Randomized,double‐blind,placebo‐controlled glucosamine discontinuation trial in knee osteoarthritis

Objective

To assess the efficacy of glucosamine sulfate in knee osteoarthritis (OA).

Methods

A 4‐center, 6‐month, randomized, double‐blind, placebo‐controlled glucosamine discontinuation trial was conducted in 137 current users of glucosamine with knee OA who had experienced at least moderate improvement in knee pain after starting glucosamine. Study medication dosage was equivalent to the dosage of glucosamine taken prior to the study (maximum 1,500 mg/day). Followup continued for 6 months or until disease flare, whichever occurred first. The primary outcome was the proportion of disease flares in the glucosamine and placebo groups using an intent‐to‐treat analysis. Secondary outcomes included time to disease flare; analgesic medication use; severity of disease flare; and change in pain, stiffness, function and quality of life in the glucosamine and placebo groups.

Results

Disease flare was seen in 28 (42%) of 66 placebo patients and 32 (45%) of 71 glucosamine patients (difference ?3%; 95% confidence interval [95% CI] ?19, 14; P = 0.76). In the Cox regression analysis, after adjustment for sex, study site, and OA radiographic severity, time to disease flare was not significantly different in the glucosamine compared with placebo group (hazard ratio of flare = 0.8; 95% CI 0.5, 1.4; P = 0.45). At final study visit, acetaminophen was used in 27% and 21% of placebo and glucosamine patients, respectively (P = 0.40), nonsteroidal antiinflammatory drugs were used in 29% and 30% (P = 0.92), and both were used in 20% and 21% (P = 0.84). No differences were found in severity of disease flare or other secondary outcomes between placebo and glucosamine patients.

Conclusion

In patients with knee OA with at least moderate subjective improvement with prior glucosamine use, this study provides no evidence of symptomatic benefit from continued use of glucosamine sulfate.

     

Symptomatic effects of chondroitin 4 and chondroitin 6 sulfate on hand osteoarthritis: A randomized,double‐blind,placebo‐controlled clinical trial at a single center

Objective

To evaluate the symptomatic effects of highly purified chondroitin 4 and chondroitin 6 sulfate (CS) therapy in patients with osteoarthritis (OA) of the hand.

Methods

This investigator‐initiated, single‐center, randomized, double‐blind, placebo‐controlled clinical trial included 162 symptomatic patients with radiographic evidence of hand OA (American College of Rheumatology criteria). Inclusion criteria included patient's assessment of global spontaneous hand pain of at least 40 mm on a 0–100‐mm visual analog scale (VAS) and functional impairment of at least 6 (0–30 scale) on the Functional Index for Hand OA (FIHOA) in the most symptomatic hand. Patients received either 800 mg of CS (n = 80 patients) or placebo (n = 82 patients) once daily for 6 months and were analyzed in an intent‐to‐treat approach. The two primary outcomes were the change in the patient's assessment of global spontaneous hand pain and in hand function (by FIHOA score) from baseline to month 6. Secondary outcomes were improvement in grip strength, duration of morning stiffness, acetaminophen consumption, and the investigator's global impression of treatment efficacy.

Results

There was a significantly more pronounced decrease in the patient's global assessment of hand pain in the CS group than in the placebo group (difference VAS scores −8.7 mm; P = 0.016). Hand function improved significantly more in the CS group than in the placebo group (difference in FIHOA scores −2.14; P = 0.008). There was a statistically significant between‐group difference in favor of CS for the duration of morning stiffness and for the investigator's global impression of treatment efficacy. Changes in grip strength, acetaminophen consumption, and safety end points were not significantly different between the two groups.

Conclusion

This study demonstrates that CS improves hand pain and function in patients with symptomatic OA of the hand and shows a good safety profile.

     

Long‐term effects of chondroitins 4 and 6 sulfate on knee osteoarthritis: The study on osteoarthritis progression prevention,a two‐year,randomized, double‐blind,placebo‐controlled trial

Objective

To assess the long‐term effects of chondroitins 4 and 6 sulfate (CS) on the radiographic progression of, and symptom changes associated with, knee osteoarthritis (OA).

