Selecting Nonsteroidal Anti-Inflammatory Drugs: J Am Board Fam Pract: first published as 10.3122/jabfm.2.4.257 on 1 October 1989. Downloaded from Pharmacologic And Clinical Considerations Lucinda G. Miller, Pharm.D., andJohn G. Prichard, M.D.
Abstract: An increasing number of nonsteroidal anti·infIammatory drugs (NSAIDs) are available to treat a variety of conditions. There exist little comparative data examining efficacy for all NSAIDs for a particular illness. The major factors governing selection of these agents relate to the patient's condition and the drug's characteristics. Once efficacy has been established, selection of an NSAID is then determined by side-effect profile, potential for drug interactions, dosing frequency, and cost. This review presents a listing of commerciaIly available NSAIDs, cost comparisons for average daily doses of NSAIDs, and the conditions and drug characteristics that might influence the choice of an NSAID.(J Am Bd Fam Pract 1989; 2:257·71.)
Initially, nonsteroidal anti-inflammatory drugs the issue of potency is a minimal consideration (NSAIDs) were developed to provide aspirin when selecting therapy, as dosage recommenda alternatives that would have fewer side effects. tions accommodate this factor. Phenylbutazone was first released in 1949, fol NSAIDs differ in potency, duration of action, lowed by oxyphenbutazone, I but their use has side-effect profile, potential for drug interactions, been limited by associated blood dyscrasias. In and cost. There exists considerable variability in 1963, indomethacin was introduced and repre clinical response to the same agent by different sented an improvement in the side-effect pro patients. Although each NSAID must fulfill cri file of NSAIDs. I teria of excellent potency, efficacy, and apparent Today there are more than a dozen non safety during clinical trials, some agents, such as aspirin NSAIDs available in the United States benoxaprofen, zomepirac, and suprofen, have (Table 1), and approximately 70 million pre been withdrawn from the market, because of the scriptions are dispensed annually. Consumers later discovery of side effects. spend nearly $1 billion annually for NSAIDs; This review summarizes the distinguishing hence, manufacturers continue to introduce features of the various NSAIDs and offers guide new agents to the market. 2 Despite the increas lines for selecting them based on pharmacologic http://www.jabfm.org/ ing number of NSAIDs available, there are few and clinical considerations. data comparing the old and new agents for effi cacy and safety, and there are few guidelines Pharmacology governing choices of NSAIDs for particular pa Mechanism ofAction tients. For example, carprofen and diclofenac The nonsteroidal agents have antipyretic and
sodium have recently been approved in the analgesic properties as well as anti-inflamma on 26 September 2021 by guest. Protected copyright. United States, but no particular niche' has yet tory effects. The mechanism of action in de evolved for them. creasing inflammation is not completely de Despite claims of superiority, few NSAIDs fined. Theories have focused on the ability of consistently show greater efficacy than the oth NSAIDs to inhibit free-oxygen radicals, im ers. When evaluating these claims, it is important mune responses, and prostaglandin synthesis. 3 to note the dosage used, because the "less effec Inhibition of prostaglandin synthetase causes a tive" drug may have been prescribed only in an decrease in the formation of prostaglandins algesic doses, not in higher, anti-inflammatory and, consequently, a decrease in prostaglandin amounts required for valid comparisons. Presently, mediated pain and inflammation (Figure O. In domethacin is one of the most potent inhibitors, which contributes not only to its efficacy but its From the Department of Family Medicine, Baylor College of side-effect profile as well. Medicine, Houston, and Ventura County Medical Center, Ven tura, CA. Address reprint requests to Lucinda G. Miller, Differences in effectiveness may depend Pharm.D., 5510 Greenbriar, Houston, TX 77005. upon the patient's primary disorder, e.g., exces-
NSAlDs 257 Table 1. Commercially Available Nonsteroidal Anti-Inflamma Side Effects J Am Board Fam Pract: first published as 10.3122/jabfm.2.4.257 on 1 October 1989. Downloaded from tory Drugs. Gastrointestinal All NSAI Ds arc organic acids, and they arc Cll\S Class (;eneric Name Brand Name tic, resulting in gastrointestinal side effects in 15 -2 5 percent of patients.(> They produce gastro Fenamates l\lecle.fenamatc l\leclolllcn intestinal irritation by affecting the mucosal bar I\lefcnamic acid I'onstd 7 Int/oles lndonlcthacin Indocin rier and by prostaglandin inhibition. Conse Slliindac Clinoril quent to the latter, gastric mucus and bicarbonate Tollllctin Tolectin production arc inhibited, and a decrease in sub (hicams I'iroxicam Fddene 7 Pl'Opion ic acids Fenoprofcn Nalfon mucosal blood flow occurs. -1) Ulceration may re Ihllprofen Motrin, Rllfen, etc. sult but, despite continued NSAID therapy, also Keropl'Ofon ( )rlldis may heal without having been recognized.? Naproxen Naprosyn Napl'Oxen sodiulll Anal'rox Another potential consequence of NSAI D Carprofen Rimadyl induced prostaglandin inhibition is reactivation lo I PITazolone Phenylbut:lzeHle Butazolidin of quiescent inflammatory bowel disease. - ] A Phenylacetic acid Dieiofenac Voltaren decrease of prostaglandins in the colonic mucosa leads to relapse in some patients with ulcerative colitis I I; therefore, the use of NSAI Ds in patients with ulcerative colitis or Crohn disease should be sive prostaglandin production in dysmenor undertaken with caution, if at all. rhea, or immune injury in systemic lupus ery A comparative trial of all the NSAIDs for thematosis (SLI,~)."