Evaluations on New Drugs Drugs 9: 326-363 (1975)
Naproxen: A Review of its Pharmacological Properties and Therapeutic Efficacy and Use R.N. Brogden, R.M. Pinder, Phyllis R. Sawyer, T.M. Speight and G.S. Avery Australasian Drug Information Services, Auckland Manuscript reviewed by: B.M Ansell, MRC, Rheumatism Unit, Canadian Red Cross Memorial Hospital, Maidenhead, England; F.D. Hart, Rheumatism Clinic, Westminster Hospital, London, England; HoF.H. Hill, Oxford Regional Rheumatic Diseases Research Centre, Stoke Mandeville Hospital, Aylesbury, England; R. Go Robinson, North Shore Medical Centre, Sydney, Australia; B.S. Rose, Rheumatologist, Waikato Hospital, Hamilton, New Zealand; J. Ruedy, Division of Clinical Pharmacology, Montreal General Hospital, Montreal, Canada; J.Bo Stetson, Department of Anaesthesiology, School of Medicine and Dentistry, University of Rochester, New York, USA
Table of Contents Summary . 1. Animal Pharmacology 1.1 Pharmacodynamic Studies . 1.1.1 Anti-Inflammatory Activity 1.1.2 Analgesic Activity 1.1.3 Antipyretic Activity 1.1.4 Immunological Effects 1.1.5 Effect on Gastric Mucosa 1.1.6 Other Effects 1.1.7 Mode of Action 1.2 Animal Pharmacokinetics 1.2.1 Absorption 1.2.2 Distribution 1.2.3 Metabolism and Excretion 2. Human Pharmacodynamics 2.1 Effect on Collagen Metabolism 2.2 Effect on Gastric Mucosa and Blood Loss 2.3 Effect on Bleeding Time and Platelet Aggregation 3. Human Pharmacokinetics '" 3.1 Absorption 3.1.1 Effect of Food on Absorption . . • . . . . . . . . . . . . . . . . . . . . 3.1.2 Bioavailability 0
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327 330 330 330 331 331 332 332 333 333 334 334 334 335 335 335 335 336 338 338 338 339
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3.1.3 Effect on Absorption of Antacids 339 3.1.4 Plasma Half-Life 340 3.2 Plasma Protein Binding 341 341 3.3 Placental Transfer, Breast Milk 3.4 Metabolism and Excretion 341 4. Therapeutic Trials 342 4.1 Rheumatoid Arthritis 342 4.1.1 Open Studies - Short-term 342 4.1.2 Long-term Open Studies 343 4.1.3 Long-term Studies in Patients with Gastro-Intestinal disease and/or Intolerance of Other Antirheumatic Drugs . . . . . . . . . . . . . . . . . . . . 345 4.1.4 Placebo-Controlled Trials 345 4.1.5 Naproxen versus Aspirin 347 4.1.6 Naproxen plus Aspirin 348 4.1. 7 Naproxen Compared with Indomethacin 349 4.1.8 Comparison with Fenoprofen and Ibuprofen 349 4.1.9 Comparison with Flufenamic Acid 351 4.2 Ankylosing Spondylitis 351 4.3 Degenerative Joint Disease 352 4.4 Gout ' 354 4.5 Pain States . . . . . . . . . . . . . . . . . . . . . . . . . 355 5. Side-Effects 357 5.1 Gastro-Intestinal Side-Effects 358 5.2 Central Nervous System and Autonomic Effects 358 5.3 Other Side-Effects 359 6. Drug Interactions 359 7. Precautions 360 8. Dosage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
Key words' Summary Ankylosing spondylitis Synopsis: Naproxen", (+)-6-methoxY-et-methyl-2-naphthaAnti-inflammatory agents lene acetic acid, is a new non-steroidal anti-inflammatory agent advocated for use in rheumatoid arthritis, degenerative joint Aspirin Gastro-intestinal irritation disease and anleylosing spondylitis. Gout Published data suggest that in rheumatoid arthritis, naproxen 500mg daily is comparable in efficacy with moderate Indomethacin doses of aspirin (3.6 to 4g daily) or 150mg daily of indo- Naproxen methacin, but generally causes fewer and milder side-effects Osteoarthrosis than these drugs at the dOSllges used and can be given less Rheumatoid arthritis frequently (12-hourly). Encouraging initial results have been reported from its use in other inflammatory joint disorders, including acute gout and juvenile rheumatoid arthritis. It has compared favourably with indomethacin in osteoarthrosis of the hip or knee. Its exact place in the management of ankylosing spondylitis remains to be determined. 1 See subject index in each issue for further indexing terms. 2 'Naprosyn'; 'Naprosine'; 'Naxen'; 'Proxen'; 'Synaxsyn' (Syntex).
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Experimental studies in healthy subjects and open trials in patients intolerant of other non-steroidal anti-inflammatory agents suggest that naproxen causes less upper gastrointestinal irritation and bleeding than aspirin. However, gastro-intestinal bleeding associated with the use ofnaproxen has been reported occasionally since its wider use, but it is still too early to determine the incidence and risk of gastro-intestinal bleeding with naproxen relative to that with non-steroidal anti-inflammatory agents other than aspirin. Side-effects have generally been mild and have mostly involved the upper gastro-intestinal tract (abdominal pain, indigestion) and the central nervous system (headache, lightheadedness, drowsiness). Animal studies have demonstrated that oral naproxen possesses dose-related antiinflammatory, analgesic and antipyretic activity which was greater than that of phenylbutazone and aspirin, and equal to or less than that of indomethacin. Naproxen inhibited carrageenin-induced paw oedema, and granuloma tissue formation following cotton pellet implantation in both intact and in adrenalectomised rats. The analgesic potency of oral naproxen relative to that of other non-steroidal anti-inflammatory agents has varied with the method used to induce pain, but was greater than that of phenylbutazone and aspirin in all tests but less than that of indomethacin. Naproxen has an eroding effect on the gastric mucosa of starved rats. Like indomethacin, phenylbutazone and mefenamic acid, but unlike aspirin, naproxen caused gastric erosion when given either orally or subcutaneously. Thus, it seems that aspirin-induced gastric lesions result from a direct topical effect, whereas naproxen and the other drugs in the same therapeutic class exert a general systemic effect as well as a topical effect. The mode of action of naproxen is not clear, but it seems to exert a direct action not mediated through the release of endogenous corticosteroids from adrenal tissue or other sites. There is evidence that naproxen, like aspirin and indomethacin, inhibits prostaglandin biosynthesis in vitro and in vivo in rats, and it is possible that its anti-inflammatory activity may be related to its ability to inhibit synthesis of prostaglandins; substances which are involved in inflammation and have been implicated in pyresis and pain. In animals, as in man (vide infra) naproxen is completely absorbed after oral administration, and is widely distributed in the body tissues of rats. In all animals tested, except the dog, the great majority of an ingested dose is excreted in the urine. Human Pharmacology: Naproxen has been shown to reduce the urinary excretion of 4 hydroxyproline in patients with inflammatory joint disease. It has been postulated that changes in the blood and urinary concentration of this amino acid reflect the metabolism of collagen and that the variations in the amino acid levels can be used as an indication of a drug's anti-inflammatory effect. Effective treatment of collagen diseases is also thought to result in a decrease in urinary hydroxyproline. It appears that naproxen has less adverse effect on the human gastric mucosa and causes less gastro-intestinal blood loss than aspirin, when either drug is given at dosages similar to those used in the treatment of rheumatic disorders. To date there have been no comparisons of the effects on the upper gastro-intestinal tract of naproxen and enteric coated aspirin or aloxiprin, two widely used alternatives to ordinary aspirin in rheumatic disorders. Gastro-intestinal bleeding has been reported recently in a few cases, but it is too early to determine the incidence and risk of gastro-intestinal bleeding during long-term administration, relative to that with other non-steroidal anti-inflammatory agents. Like aspirin, naproxen prolongs the bleeding time in healthy subjects but appears to have a different action on platelets. Open studies, and cross-over studies with oral and intravenous naproxen in very small numbers of subjects, suggest that naproxen is essentially completelyabsorbed. Plasma levels
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rise proportionately with dosage until a single dose of 500mg is reached, but rise more slowly at higher dose levels as a result of an increased renal clearance rate at high doses and possibly an increased rate of distribution into tissues. Absorption of naproxen is not adversely affected by the presence of food, or by the concomitant administration of commercial magnesium aluminium hydroxide gel or sodium bicarbonate. On the other hand, absorption of naproxen is clearly reduced by the concomitant use of the antacids magnesium oxide and aluminium hydroxide. Its plasma half-life of 12 to 15 hours, make it suitable for twice daily administration. At plasma levels attained after usual therapeutic doses, naproxen is highly bound to plasma protein, only about 0.4% being in the free unbound form. The free fraction rises as plasma concentrations rise and appears responsible for the plateau effect with increasing doses. Nearly all of the ingested dose is excreted in the urine. 70% of an oral or intravenous dose of naproxen is excreted either as the unchanged drug or largely as conjugated naproxen. Therapeutic trials: Results of controlled studies in which naproxen has been compared with aspirin, indomethacin and placebo, have demonstrated the efficacy of naproxen in rheumatoid arthritis, ankylosing spondylitis, degenerative joint diseases, acute gout, and in acute moderate pain states. Naproxen 500mg daily has generally provided symptomatic relief statistically indistinguishable from that obtained with aspirin 3.6 to 4g daily or with indomethacin l50mg daily and superior to that provided by placebo, buprofen or fenoprofen. Although it is possible that naproxen and aspirin or indomethacin were in fact equally efficacious at the dosages chosen, it is also possible that no difference could be detected because there were insufficient numbers of patients in the trials to detect differences between drugs expected to produce a similar effect. Side-effects have usually been less frequent with naproxen than with aspirin or indomethacin. Clinical impressions gained during long-term open studies in patients with definite or classical rheumatoid arthritis, are that in many patients signs and symptoms continued to regress during treatment. Long-term open studies in patients with rheumatoid arthritis who had upper gastro-intestinal tract disease and/or were intolerant of other commonly used non-steroidal anti-inflammatory agents, indicated that naproxen was well tolerated by over half of these patients. Although pharmacological studies have shown that the simultaneous administration of aspirin and naproxen may result in lower than expected serum levels of naproxen, this appears to be of little clinical significance. The efficacy of combined aspirin and naproxen therapy is greater than that of aspirin alone. In an open trial in patients with ankylosing spondylitis an increasing proportion were symptom-free or experienced only mild symptoms over a period of 6 months' treatment with naproxen 500mg daily, and morning stiffness and the time of onset of immobility stiffness were significantly reduced. Suppositories of naproxen (500mg) are effective in alleviating night pain in ankylosing spondylitis. However, the exact place of naproxen relative to that of other non-steroidal anti-inflammatory agents in the management of ankylosing spondylitis has yet to be determined. Comparative studies have shown naproxen 400 to 600mg to be well tolerated in patients with osteoarthrosis of the hip and knee and to produce improvement indistinguishable from that obtained with indomethacin 100mg daily and superior to that obtained with aluminium flufenamate 750mg daily or placebo. Double-blind studies have demonstrated that naproxen in daily doses of 400mg to 750mg can reduce the need for oral corticosteroids in some patients with rheumatoid arthritis receiving stabilised minimum maintenance doses of systemic steroids. Initial results with naproxen in acute gout have been favourable, but further studies will be necessary to determine the best dosage regimen and the pattern of response of
