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Rheumatology Advance Access originally published online on April 10, 2006
Rheumatology 2006 45(11):1389-1394; doi:10.1093/rheumatology/kel100
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Acetaminophen, like conventional NSAIDs, may reduce synovitis in osteoarthritic knees

Kenneth D. Brandt, Steven A. Mazzuca and Kenneth A. Buckwalter1

Department of Medicine, Rheumatology Division and 1Department of Radiology, Indiana University School of Medicine (IUSM), Indianapolis, USA.

Correspondence to: Steven A. Mazzuca, PhD, Indiana University School of Medicine, Department of Medicine, Rheumatology Division, Long Hospital Room 545, 1110 W. Michigan St., Indianapolis, IN 46202-5100, USA. E-mail: smazzuca{at}iupui.edu.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Objective. To determine the extent to which treatment of patients with symptomatic knee osteoarthritis (OA) with non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (ACET) reduces total effusion volume and synovial tissue volume, as quantified by magnetic resonance imaging (MRI).

Methods. Sequential pilot studies used subjects whose knee OA was treated with NSAIDs (n=10) or with ACET ≤4 g/day (n=20), respectively. After a five half-lives washout of their pain medication, the OA knee with the higher pain score ≥15 of 25 on the Western Ontario and McMaster Universities’ pain scale underwent l.5T MRI. Effusion was quantified in axial short tau inversion recovery images; to measure synovial tissue volume, fat-suppressed T1-weighted axial images were obtained 3 min after i.v. injection of gadolinium contrast. After the initial MRI examination, patients resumed their customary pain medications until the severity of knee pain returned to baseline, when pain was again measured and the MRI was repeated.

Results. Pain severity after washout was similar in subjects taking ACET and NSAIDs. Reinstitution of ACET resulted in a 50% decrease in the mean of pain scores (P=1.7 x 10–12) that was comparable with that seen after the reinstitution of NSAID (49%, P=6.0 x 10–7). The mean total effusion volume measured during the flare of knee pain induced by the withdrawal of the two drugs was comparable (ACET 16.9 ml, NSAID 16.2 ml; P=0.884). Significant decreases in mean total effusion volume were observed after reinstitution of both ACET (–4.5 ml, P=0.009) and NSAID (–3.3 ml, P=0.013); the difference between drugs was not significant. Analyses of synovial volume yielded similar results.

Conclusion. While uncontrolled and derived from small samples, these data suggest that ACET may have a significant anti-inflammatory effect in patients with knee OA, comparable with that achieved with NSAIDs, possibly through an effect on neurogenic inflammation. Joint pain is the clinical feature of OA that most often leads the affected individual to seek medical attention. Because many patients with OA improve symptomatically with the use of NSAIDs, it has been widely assumed that the pain of OA is due to synovial inflammation. However, the origins of OA pain are numerous and may vary from patient to patient and, within the same subject, from visit to visit. Although the articular cartilage is usually the site of the most obvious pathological changes in this disease, it is aneural and, therefore, is not the source of joint pain. However, in addition to the synovium, the subchondral bone, joint capsule, osteophytes, menisci, ligaments, periarticular tendons, entheses and bursae all contain nociceptive nerve endings, stimulation of which by chemical or physical mediators may be a basis for OA pain.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 References
 
There is no doubt that some patients with osteoarthritis (OA) find a non-steroidal anti-inflammatory drug (NSAID) more efficacious than acetaminophen (ACET). However, in a study of patients with painful knee OA, we showed that the efficacy of ACET, 1000 mg four times a day was, on average, comparable with that of either an analgesic or an anti-inflammatory dose of ibuprofen (1200 mg/day or 2400 mg/day, respectively), leading us to conclude that adequate relief of OA pain could be achieved in some cases with an analgesic, i.e. a drug without an anti-inflammatory effect [1]. In support of those findings, previous evidence indicated that ibuprofen 1200 mg/d, i.e. a dose that has only minimal anti-inflammatory effect, is as effective in relieving joint pain in patients with OA as several other NSAIDs, even when the latter were given in anti-inflammatory doses [2–4].