·5 Not all NSAI Ds are alike gastrointestinal tolerability is lacking; however, a in their immunomodulating properties. Indo recent report by Carson, et al. included the methacin is associated with a decrease in the majority of NSAIDs commercially available. I 3 production of rheumatoid factor6; ibuprofen in They found sulindac to be associated with the hibits monocyte chemotaxis; but indomethacin, highest rate of upper gastrointestinal tract bleed naproxen, and salicylates do not. 6 The extent to ing. It was the only drug whose toxicity rate was which these observations may serve as a ra significantly different from ibuprofen. I 3 How tionale for selecting one NSAID over another is ever, sulindac was administered in an average not known. daily dose that was closest to the maximum rec ommended, in contrast to other NSAIDs, which were administered in lower relative doses. Be http://www.jabfm.org/ cause sulindac is a prod rug (not active until ab sorbed and metabolized by the liver to its active NSAIDS I I form, sulindae sulfide), it was believed at first to be of low ulcerogenic potential and was preferred IArachadonic Acidl 1/ in patients prone to, or unable to tolerate, gastro
intestinal side effects. The study, however, by on 26 September 2021 by guest. Protected copyright. ICyclooxygenase] Carson, et al. suggests otherwise. Nonacetylated salicylates, such as choline magnesium trisalicy late (Trilisate'M) or salsalate (Disalcid'M) may he used as alternatives to other NSAIDs, because they are associated with a low rate of gastrointes tinalupset. 1-1 Seventy-five percent of patients not able to tolerate indomethacin will be able to take tolmetin sodium. 15 An analgesic dose of enteric coated aspirin (or ibuprofen 1200 mg/day) causes little or no mucosal damage. 16 Buffering, al though it enhances the rate of dissolution, docs Figure 1. Proposed site of action of nonsteroidal anti-inflam not appreciably reduce mucosal damage.') Meclo matory drugs (NSAIDs). fenamate sodium causes diarrhea in 10-35 per-
2 SH JABFP Octobcr-Deccmher 19S9 Vol. 2 No. of cent of patients,17 and its use should not extend tered orally (1 g 4 times a day), sucralfate was J Am Board Fam Pract: first published as 10.3122/jabfm.2.4.257 on 1 October 1989. Downloaded from beyond 1 week to minimize gastrointestinal irri more effective than the placebo in relieving tation. Available studies suggest that when gastrointestinal symptoms and gastric lesions in NSAIDs are used in comparable doses, there are patients receiving NSAIDs.25 This effect oc minimal differences in gastrointestinal symptoms. curred without impairing absorption or bioavail Additional controlled studies are needed to deter ability of the drug. 26 Improvement was better in mine whether significant differences exist among patients receiving long half-life NSAIDs, such as NSAIDs in producing gastrointestinal injury. piroxicam, diflunisal, naproxen, and sulindac, Concurrent therapy to minimize gastrointesti than in those treated with short-acting agents. nal effects associated with NSAIDs has been in When administered for protective effects against vestigated. In patients who have gastric distress aspirin-associated gastrointestinal injury, sucral due to NSAID therapy, antacids may alleviate fate's effects were negated by preadministration some symptoms, but because they do not alter of indomethacin.27 This suggests that, in order to the NSAID-induced effects on the gastric muco be effective, sucralfate must be prescribed when sal barrier, complete relief will not be afforded. NSAID therapy is begun. The effectiveness and The use of histamine receptor type 2 (H2) an cost of this approach need to be explored further. tagonists also has been studied as a means of The use of exogenous prostaglandins to protect decreasing NSAID-associated gastrointestinal up the gastrointestinal mucosa from NSAID-medi set,18 but the results are variable. In a double ated injury holds promise. Misoprostol, a syn blind comparison, cimetidine (200 mg) protected thetic analogue of prostaglandin E I protected the gastric mucosa from the hemorrhagic effects against injurious effects of naproxen and aspi of a single 1300 mg dose of aspirin. 19 Ranitidine rin. 28-3o In an endoscopic study of 140 men, miso hydrochloride is also effective in protecting the prostol (200 J,l.g) protected 50-70 percent ofthose gastric mucosa in studies of aspirin-induced in exposed to 1300 mg aspirin as a single dose versus jury of 3-30 days duration.20 In a study of 24 20 percent in the placebo group.29 Misoprostol patients, ranitidine (300 mg/day) reduced muco also significantly decreased fecal blood loss in 41 sal damage from aspirin (650 mg orally 4 times a patients enrolled in a placebo-controlled study day).21 Additionally, ranitidine (300 mg) retained who received aspirin (975 mg 4 times a day) for at its anti-ulcer efficacy in 15 patients with gastric least 2 weeks. 