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330
repeated episodes. It appeared that best results were obtained when a loading dose of 750mg was used followed by 250mg 8-hourly for 72 hours before tapering the dose. Initial results with naproxen in pain states have shown naproxen to be an effective analgesic in patients with moderate pain resulting from orthopaedic, dental and other surgical procedures. A single dose of naproxen 400mg was thought to provide analgesia between that of single oral doses of 75 or 150mg of pethidine. Greater analgesia is obtained with naproxen 600mg than with a dose of 400mg. At dosages used in the treatment of rheumatic diseases naproxen has generally been well tolerated during both long-term and short-term studies. Gastro-intestinal effects such as indigestion, abdominal discomfort and pain, nausea, vomiting and heartburn, and central nervous system effects such as headache, vertigo or light-headedness and drowsiness have been reported most frequently. These latter effects have generally been less frequent with naproxen than with indomethacin. As naproxen is highly bound to plasma protein, it has a potential for interaction with other albumin-bound drugs such as warfarin, sulphonylureas, hydantoins and aspirin. Although naproxen has been well tolerated by some patients exhibiting dyspepsia with other non-steroidal anti-inflammatory agents, episodes of gastro-intestinal bleeding have been reported and naproxen should be given with caution in patients with a known or suspected history of upper gastro-intestinal disease. The usual starting dose, and maintenance dose, of naproxen is 250mg twice daily.
1. Animal Pharmacology
1.1 Pharmacodynamic Studies Early studies of the anti-inflammatory activity of various non-nitrogenous compounds including substituted 2-naphthy1acetic acids and derivatives (Harrison et al., 1970) indicated that naproxen, the dextrorotatory isomer of (+)-6-methoxy-a-methyl-2-naphthalene acetic acid (fig. 1) was amongst the most potent, on a weight for weight basis, of those tested (Harrison et al., 1970, 1973). Subsequent studies in rats and mice demonstrated that naproxen possessed dose-related anti-inflammatory, analgesic and antipyretic potency which was generally equal to or less than that of indomethacin, but always greater than that of phenylbutazone or aspirin (table I) (Roszkowski et al., 1971, 1973;Rooksetal., 1973;Ozawaetal., 1972b). 1.1.1 Anti-Inflammatory Activity Inflammation induced in the hind paw of rats by injection of carrageenin, was inhibited by prior administration of oral naproxen (Ozawa et al., 1972a; Rooks et al., 1973; Roszkowski et al., 1971). The relative potency ofnaproxen in inhibiting the oedema was 11 times that of phenylbutazone (see table I). Although Ozawa et al. (1972a) found naproxen to be more effective than indomethacin, other investigators found indomethacin to be the more active drug.
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Naproxen was also shown to be effective in reducing the formation of granuloma tissue following the subcutaneous implantation of carrageenin impregnated cotton pellets in rats (Ozawa et al., 1972a; Roszkowski et al., 1971; Rooks et al., 1973). In this regard, naproxen was equal in potency to hydrocortisone, more active than mefenamic acid or phenylbutazone, and less active than indomethacin. In adrenalectomised rats oral naproxen inhibited granuloma tissue formation without exhibiting a thymolytic effect like the corticosteroids (Rooks et al., 1973; Roszkowski et al., 1971). A topical anti-inflammatory effect was also demonstrated when 2mg of naproxen was added to an inflammationinducing vehicle which was applied to the ear of rats.
1.1.2 AnalgesicActivity The analgesic potency of oral naproxen relative to that of other nonsteroidal anti-inflammatory agents tested, varied with the method used to induce pain. Naproxen was more potent relative to other drugs in reducing the writhing response to an injection of phenylquinone, than in raising the threshold to pain induced by compression of inflamed paws (Rooks et al., 1973; Roszkowski et al., 1971). Nevertheless, naproxen was more active than aspirin and phenylbutazone in all tests and less active than indomethacin (see table I). 1.1.3 Antipyretic Effect The antipyretic effect of oral naproxen was greater than that of phenylbutazone and aspirin and similar to that of indomethacin, as evidenced by the effect
Fig. 1. Chemical structural formula ofnaproxen.
332
Naproxen: A Review
Table L Pharmacological properties of oral naproxen; potency relative to that of oral phenylbutazone, indomethacin and aspirin in studies in intact rats and mice (after Rooks etal., 1973) Test
Anti-inflammatory effect Carageenin paw oedema Cotton granuloma Analgesic activity Phenylquinone writhing Pressure on carageenin-induced paw oedema Pressure on yeast-induced paw oedema Antipyretic effect Yeast-induced pyrexia
Relative potency of naproxen I Phen?
Ind
Aspirin
11
0.7 0.1-0.2
55
10
9 1-2 "'3
0.1 0.5-1 0.2
7 20 "'10
1.2
22
7
1 Relative potency based on doses of each drug required to produce a comparable effect. The figures given are those for naproxen when the potency of the other test drugs is 1. 2 Abbreviations: Phen = phenylbutazone; Ind = indomethacin.
of these drugs in alleviating fever in rats induced by subcutaneous injection of yeast (Rooks et al., 1973; Roszkowski et al., 1971) (table I). 1.1.4 Immunological Effects The injection of Forssman antiserum into guinea pigs results in an anaphylactic reaction consisting of 2 phases. Phase I occurs immediately after injection of the antiserum, lasts for 30 to 90 seconds and produces a two-fold increase in pulmonary pressure. This phase is thought to result from release of histamine and/or 5-hydroxytryptamine (serotonin) and other mediators, and is selectively blocked by aminophylline and phenylephrine. Phase II which occurs immediately after the first phase, is less' rapid in onset, but is as intense, is irreversible, and due to pulmonary oedema and obstruction. Non-steroidal antiinflammatory agents including naproxen selectively block phase II, whilst sodium cromoglycate blocks both phases (Pelczarska and Roszkowski, 1973). 1.1.5 Effect on Gastric Mucosa Naproxen has an eroding effect on the gastric mucosa of starved rats which is similar to that of the other non-steroidal anti-inflammatory agents, but this does not occur in normally fed rats. The eroding effect on gastric mucosa
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333
occurred whether naproxen was given orally or subcutaneously. The same applied to indomethacin, phenylbutazone and mefenamic acid, but aspirin caused erosions of the gastric mucosa only after oral administration. These fmdings suggest that the drugs tested, other than aspirin, exert a general systemic effect as well as a topical effect. On the other hand, aspirin-induced gastric lesions appear to result from a direct topical effect (Roszkowski et al., 1971). 1. 1. 6 Other Effects
Studies in mice, indicated that naproxen has little or no anticonvulsant activity or central nervous system effects (Ozawa et al., 1972a). 1.1. 7 Mode ofAction
The mode of action of naproxen as evidenced by findings in animals, is not clear, but it seems to exert a direct action not mediated through the release to endogenous corticosteroids from adrenal tissue or other sites. This is supported by the finding that naproxen exerts a local anti-inflammatory effect (section 1.1.1), that it is effective in inhibiting inflammatory responses in adrenalectomised rats (section 1.1.1), and that it has no thymolytic activity (Roszkowski et al., 1971). It has also been demonstrated that naproxen, like aspirin and indomethacin (Ferreira et al., 1971; Vane, 1971), inhibits prostaglandin production by inhibiting prostaglandin synthesis in vitro (Tomlinson et al., 1972; Takeguchi and Sih, 1972). There appears to be some degree of correlation between the anti-inflammatory effect in animals of the non-steroidal antiinflammatory drugs and their ability to inhibit the biosynthesis of prostaglandins in vitro (Takeguchi and Sih, 1972; Tomlinson et al., 1972), and in this regard, naproxen (dextrorotatory) is more potent than its enantiomer (laevorotatory) and aspirin, but less potent than indomethacin (Tomlinson et al., 1972). Naproxen appears to also inhibit prostaglandin synthesis in vivo as evidenced by its effect in reducing the frequency of premature delivery in ovariectomised, and therefore oestrogen and progesterone deficient, pregnant rats which have been either untreated or treated with oestrogen. It is thought that uterine threshold is regulated by the ratio of progesterone to prostaglandins, and that in progesterone deficiency less prostaglandin is needed to stimulate uterine activity. It is thus reasoned that inhibition of prostaglandin synthesis reduced premature delivery in ovariectomised rats (Csapo et al., 1973b). That naproxen inhibits prostaglandin synthesis in vivo is further supported by the finding that naproxen prolongs pregnancy and delays spontaneous labour in pregnant rats (Csapo et al., 1973a). From the results of Tomlinson et al. (1972) in which there was a positive correlation between the inhibition of prostaglandin synthesis in vitro and in vivo anti-inflammatory effect as reported in other studies, it is possible that the anti-inflammatory activity of the non-steroidal anti-inflammatory agents,
334
Naproxen: A Review
Table II Some pharmacokinetic properties of naproxen in various animal species (after Runkel et al., 1973) Animal species
Rat Dog Guinea-pig Rhesus monkey Mini pig
Plasma half-life
5.1 2 35.0h 8.7h 1.9h 4.8h
Vol. dist.'