Since that time, for reasons of safety, efficacy and cost, ACET has been considered to be the initial drug of choice for treatment of OA pain [5–7]. In view of the concerns that have surfaced recently with respect to the cardiovascular safety of both non-selective cyclo-oxygenase (COX) inhibitors and COX-1-sparing NSAIDs (coxibs) [8, 9], the use of alternatives to NSAIDS, such as ACET, for treatment of OA pain has grown.

To gain a better understanding of the relationship between synovial inflammation and joint pain in patients with knee OA treated with NSAIDs, we recently undertook a pilot study to examine the sensitivity of various imaging modalities in quantifying changes in synovitis in patients with OA. We found that magnetic resonance imaging (MRI), with and without gadolinium contrast, detected changes in the volume of synovial membrane and volume of knee effusion, respectively, following NSAID withdrawal, whereas neither positive emission tomography with 18F-NaF nor the flow phase of bone scintigraphy with 99mTc-MDP were sensitive to such changes. The results presented subsequently document changes in the volume of joint effusion and synovium in the aforesaid pilot study and in a later similar pilot study of patients with OA who were taking ACET, rather than an NSAID, for their knee pain.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 References
 
Experimental design
The procedures, benefits, risks and associated safeguards in this study were approved by the Institutional Review Boards (IRB) affiliated with Indiana University—Purdue University at Indianapolis.

Subjects for both studies were required to have unilateral or bilateral knee OA (Kellgren and Lawrence criteria [10]); to be taking an NSAID to control their knee pain (Table 1); to report knee pain of at least moderate severity after washout of the drug [i.e. a Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index [11] pain score ≥15 on a scale of 5–25]; and to have no contraindication to MRI (e.g. claustrophobia, pacemaker and metal implants).


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  		TABLE 1. NSAIDs used by subjects in Study 1

 
In the first study, after the determination of the subject's eligibility and procurement of informed consent, 10 patients with definite knee OA who reported no more than mild or moderate knee pain while taking an anti-inflammatory dose of NSAID (Table 1) underwent a washout of their NSAID (five half-lives), during which they were permitted to take ACET, 1 g, up to four times a day, as rescue analgesia, except for the final 24 h of the washout period. During the final 24 h, the subject was contacted by the Study Coordinator and the WOMAC pain scale was administered by telephone [12]. Subjects who rated their knee pain ≥15 (possible range, 5–25) underwent a baseline MRI examination within the next 24–48 h. Those whose knee pain had not flared to a qualifying level were asked to extend the analgesic washout period for another 24 h, after which they were re-assessed by phone for the presence of a flare. If necessary, this procedure was repeated every 24 h for a maximum of 6 days. Subjects who declined to extend the washout period or failed to exhibit a qualifying flare of knee pain after the extended washout period were excluded from the study. The mean duration of the washout period was 4 days and the median duration, 4.5 days.

Immediately after the baseline MRI examination, subjects were instructed to resume their customary NSAID regimen and were scheduled for a repeat MRI study 14 days later. Within 24 h preceding the scheduled date for the repeat assessment, the Study Coordinator again contacted the subjects by telephone and re-administered the WOMAC pain scale. Subjects who exhibited ≥50% reduction of WOMAC pain after resumption of their NSAID dose were asked to return to the Nuclear Medicine Department for a repeat MRI examination, which followed identical procedures as those for the baseline examination (see subsequently).

In the second pilot study, the effects of ACET withdrawal on knee effusion volume and synovial tissue volume were studied. Subjects were recruited as described earlier and also from the public-at-large through newspaper advertisements that targeted individuals who had knee ‘arthritis’ and could manage their joint pain satisfactorily with ACET, up to 4 g/day. Volunteers recruited from the public were required to have a radiograph confirming the presence of knee OA (Kellgren and Lawrence grade ≥2).

Subjects who met eligibility criteria for the study were asked to discontinue their use of ACET. The duration of the washout period was 30 h for subjects taking 325 or 500 mg formulations of ACET, and 40 h for those taking Tylenol® Arthritis Pain Extended Relief Caplets. After the washout period, subjects were contacted by the Study Coordinator, who administered the WOMAC pain scale by phone. When their WOMAC pain score rose to a level ≥15, the subjects underwent a baseline MRI examination. The remainder of the study protocol was exactly as described for the first study. Immediately, following completion of the MRI, subjects were asked to resume their customary dose of ACET for their knee pain, up to 1 g four times a day, as needed.