31 Nearly 60 percent (11/19) of the ulcer and 30 patients with duodenal ulcer: who patients treated with misoprostol had at least a 50 were taking carprofen (300 mg/day).22 In other percent reduction in blood loss, whereas only 1 of studies, however, cimetidine therapy did not im 22 patients receiving the placebo experienced http://www.jabfm.org/ prove the rate of healing of NSAID-induced gas such a reduction (P = 0.003).30 In 32 patients tric irritation better than the placebo.7.13 In an treated with naproxen (500 mg twice daily) con endoscopic study of 104 patients who used currently with either misoprostol (200 J,l.g) or the NSAIDs, 56 percent (22/43) receiving cimetidine placebo, the endoscopic score was 1.24 ± 0.09 (300 mg 4 times a day) and 52 percent (22/42) with the placebo and 0.2 ± 0.07 with misoprostol receiving the placebo showed worsening of endo (P < 0.001).31 Enthusiasm for the use of miso on 26 September 2021 by guest. Protected copyright. scopic lesions over an 8-week period.23 In another prostol, however, needs to be tempered, given the study, no statistical difference between cimeti recent finding that misoprostol reduced the steady dine and the placebo was found in the healing state plasma levels of indomethacin 20 to 60 per ratios in patients with gastroscopically proved cent by days 2 to 6 when administered concur peptic ulcers who were maintained on NSAID rently.32 Thus, misoprostol holds considerable therapy.7 Studies have yet to be published about promise for protecting the gastrointestinal mucosa the efficacy, if any, of famotidine and nizatidine from NSAID effects, but more study is needed. when given concurrently with NSAIDs. Because H2 antagonist therapy is not uniformly effective, Hematologic alternative therapy should be sought. NSAIDs inhibit platelet aggregation in varying Sucralfate, a polysaccharide, forms a barrier to degrees and prolong the bleeding time. This is acid by forming a complex with proteinaceous important both to patients planning elective sur exudate within gastric mucosa.24 When adminis- gery and those who develop gastric ulceration
NSAIDs 259 and hleeding. Two factors determine the time NSAI Ds, when used hy healthy patients, will J Am Board Fam Pract: first published as 10.3122/jabfm.2.4.257 on 1 October 1989. Downloaded from requin:d for hleeding to become normal follow not produce a significant change in renal func ing cessation of NSAI D usc: (1) half-life of the tion. \(,,17 IIowever, healthy persons treated NSAID, and (2) the nature of the binding to with diuretics or placed on low-sodium diets cyclo-oxygenase. Aspirin irreversih~y binds to come to rely upon prostaglandin-mediated vas cyclo-oxygenase; thus, new platelet produc odilatation of the renal vasculature to maintain tion, which requires 7 -12 days, will be required a normal glomerular filtration rate (CFR).3H before the bleeding time returns to normal. For This phenomenon may occur in any condition NSAI Ds revcrsih~y binding to cyclo-oxygenase, that compromises renal perfusion, such as vol the half-life of the agent is the main determi ume depletion (diuretic use, blood loss), heart nant, because antiplatelet effects last only as failure, cirrhosis, or atherosclerotic vascular long as there is an effective drug concentra- disease. Prostaglandin inhibition induced by tton.. P-,.. II I'• or exampI" e, piroxicam Ilas ala I It'- I't-1 e NSAI D therapy reverses this compensatory of approximately 50 hours, and five half-lives mechanism, resulting in renal vasoconstriction are required for it to decline to negligible levels with consequent diminution in GFR. Serum after discontinuation. Approximately 250 hours creatinine and urea nitrogen increase and oligu would be required before platelet effects are ria may result. Serum potassium increases and reversed. is often out of proportion to the increase in se Sulindac and ibuprofen have only transient rum creatinine because of NSAID inhibition of effects on platelet function. In some patients, the renin angiotensin system. 39 Patients with however, up to 24 hours is required for the systemic lupus erythematosus also depend on bleeding time to return to normal following ex the prostaglandins for renal vasodilatation, be posure to ibuprofen.ll Nonacetylated sal icy cause they have increased synthesis of the vaso lates, which have a negligible effect on platelet constrictor, thromboxane A2. 39,40 This vasocon function, are an alternative to NSAIDs for pa stricting effect is attenuated, however, by tients in whom platelet dysfunction must be chronic glomerular disease of Iupus nephritis.40 avoided. Table 2 lists the time required for Intrinsic vascular disease, such as long-stand platelet function to become normal following ing hypertension, diabetes mellitus, or athero use of various NSAIDs. sclerosis, may also predispose the patient to de pendence upon prostaglandin-mediated renal Renal vasodilatation.41 NSAIDs can affect the kidney adversely, pro All NSAIDs that inhibit renal cyclo-oxygenase http://www.jabfm.org/ ducing either nephrotic syndrome, acute inter will suppress prostaglandin-mediated vasodilata stitial nephritis, or tubular necrosis. Acute tion and result in adverse renal hemodynamics. interstitial nephritis can occur with or with When used at full anti-int1ammatory doses, out proteinuria. Fenoprofen is reportedly the NSAIDs reduce urinary prostaglandin excretion NSAID with the greatest nephrotoxicity, ac counting for 50 percent of the reports of on 26 September 2021 by guest. Protected copyright. nephrotic syndrome, 30 percent with acute tu Table 2. Time Required for Return of Normal Platelet Function bular necrosis, and 28 percent with acute inter Following Cessation of NSAIDs. stitial nephritis. H Episodes of renal insufficiency arc estimated at Time Required ti.r Return 1 per 1000 or more patient days of therapy for Drug to Normal Platelet Function each of the NSAIDs used. 3S The mean duration of NSAID therapy before development of renal Piroxicam 2 weeks Aspirin 7~12days insufficiency has been estimated at 4.2 days, Tolmetin 3 days while the time to return to baseline renal function Ibuprofen 24 hours after NSAID discontinuation is 5.3 days.35 The Indomethacin (ISO mgl 1H~32 hours rapidity of onset and resolution of renal insufti Indomethacin (35.5 mgl ]()"'12 hours Sulindac No appreciable effect ciency reflects alterations in renal hemodynamics Nonacet~'lated salicylatcs No appreciable effect during NSAID therapy.