Excretion %
(l/kg)
0.18 0.12 0.12 0.10 0.12
urine
faeces
78 29 89 78 87
2 50 5 1 1
1 Vol. dist. =Volume of distribution 2 All figures are mean values
including naproxen, may be related to their ability to inhibit the biosynthesis of prostaglandins; substances which are involved in inflammation (Karim and Hillier, 1974) and have been implicated in pyresis and pain (Vane, 1971).
1.2 Animal Pharmacokinetics
1.2.1 Absorption Studies performed in beagle dogs by Runkel et al. (1972a, 1973) indicated that naproxen is 100% absorbed after oral administration. Although peak plasma levels were higher after intravenous than after oral administration, the total area under the plasma level-time curves was essentially the same after the drug was administered by either route. Absorption was complete irrespective of whether or not the drug was micronised or the sodium or calcium salts were given. However, the rate of absorption is increased with the salts compared with naproxen itself although peak serum levels are attained in 10 to 20 minutes after oral administration of naproxen (Runkel et al., 1973). The plasma half-life of naproxen varies considerably in different animal species, ranging from 1.9 hours in the rhesus monkey to 34 hours in the dog (table II) (Runkel et al., 1973). 1.2.2 Distribution After intravenous administration of 3mg/kg in rats, naproxen is widely distributed in body tissues (Runkel etal., 1973). Only a small proportion of the administered dose remains in the tissues longer than 24 hours after a single dose, and there was no preferential uptake by any of the tissues examined. Nearly all of the residual radioactivity detected 24 hours after a single intravenous dose
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335
was present in the faeces and in the digestive system. The apparent volume of distribution of naproxen is low, probably as a result of the high degree (99.9%) of protein binding to undiluted plasma (Ellis and Martin, 1971). 1.2.3 Metabolism and Excretion Naproxen is largely biotransformed in animals, the metabolites varying with different species. The pattern of biotransformation in the rat and pig most closely resembles that in the human (Thompson and Collins, 1973) (section 3.3). In all animals except in the dog, the vast majority of the radioactive naproxen is excreted in the urine. Faecal recovery accounts for 1 to 5% of the dose in the rat, guinea pig, rhesus monkey or the mini pig, but accounts for 50% ofthe dose in the dog. (Runkel et al., 1973) (table II).
2. Human Pharmacodynamics
2.1 Effect on CollagenMetabolism It has been postulated that changes in the urinary and blood concentration of 4-hydroxyproline, an amino acid found almost exclusively in collagen, reflect the metabolism of collagen. It is further considered that effective treatment of collagen diseases (Krel, 1971 - cited in Tiselius, 1973) with anti-inflammatory agents results in a decrease of urinary hydroxyproline, and that these variations in the amino acid levels can be used as an indication of the anti-inflammatory activity of a drug. In a study of the urinary levels of hydroxyproline in patients with inflammatory joint disease receiving treatment with naproxen, Tiselius (1973) found that urinary hydroxyproline decreased to some extent in 6 of 8 patients studied, and was associated with clinical improvement. The most striking decreases in urinary excretion of 4-hydroxyproline occurred in some patients with initially high (>50mg) excretion values (normal values are between 15 and 45mg). No definite correlation between changes in urinary hydroxyproline and in erythrocyte sedimentation rate was observed.
2.2 Effect on Gastric Mucosa and Blood Loss Naproxen appears to have less adverse effect on the human gastric mucosa than aspirin when either drug is given at dosages similar to those used in the treatment of rheumatic disorders. In a gastroscopic study (Halvorsen et al., 1973a, b) naproxen 500mg daily (250mg twice daily) caused less acute pathology of the gastric mucosa than 4.8g
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336
(1.2g four times daily) of aspirin. The 12 subjects without a past or recent history of gastro-intestinal complaints were given either drug postprandially in random order for 7 days. A 4-week drug-free period was allowed between the two drugs. After 7 days of aspirin, the gastric mucosa appeared abnormal on gastroscopy in all subjects and single or multiple ulceration was present in all but one subject (table III). In contrast, findings were abnormal in 2 subjects after naproxen and in one of these the appearance of the gastric mucosa was the same after a period of 3 weeks without any drug treatment. The differences between the effects of the two drugs may have been less dramatic if a lower dose of aspirin had been compared with naproxen, or if enteric coated aspirin had been used. An estimation of gastro-intestinal blood loss in 12 volunteers by radiochromium assay during 2 week's administration of either aspirin (2.7 to 4.5g daily), naproxen (500mg daily) or placebo, indicated that blood loss was significantly lower during placebo or naproxen than during aspirin (Lussier et al., 1973b; Arsenault et al., 1975). The mean daily blood loss in 6 subjects was 7.08 and 7.83m1 (range 4.08 to 11.28) during weeks 1 and 2 respectively during aspirin ingestion, compared with 1.72 and 1.16m1 (range 0.72 to 2.64) during the first and second weeks of naproxen administration. Similarly blood loss in the other 6 subjects was 6.56 and 5.44m1 daily (range 2.4 to 12.24) during the first and second weeks of aspirin ingestion and 1.32m1(range 0.48 to 3.12) daily during both weeks that placebo was given. In an open study in 6 patients with rheumatic disease (Curtarelli and Romussi, 1973), the simultaneous measurement of blood and faecal radioactivity after injection of 51 Cr-labelled erythrocytes, failed to detect any faecal radioactivity outside normal limits, and therefore, abnormal increase in gastrointestinal blood loss. A prolonged red blood cell half-life was noted in 4 of the 6 patients, but the significance of this was not known.
2.3 Effect on Bleeding Time and Platelet Aggregation The effects of aspirin 3.6g daily, placebo and naproxen 500mg daily on bleeding time and platelet aggregation were determined in 19 healthy adult subjects (Nadell et al., 1974). 2 hours after the last dose the bleeding times were significantly prolonged by both aspirin and naproxen (pP
N>P
0
x
(II
?
>
::c (II
Helby-Petersen et al. (1973)
58
500
DB w-p (14 days)
N= p 3
Lussier et al. (1973a)
19
300-500
DB w-p (14 days)
N>P
N>P
N>P
Messias et al. (1974)
18
500
DB w-p (20 days)
N>P
N>P
N>P
Segre (1973b)
67
500
DB w-p (14 days)
N>P
N>P
N>P
Willkens (1973)'
24
500
DB w-p (14 days)
N>P
N>P
N>P
1 2 3 4
DB w-p = double-blind within-patient Anti-inflammatory effect judged on one or both of the following:Abbreviations: N = naproxen; P = placebo This study is one of those discussed briefly by Segre (1973b).