Methods

We performed an international, randomized, double‐blind, placebo‐controlled trial in which 622 patients with knee OA were randomly assigned to receive either 800 mg CS (n = 309 patients) or placebo (n = 313 patients) once daily for 2 years. Radiographs of the target knee, using the Lyon schuss view, were obtained at the time of enrollment and at 12, 18, and 24 months. The minimum joint space width (JSW) of the medial compartment of the tibiofemoral joint was assessed by digital image analysis. The primary outcome was the loss in minimum JSW over 2 years.

Results

The intent‐to‐treat analysis demonstrated a significant reduction (P < 0.0001) in minimum JSW loss in the CS group (mean ± SEM −0.07 ± 0.03 mm) as compared with the placebo group (−0.31 ± 0.04 mm). The percentage of patients with radiographic progression ≥0.25 mm was significantly reduced in the CS group compared with the placebo group (28% versus 41% [P < 0.0005]; relative risk reduction 33% [95% confidence interval 16–46%]). The number of patients needed to treat was 8 (95% confidence interval 5–17). Pain improved significantly faster in the CS group than in the placebo group (P < 0.01). There were no differences in safety between groups.

Conclusion

The long‐term combined structure‐modifying and symptom‐modifying effects of CS suggest that it could be a disease‐modifying agent in patients with knee OA.

     

Evaluation of the structure‐modifying effects of diacerein in hip osteoarthritis: ECHODIAH,a three‐year,placebo‐controlled trial

Objective

To evaluate the ability of diacerein, an interleukin‐1β inhibitor, to slow the progressive decrease in joint space width observed in patients with hip osteoarthritis (OA).

Methods

In this randomized, double‐blind, placebo‐controlled 3‐year study, 507 patients with primary OA of the hip (by the American College of Rheumatology criteria) received diacerein (50 mg twice a day) or placebo. The minimal hip joint space width was measured by a central reader on yearly pelvic radiographs, using a 0.1‐mm–graduated magnifying glass.

Results

Baseline characteristics were comparable in the 2 treatment groups (255 patients receiving diacerein, 252 receiving placebo); 238 patients (47%) discontinued the study, mainly because of adverse events in the diacerein group (25% versus 12% with placebo) and because of inefficacy in the placebo group (14% versus 7% with diacerein). The percentage of patients with radiographic progression, defined by a joint space loss of at least 0.5 mm, was significantly lower in patients receiving diacerein than in patients receiving placebo, both in the intent‐to‐treat analysis and in the completer analysis (50.7% versus 60.4% [P = 0.036] and 47.3% versus 62.3% [P = 0.007], respectively). In those patients who completed 3 years of treatment, the rate of joint space narrowing was significantly lower with diacerein (mean ± SD 0.18 ± 0.25 mm/year versus 0.23 ± 0.23 mm/year with placebo; P = 0.042). Diacerein had no evident effect on the symptoms of OA in this study. However, a post hoc covariate analysis that took into account the use of analgesics and antiinflammatory drugs showed an effect of diacerein on the Lequesne functional index. Diacerein was well tolerated during the 3‐year study. The most frequent adverse events were transient changes in bowel habits.

Conclusion

This study confirms previous clinical findings indicating that the demonstration of a structure‐modifying effect in hip OA is feasible, and shows, for the first time, that treatment with diacerein for 3 years has a significant structure‐modifying effect as compared with placebo, coupled with a good safety profile. The clinical relevance of these findings requires further investigation.

     

Intraarticular injection of anakinra in osteoarthritis of the knee: A multicenter,randomized, double‐blind,placebo‐controlled study

Objective

To evaluate the clinical response, safety, and tolerability of a single intraarticular injection of anakinra in patients with symptomatic osteoarthritis (OA) of the knee.