260 JABFP Octobcr~[)ecember 1989 VoL 2 No, 4 by at least 50 percent, with a maximal reduction causes. The conditions for which the NSAID is J Am Board Fam Pract: first published as 10.3122/jabfm.2.4.257 on 1 October 1989. Downloaded from of 60-80 percent.40 The exception to this NSAID prescribed may themselves be associated with effect is sulindac. Renal oxidative enzymes ap liver involvement. Twenty-five to 50 percent of parently metabolize sulindac sulfide to the inac patients with rheumatoid arthritis not receiving tive prodrug sulindac sulfoxide as well as to the drug therapy have elevated serum alkaline inactive metabolite sulindac sulfone. The renal phosphatase.49-51 Of patients with SLE, 25 cortical sites of cyclo-oxygenase activity are percent may have jaundice, and 21 percent have thereby protected.42 Indomethacin reduces renal twofold elevations of liver function tests at synthesis of prostaglandins, as measured by uri some time in the course of their illness. 52 These nary prostaglandin excretion, by more than 50 effects may occur independently of NSAID percent, whereas sulindac spares renal prosta exposure. glandin synthesisY-45 Consequently, indometha Although liver toxicity is rare, it occurs to cin causes a tenfold greater frequency of renal some extent with nearly all NSAIDs.53 Benoxa insufficiency than does sulindac.41 profen; a member of the propionic acid family In view of other reports of compromised renal was withdrawn from the market worldwide in function associated with sulindac, its renal-spar 1982 after 60 fatalities were reported, many of ing effect is questioned. In patients with chronic which involved hepatotoxicity. 54 NSAIDs from renal failure, sulindac decreased urinary prosta the pyrazolone, indole, and propionic acid classes glandin E2 excretion by 47 percent.46 Moreover, (Table 1) are associated with the greatest number sulindac is not exempt from inducing immune of reports of adverse hepatic reactions. 5 3 Gener mediated renal diseases. 35 While sulindac appears ally, fewer than 5 percent of the adverse drug to be the least offensive NSAID in patients with reactions associated with currently available pro potential or established renal insufficiency, close pionic acids are hepatic in nature.53 monitoring is required regardless of which Hepatotoxicity, well recognized from phenyl NSAID is prescribed. butazone and oxyphenbutazone, is evenly dis I 53 Monitoring should focus on patients at increased tributed between men and women. • An exact risk. Risk factors include age greater than 60 years, frequency of hepatotoxicity has not been as diuretic use, gout, and atherosclerotic cardiovascu cribed to sulindac, and fewer than 5 percent of all lar disease.41 Other conditions, cited above, that adverse reactions associated with indomethacin 53 55 compromise renal hemodynamics would also pre are hepatic in nature. • No hepatotoxicity is dispose the patient to NSAID-induced renal insuf ascribed to tolmetin to date. 5 3 ficiency. A rapid rise in blood urea nitrogen Liver function tests (LFfs) may allow early http://www.jabfm.org/ (BUN), serum creatinine, and a transient increase detection of evolving hepatic injury due to in serum potassium or gain in body weight despite NSAIDtherapy. It has been suggested that test diuretic therapy may indicate evolving NSAID ing of alanine aminotransferase (ALT, SGPT) associated nephropathy, and NSAID therapy should be conducted every 6 weeks for patients should be discontinued.41 Renal recovery may oc taking sulindac or phenylbutazone,s 3 but this rec cur as early as 8-24 hours.41 ommendation is difficult to defend because pro on 26 September 2021 by guest. Protected copyright. All NSAIDs are excreted by the kidneys. Indo spective toxicity data are lacking. For agents with methacin and sulindac also undergo enterohepatic a lesser risk of hepatotoxicity (i.e., tolmetin, na recirculationY The extent to which the NSAIDs proxen, ibuprofen, and the fenamates), testing accumulate once renal insufficiency occurs or to should be conducted every 6 weeks during the what extent there is additional compromise of renal first 3 months of therapy. 53 Thereafter, testing function has not been detennined. It has been every 2-3 months, in the absence of elevated val shown that end-stage renal failure impairs the re ues, is recommended. 5 3 If an abnormality is de duction of sulindac to the active sulfide, while oxi tected but subsides or does not progress, therapy dation to the inactive sulfone remains intact.48 can be continued, although monthly evaluation is then recommended. If a test value exceeds 3 Hepatic times the upper limit of normal, or if symptoms Before assigning adverse hepatic effects to of liver disease develop, the NSAID should be NSAIDs, it is important to exclude other discontinued. 53 For patients with preexisting
NSAIDs 261 J Am Board Fam Pract: first published as 10.3122/jabfm.2.4.257 on 1 October 1989. Downloaded from liver disease and elevated LFTs, therapy with an Indomethicin > Aspirin> Ketoprofen NSAID may be initiated if the LFT elevation is Naproxen Ibuprofen less than twice the upper limit of normal. Fre Diclofenac quent monitoring (weekly or biweekly during the tirst month) should be initiated. If the abnormali Figure 2. Patient ranking of analgesic properties of NSAIDs. ties remain stable or resolve, therapy may be con tinued using the standard monitoring schedule. If the LFTs worsen, NSAID therapy should be dis ceived ketoprofen 20 mg/kg/day and developed continued. If the LFTs return to baseline, initiat headache, vomiting, bilateral abducens palsy, and ing NSAID therapy again with a drug from an papilledema.62 In both cases, pseudotumor cere other class may be considered. Piroxicam is a bri was attributed to water and sodium retention member of the oxicam family that appears to be caused by the NSAID. Both cases resolved 3-4 the least offensive to the liver and may be the weeks after discontinuation of the drug. preferred agent for patients who are predisposed to hepatotoxicity. Fenamates are also associated Uses of NSAIDs with a low frequency of liver toxicity. Members NSAIDs have found greater use for specific con of the pyrazolone, indole, and propionic classes ditions. It is doubtful, however, that this reflects should be avoided if possible. Large-scale retro a true difference in efficacy. In certain condi spective or prospective studies evaluating relative tions, a nonsteroidal agent is avoided because of hepatotoxicities of the NSAIDs are needed. interplay between adverse drug effects and the condition itself. The potential for interactions Central Nervous System with the NSAID and drugs used to treat a par All NSAIDs have the potential to produce ad ticular disease precludes the use of certain agents. verse effects on the central nervous system. Com The following discussion presents the rationale monly encountered are somnolence, dizziness, for these choices. tremor, confusion, depression, disorientation, in somnia, and headache. I Headaches are the result Rheumatoid Arthritis of NSAID-induced cerebral vasoconstriction; Few objective comparisons have been reported to they occur in greatest frequency with indometh help select NSAIDs for patients with rheumatoid acin and are dose related. When the total dose arthritis. When interpreting available studies, exceeds 100 mg/day, 50 percent of patients will close attention should be paid to study design http://www.jabfm.org/ experience headache. 