;S. (II
:E
joint circumference; duration of morning stiffness w
4>0
0\
Naproxen: A Review
347
3 weeks in all studies, although the studies of Lussier et al. (1973a, b, c) differ from the others in that the double-blind phase was conducted in patients shown to respond to individualised doses of naproxen during an initial open study. Exclusion criteria based on previous treatment differed between the studies. Dr Lussier and his associates excluded patients who had received treatment with gold compounds or with antimalarial drugs within 6 months of the trial, whilst Helby-Petersen et al. (1973) excluded those who had been treated with corticosteroids or gold in the last 6 months, or with other anti-inflammatory drugs within 4 weeks of the trial. On the other hand, Segre (1973b) and Willkens (1973) permitted continued treatment with fixed stabilised doses of gold compounds or corticosteroids during the study. All other non-steroidal antiinflammatory agents were discontinued by Segre (1973b), Willkens (1973) and by Dr Lussier and his colleagues, but aspirin (in unstated doses) was permitted as often as necessary by Helby-Petersen et al. (1973). The lack of clear antiinflammatory activity of naproxen reported by these investigators may have resulted in part from the continued administration of supplementary aspirin throughout the trial. Objective criteria, including the change in the number of swollen, painful and/or tender joints, duration of early morning stiffness, and grip strength were employed in all studies, along with the patient's and/or doctor's drug preference. The good tolerance of naproxen was demonstrated in the studies of HelbyPetersen et al. (1973), Segre (1973b) and Willkens (1973) in which adverse reactions were of the same nature and frequency during both naproxen and placebo periods. The study protocol of Segre (1973b) and of Willkens (1973) provided for naproxen to be substituted for placebo, or viceversa before the end of the first 2 week treatment period in the event of severe exacerbation of symptoms. 23 patients experienced exacerbation of their disease whilst on placebo and were prematurely placed on naproxen, but only 1 patient failed to complete the 2 weeks on naproxen. A high overallelimination rate was reported by Messias et al. (1975) because patients resorted to self-medication. 4.1.5 Naproxen versus Aspirin
In the studies comparing naproxen 500mg daily with 3.6 to 4.8g daily of aspirin, no clear difference between the therapeutic effects of the drugs could be detected (Bowers et al., 1975; Diamond et al., 1973; Hill et al., 1973a, b). In another study (Katona et al., 1971) there was a clear tendency for aspirin 3.6g daily to be more effective in reducing the number of painful, swollen and tender joints than 75 or 150mg daily of naproxen, and a trend for 3.6g daily of aspirin to be slightly more effective than naproxen 300mg daily givenas a single dose. Although it is possible that the effects of the two drugs were in fact equal at the dosages chosen, it also seems possible that no difference could be detected because there were insufficient numbers of patients in the trials. Very large
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348
numbers of patients are required to detect statistically significant differences in drug trials comparing drugs expected to exert a similar effect. In none of the studies was there any mention of blood levels of salicylate attained during treatment. Doses of aspirin were those usually given in rheumatoid arthritis, but it cannot be assumed that levels of salicylate required to produce an antiinflammatory effect were consistently obtained in all patients. In all studies, side-effects were more frequent during aspirin administration than during naproxen therapy. In a multicentre trial involving 119 adult patients with definite or classical rheumatoid arthritis, Diamond et al. (1973) found naproxen 500mg daily to be better tolerated than aspirin 3.6g daily, but no difference in the efficacy of the two drugs could be detected at these dosage levels. Similar findings were reported by Hill et al. (1973a, b) in a multicentre trial in which 44 patients with rheumatoid arthritis completed at least 2 weeks on each drug, and 39 completed 4 weeks on each. A somewhat longer period of 16 weeks on either naproxen 750mg daily or aspirin 4.8g daily was employed by Bowers et al. (1975) who found little difference in the efficacy of the two drugs in 80 patients with rheumatoid arthritis, although grip strength improved more on aspirin than on naproxen. However, the disease was more advanced at the beginning of the trial in the group allocated at random to receive naproxen. On the basis of the physician's assessment, more patients experienced a very good or good response to naproxen (67%) than to aspirin (55%). These studies employed a wide range of objective criteria for assessment as well as patient and physician assessment, and subjected all fmdings to statistical analysis, whereas Katona et al. (1971) relied more on subjective criteria and did not employ statistical methods of analysis. The erythrocyte sedimentation rate (ESR) was lowered more by aspirin than by naproxen (Diamond et al., 1973;Hill'et al., 1973a, b).
4.1.6 Naproxen plus Aspirin As aspirin, in one form or another, remains the mainstay of initial treatment of rheumatoid arthritis in which inflammatory features dominate, the effect of existing aspirin therapy on the efficacy of other non-steroidal anti-inflammatory agents needs to be determined 3 • In a double-blind study involving 36 adults with classical or defmite rheumatoid arthritis who had been on continuous aspirin therapy (mean dose 3.25g daily) for at least 3 months, Willkens and Segre (1975) found naproxen plus aspirin more effective than aspirin alone on the basis of patient and observer preference. Statistically significant differences in favour of combined treatment 3 Pharmacological studies have demonstrated that the simultaneous administration of aspirin and naproxen results in lower plasma levels of naproxen than after ingestion of naproxen alone (Segre et al., 1974b), but this appears to be of little clinical significance.
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were recorded for duration of morning stiffness, grip strength and the time taken to walk 50 feet. There were no significant differences in the nature, severity or frequency of side-effects between the two treatment regimens. However, one patient in whom naproxen was added to existing therapy with aspirin 4.8g daily and prednisone 7.5mg daily, experienced probable upper gastro-intestinal bleeding.
4.1.7 Naproxen Compared with Indomethacin To date, naproxen has been compared with indomethacin in only small numbers of patients with rheumatoid arthritis, and no clear differences between the therapeutic efficacy of naproxen 500mg daily and indomethacin 150mg daily have been demonstrated in the trials which have been completed (Kogstad, 1973;D' Omezon, 1973; Szanto, 1974). Although Haslock et al. (1973) reported that the number of joints painful on active movement and the duration of morning stiffness were significantly decreased by naproxen, but not by indomethacin, results were available in only the first 11 patients. Patients shown to be intolerant of 75mg daily of indomethacin during previous treatment were excluded by Kogstad (1973), but despite this, side-effects were more frequent with indomethacin than with naproxen (see also section 5). However, the dose of indomethacin chosen for these studies is probably higher than that generally used by some rheumatoid arthritis clinics because of many patients' intolerance of the drug. Whereas aspirin was shown to lower the ESR more than naproxen (section 4.1.5), Kogstad (1973) reported that the ESR was significantlylower in patients treated with naproxen than in those given indomethacin. Because of the small. numbers of patients involved in these studies it cannot be concluded that naproxen 500mg!day and indomethacin l50mg!day are equally effective, but only that no difference could be detected under the conditions of these studies. A summary of results obtained in studies comparing naproxen with aspirin (section 4.1.5) and with indomethacin is given in table V. 4.1.8 Comparison with Fenoprofen and Ibuprofen
In a double-blind between patient study (Reynolds and Whorwell, 1974) which compared two-weeks' treatment with fenoprofen 2Ag daily, ibuprofen 2Ag daily and naproxen 750mg daily in 25 outpatients with rheumatoid arthritis, antirheumatic activity tended to be greatest with naproxen and least with ibuprofen. This was evidenced by differences in effect on the duration of morning stiffness, pain severity and joint tenderness, but only the first reached statistical significance(0.05Ind
Ind >N
Kogstad (1973)
26
Nap 500 Ind 150
N=Ind
N=Ind
N=Ind
Ind>N
D'Omezon (1973)
44
Nap 500 Ind 150
N= Ind
N= Ind
N= Ind
Ind=N
Szanto (1974)
21
Nap 500 Ind 150
N= Ind
N= Ind
N=Ind
Ind>N
1 2 3 4 5
Number of patients who completed the study Anti-inflammatory effect judged on one or both of the following:- joint circumference; duration of morning stiffness. Abbreviations: Nap = naproxen; ASA = aspirin; Ind = indomethacin. Results in first 11 patients in an ongoing study Differences between the effect of the two drugs in reducing the number of painful joints not stated.
w
til
0
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total PIP joint measure. This difference in findings could be due to various factors such as observer variation, differences in the time of day that measurements were made, and a differing proportion of patients with irreversible joint swelling. Patient preference was strongly in favour of naproxen although differences were not statistically significant in this small number of patients. Side-effects necessitated withdrawal of treatment in 4 patients on ibuprofen and in 1 receiving naproxen. 4.1.9 Comparison with Flufenamic Acid In a multicentre double-blind trial in Japan (Okada and Sakuma, 1973) naproxen 500mg daily was found to be significantly more effective than the same dose of flufenamic acid in 131 patients with rheumatoid arthritis. Naproxen also caused fewer side-effects.