Methods

Patients with OA of the knee were enrolled in a multicenter, double‐blind, placebo‐controlled study and randomized 2:1:2 to receive a single intraarticular injection of placebo, anakinra 50 mg, or anakinra 150 mg in their symptomatic knee. Patients were evaluated for 12 weeks postinjection. The primary end point was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score from baseline to week 4. Safety assessments included the evaluation of adverse events (AEs), laboratory tests, and vital signs. Pharmacokinetic parameters were assessed in a subset of patients.

Results

Of 170 patients who enrolled, 160 (94%) completed the study. The mean improvements from baseline to week 4 in the WOMAC score were not statistically different between the placebo group and the patients who received 50 mg of anakinra (P = 0.67) or 150 mg of anakinra (P = 0.77). Anakinra was well tolerated. No withdrawals due to AEs or serious AEs, and no serious infections or deaths were reported. No clinically significant trends were noted in laboratory values or vital signs. Pharmacokinetic parameters demonstrated that the mean terminal half‐life of anakinra in serum after intraarticular injection was ∼4 hours.

Conclusion

Anakinra was well tolerated as a single 50‐mg or 150‐mg intraarticular injection in patients with OA of the knee. However, anakinra was not associated with improvements in OA symptoms compared with placebo.

     

A randomized controlled trial to evaluate the slow‐acting symptom‐modifying effects of colchicine in osteoarthritis of the knee: A preliminary report

Objective

To determine if colchicine added to nimesulide may have a beneficial effect on osteoarthritis (OA) of the knee.

Methods

Colchicine 0.5 mg twice daily or placebo was added to nimesulide (a nonsteroidal antiinflammatory drug) in 36 patients with OA of the knee in a randomized, double‐blind, placebo‐controlled trial over a 5‐month period.

Results

The 30% improvement rate at 20 weeks was higher in the colchicine group than in the control group receiving placebo, as measured by total Western Ontario and McMaster University Osteoarthritis scores (57.9% versus 23.5%) and visual analog scale for index knee pain (52.6% versus 17.6%) (primary measures of response). The significance persisted on combined analysis by Mantel‐Haenszel test (P = 0.062). Comparison of means also showed significant improvement in the colchicine group versus the control group in a multivariate analysis performed using T² test (P = 0.0115).

Conclusion

Among patients with OA of the knee, the group receiving colchicine plus nimesulide exhibited significantly greater symptomatic benefit at 20 weeks than did the control group receiving nimesulide plus placebo.

     

Steroid injection for osteoarthritis of the hip: A randomized,double‐blind,placebo‐controlled trial

Objective

To determine the efficacy of fluoroscopically guided corticosteroid injection for hip osteoarthritis (OA) in a randomized, double‐blind, placebo‐controlled trial.

Methods

Fifty‐two patients with symptomatic hip OA were randomly allocated to receive placebo (10 mg bipuvicaine, 2 ml saline) (n = 21) or corticosteroid treatment (10 mg bipuvicaine, 40 mg triamcinolone hexacetonide) (n = 31). Patients were followed up for 1, 2, 3, and 6 months. The primary outcome measure was the pain improvement response, defined as a 20% decrease in the Western Ontario and McMaster Universities OA Index (WOMAC) pain score (on 5 100‐mm visual analog scales [VAS]) (WOMAC20) from baseline to 2 months postinjection. Secondary outcomes were a 50% decrease in the WOMAC pain score (WOMAC50), changes in other WOMAC subscale scores, patient's global assessment of health (on a 100‐mm VAS), and Short Form 36 (SF‐36) quality of life indices. Analyses were based on the intent‐to‐treat principle.