56 Although sulindac is and assessment. Finding the right drug for a par structurally similar to indomethacin, it has far ticular patient is often a matter of trial and error, fewer central nervous system side effects. 15 Tol balancing efficacy with side effects. Each drug metin, a member of the indole class as well, also should be given a trial for a minimum of 2 weeks, has fewer CNS side effects. 57 Ibuprofen and na preferably 6 weeks, before selecting another proxen are rarely associated with headache. NSAID.63
Aseptic meningitis, an uncommon complica In the United States, no study exists that com on 26 September 2021 by guest. Protected copyright. tion, is associated with tolmetin, sulindac, and ibu pares objectively all NSAIDs used to treat rheu 5H 6o profen. - Most cases of ibuprofen-associated matoid arthritis. One study, conducted in Fin aseptic meningitis are in patients with SLE. 5H land in 1984, of patients with rheumatoid Progression from onset of headache to meningi arthritis ranked various NSAIDs in terms of sub 5H tis-like symptoms may occur within 48 hours. jective pain relief, as opposed to anti-inflamma A hypersensitivity mechanism has been proposed tory effects, which usually require higher doses. as the causative factor. Figure 2 lists the results of that ranking.64 The Pseudotumor cerebri may develop with study had a small number of patients, used sub NSAID-use in patients with the Bartter syn jective analysis, and must be viewed cautiously. 61 drome. ,('2 Bilateral abducens palsy and papille The results cannot be extrapolated to other con dema were observed in a lO-year-old girl who ditions such as osteoarthritis. received indomethacin, 75 mg/day.61 A 7-year In a second study, aspirin, indomethacin, na old patient, also with the Bartter syndrome, re- proxen, fenoprofen, ibuprofen, and tolmetin were
262 JABFP October-December 19W) Vol. 2 No.4 equally effective in the treatment of rheumatoid excellent responses encountered in 75 to 90 per J Am Board Fam Pract: first published as 10.3122/jabfm.2.4.257 on 1 October 1989. Downloaded from arthritis.65 Efficacy was also comparable between cent of patients.77 High doses are usually given naproxen (250 mg twice daily), naproxen (500 mg for the first 48 hours of therapy, followed by re at bedtime), and indomethacin (25 mg 4 times a duction to a maintenance level of approximately day).66 Naproxen was, however, better tolerated half the initial dose. 77 For acute gout, naproxen than indomethacin. is usually given in a loading dose (750 mg) fol Ketoprofen, 200 mg/day, was compared in a lowed by 250 mg every 8 hours until the attack third study with ibuprofen, 1200 mg/day, in pa subsides. Sloan78 reported that phenylbutazone tients with rheumatoid arthritis.67 The authors and indomethacin are the superior NSAIDs for concluded that ketoprofen is significantly better acute gout and for the management of chronic than ibuprofen for pain on pressure and move gouty arthropathy. Phenylbutazone is given ment, night pain, pain at walking, and the inflam initially (400-600 mg/day) and then tapered mation index. While the dose used for ibuprofen over the following 7 days.78 Its use is limited by had analgesic effects, it was not optimal for coun its assoCiated blood dyscrasias. Indomethacin is tering inflammation. Thus, these results must prescribed for gout (l00-200 mg/day) using also be interpreted with caution. doses in the upper end of the range during the first 24 hours. 78 A trial comparing all of the Osteoartbritls NSAIDs for use in acute gout and gouty arthri Indomethacin is purported to provide the greatest tis is lacking. relief for osteoarthritis of the hip,68 with other os teoarthritic joints treated with indomethacin not as Analgesia responsive.68 Studies comparing indomethacin NSAIDs are frequently prescribed for nonar with naproxen (250 mg twice daily), isoxicam (200 thritic musculoskeletal pain syndromes, dental mglday*), and ketoprofen (25 mg 4 times a day), pain, or following mild trauma. In these in however, found these medications to be equal in stances, agents such as naproxen or ibuprofen efficacy, but the latter three had fewer side effects should be considered because of their perceived than indomethacin.69-71 Again, selection should be greater analgesic properties (Figure 2) and short based on what is effective for the individual patient half-life. and the side-effect profile of the NSAID. Dysmenorrbea Ankylosing Spondylitis Not all NSAIDs are marketed for dysmenorrhea, Indomethacin is the standard reference drug in but by virtue of their ability to inhibit prostaglan http://www.jabfm.org/ NSAID trials for ankylosing spondylitis and is din synthesis, all possess a pharmacologic basis associated with 90 percent efficacy.72 Diclofenac for efficacy. NSAIDs are associated with a re and tolmetin are equally efficacious with fewer sponse rate of 84 percent in patients with dys side effects. 72-7 5 The slow release formulation of menorrhea.79 Comparative studies do not show indomethacin, however, maintains effectiveness one agent to be superior to another.s Selection 76 while decreasing side effects. . . should be based on the side-effect profile and on 26 September 2021 by guest. Protected copyright. To date, only one trial has compared a group of number of doses per day. Naproxen and na NSAIDs for the treatment of ankylosing spondyli proxen sodium are widely accepted due to their tis. Indomethacin, naproxen, and fenoprofen are efficacy and enhanced compliance because of 65 superior to aspirin, ibuprofen, and tolmetin. The twice daily doses.5,8o-83 Therapy may be started determinants of these differences are unknown, but 1-2 days before onset and continued through the results may be helpful when selecting a drug. menses,5 or alternatively, one may wait until the first symptom of dysmenorrhea to begin NSAID Gout therapy.81 Most NSAIDs have the same degree of effective ness in treating symptoms of gout with good-to- Headache Syndromes Naproxen and aspirin are preferred for the treat ment of muscle contraction headache, whereas *Investigational in the United States. indomethacin should be avoided.1!4,85 Indometha-