4.2 Ankylosing Spondylitis A placebo controlled study (Hill and Hill, 1973b) has shown oral naproxen to be better than placebo in ankylosing spondylitis, whilst in a comparison of naproxen suppositories (500mg) with indomethacin suppositories (lOOmg)both drugs were effective in relieving night pain (peter and Veress, 1974). However, the exact place of naproxen relative to other non-steroidal anti-inflammatory agents in the management of ankylosing spondylitis has yet to be determined. Hill and Hill (l973b) reported that at the end of the first month of open assessment, naproxen 500mg daily was considered by 32 of the 33 patients with radiographic evidence of sacro-iliitis to be equal to, or better than, previous therapy. In the double-blind phase 8 of the 10 patients correctly identified the placebo. Objective assessment was based on fmger-floor and occiput-wall distance, right and left lateral flexion, total spinal flexion, chest expansion, duration of morning stiffness, and the time of onset of 'immobility stiffness'. This last measurement was the length of time a patient could sit before becoming uncomfortably stiff, the shorter the time the greater the disability. During the course of the open study the duration of morning stiffness and the time of onset of immobility stiffness were Significantly reduced (p
Naproxen: A Review of its Pharmacological Properties and Therapeutic Efficacy and Use R.N. Brogden, R.M. Pinder, Phyllis R. Sawyer, T.M. Speight and G.S. Avery Australasian Drug Information Services, Auckland Manuscript reviewed by: B.M Ansell, MRC, Rheumatism Unit, Canadian Red Cross Memorial Hospital, Maidenhead, England; F.D. Hart, Rheumatism Clinic, Westminster Hospital, London, England; HoF.H. Hill, Oxford Regional Rheumatic Diseases Research Centre, Stoke Mandeville Hospital, Aylesbury, England; R. Go Robinson, North Shore Medical Centre, Sydney, Australia; B.S. Rose, Rheumatologist, Waikato Hospital, Hamilton, New Zealand; J. Ruedy, Division of Clinical Pharmacology, Montreal General Hospital, Montreal, Canada; J.Bo Stetson, Department of Anaesthesiology, School of Medicine and Dentistry, University of Rochester, New York, USA
Table of Contents Summary . 1. Animal Pharmacology 1.1 Pharmacodynamic Studies . 1.1.1 Anti-Inflammatory Activity 1.1.2 Analgesic Activity 1.1.3 Antipyretic Activity 1.1.4 Immunological Effects 1.1.5 Effect on Gastric Mucosa 1.1.6 Other Effects 1.1.7 Mode of Action 1.2 Animal Pharmacokinetics 1.2.1 Absorption 1.2.2 Distribution 1.2.3 Metabolism and Excretion 2. Human Pharmacodynamics 2.1 Effect on Collagen Metabolism 2.2 Effect on Gastric Mucosa and Blood Loss 2.3 Effect on Bleeding Time and Platelet Aggregation 3. Human Pharmacokinetics '" 3.1 Absorption 3.1.1 Effect of Food on Absorption . . • . . . . . . . . . . . . . . . . . . . . 3.1.2 Bioavailability 0
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327 330 330 330 331 331 332 332 333 333 334 334 334 335 335 335 335 336 338 338 338 339
Naproxen: A Review
327
3.1.3 Effect on Absorption of Antacids 339 3.1.4 Plasma Half-Life 340 3.2 Plasma Protein Binding 341 341 3.3 Placental Transfer, Breast Milk 3.4 Metabolism and Excretion 341 4. Therapeutic Trials 342 4.1 Rheumatoid Arthritis 342 4.1.1 Open Studies - Short-term 342 4.1.2 Long-term Open Studies 343 4.1.3 Long-term Studies in Patients with Gastro-Intestinal disease and/or Intolerance of Other Antirheumatic Drugs . . . . . . . . . . . . . . . . . . . . 345 4.1.4 Placebo-Controlled Trials 345 4.1.5 Naproxen versus Aspirin 347 4.1.6 Naproxen plus Aspirin 348 4.1. 7 Naproxen Compared with Indomethacin 349 4.1.8 Comparison with Fenoprofen and Ibuprofen 349 4.1.9 Comparison with Flufenamic Acid 351 4.2 Ankylosing Spondylitis 351 4.3 Degenerative Joint Disease 352 4.4 Gout ' 354 4.5 Pain States . . . . . . . . . . . . . . . . . . . . . . . . . 355 5. Side-Effects 357 5.1 Gastro-Intestinal Side-Effects 358 5.2 Central Nervous System and Autonomic Effects 358 5.3 Other Side-Effects 359 6. Drug Interactions 359 7. Precautions 360 8. Dosage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
Key words' Summary Ankylosing spondylitis Synopsis: Naproxen", (+)-6-methoxY-et-methyl-2-naphthaAnti-inflammatory agents lene acetic acid, is a new non-steroidal anti-inflammatory agent advocated for use in rheumatoid arthritis, degenerative joint Aspirin Gastro-intestinal irritation disease and anleylosing spondylitis. Gout Published data suggest that in rheumatoid arthritis, naproxen 500mg daily is comparable in efficacy with moderate Indomethacin doses of aspirin (3.6 to 4g daily) or 150mg daily of indo- Naproxen methacin, but generally causes fewer and milder side-effects Osteoarthrosis than these drugs at the dOSllges used and can be given less Rheumatoid arthritis frequently (12-hourly). Encouraging initial results have been reported from its use in other inflammatory joint disorders, including acute gout and juvenile rheumatoid arthritis. It has compared favourably with indomethacin in osteoarthrosis of the hip or knee. Its exact place in the management of ankylosing spondylitis remains to be determined. 1 See subject index in each issue for further indexing terms. 2 'Naprosyn'; 'Naprosine'; 'Naxen'; 'Proxen'; 'Synaxsyn' (Syntex).
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Experimental studies in healthy subjects and open trials in patients intolerant of other non-steroidal anti-inflammatory agents suggest that naproxen causes less upper gastrointestinal irritation and bleeding than aspirin. However, gastro-intestinal bleeding associated with the use ofnaproxen has been reported occasionally since its wider use, but it is still too early to determine the incidence and risk of gastro-intestinal bleeding with naproxen relative to that with non-steroidal anti-inflammatory agents other than aspirin. Side-effects have generally been mild and have mostly involved the upper gastro-intestinal tract (abdominal pain, indigestion) and the central nervous system (headache, lightheadedness, drowsiness). Animal studies have demonstrated that oral naproxen possesses dose-related antiinflammatory, analgesic and antipyretic activity which was greater than that of phenylbutazone and aspirin, and equal to or less than that of indomethacin. Naproxen inhibited carrageenin-induced paw oedema, and granuloma tissue formation following cotton pellet implantation in both intact and in adrenalectomised rats. The analgesic potency of oral naproxen relative to that of other non-steroidal anti-inflammatory agents has varied with the method used to induce pain, but was greater than that of phenylbutazone and aspirin in all tests but less than that of indomethacin. Naproxen has an eroding effect on the gastric mucosa of starved rats. Like indomethacin, phenylbutazone and mefenamic acid, but unlike aspirin, naproxen caused gastric erosion when given either orally or subcutaneously. Thus, it seems that aspirin-induced gastric lesions result from a direct topical effect, whereas naproxen and the other drugs in the same therapeutic class exert a general systemic effect as well as a topical effect. The mode of action of naproxen is not clear, but it seems to exert a direct action not mediated through the release of endogenous corticosteroids from adrenal tissue or other sites. There is evidence that naproxen, like aspirin and indomethacin, inhibits prostaglandin biosynthesis in vitro and in vivo in rats, and it is possible that its anti-inflammatory activity may be related to its ability to inhibit synthesis of prostaglandins; substances which are involved in inflammation and have been implicated in pyresis and pain. In animals, as in man (vide infra) naproxen is completely absorbed after oral administration, and is widely distributed in the body tissues of rats. In all animals tested, except the dog, the great majority of an ingested dose is excreted in the urine. Human Pharmacology: Naproxen has been shown to reduce the urinary excretion of 4 hydroxyproline in patients with inflammatory joint disease. It has been postulated that changes in the blood and urinary concentration of this amino acid reflect the metabolism of collagen and that the variations in the amino acid levels can be used as an indication of a drug's anti-inflammatory effect. Effective treatment of collagen diseases is also thought to result in a decrease in urinary hydroxyproline. It appears that naproxen has less adverse effect on the human gastric mucosa and causes less gastro-intestinal blood loss than aspirin, when either drug is given at dosages similar to those used in the treatment of rheumatic disorders. To date there have been no comparisons of the effects on the upper gastro-intestinal tract of naproxen and enteric coated aspirin or aloxiprin, two widely used alternatives to ordinary aspirin in rheumatic disorders. Gastro-intestinal bleeding has been reported recently in a few cases, but it is too early to determine the incidence and risk of gastro-intestinal bleeding during long-term administration, relative to that with other non-steroidal anti-inflammatory agents. Like aspirin, naproxen prolongs the bleeding time in healthy subjects but appears to have a different action on platelets. Open studies, and cross-over studies with oral and intravenous naproxen in very small numbers of subjects, suggest that naproxen is essentially completelyabsorbed. Plasma levels
Naproxen: A Review
329
rise proportionately with dosage until a single dose of 500mg is reached, but rise more slowly at higher dose levels as a result of an increased renal clearance rate at high doses and possibly an increased rate of distribution into tissues. Absorption of naproxen is not adversely affected by the presence of food, or by the concomitant administration of commercial magnesium aluminium hydroxide gel or sodium bicarbonate. On the other hand, absorption of naproxen is clearly reduced by the concomitant use of the antacids magnesium oxide and aluminium hydroxide. Its plasma half-life of 12 to 15 hours, make it suitable for twice daily administration. At plasma levels attained after usual therapeutic doses, naproxen is highly bound to plasma protein, only about 0.4% being in the free unbound form. The free fraction rises as plasma concentrations rise and appears responsible for the plateau effect with increasing doses. Nearly all of the ingested dose is excreted in the urine. 