MRI examination
A 60 min scheduling time slot was accorded for each examination. The MRI examination was performed at 1.5 T on a GE 1.5T MR Scanner (GE Medical Systems), using a phased-array knee coil. Axial images (n = 26–30) were acquired with a 15 cm field of view, 4 mm thick slices and 1 mm gap, 192 phase encodes, 256 matrix, and 2 signal averages (NEX). T1-weighted images (effusion volume) were obtained using a time to repetion (TR) = 450–700 ms and minimum time to echo (TE). Axial short tau inversion recovery images (STIR) were obtained with TR = 2000–5000 ms, TE = 34 ms and time to inversion (TI) = 150 ms; the echo train length was eight. Post-contrast images (synovial tissue volume) were obtained 3 min after the injection of 0.1 mM/kg gadolinium (gadopenetate dimeglumine, Berlex Magnevist, Montville and Wayne, NJ) [13, 14] with a fat-suppressed, fast multiplanar spoiled gradient-echo sequence (FMSPGR) using a TR = 80 ms, TE = 1.8, and a 60° flip angle.

Image analysis
The MRI images were transferred from the scanner to a three-dimensional workstation for analysis. Axial STIR images, in which fluid is the brightest tissue, were used to estimate the volume of effusion (Fig. 1). An operator experienced in the use of the workstation manually traced the outline of the joint fluid in each slice. The workstation software provided the total pixel count and area of effusion for each region of interest. Total effusion volume was calculated by summing the areas of effusion in the individual slices and multiplying the total area by the slice thickness (4 mm). To avoid overestimating the total volume of joint fluid, the first and last slices that contained fluid were multiplied by half to correct for partial volume effects of the adjacent slices. In a similar fashion, the total synovial volume was determined by manually tracing the enhanced synovial outlines on the post-contrast axial fat-suppressed T1-weighted images (Fig. 2).


Figure 1
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  		FIG. 1. Axial STIR image of knee before injection of gadolinium. The bright white region (arrow) represents synovial effusion.

 

Figure 2
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  		FIG. 2. Axial image of knee 3 min after injection of gadolinium. Fat-suppressed T1-weighted image. The arrows indicate synovium.

 
Volumes in the images from the two pilot studies were calculated simultaneously by the same operator (reader), who was blinded to the hypothesis of the study and to the patient's analgesic/NSAID treatment, but not to the chronologic order of the MRI examinations. However, the intra-reader reproducibility of original pre- and post-treatment estimates of total effusion and synovial volume, in comparison with measurements from images from five subjects in which the sequence of the examinations was random (ICC = 0.88 for total effusion volume and 0.85 for synovial volume), suggested that the absence of blinding with respect to the order of examination was not a significant source of error in the original measurements.

Statistical analysis
For each subject, an index knee, defined as the more symptomatic OA knee at baseline (i.e. after washout of NSAID or ACET) was designated for analysis. The significance of changes in knee pain, effusion volume and synovial volume associated with the resumption of NSAID or ACET therapy was evaluated by the paired t-test for correlated data. The association between changes in knee pain and changes in effusion volume or synovial volume was estimated by Pearson's product–moment correlation.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 References
 
The mean age of the subjects in both pilot studies was approximately 62 yrs. All subjects in study 1 and 19 of the 20 subjects in study 2 were female. The radiographic severity of OA, based on the proportion of subjects with Kellgren and Lawrence grade III or IV OA, vs that with grade II OA, tended to be greater in the NSAID study than in the ACET study (80 vs 55%), but the difference was not statistically significant (two-tailed Fisher's exact P = 0.247).

Pilot study 1—effect of NSAIDs
All 10 clinically and radiographically eligible volunteers for this study exhibited a qualifying flare of knee pain. As shown in Table 2, the mean (±S.D.) baseline WOMAC pain score after washout of the patient's NSAID was 19.4±3.2 (scale range: 5–25). After resumption of their NSAID, nine subjects required 2–3 weeks for their knee pain to fall to its usual level, while the tenth subject required 6 weeks. At the second examination, the change in the mean of WOMAC scores (–9.6±2.5, P = 6.0 x 10–7) represented a 49% decrease in pain, relative to that at the time of the flare.