NSAIDs 263 cin, which is chemically similar to serotonin, can Until Illore comparative data arc available re J Am Board Fam Pract: first published as 10.3122/jabfm.2.4.257 on 1 October 1989. Downloaded from produce severe headache by virtue of its ability to garding NSAI [) usc in diabetic neuropathy, it is H act as a direct vasoconstrictor. -+ Aspirin and na not possible to determine which NSAID is most proxell are completely devoid of such actions on effective for this indication. Sulindac, with its fa cerebral vasculature. H-+ vorable results in diabetic neuropathy, combined III contrast, indomethacin is the drug of choice with its renal-sparing effects, should be the first for chronic paroxysmal hemicnlnia and hemi- NSAID considered. However, the first approach crania• contlllua.• H(,-<)() ('I',1rOJllC paroxysma I I1eml- . to therapy should be directed at optimizing con crania, characterii'.ed by daily headaches with an trol of hyperglycemia. Initial treatment with tri attack frequency of greater than 15 episodes per cyclic antidepressants (e.g., amitriptyline) or 24 hours, is aborted by indomethacin.C)() A re phenytoin may be considered because there is sponse to 25 mg of oral indomethacin may occur greater experience with these agents. w within 2 hours after the first dose. , Continuous therapy is usually required, because remissions Porphyria have been reported.H7 Hemicrania continua, which Reports of acute porphyria are associated with keto differs from chronic paroxysmal hemicrania in its profen, phenylbutazone, and diclofenac.9H NSAIDs pain pattern, absence of pupil changes, and other considered safe for use in patients at risk for por accompanying symptoms, also responds dramati phyria include indomethacin, mefenamic acid, ibu cally to indomethacin.KH-
Diabetic Neuropathy decreased lithium excretion by 23 percent with a on 26 September 2021 by guest. Protected copyright. The discovery of aldose reductase inhibiting 40 percent increase in blood levels. )()) Diclofenac properties of NSAIDs has led to interest in their increased in blood levels by 20 percent, while usc to treat peripheral neuropathy associated ibuprofen was associated with 50 percent in with diabetes mellitus.')S-97 It has been proposed crease. )IH, )()S The effect of ibuprofen, however, on that inhibition of aldose reductase may facilitate lithium concentration is inconsistent. )()3, )IH This nerve conduction and decrease neuropathic pain. is in contrast to aspirin, which increased lithium In one study enrolling 18 men outpatients, sulindac excretion only 6 percent and had no effect on
(200 mg twice daily) was more effective than ibu blood levels. )()2 Sulindac also had a lithium-spar profen (600 mg 4 times a day) for moderate pain.')? ing effect, causing a transient decrease in blood Combined use with investigational aldose reduc levels, which returned to baseline without dosage tase inhibitors, sorbinil or tolrenstat, would be of adjustments. )()r. If NSAID therapy must be initi interest for treatment of severe diabetic neuropathy atcd in a patient receiving lithium therapy, sui in where NSAID therapy alone is ineffective. dac or aspirin should be considered.
264 JABFP October-December I'lH<) Vol. 2 No.4 NSAIDs may antagonize blood pressure and pressure. Consequently, of the NSAIDs studied, J Am Board Fam Pract: first published as 10.3122/jabfm.2.4.257 on 1 October 1989. Downloaded from lower the effects of antihypertensive medica sulindac appears to be the least offensive to the tions. 107 Antihypertensive effects of propranolol hypertensive patient, but close monitoring of and pindolol were decreased or abolished during blood pressure is still warranted. If, however, a lO-day period by indomethacin. 108 The pressor other NSAIDs are used, it is possible that, with effect of NSAIDs is primarily related to renal continued therapy, the pressor effects will dimin cyclo-oxygenase inhibition and renal retention of ish. Additional long-term studies concerning the 107 109 sodium. - Indomethacin, which caused a 78 pressor effects of NSAIDs, and interactions with percent reduction in PGE2 excretion, was associ antihypertensive agents, are needed. ated with increased blood pressure (11 mmHg There are reports of increased toxicity when systolic and 4 mmHg diastolic) by the end of the methotrexate is coadministered with NSAIDs. 112 first week of therapy. In contrast, sulindac, which Phenylbutazone, oxyphenbutazone, indometha did not cause reduction in PGE2 excretion, pro cin, ketoprofeo and naproxen are all implicated. duced a fall in blood pressure similar to that seen Methotrexate clearance decreased by two-thirds with patients treated with a placebo. l07 Ibupro as a result of combination therapy with fen, in doses as high as 2400 mg/day for up to 7 NSAIDs. 112 Considering the increased use of days in healthy persons had no effect on blood methotrexate for refractory rheumatoid arthritis, pressure. 110 In a dose of 100 mg/day in hyperten there is greater opportunity for this interaction. sive patients, however, ibuprofen significantly in Coadministration of NSAIDs with methotrexate creased blood pressure. III It was suggested that a warrants extreme caution and close monitoring threshold of prostaglandin inhibition must be because the interactions may be fatal. 113 achieved before the pressor effect is seen. Thus, the pressor effect of the potent PG inhibitor, in Cost and Adherence domethacin, is readily noted clinically, while su Once the issues of efficacy, tOXICIty, and drug lindac in normal doses exerts minimal, if any, interactions are considered, cost and adherence pressor effect. Blood pressure elevation with in to a regimen should be reviewed. Table 3 lists the domethacin was maximum at day 7 but ap average minimum anti-inflammatory dosage and proached baseline by day 28 despite continued the cost of therapy per month for brand-name therapy. I 07 Apparently, compensatory mecha NSAIDs. Where available, the cost of the generic nisms attentuate sustained elevations of blood medication is also tabulated. There are no data to http://www.jabfm.org/
Table 3. Monthly Cost Comparisons for Average Daily NSAID Doses.