70% of an oral or intravenous dose of naproxen is excreted either as the unchanged drug or largely as conjugated naproxen. Therapeutic trials: Results of controlled studies in which naproxen has been compared with aspirin, indomethacin and placebo, have demonstrated the efficacy of naproxen in rheumatoid arthritis, ankylosing spondylitis, degenerative joint diseases, acute gout, and in acute moderate pain states. Naproxen 500mg daily has generally provided symptomatic relief statistically indistinguishable from that obtained with aspirin 3.6 to 4g daily or with indomethacin l50mg daily and superior to that provided by placebo, buprofen or fenoprofen. Although it is possible that naproxen and aspirin or indomethacin were in fact equally efficacious at the dosages chosen, it is also possible that no difference could be detected because there were insufficient numbers of patients in the trials to detect differences between drugs expected to produce a similar effect. Side-effects have usually been less frequent with naproxen than with aspirin or indomethacin. Clinical impressions gained during long-term open studies in patients with definite or classical rheumatoid arthritis, are that in many patients signs and symptoms continued to regress during treatment. Long-term open studies in patients with rheumatoid arthritis who had upper gastro-intestinal tract disease and/or were intolerant of other commonly used non-steroidal anti-inflammatory agents, indicated that naproxen was well tolerated by over half of these patients. Although pharmacological studies have shown that the simultaneous administration of aspirin and naproxen may result in lower than expected serum levels of naproxen, this appears to be of little clinical significance. The efficacy of combined aspirin and naproxen therapy is greater than that of aspirin alone. In an open trial in patients with ankylosing spondylitis an increasing proportion were symptom-free or experienced only mild symptoms over a period of 6 months' treatment with naproxen 500mg daily, and morning stiffness and the time of onset of immobility stiffness were significantly reduced. Suppositories of naproxen (500mg) are effective in alleviating night pain in ankylosing spondylitis. However, the exact place of naproxen relative to that of other non-steroidal anti-inflammatory agents in the management of ankylosing spondylitis has yet to be determined. Comparative studies have shown naproxen 400 to 600mg to be well tolerated in patients with osteoarthrosis of the hip and knee and to produce improvement indistinguishable from that obtained with indomethacin 100mg daily and superior to that obtained with aluminium flufenamate 750mg daily or placebo. Double-blind studies have demonstrated that naproxen in daily doses of 400mg to 750mg can reduce the need for oral corticosteroids in some patients with rheumatoid arthritis receiving stabilised minimum maintenance doses of systemic steroids. Initial results with naproxen in acute gout have been favourable, but further studies will be necessary to determine the best dosage regimen and the pattern of response of
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repeated episodes. It appeared that best results were obtained when a loading dose of 750mg was used followed by 250mg 8-hourly for 72 hours before tapering the dose. Initial results with naproxen in pain states have shown naproxen to be an effective analgesic in patients with moderate pain resulting from orthopaedic, dental and other surgical procedures. A single dose of naproxen 400mg was thought to provide analgesia between that of single oral doses of 75 or 150mg of pethidine. Greater analgesia is obtained with naproxen 600mg than with a dose of 400mg. At dosages used in the treatment of rheumatic diseases naproxen has generally been well tolerated during both long-term and short-term studies. Gastro-intestinal effects such as indigestion, abdominal discomfort and pain, nausea, vomiting and heartburn, and central nervous system effects such as headache, vertigo or light-headedness and drowsiness have been reported most frequently. These latter effects have generally been less frequent with naproxen than with indomethacin. As naproxen is highly bound to plasma protein, it has a potential for interaction with other albumin-bound drugs such as warfarin, sulphonylureas, hydantoins and aspirin. Although naproxen has been well tolerated by some patients exhibiting dyspepsia with other non-steroidal anti-inflammatory agents, episodes of gastro-intestinal bleeding have been reported and naproxen should be given with caution in patients with a known or suspected history of upper gastro-intestinal disease. The usual starting dose, and maintenance dose, of naproxen is 250mg twice daily.
1. Animal Pharmacology
1.1 Pharmacodynamic Studies Early studies of the anti-inflammatory activity of various non-nitrogenous compounds including substituted 2-naphthy1acetic acids and derivatives (Harrison et al., 1970) indicated that naproxen, the dextrorotatory isomer of (+)-6-methoxy-a-methyl-2-naphthalene acetic acid (fig. 1) was amongst the most potent, on a weight for weight basis, of those tested (Harrison et al., 1970, 1973). Subsequent studies in rats and mice demonstrated that naproxen possessed dose-related anti-inflammatory, analgesic and antipyretic potency which was generally equal to or less than that of indomethacin, but always greater than that of phenylbutazone or aspirin (table I) (Roszkowski et al., 1971, 1973;Rooksetal., 1973;Ozawaetal., 1972b). 1.1.1 Anti-Inflammatory Activity Inflammation induced in the hind paw of rats by injection of carrageenin, was inhibited by prior administration of oral naproxen (Ozawa et al., 1972a; Rooks et al., 1973; Roszkowski et al., 1971). The relative potency ofnaproxen in inhibiting the oedema was 11 times that of phenylbutazone (see table I). Although Ozawa et al. (1972a) found naproxen to be more effective than indomethacin, other investigators found indomethacin to be the more active drug.
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331
Naproxen was also shown to be effective in reducing the formation of granuloma tissue following the subcutaneous implantation of carrageenin impregnated cotton pellets in rats (Ozawa et al., 1972a; Roszkowski et al., 1971; Rooks et al., 1973). In this regard, naproxen was equal in potency to hydrocortisone, more active than mefenamic acid or phenylbutazone, and less active than indomethacin. In adrenalectomised rats oral naproxen inhibited granuloma tissue formation without exhibiting a thymolytic effect like the corticosteroids (Rooks et al., 1973; Roszkowski et al., 1971). A topical anti-inflammatory effect was also demonstrated when 2mg of naproxen was added to an inflammationinducing vehicle which was applied to the ear of rats.
1.1.2 AnalgesicActivity The analgesic potency of oral naproxen relative to that of other nonsteroidal anti-inflammatory agents tested, varied with the method used to induce pain. Naproxen was more potent relative to other drugs in reducing the writhing response to an injection of phenylquinone, than in raising the threshold to pain induced by compression of inflamed paws (Rooks et al., 1973; Roszkowski et al., 1971). Nevertheless, naproxen was more active than aspirin and phenylbutazone in all tests and less active than indomethacin (see table I). 1.1.3 Antipyretic Effect The antipyretic effect of oral naproxen was greater than that of phenylbutazone and aspirin and similar to that of indomethacin, as evidenced by the effect
Fig. 1. Chemical structural formula ofnaproxen.
332
Naproxen: A Review
Table L Pharmacological properties of oral naproxen; potency relative to that of oral phenylbutazone, indomethacin and aspirin in studies in intact rats and mice (after Rooks etal., 1973) Test
Anti-inflammatory effect Carageenin paw oedema Cotton granuloma Analgesic activity Phenylquinone writhing Pressure on carageenin-induced paw oedema Pressure on yeast-induced paw oedema Antipyretic effect Yeast-induced pyrexia
Relative potency of naproxen I Phen?
Ind
Aspirin
11
0.7 0.1-0.2
55
10
9 1-2 "'3
0.1 0.5-1 0.2
7 20 "'10
1.2
22
7
1 Relative potency based on doses of each drug required to produce a comparable effect. The figures given are those for naproxen when the potency of the other test drugs is 1. 2 Abbreviations: Phen = phenylbutazone; Ind = indomethacin.
of these drugs in alleviating fever in rats induced by subcutaneous injection of yeast (Rooks et al., 1973; Roszkowski et al., 1971) (table I). 1.1.4 Immunological Effects The injection of Forssman antiserum into guinea pigs results in an anaphylactic reaction consisting of 2 phases. Phase I occurs immediately after injection of the antiserum, lasts for 30 to 90 seconds and produces a two-fold increase in pulmonary pressure. This phase is thought to result from release of histamine and/or 5-hydroxytryptamine (serotonin) and other mediators, and is selectively blocked by aminophylline and phenylephrine. Phase II which occurs immediately after the first phase, is less' rapid in onset, but is as intense, is irreversible, and due to pulmonary oedema and obstruction. Non-steroidal antiinflammatory agents including naproxen selectively block phase II, whilst sodium cromoglycate blocks both phases (Pelczarska and Roszkowski, 1973). 1.1.5 Effect on Gastric Mucosa Naproxen has an eroding effect on the gastric mucosa of starved rats which is similar to that of the other non-steroidal anti-inflammatory agents, but this does not occur in normally fed rats. The eroding effect on gastric mucosa
Naproxen: A Review
333
occurred whether naproxen was given orally or subcutaneously. The same applied to indomethacin, phenylbutazone and mefenamic acid, but aspirin caused erosions of the gastric mucosa only after oral administration. These fmdings suggest that the drugs tested, other than aspirin, exert a general systemic effect as well as a topical effect. On the other hand, aspirin-induced gastric lesions appear to result from a direct topical effect (Roszkowski et al., 1971). 1. 1. 6 Other Effects
Studies in mice, indicated that naproxen has little or no anticonvulsant activity or central nervous system effects (Ozawa et al., 1972a). 1.1. 7 Mode ofAction
The mode of action of naproxen as evidenced by findings in animals, is not clear, but it seems to exert a direct action not mediated through the release to endogenous corticosteroids from adrenal tissue or other sites. This is supported by the finding that naproxen exerts a local anti-inflammatory effect (section 1.1.1), that it is effective in inhibiting inflammatory responses in adrenalectomised rats (section 1.1.1), and that it has no thymolytic activity (Roszkowski et al., 1971). It has also been demonstrated that naproxen, like aspirin and indomethacin (Ferreira et al., 1971; Vane, 1971), inhibits prostaglandin production by inhibiting prostaglandin synthesis in vitro (Tomlinson et al., 1972; Takeguchi and Sih, 1972). There appears to be some degree of correlation between the anti-inflammatory effect in animals of the non-steroidal antiinflammatory drugs and their ability to inhibit the biosynthesis of prostaglandins in vitro (Takeguchi and Sih, 1972; Tomlinson et al., 1972), and in this regard, naproxen (dextrorotatory) is more potent than its enantiomer (laevorotatory) and aspirin, but less potent than indomethacin (Tomlinson et al., 1972). Naproxen appears to also inhibit prostaglandin synthesis in vivo as evidenced by its effect in reducing the frequency of premature delivery in ovariectomised, and therefore oestrogen and progesterone deficient, pregnant rats which have been either untreated or treated with oestrogen. It is thought that uterine threshold is regulated by the ratio of progesterone to prostaglandins, and that in progesterone deficiency less prostaglandin is needed to stimulate uterine activity. It is thus reasoned that inhibition of prostaglandin synthesis reduced premature delivery in ovariectomised rats (Csapo et al., 1973b). That naproxen inhibits prostaglandin synthesis in vivo is further supported by the finding that naproxen prolongs pregnancy and delays spontaneous labour in pregnant rats (Csapo et al., 1973a). From the results of Tomlinson et al. (1972) in which there was a positive correlation between the inhibition of prostaglandin synthesis in vitro and in vivo anti-inflammatory effect as reported in other studies, it is possible that the anti-inflammatory activity of the non-steroidal anti-inflammatory agents,
334
Naproxen: A Review
Table II Some pharmacokinetic properties of naproxen in various animal species (after Runkel et al., 1973) Animal species
Rat Dog Guinea-pig Rhesus monkey Mini pig
Plasma half-life
5.1 2 35.0h 8.7h 1.9h 4.8h
Vol. dist.'
