monitor at 1, 3, and 13 weeks. Determinations at initiation, at 3 weeks, and then every 6 months thereafter would appear prudent); and 2) discontinuing the drug and measuring liver enzymes if non-specific symptoms of nausea, vomiting, abdominal pain, and weakness appear.

Preventive measures. No definite methods of prevention exist, but strategies that can minimize occurrence include avoiding acetylsalicylic acid (ASA) use in children and avoiding high doses of any non-steroidal anti-inflammatory drug.

The gastrointestinal effects of non-steroidal anti-inflammatory drugs range from dyspepsia to gastric ulceration, hemorrhage, and perforation. Minor symptoms of gastrointestinal discomfort are reported in 10% to 40% of patients using non-steroidal anti-inflammatory drugs. Gastric ulcers occur in up to 20% of chronic non-steroidal anti-inflammatory drug (NSAID) users. Of these patients, only a small proportion go on to develop bleeding and perforations; major gastrointestinal bleeding is reported in 0.3% of patients taking acetylsalicylic acid (ASA) alone or non-ASA non-steroidal anti-inflammatory drugs. It has been estimated that the general practitioner with approximately 1500 patients would encounter these serious complications only once in 10 years. Small intestine, large bowel, and esophageal irritation are rare.

Gastric effects of non-steroidal anti-inflammatory drugs are currently thought to involve both prostaglandin inhibition and a direct local irritant effect. Prostaglandins protect the gastrointestinal tract by increasing mucus production, increasing mucosal blood flow, decreasing acid secretion, and enhancing repair mechanisms. Because all non-steroidal anti-inflammatory drugs can inhibit gastric prostaglandin synthesis, the potential for gastrointestinal adverse effects is inseparable from their beneficial anti-inflammatory effects and can occur with any dosage form.

That a direct local irritant effect also contributes to gastric damage, at least with acetylsalicylic acid, is supported by the observation that enteric-coated forms are less damaging. Other possible mechanisms include an increase in back diffusion of hydrogen ions by ASA, increased leukotriene synthesis, and increased free radical formation by non-ASA non-steroidal anti-inflammatory drugs.

Patients at risk. The populations at risk for the development of ulcers, hemorrhage, and perforation have not yet been precisely identified. In epidemiological studies, the association between non-steroidal anti-inflammatory drug use and hemorrhage or perforation appears to be strongest for elderly women, although this could simply reflect the high use of non-steroidal anti-inflammatory drugs in the elderly female population. Others have reported that male patients are more likely to bleed than female patients. Gastric hemorrhage is a particularly serious event in elderly patients, commonly associated with hospitalization and morbidity.

Other populations at risk include those with a bleeding diathesis, a history of previous gastrointestinal ulceration, and perhaps those with varies secondary to alcoholism or portal hypertension. Patients with inflammatory bowel disease are at risk for activation of the disease.

Other than a high incidence of gastrointestinal bleeding associated with high-dose acetylsalicylic acid (ASA) use, there is no evidence that any specific non-steroidal anti-inflammatory drugs produce less gastropathy than others when used in equivalent anti-inflammatory doses. All can cause gastrointestinal damage.

Monitoring. Monitoring is complicated by the fact that the gastrointestinal side effects of non-steroidal anti-inflammatory drugs are often silent; most patients are asymptomatic before bleeding. Nor do symptoms correlate well with endoscopic results. In a study by Caruso and Biancho Porro, 41% of patients without symptoms had endoscopically confirmed lesions, while 79% of patients with symptoms of discomfort had lesions. These results suggest that, while a lack of symptoms is not predictive, the presence of symptoms calls for further investigation. Epigastric tenderness on physical examination may further indicate the likelihood of lesions, but is uncommon.

Monitoring for occult fecal blood loss is a poor indicator of upper gastrointestinal lesions. Collins and Du Toit found that approximately half of their patients with gastric ulcerations did not have detectable occult blood, while approximately half of those with no endoscopic signs of gastric lesions were positive for occult blood. Iron-deficiency anemia can signal gastrointestinal blood loss.- While some authors have reported that bleeding is most likely to occur within the first 3 to 4 months of treatment, gastrointestinal bleeding has been reported after anywhere from 6 days to 2 years of non-steroidal anti-inflammatory drug use. Long-term monitoring is thus needed. Because symptoms of gastrointestinal complications are infrequent and vague, they cannot be relied upon for the purpose of monitoring. Some strategies can help prevent gastrointestinal problems (Table 1).