Cost of Cost of Average Minimum Anti- Brand-Name Product Generic Product Generic Name Brand Name Inflammatory Daily Dosage Per Month* Per Month* on 26 September 2021 by guest. Protected copyright. Ibuprofen Motrin 400 mg qid $22.60 $8.25 Naproxen sodium Anaprox 275 mg bid $31.02 NA Tolmetin Tolectin 200 mg tid $31.39 NA Meclofenamate Meclomen 100 mg bid $31.81 $26.40 Naproxen Naprosyn 250 mg bid $32.03 NA Ketoprofen Orudis 75 mg bid $32.67 NA Fenoprofen Nalfon 300 mg tid $32.85 NA Indomethacin Indocin 25 mg tid $35.67 $6.30 Phenylbutazone Burwlidin 100 mg tid $37.48 $6.08 Sulindac CHnoril 150 mg bid $41.65 NA Piroxicam Feldene 20 mgd $42.30 NA Indomethicin; sustained Indocin SR 75 mg bid $57.34 $43.13 release
'AWP = Average wholesale price hased on Redhook Drug Topics 1988. This is the cost to the pharmacy; prices charged to the patient will vary markedly. NA = Drug not availahle in generic formulation.
NSAIDs 265 indicatc that FDA-approved generic formula tivity between sulinLiac and aspIrIn. Sodium or J Am Board Fam Pract: first published as 10.3122/jabfm.2.4.257 on 1 October 1989. Downloaded from tions are inferior to brand-name products. choline salicylate may be tried in these patients Determinants of adherence to a therapeutic with caution and close monitoring. It is believed regimen include cost and dosing frequency. that among the salicylates, the reaction is specific Once-daily administration, as with piroxicam, for acetylsalicylic acid and not the metabolite (so may be more acceptable than ibuprofen, which is dium salicylate). I 14 administered -+ times daily. Products adminis For patients who develop urticaria upon ex tered twice daily are well accepted and should he posure to aspirin, an immunological mechanism considered for patients who require a simpler is probably involved, IJ(., 117 and all salicylates reg"nen. should he avoided. It is thought that the salicylate radical Of its metabolite is responsible for the im Allergy munological response. I 1(, There is no cross-reac Once a patient shows an allergy to an agent, fur tivity with the structurally dissimilar NSAIDs, thtT use of that drug or other NSAI Ds is con but it is prudent to avoid their use until more traindicated. Methods of oral challenge are avail definite data are available. able to confirm hypersensitivity. I H There is a high degree of "cross-sensitivity" Summary between aspirin and NSAIDs in patients who The NSAIDs, though similar in pharmacology, have symptoms of rhinitis or asthma. 114, lIS The differ in their side effects, indications for use, degree of sensitivity correlates with the prosta potential for drug interactions, and effects upon glandin inhibition potency and appears to be a associated illnesses. The physician should be pharmacologic effect rather than an immunologic come familiar with the use of a few, selected response, 114 In one study, asthmatic patients who NSAI Ds. Members of the pyrazolone (e.g., phe were aspirin sensitive were sensitive to indo nylbutazone) and fenamate families (e.g., mec methacin, fenoprofen, naproxen, and tolmetin. 114 lofenamate) Crable 1) should rarely be used be A single case report showed a similar cross-sensi- cause of side effects. Selection from the remain-
Table 4. Conditions and Drug Characteristics that Might Influence the Choice of an NSAID.
(;, ,nsiderations Comments http://www.jabfm.org/
(;astTointestinal inrolcrance Select ihuprofen or perhaps sulindac; when used in comparahle doses, NSAI Ds diller mini Illally in (;1 s\"lllptoms Platekt function Select s\\lindac, ihuprokn or nonacetylated salicylates; avoid aspirin Renal function Sulindac is the preferred agent hilt monitor ciosely in patients with chronic renal insulli- cienn'; 'l\"oid indoillethacin Ilcpatotoxicin' Piroxic;m or a fenalllate is prderred; avoid members of pynu.olone, indole, or propionic ciasses
1le'ldachc, Illllscle conrraction Ibllprofen, aspirin. or naproxen arc preferred; avoid indomethacin on 26 September 2021 by guest. Protected copyright. Ilead'Khe, chronic paroxyslllal IIHicllllethacin is the drug of choice or helnicrania cOlltinia i{llellmatoid arthritis NSAIDs appear to be eqllally dlicKimlS; base selection on side-elfect profile and patient C<)(l~i(tcrati(H1s ( htl'Oarthritis NS,\IDs appear to he eqllallv dlicacious; base selection on side-dkct profile and patienr cc'nsiderati'lIls :\nhlosing spondylitis I ndoillethacin, naproxen, and fcnoproten arc the preferred agents { ;olll COlllparative d'lta arc lacking; indomethacin, phenylhutawne, and naproxcn have been IIsed successflllh' ;\nalgesia Naproxen or'illliproten is prelerred 1)vsmenorrhea ,\11 NS:\IDs possess the pharmacologic basis till' dncacy'; naproxen is widely IIsed 1)iabetic neuropath\' Sulindac 111<1\' be the preferred NSAID; Illore stlldy in this area is needed Porphyria Preferred agents arc ihuprofen, sulindac, naproxcn, tenoprofcn, indomethacin, and mdimamic acid; amid ketoproten, phenylhutazone, and diciofenac I.ithiulll Aspirin or slliindac is prderrcd; 'l\"oid indolllethacin or dicIofcnac .\nrih\'l,crtcnsives Fttectiveness of antihypertensi\'es attenuated hy concolllirranr NSf\ID rherap" during the tirst month; compensatory mecilanislllS may allC\'iate untoward interactions .\ kth, ,trexarc ,\void NS.\IDs if possihle; co-administration may result in methotrexate toxicity