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  		TABLE 2. Changes in WOMAC pain score* and in MRI results (mean±S.D.) associated with the treatment of an induced flare of OA knee pain

 
The mean volume (±S.D.) of joint effusion during the flare of knee pain was 16.2±8.7 ml. After resumption of NSAID use, a moderate (20%), but statistically significant, decrease in the size of the effusion, relative to baseline, was observed (mean change = –3.3±3.4 ml, P = 0.013). The mean synovial tissue volume at baseline (10.3±5.6 ml) exhibited a decrease of comparable magnitude (18%) after the resumption of NSAID dosing (mean change = –1.9±1.4 ml, P = 0.002).

Pilot study 2—effects of ACET
The sample size requirements for the second pilot study were based on the experience in the first study (see previous discussion), in which, after washout and reinstitution of NSAID therapy, we were able to detect a mean decrease in effusion volume roughly equal to the S.D. of change (–3.3±3.4 ml) with 10 subjects. The sample size for the second study (n = 20) was determined so as to afford adequate power to detect a decrease in effusion volume with ACET that was half the magnitude of that observed with NSAIDs. Of the 24 clinically and radiographically eligible volunteers who underwent washout of ACET, 20 exhibited a qualifying flare of knee pain.

Changes in pain and effusion and synovial volume associated with the withdrawal and reinstitution of ACET therapy are presented in Table 2. After the washout of ACET, the mean (±S.D.) of WOMAC pain scores was 18.1±2.4, on a scale of 5–25. The reinstitution of ACET resulted in a 50% decrease in the mean of WOMAC pain scores was (P = 1.7 x 10–12). The mean change in effusion volume associated with the reinstitution of ACET therapy was also highly statistically significant (–4.5±6.9 ml, P = 0.009), as was the change in mean synovial volume (–2.7±3.4 ml, P = 0.002).

Comparison of ACET and NSAID
Although the two pilot studies were performed sequentially, it is notable that the magnitude of pain flares associated with drug washout and the changes in knee pain, effusion volume and synovial volume following the reinstitution of NSAID and ACET, respectively, were similar (Table 2). The mean WOMAC pain score after the washout of ACET in the second study was similar to that after the washout of NSAIDs in the first study (18.1 vs 19.4, P = 0.221). The mean decrease in pain scores recorded after the reinstitution of treatment with ACET was comparable with that after the reinstitution of NSAID (–9.0 vs –9.6, P = 0.541).

The mean total effusion volume measured during the flare of knee pain induced by the withdrawal of ACET was comparable with that during the flare precipitated by NSAID withdrawal (16.9 vs 16.2 ml, P = 0.884). The same was true of the mean of synovial volume (11.1 vs 10.3 ml, P = 0.759). The mean decrease in total effusion was slightly smaller and less variable in the NSAID withdrawal study than in the ACET withdrawal study (–3.3±3.4 vs –4.5±6.9 ml), but the difference was not significant (P = 0.610). Both means were inflated somewhat by outliers, albeit to a greater extent in the ACET withdrawal study. However, the medians in Study 1 and Study 2 (–3.0 and –1.8 ml, respectively) and the corresponding inter-quartile ranges (IQRs; –0.8 to –4.0 ml and –1.1 to –5.1 ml) indicate that subjects in both studies exhibited measurable decreases in effusion volume after the reinstitution of NSAID or ACET.

Comparison of the effects of NSAIDs and ACET on synovial tissue volume yielded similar results, as reflected both in the mean and S.D. of change (–1.9±1.4 vs –2.7±3.4 ml, P = 0.484), and in the corresponding medians and IQRs (–1.3, –1.1 to –3.0 ml and –1.8, –0.9 to –2.6 ml).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 References
 
The mechanism underlying the analgesic action of ACET is unknown, but the prevailing evidence suggests that it involves a central component. In vitro studies have suggested several actions. The oldest proposal is that ACET inhibits COX-1 in the central nervous system [15]. Another suggestion is that ACET inhibits a specific type of COX-2 activity, such as that present in transformed monocytes/macrophages undergoing NSAID-induced apoptosis [16]. However, the activity of this COX-2 variant is highly cell-specific.