Excretion %
(l/kg)
0.18 0.12 0.12 0.10 0.12
urine
faeces
78 29 89 78 87
2 50 5 1 1
1 Vol. dist. =Volume of distribution 2 All figures are mean values
including naproxen, may be related to their ability to inhibit the biosynthesis of prostaglandins; substances which are involved in inflammation (Karim and Hillier, 1974) and have been implicated in pyresis and pain (Vane, 1971).
1.2 Animal Pharmacokinetics
1.2.1 Absorption Studies performed in beagle dogs by Runkel et al. (1972a, 1973) indicated that naproxen is 100% absorbed after oral administration. Although peak plasma levels were higher after intravenous than after oral administration, the total area under the plasma level-time curves was essentially the same after the drug was administered by either route. Absorption was complete irrespective of whether or not the drug was micronised or the sodium or calcium salts were given. However, the rate of absorption is increased with the salts compared with naproxen itself although peak serum levels are attained in 10 to 20 minutes after oral administration of naproxen (Runkel et al., 1973). The plasma half-life of naproxen varies considerably in different animal species, ranging from 1.9 hours in the rhesus monkey to 34 hours in the dog (table II) (Runkel et al., 1973). 1.2.2 Distribution After intravenous administration of 3mg/kg in rats, naproxen is widely distributed in body tissues (Runkel etal., 1973). Only a small proportion of the administered dose remains in the tissues longer than 24 hours after a single dose, and there was no preferential uptake by any of the tissues examined. Nearly all of the residual radioactivity detected 24 hours after a single intravenous dose
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335
was present in the faeces and in the digestive system. The apparent volume of distribution of naproxen is low, probably as a result of the high degree (99.9%) of protein binding to undiluted plasma (Ellis and Martin, 1971). 1.2.3 Metabolism and Excretion Naproxen is largely biotransformed in animals, the metabolites varying with different species. The pattern of biotransformation in the rat and pig most closely resembles that in the human (Thompson and Collins, 1973) (section 3.3). In all animals except in the dog, the vast majority of the radioactive naproxen is excreted in the urine. Faecal recovery accounts for 1 to 5% of the dose in the rat, guinea pig, rhesus monkey or the mini pig, but accounts for 50% ofthe dose in the dog. (Runkel et al., 1973) (table II).
2. Human Pharmacodynamics
2.1 Effect on CollagenMetabolism It has been postulated that changes in the urinary and blood concentration of 4-hydroxyproline, an amino acid found almost exclusively in collagen, reflect the metabolism of collagen. It is further considered that effective treatment of collagen diseases (Krel, 1971 - cited in Tiselius, 1973) with anti-inflammatory agents results in a decrease of urinary hydroxyproline, and that these variations in the amino acid levels can be used as an indication of the anti-inflammatory activity of a drug. In a study of the urinary levels of hydroxyproline in patients with inflammatory joint disease receiving treatment with naproxen, Tiselius (1973) found that urinary hydroxyproline decreased to some extent in 6 of 8 patients studied, and was associated with clinical improvement. The most striking decreases in urinary excretion of 4-hydroxyproline occurred in some patients with initially high (>50mg) excretion values (normal values are between 15 and 45mg). No definite correlation between changes in urinary hydroxyproline and in erythrocyte sedimentation rate was observed.
2.2 Effect on Gastric Mucosa and Blood Loss Naproxen appears to have less adverse effect on the human gastric mucosa than aspirin when either drug is given at dosages similar to those used in the treatment of rheumatic disorders. In a gastroscopic study (Halvorsen et al., 1973a, b) naproxen 500mg daily (250mg twice daily) caused less acute pathology of the gastric mucosa than 4.8g
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336
(1.2g four times daily) of aspirin. The 12 subjects without a past or recent history of gastro-intestinal complaints were given either drug postprandially in random order for 7 days. A 4-week drug-free period was allowed between the two drugs. After 7 days of aspirin, the gastric mucosa appeared abnormal on gastroscopy in all subjects and single or multiple ulceration was present in all but one subject (table III). In contrast, findings were abnormal in 2 subjects after naproxen and in one of these the appearance of the gastric mucosa was the same after a period of 3 weeks without any drug treatment. The differences between the effects of the two drugs may have been less dramatic if a lower dose of aspirin had been compared with naproxen, or if enteric coated aspirin had been used. An estimation of gastro-intestinal blood loss in 12 volunteers by radiochromium assay during 2 week's administration of either aspirin (2.7 to 4.5g daily), naproxen (500mg daily) or placebo, indicated that blood loss was significantly lower during placebo or naproxen than during aspirin (Lussier et al., 1973b; Arsenault et al., 1975). The mean daily blood loss in 6 subjects was 7.08 and 7.83m1 (range 4.08 to 11.28) during weeks 1 and 2 respectively during aspirin ingestion, compared with 1.72 and 1.16m1 (range 0.72 to 2.64) during the first and second weeks of naproxen administration. Similarly blood loss in the other 6 subjects was 6.56 and 5.44m1 daily (range 2.4 to 12.24) during the first and second weeks of aspirin ingestion and 1.32m1(range 0.48 to 3.12) daily during both weeks that placebo was given. In an open study in 6 patients with rheumatic disease (Curtarelli and Romussi, 1973), the simultaneous measurement of blood and faecal radioactivity after injection of 51 Cr-labelled erythrocytes, failed to detect any faecal radioactivity outside normal limits, and therefore, abnormal increase in gastrointestinal blood loss. A prolonged red blood cell half-life was noted in 4 of the 6 patients, but the significance of this was not known.
2.3 Effect on Bleeding Time and Platelet Aggregation The effects of aspirin 3.6g daily, placebo and naproxen 500mg daily on bleeding time and platelet aggregation were determined in 19 healthy adult subjects (Nadell et al., 1974). 2 hours after the last dose the bleeding times were significantly prolonged by both aspirin and naproxen (pP
N>P
0
x
(II
?
>
::c (II
Helby-Petersen et al. (1973)
58
500
DB w-p (14 days)
N= p 3
Lussier et al. (1973a)
19
300-500
DB w-p (14 days)
N>P
N>P
N>P
Messias et al. (1974)
18
500
DB w-p (20 days)
N>P
N>P
N>P
Segre (1973b)
67
500
DB w-p (14 days)
N>P
N>P
N>P
Willkens (1973)'
24
500
DB w-p (14 days)
N>P
N>P
N>P
1 2 3 4
DB w-p = double-blind within-patient Anti-inflammatory effect judged on one or both of the following:Abbreviations: N = naproxen; P = placebo This study is one of those discussed briefly by Segre (1973b).