2M, JABFP Octohcr-Ikcemher 19H') Vol. 2 No.4 J Am Board Fam Pract: first published as 10.3122/jabfm.2.4.257 on 1 October 1989. Downloaded from ing classes should be based on adverse effects, References potential for drug interactions, cost, and dosing 1. Corre KA. Nonsteroidal anti-inflammatory drugs. frequency. Efficacy is rarely at issue, as individ Top Emerg Med 1986; 8:12-25. ual variability, rather than pharmacology, is usu 2. Flower RJ, Moncada S, Vane JR. Analgesic-antipy ally the basis for the variance. If one drug does retics and anti-inflammatory agents. In: Gilman not prove efficacious after 1-3 weeks at the maxi AG, Goodman LS, Rail TH, Murat F, eds. The mally tolerated dose, another agent should be pharmacologic basis of therapeutics. 7th cd. New York: MacMillan Publishing Company, 1985: substituted. I A favorable response from a mem 690-704. ber of the same NSAID class is not precluded. I IS 3. Serafin WE, Austen KF. Mediators of immediate There is no proved advantage to using more than hypersensitivity reactions. N Engl J Med 1987; one NSAID at a time unless a rapid onset of 317:30-4. action is needed. I Table 4 presents a synopsis of 4. Lundstrom V, Green K, Svanborg K. Endogenous pertinent conditions and characteristics for prostaglandins in dysmenorrhea and the effect of choosing NSAIDs. prostaglandin synthetase (PGSI) inhibitors on For patients with gastric intolerance to one uterine contractility. Acta Obstet Gynecol Scand NSAID, alternative therapy from another class 1979; 87(Suppl):51-6. should be considered. If unsuccessful, therapy 5. Furniss LD. Nonsteroidal anti-inflammatory with choline magnesium trisalicylate (Trili agents in the treatment of primary dysmenorrhea. sate TM), salsalate (Discalcid TM), or enteric-coated Clin Pharm 1982; 1:327-33. aspirin may prove useful. The addition of sucral 6. Goodwin JS. Mechanism of action of nonsteroidal fate to the regimen may prove helpful, but cost anti-inflammatory agents. Am ] Med 1984; 13: 57-64. and efficacy issues have yet to be completely re 7. Davies], Collins A], Dixon A. The influence of solved. When adverse effects of NSAIDs on cimetidine on peptic ulcer in patients with arthritis platelets are of concern, sulindac or ibuprofen taking anti-inflammatory drugs. Br ] Rheumatol should be considered, with nonacetylated sal icy 1986; 25:54-8. lates as alternatives. If renal function is compro 8. Rainsford KD. The biochemical pathology of aspi mised, avoid NSAIDs, especially fenoprofen if rin-induced gastric damage. Agents Actions 1975; possible; sulindac is perhaps the least offensive 5:326-44. agent, but close monitoring should be instituted. 9. Flemstrom G. Active alkalinization by amphibian Piroxicam is presently the NSAID of choice gastric fundic mucosa in vitro. Am] PhysioI1977; where potential for hepatotoxicity exists. Fena 233:EI-12. http://www.jabfm.org/ mates may be considered as alternatives. When 10. Kaufmann H], Taubin HL. Nonsteroidal anti-in central nervous system side effects such as head flammatory drugs activate quiescent inflammatory bowel disease. Ann Intern Med 1987; 107:513-6. ache occur, aspirin or naproxen may be used. For 11. Rampton DS, McNeil NI, Sarner M. Analgesic in patients taking lithium, sulindac is preferred, and gestion and other factors preceding relapse in ulcer indomethacin should be avoided. In hypertensive ative colitis. Gut 1983; 24:187-9. patients, blood pressure control may be dimin 12. Walt RP, Hawkey Cj, Langman M]. Colitis associ ished, or lost, during the first week of NSAID ated with non-steroidal anti-inflammatory drugs. on 26 September 2021 by guest. Protected copyright. therapy. Pressor effects may be minimized by Br Med] 1984; 288:238. prescribing sulindac and avoiding indomethacin. 13. Carson ]L, Strom BL, Morse ML, et al. The relative It would be prudent to avoid all NSAIDs in pa gastrointestinal toxicity of the nonsteroidal anti tients taking methotrexate until a particular inflammatory drugs. Arch Intern Med 1987; 147: NSAID has been proved consistently safe. For 1054-9. patients thought to be allergic to NSAIDs, fur 14. Blechman W], Lechner BL. Clinical comparative ther questioning as to the nature of the reaction evaluation of choline magnesium trisalcylate and acetylsalicylic acid in rheumatoid arthritis. Rheum (rhinitis and asthma versus urticaria) must be Rehabil 1979; 18: 119-24. pursued before determining if therapy with an 15. Simon LS, Mills ]A. Nonsteroidal antiinflamma other NSAID would be appropriate. tory drugs (second of two parts). N Engl ] Med The helpful reviews of Christine Matson, M.D., and 1980; 302:1237-43. Michael Noel, M.D., Department of Family Medicine, 16. Semble EL, Wu We. NSAID-induced gastric mu Baylor College of Medicine, are gratefully acknowledged. cosal damage. Am Fam Physician 1987; 35:101-8.
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This year marks the twentieth anniversary of the American Board of Family Practice 1969-1989
"Twenty Years of Commitment to Family Practice" http://www.jabfm.org/
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