Recently, a third isoform of COX (i.e. COX-3) was identified and shown to be a product of the COX-1 gene [17]. In human tissues, COX-3 expression appears to be greatest in heart and brain. The suggestion has been made that COX-3 in brain may be the target on which ACET acts to exert its analgesic and antipyretic effect. COX-3 is considerably more sensitive to inhibition by ACET than either COX-1 or COX-2, but is susceptible to inhibition by non-selective NSAIDs much more than by ACET.

Although ACET is a non-selective inhibitor of COX-1 and COX-2 in vitro [18], the concentration of the drug required to demonstrate this action is very high and it is generally considered that ACET does not have a significant anti-inflammatory effect in peripheral tissues in vivo. Catella-Lawson et al. [19] found that a single 1000 mg dose of ACET provided weak, reversible, isoform-non-specific COX inhibition that did not inhibit platelet function.

It is notable, therefore, that in a randomized double-blind crossover trial of ACET 4 g/day and ibuprofen 2400 mg/day, each for 3 days, in subjects who underwent bilateral third molar extraction, Bjørnsson et al. [20] found no statistically significant difference between the two treatments with respect to their effect on either acute post-operative pain or swelling, which was measured quantitatively with a standardized face bow. Thus, although ibuprofen has been considered to be a better anti-inflammatory drug than ACET, in that trial even a high dose regimen of ibuprofen, i.e. 600 mg four times daily, had no greater anti-inflammatory effect than ACET 1000 mg four times a day. Similarly, in a study of swelling after third molar extraction by Voigt [21], in which swelling was also measured objectively, the decrease in swelling was no greater with ibuprofen than with ACET.

Although neither of the above studies employed a placebo group, in a placebo-controlled double-blind crossover study in subjects undergoing surgical removal of bilateral impacted wisdom teeth, with treatment started on the day of surgery, Skjelbred and Løkken [22] found that ACET, 1 g four times a day for 2 days, followed by 500 mg four times a day for the next 2 days, decreased swelling on the third day after operation by 30%, in comparison with placebo (P<0.05). Pain scores also favoured ACET. In a subsequent study by the same group of investigators [23], in which treatment was not initiated until 3 h after surgery, ACET reduced post-operative swelling by 31% on day 3 and by 60% on day 6, in comparison with placebo. ACET also resulted in significantly greater decreases in temperature at the site of surgery and in the degree of impairment of jaw-opening ability, in comparison with placebo. Although ACET is not considered to have significant anti-inflammatory properties, these data indicate that it is capable of reducing an acute post-traumatic inflammatory reaction.

Although an increase in the rate of serious gastrointestinal (GI) adverse events in OA patients taking ACET had not been noted heretofore [24–30], García Rodríguez and Hernández-Diaz [31] recently concluded from the results of a nested case-control study that ACET intake in therapeutic doses higher than 2000 mg/day resulted in a greater relative risk of upper GI complications than a moderate dose of NSAID. That study, however, was confounded by indication (i.e. ACET was prescribed preferentially for patients who would be at high risk for adverse events if treated with the most commonly used alternatives to ACET such as aspirin or other NSAIDs).

Based on the results of a retrospective cohort study, Rahme et al. [32] also recently raised a question about the risks of upper GI bleeding with the use of ACET. However, that study was confounded by a greater incidence of underlying risk factors for GI bleeding in ACET users than in controls, i.e. those who bled were likely to have had a greater incidence of GI bleeding even if they had not used ACET. Although García Rodríguez and Hernández-Díaz [31] suggested that their findings might be explained by the inhibition by ACET of prostaglandin synthesis in the gastrointestinal tract, in an ex vivo study, Cryer and Feldman [33] showed that, although naproxen 100 mM inhibited COX-1 synthesis by gastric mucosa by >90%, ACET—like the COX-1-sparing NSAIDs, celecoxib and rofecoxib—had no effect in clinically relevant concentrations. On the other hand, Högestätt et al. [34] recently showed that in brain and spinal cord, after deacetylation to its primary amine form, ACET is conjugated with arachidonic acid to form N-arachydonylphenolamine (AM404), a potent TRPV1 (transient receptor potential vanniloid 1, previously known as vanilloid receptor 1 or VM1) agonist that also inhibits prostaglandin synthesis and COX-1 and COX-2 in lipopolysaccharide-stimulated macrophages [34]. Whether fatty acid conjugation is a pathway for ACET metabolism in peripheral tissues, such as synovium, as well as in the central nervous system, is unknown.