Preventive measures. The use of cytoprotective agents is still controversial. Because the patients at risk have not been precisely defined, it is not clear which groups should receive preventive agents. It is difficult to justify administering a drug, with its own inherent toxicities, just to prevent toxicity from another drug, unless the risk is high.

Sucralfate: Sucralfate has been shown to increase gastric prostaglandin E₂ secretion in rats. However, a similar effect on prostaglandins did not appear in humans treated with non-steroidal anti-inflammatory drugs. Evidence of preventive benefit in patients taking NSAIDs is weak. Further studies on sucralfate are warranted, because it is a drug of relatively low toxicity lacking the systemic interactions seen with cimetidine.

Cimetidine: Studies with cimetidine have established that doses of 200 to 400 mg are effective in preventing the acute injury associated with the administration of a single 1300-mg dose of acetylsalicylic acid (ASA) to healthy subjects. However, evidence of preventive benefits in long-term studies is required before routine prophylaxis can be recommended.

Misoprostol: Several recent studies have investigated the value of misoprostol, a synthetic analog of PGE, in the prevention of NSAID-related ulceration. It acts by augmenting prostaglandin-mediated mu-cosal defenses. In healthy subjects taking ASA, ibuprofen, or tolmetin for 7 days, misoprostol (200 µg) taken concomitantly four times a day has been shown to be significantly superior to placebo in preventing the occurrence and reducing severity of en-doscopically demonstrated gastric and duodenal ulceration.

The only study investigating long-term gastrointestinal protection reported that both 100- µg and 200- µg misoprostol doses significantly reduced the frequency of gastric ulcers in patients with osteoarthritis taking their usual doses of ibuprofen, piroxicam, or naproxen. Although these initial studies are promising and the mechanism involved intuitively seems appropriate, more studies (particularly long-term ones) are required before misoprostol can be recommended for the routine prevention of non-steroidal anti-inflammatory drug gastropathy.

Comparative performance: In a study comparing misoprostol (200 µg QID) with cimetidine (300 µg QID) over 7 days in the prevention of tolmetin-related (400 mg QID) gastroduodenal ulceration in healthy subjects, both were significantly better than placebo. Misoprostol was more effective than cimetidine in preventing gastric ulcer, but not duodenal ulcer.

How many of your patients chronically take non-steroidal anti-inflammatory drugs (NSAIDs)? In a recent Saskatchewan survey, approximately 13% of the general population had filled a prescription for an NSAID during the preceding year. In British Columbia these drugs accounted for 6.4% of total claims and 9.8% of drug cost to the Pharmacare Program.

This frequent prescribing reflects the benefit derived from NSAIDs in the symptomatic relief of arthritis and other conditions. Yet, although most patients tolerate this group of drugs well, serious and sometimes fatal reactions have been reported. Patients receiving long-term non-steroidal anti-inflammatory drug treatment should be carefully monitored. We review the gastrointestinal, renal, hepatic, and hematologic adverse effects associated with NSAID therapy and recommend preventive measures and monitoring protocols for patients at risk.

Pharmacology

All non-steroidal anti-inflammatory drugs exhibit dose-related inhibition of the enzyme cyclooxygenase, resulting in decreased prostaglandin synthesis. Non-steroidal anti-inflammatory drugs can thereby decrease inflammation, pain, and fever. The inhibition of cyclooxygenase is reversible for all NSAIDs except acetylsalicylic acid, so prostaglandin-related effects should be rapidly reversible in most cases. But other mechanisms of toxicity also exist.

Pharmacokinetics

Non-steroidal anti-inflammatory drugs share several basic pharmacokinetic properties: high plasma albumin binding (99%), hepatic metabolism, and the excretion of a small amount unchanged by the kidneys. Hypoalbuminemia, liver dysfunction, and reduced renal function can therefore place patients at risk for increased plasma levels and toxicity.

While reduced albumin concentration, liver function, and renal function are all associated with aging, in general, the pharmacokinetics of non-steroidal anti-inflammatory drugs are not changed significantly in the elderly. Age-related decreases in clearance have been reported for piroxicam, naproxen, and ketoprofen, but the clinical relevance is unknown.