;S. (II
:E
joint circumference; duration of morning stiffness w
4>0
0\
Naproxen: A Review
347
3 weeks in all studies, although the studies of Lussier et al. (1973a, b, c) differ from the others in that the double-blind phase was conducted in patients shown to respond to individualised doses of naproxen during an initial open study. Exclusion criteria based on previous treatment differed between the studies. Dr Lussier and his associates excluded patients who had received treatment with gold compounds or with antimalarial drugs within 6 months of the trial, whilst Helby-Petersen et al. (1973) excluded those who had been treated with corticosteroids or gold in the last 6 months, or with other anti-inflammatory drugs within 4 weeks of the trial. On the other hand, Segre (1973b) and Willkens (1973) permitted continued treatment with fixed stabilised doses of gold compounds or corticosteroids during the study. All other non-steroidal antiinflammatory agents were discontinued by Segre (1973b), Willkens (1973) and by Dr Lussier and his colleagues, but aspirin (in unstated doses) was permitted as often as necessary by Helby-Petersen et al. (1973). The lack of clear antiinflammatory activity of naproxen reported by these investigators may have resulted in part from the continued administration of supplementary aspirin throughout the trial. Objective criteria, including the change in the number of swollen, painful and/or tender joints, duration of early morning stiffness, and grip strength were employed in all studies, along with the patient's and/or doctor's drug preference. The good tolerance of naproxen was demonstrated in the studies of HelbyPetersen et al. (1973), Segre (1973b) and Willkens (1973) in which adverse reactions were of the same nature and frequency during both naproxen and placebo periods. The study protocol of Segre (1973b) and of Willkens (1973) provided for naproxen to be substituted for placebo, or viceversa before the end of the first 2 week treatment period in the event of severe exacerbation of symptoms. 23 patients experienced exacerbation of their disease whilst on placebo and were prematurely placed on naproxen, but only 1 patient failed to complete the 2 weeks on naproxen. A high overallelimination rate was reported by Messias et al. (1975) because patients resorted to self-medication. 4.1.5 Naproxen versus Aspirin
In the studies comparing naproxen 500mg daily with 3.6 to 4.8g daily of aspirin, no clear difference between the therapeutic effects of the drugs could be detected (Bowers et al., 1975; Diamond et al., 1973; Hill et al., 1973a, b). In another study (Katona et al., 1971) there was a clear tendency for aspirin 3.6g daily to be more effective in reducing the number of painful, swollen and tender joints than 75 or 150mg daily of naproxen, and a trend for 3.6g daily of aspirin to be slightly more effective than naproxen 300mg daily givenas a single dose. Although it is possible that the effects of the two drugs were in fact equal at the dosages chosen, it also seems possible that no difference could be detected because there were insufficient numbers of patients in the trials. Very large
Naproxen: A Review
348
numbers of patients are required to detect statistically significant differences in drug trials comparing drugs expected to exert a similar effect. In none of the studies was there any mention of blood levels of salicylate attained during treatment. Doses of aspirin were those usually given in rheumatoid arthritis, but it cannot be assumed that levels of salicylate required to produce an antiinflammatory effect were consistently obtained in all patients. In all studies, side-effects were more frequent during aspirin administration than during naproxen therapy. In a multicentre trial involving 119 adult patients with definite or classical rheumatoid arthritis, Diamond et al. (1973) found naproxen 500mg daily to be better tolerated than aspirin 3.6g daily, but no difference in the efficacy of the two drugs could be detected at these dosage levels. Similar findings were reported by Hill et al. (1973a, b) in a multicentre trial in which 44 patients with rheumatoid arthritis completed at least 2 weeks on each drug, and 39 completed 4 weeks on each. A somewhat longer period of 16 weeks on either naproxen 750mg daily or aspirin 4.8g daily was employed by Bowers et al. (1975) who found little difference in the efficacy of the two drugs in 80 patients with rheumatoid arthritis, although grip strength improved more on aspirin than on naproxen. However, the disease was more advanced at the beginning of the trial in the group allocated at random to receive naproxen. On the basis of the physician's assessment, more patients experienced a very good or good response to naproxen (67%) than to aspirin (55%). These studies employed a wide range of objective criteria for assessment as well as patient and physician assessment, and subjected all fmdings to statistical analysis, whereas Katona et al. (1971) relied more on subjective criteria and did not employ statistical methods of analysis. The erythrocyte sedimentation rate (ESR) was lowered more by aspirin than by naproxen (Diamond et al., 1973;Hill'et al., 1973a, b).
4.1.6 Naproxen plus Aspirin As aspirin, in one form or another, remains the mainstay of initial treatment of rheumatoid arthritis in which inflammatory features dominate, the effect of existing aspirin therapy on the efficacy of other non-steroidal anti-inflammatory agents needs to be determined 3 • In a double-blind study involving 36 adults with classical or defmite rheumatoid arthritis who had been on continuous aspirin therapy (mean dose 3.25g daily) for at least 3 months, Willkens and Segre (1975) found naproxen plus aspirin more effective than aspirin alone on the basis of patient and observer preference. Statistically significant differences in favour of combined treatment 3 Pharmacological studies have demonstrated that the simultaneous administration of aspirin and naproxen results in lower plasma levels of naproxen than after ingestion of naproxen alone (Segre et al., 1974b), but this appears to be of little clinical significance.
Naproxen: A Review
349
were recorded for duration of morning stiffness, grip strength and the time taken to walk 50 feet. There were no significant differences in the nature, severity or frequency of side-effects between the two treatment regimens. However, one patient in whom naproxen was added to existing therapy with aspirin 4.8g daily and prednisone 7.5mg daily, experienced probable upper gastro-intestinal bleeding.
4.1.7 Naproxen Compared with Indomethacin To date, naproxen has been compared with indomethacin in only small numbers of patients with rheumatoid arthritis, and no clear differences between the therapeutic efficacy of naproxen 500mg daily and indomethacin 150mg daily have been demonstrated in the trials which have been completed (Kogstad, 1973;D' Omezon, 1973; Szanto, 1974). Although Haslock et al. (1973) reported that the number of joints painful on active movement and the duration of morning stiffness were significantly decreased by naproxen, but not by indomethacin, results were available in only the first 11 patients. Patients shown to be intolerant of 75mg daily of indomethacin during previous treatment were excluded by Kogstad (1973), but despite this, side-effects were more frequent with indomethacin than with naproxen (see also section 5). However, the dose of indomethacin chosen for these studies is probably higher than that generally used by some rheumatoid arthritis clinics because of many patients' intolerance of the drug. Whereas aspirin was shown to lower the ESR more than naproxen (section 4.1.5), Kogstad (1973) reported that the ESR was significantlylower in patients treated with naproxen than in those given indomethacin. Because of the small. numbers of patients involved in these studies it cannot be concluded that naproxen 500mg!day and indomethacin l50mg!day are equally effective, but only that no difference could be detected under the conditions of these studies. A summary of results obtained in studies comparing naproxen with aspirin (section 4.1.5) and with indomethacin is given in table V. 4.1.8 Comparison with Fenoprofen and Ibuprofen
In a double-blind between patient study (Reynolds and Whorwell, 1974) which compared two-weeks' treatment with fenoprofen 2Ag daily, ibuprofen 2Ag daily and naproxen 750mg daily in 25 outpatients with rheumatoid arthritis, antirheumatic activity tended to be greatest with naproxen and least with ibuprofen. This was evidenced by differences in effect on the duration of morning stiffness, pain severity and joint tenderness, but only the first reached statistical significance(0.05Ind
Ind >N
Kogstad (1973)
26
Nap 500 Ind 150
N=Ind
N=Ind
N=Ind
Ind>N
D'Omezon (1973)
44
Nap 500 Ind 150
N= Ind
N= Ind
N= Ind
Ind=N
Szanto (1974)
21
Nap 500 Ind 150
N= Ind
N= Ind
N=Ind
Ind>N
1 2 3 4 5
Number of patients who completed the study Anti-inflammatory effect judged on one or both of the following:- joint circumference; duration of morning stiffness. Abbreviations: Nap = naproxen; ASA = aspirin; Ind = indomethacin. Results in first 11 patients in an ongoing study Differences between the effect of the two drugs in reducing the number of painful joints not stated.
w
til
0
Naproxen: A Review
351
total PIP joint measure. This difference in findings could be due to various factors such as observer variation, differences in the time of day that measurements were made, and a differing proportion of patients with irreversible joint swelling. Patient preference was strongly in favour of naproxen although differences were not statistically significant in this small number of patients. Side-effects necessitated withdrawal of treatment in 4 patients on ibuprofen and in 1 receiving naproxen. 4.1.9 Comparison with Flufenamic Acid In a multicentre double-blind trial in Japan (Okada and Sakuma, 1973) naproxen 500mg daily was found to be significantly more effective than the same dose of flufenamic acid in 131 patients with rheumatoid arthritis. Naproxen also caused fewer side-effects.
4.2 Ankylosing Spondylitis A placebo controlled study (Hill and Hill, 1973b) has shown oral naproxen to be better than placebo in ankylosing spondylitis, whilst in a comparison of naproxen suppositories (500mg) with indomethacin suppositories (lOOmg)both drugs were effective in relieving night pain (peter and Veress, 1974). However, the exact place of naproxen relative to other non-steroidal anti-inflammatory agents in the management of ankylosing spondylitis has yet to be determined. Hill and Hill (l973b) reported that at the end of the first month of open assessment, naproxen 500mg daily was considered by 32 of the 33 patients with radiographic evidence of sacro-iliitis to be equal to, or better than, previous therapy. In the double-blind phase 8 of the 10 patients correctly identified the placebo. Objective assessment was based on fmger-floor and occiput-wall distance, right and left lateral flexion, total spinal flexion, chest expansion, duration of morning stiffness, and the time of onset of 'immobility stiffness'. This last measurement was the length of time a patient could sit before becoming uncomfortably stiff, the shorter the time the greater the disability. During the course of the open study the duration of morning stiffness and the time of onset of immobility stiffness were Significantly reduced (p