The results of the present study suggest that ACET may have had an anti-inflammatory effect in the OA knee. It should be emphasized, however, that the data presented here are uncontrolled and are derived from two small sequential pilot studies; that the studies were not dose-ranging; and that the effects of NSAID and ACET were not compared directly in the same individuals. Although we cannot, therefore, exclude the possibility that the changes in pain and inflammation observed in these studies reflect the natural history of OA, we consider it to be unlikely because pain scores, which increased promptly after the withdrawal of NSAID or ACET, showed no tendency to fall spontaneously in either group. It is likely that increasing synovitis accounted for at least some of the flare in joint pain, which promptly subsided to background levels when NSAID or ACET was reinstituted.

On the basis of our results in the ACET-treated subjects, the possibility must also be considered that the ACET used as rescue analgesia by the subjects in the first pilot study may have augmented their response to their customary NSAID, both with respect to improvement in knee pain and improvement in synovitis. It should be noted, however, that in both pilot studies, ACET use was prohibited for the 24 h preceding the assessment of WOMAC pain and the MRI examination.

It is likely that the daily dose of ACET that was used as rescue analgesia to supplement the patient's NSAID in the first study was lower than the dose of ACET consumed daily as the primary analgesic in the second study, but ACET pill counts, which might have confirmed this suspicion, were not performed. However, the intake of ACET as rescue analgesia in published NSAID trials is usually less than 2000 mg/day. For example, in a study by Dieppe et al. [35], in which patients were randomized to a moderate dose of diclofenac (100 mg daily) or to placebo and were permitted to take rescue ACET up to 4000 mg/day, those in the diclofenac treatment arm consumed an average of only 1700 mg of ACET daily and those in the placebo group, only 2000 mg daily.

The majority of subjects in the second pilot study took ACET in a daily dose of 3000–4000 mg/day; only three of the 20 subjects took as little as 2000 mg/day. It should be noted that the patients were instructed to use ACET for treatment of their flare in knee pain on an as-needed, rather than fixed, dosing schedule, in the fashion they had been taking ACET for their knee pain prior to this study. Given the flexibility of ACET dosing permitted and the small number of subjects, it was not possible to obtain meaningful dose-response data relative to the effect of ACET on changes in pain or on MRI findings.

These preliminary results are consistent, however, with the reduction of jaw swelling after the administration of ACET in placebo-controlled trials of dental patients after the third molar extraction cited earlier. A better understanding of the mechanism of the action of ACET in peripheral tissues may help elucidate the pharmacodynamic basis for these observations. To our knowledge, studies of COX synthesis (and, particularly, synthesis of COX-2) in synovium of patients with arthritis taking therapeutic doses of ACET, similar to those performed by Cryer and Feldman [33] of COX synthesis by gastric mucosa, have not been performed. The data presented herein suggest that they could be informative.

The possibility that ACET exerted an anti-inflammatory effect in the OA knee by inhibiting nociceptor-induced (neurogenic) inflammation should also be considered. Peripheral afferent nociceptors, including those in joints, contain polypeptide mediators, such as substance P, that are released from their terminals when the neurons are activated. Substance P is a vasodilator and a chemoattractant for leucocytes, degranulates mast cells and increases the production and release of a variety of inflammatory mediators. Levine et al. [36] have shown that the content of neuron-associated substance P and the density of innervation of nociceptive afferents in normal rats correlate with the risk for more severe joint injury after the induction of adjuvant-induced arthritis. Bjorkman [37, 38] found that ACET interferes with nociception-associated spinal activation of N-methyl-D-aspartate (NMDA) receptors through the inhibition of spinal nitric oxide (NO) mechanisms. Like substance P, NO has been implicated as an inflammatory mediator in OA. Inhibition of inducible NO synthase was reported to ameliorate the severity of OA in the canine cruciate-deficiency model of OA [39]. Whether therapeutic doses of ACET reduce the levels of substance P and/or NO in the joint is unknown.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
References
 
We thank Linda Ragozzino, RN, for her assistance with the study. Louis Rankin provided great help with the quantitative measurements of effusion volume and synovial volume, and Kathie Lane provided invaluable secretarial support. This study was supported by a research grant from McNeil Personal Products Corporation.

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 6 December 2005; revised version accepted 21 February 2006.
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