Half-lives were not prolonged in the elderly in studies with ibuprofen and diclofenac. Low doses of NSAIDs should be used in any patient with compromised liver function. Patients with poor renal function should be prescribed selected non-steroidal anti-inflammatory drugs, keeping in mind that renal dysfunction increases the risk of renal toxicity (see Renal problems).

Results of this study provide strong evidence that topical nonsteroidal anti-inflammatory drugs work by mechanisms other than local massage, since this would have been provided by placebo as well. The consistency of the trials is striking, and the effect size of the pooled results is large. An NNT of 3 means that one person in three will benefit from topical nonsteroidal anti-inflammatory drugs over and above the benefit from placebo. Canadian physicians might be justifiably reluctant to prescribe medication for a non-approved indication, even though many examples of such practices exist. Long-term safety data were not presented in the paper, but if available, they would provide a much higher comfort level for prescribing.

Bottom line

• The problem of musculoskeletal pain is enormous and growing rapidly. Nonpharmacologic approaches are valuable but the pharmacologic armamentarium is extremely limited. After acetaminophen has been tried, the remaining medications are either narcotics or nonsteroidal anti-inflammatory drugs, each of which has its own potential problems.

• Topical capsaicin is effective for some patients and might be worth trying. Newer cyclooxygenase-2 inhibitor nonsteroidal agents have recently become available, but their effectiveness and long-term adverse effect profile remain unclear. Their cost is substantially higher than the cost of many older agents.

• Many patients continue to suffer with musculoskeletal pain despite use of currently available treatments. For them, we might be justified in trying topical NSAIDs after a thorough discussion of the potential advantages and adverse effects.

• Topical nonsteroidal anti-inflammatory drugs could play a much larger role in treatment of acute and chronic musculoskeletal disorders if long-term safety data were available and if they received Canadian approval for these indications.

Results

Searches found 86 reports (10160 patients) that met inclusion criteria, 76 of which had dichotomous pain outcomes, including three unpublished reports from a pharmaceutical company. For acute conditions, 37 placebo-controlled trials were analyzed. All but one of these showed better pain reduction with the topical nonsteroidal anti-inflammatory drug (NSAID) than with placebo, for a pooled relative benefit of 1.7 (95% confidence interval [CI] 1.5 to 1.9) and a number-needed-to treat (NNT) of 3.9 (95% CI 3.4 to 4.4). Trials with higher quality scores showed the same results. Smaller-sized trials gave a larger effect size and a smaller NNT than large trials. Ketoprofen, felbinac, ibuprofen, and piroxicam were statistically superior to placebo, with NNTs of 2.6 to 4.2.

For chronic conditions, all 12 placebo-controlled trials showed better pain relief with topical nonsteroidal anti-inflammatory drugs than with placebo. Seven of these studies had statistically significant results. The pooled relative benefit for all 12 studies was 2.0 (95% CI 1.5 to 2.7), and the NNT was 3.1 (95% CI 2.7 to 3.8). Better quality studies had the same results. The effectiveness of individual drugs could not be analyzed because there were not enough studies to combine.

No significant benefit of oral over topical medication could be found in three studies of acute conditions and two of chronic conditions. Local adverse effects were found in 2.6% of subjects in studies of acute conditions (versus 3.0% for placebo) and 5.9% in studies of chronic conditions (versus 5.3% for placebo). Incidence of systemic adverse effects was about 1% for acute and chronic conditions and was the same for treatment and placebo groups.

Analysis of methodology

This study was generally well done. It addressed a focused clinical question and made use of explicit inclusion criteria. Failure to contact authors and search out abstracts might have meant important studies were missed. The authors’ own analysis suggested that some negative studies were absent from the list of those identified. Publication bias was, therefore, a problem, but likely no more of one than in other systematic overviews: especially for acute conditions, an implausibly large body of evidence would be needed to outweigh the 36 positive trials identified. Validity of the studies included was appraised, and findings did not appear to rest on poor-quality or small studies. Important steps in selecting studies for inclusion and abstracting results were done by more than one author and are probably reproducible.

The study’s major flaw reflects that of the trials included, none of which assessed outcomes beyond 30 days. Especially for chronic conditions, long-term efficacy of several months or even years would be important to patients, yet only short-term data are available. Even more problematic, adverse effects were also measured based on a short duration of treatment.

It is not clear from the study how often topical treatments should be applied, whether it matters which joints are involved, what effect concentration of the medication has on efficacy and adverse events, and how costly these medications are. It is also not clear how well blinding worked, especially if the active topical medications had a smell, appearance, or sensation on the skin that was different from placebo. Additional patient-oriented outcomes, such as function and quality of life, would be desirable. The study was sponsored by two manufacturers of topical nonsteroidal anti-inflammatory drugs (NSAIDs).

Relevance to family physicians

Musculoskeletal problems are Canada’s leading cause of long-term disability. In the general population, they are among the most frequent chronic health conditions, reasons for seeing a doctor, and reasons for using prescription and nonprescription drugs. Just over 10% of office visits to general practitioners and family physicians are attributable to these disorders. More than half of these visits are for nonspecific musculoskeletal conditions, osteoarthritis, and soft-tissue rheumatism (tendonitis, bursitis). The prevalence of arthritis is projected to increase dramatically; between 1991 and 2031, a 47% increase is expected as well as a 124% rise in the number of people affected.

Several interventions have been found to be effective for osteoarthritis, the single most frequent specific diagnosis. Aerobic and muscle-strengthening exercises and education provide benefits in the form of pain relief, increased function, and self-efficacy. Acetaminophen in adequate doses (4 g/d) provides pain relief that is comparable to that provided by oral nonsteroidal anti-inflammatory drugs (NSAIDs). Both Canadian practice guidelines under development and United States practice guidelines recommend acetaminophen as first-line therapy. Topical rubs are second-line therapy in current US recommendations; oral NSAIDs are third-line.

For patients with conditions such as osteoarthritis who do not always get adequate pain relief from non-pharmacologic interventions plus acetaminophen, a trial of oral nonsteroidal anti-inflammatory drugs is customary. Oral NSAIDs have potentially serious gastrointestinal effects: the annual attributable risk of hospitalization for gastrointestinal problems is 1.3% to 1.6% for regular users. In addition to potential gastrointestinal problems, many patients have risk factors, such as renal failure or congestive heart failure, that weigh against long-term use of nonsteroidal anti-inflammatory drugs.

The promise of an effective topical treatment for musculoskeletal conditions is appealing. An ideal medication would penetrate into the underlying joint, provide pain relief, not enter the bloodstream in appreciable amounts, cause no systemic adverse effects, and have few local reactions. Because many people already use topical rubs of various kinds, they might prefer this route of administration.

At least 15 topical nonsteroidal anti-inflammatory drugs are available worldwide. Their use in Canada has been limited, and they are not currently approved for musculoskeletal indications. Despite this, at least two agents, ketoprofen and naproxen, can be compounded by Canadian pharmacists. To date, these compounds have been used primarily in sports medicine. Canadian physicians might be asked about their use by patients who have obtained the drugs during visits to other countries.

Are these medications effective and safe? Given the lack of acceptable alternatives for pain relief for many of our patients, what should we recommend?

Overview of study and outcome

The authors included studies of topical nonsteroidal anti-inflammatory drugs that were randomized; had pain as an outcome for acute conditions (sprains, strains, sports injuries) or chronic conditions (arthritis, rheumatism); and had a comparison group that used another topical NSAID, a placebo, or an oral nonsteroidal anti-inflammatory drug. Their search strategies encompassed MEDLINE, EMBASE, and the Oxford Pain Relief Database in all languages. They identified further reports from reference lists of retrieved articles, and they contacted 12 pharmaceutical manufacturers in the United Kingdom to seek out unpublished studies. They did not contact the authors of the studies they identified, nor did they include abstracts.

Two authors screened the reports to eliminate those that definitely did not meet inclusion criteria, and then each remaining report was read by all authors independently. Trial quality was scored according to whether randomization was performed and described; blinding was present, described, and adequate; and withdrawals were described and explained. Only information available in dichotomous form was used for analysis, and analyses were framed on an intent-to-treat basis (subjects were analyzed in the groups to which they were allocated whether or not they used the assigned study medications). A measure of effectiveness was taken 1 week after start of treatment for acute conditions and 2 weeks after for chronic conditions. Treatment success was defined as a 50% or greater reduction in pain.