Results

The mean WOMAC pain score fell 49.2% (decreasing from 310.1 mm to 157.4 mm) at 2 months postinjection in patients receiving corticosteroid, compared with a decrease of 2.5% (from 314.3 mm to 306.5 mm) in the placebo group (P < 0.0001). The proportion of WOMAC20 responders at 2 months' followup was significantly higher in the corticosteroid group (67.7%) compared with the placebo group (23.8%) (P = 0.004); similar proportions of WOMAC50 responders were observed between groups (61.3% in the corticosteroid group versus 14.3% in the placebo group; P = 0.001). Response differences were maintained at 3 months' followup (58.1% responders in the corticosteroid group versus 9.5% responders in the placebo group; P = 0.004). Significant differences in the WOMAC stiffness and physical function scores (P < 0.0001), patient's global health scores (P = 0.005), and SF‐36 physical component scores (P = 0.04) were observed, with patients in the corticosteroid group showing greater improvements. There were no differences in the frequency of adverse events between groups.

Conclusion

This placebo‐controlled trial confirms that corticosteroid injection can be an effective treatment of pain in hip OA, with benefits lasting up to 3 months in many cases. Future studies should address questions related to the benefits of repeated steroid injection and the effects of this treatment on disease modification.

     

A six‐month followup of a randomized trial comparing the efficacy of a lateral‐wedge insole with subtalar strapping and an in‐shoe lateral‐wedge insole in patients with varus deformity osteoarthritis of the knee

Objective

To assess the effect of a lateral‐wedge insole with elastic strapping of the subtalar joint on the femorotibial angle in patients with varus deformity of the knee.

Methods

The efficacy of a wedged insole with subtalar straps and that of a traditional wedged insole shoe insert were compared. Sixty‐six female outpatients with knee osteoarthritis (OA) were randomized (according to birth date) to be treated with either the strapped or the traditional inserted insole. Standing radiographs with unilateral insole use were used to analyze the femorotibial angles for each patient. In both groups, the baseline and 6‐month visual analog scale (VAS) scores for subjective knee pain and the Lequesne index scores for knee OA were compared.

Results

The 61 patients who completed the 6‐month study were evaluated. At baseline, there was no significant difference in the femorotibial angle (P = 0.66) and the VAS score (P = 0.75) between the 2 groups. At the 6‐month assessment, the 29 subjects wearing the subtalar‐strapped insole demonstrated a significantly decreased femorotibial angle (P < 0.0001) and significantly improved VAS scores (P = 0.001) and Lequesne index scores (P = 0.033) compared with their baseline assessments. These significant differences were not observed in the 32 subjects assigned to the traditional shoe‐inserted wedged insole.

Conclusion

These results suggest that an insole with a subtalar strap maintained the valgus correction of the femorotibial angle in patients with varus knee OA for 6 months, indicating longer‐term clinical improvement with the strapped insert compared with the traditional insert.

     

Increase in vastus medialis cross‐sectional area is associated with reduced pain,cartilage loss,and joint replacement risk in knee osteoarthritis

Objective

Although there is evidence for a beneficial effect of increased quadriceps strength on knee symptoms, the effect on knee structure is unclear. We undertook this study to examine the relationship between change in vastus medialis cross‐sectional area (CSA) and knee pain, tibial cartilage volume, and risk of knee replacement in subjects with symptomatic knee osteoarthritis (OA).

Methods

One hundred seventeen subjects with symptomatic knee OA underwent magnetic resonance imaging of the knee at baseline and at 2 and 4.5 years. Vastus medialis CSA was measured at baseline and at 2 years. Tibial cartilage volume was measured at baseline and at 2 and 4.5 years. Knee pain was assessed by the Western Ontario and McMaster Universities Osteoarthritis Index at baseline and at 2 years. The frequency of knee joint replacement over 4 years was determined. Regression coefficients (B) and odds ratios were determined along with 95% confidence intervals (95% CIs).

Results

After adjusting for confounders, baseline vastus medialis CSA was inversely associated with current knee pain (r = −0.16, P = 0.04) and with medial tibial cartilage volume loss from baseline to 2 years (B coefficient −10.9 [95% CI −19.5, −2.3]), but not with baseline tibial cartilage volume. In addition, an increase in vastus medialis CSA from baseline to 2 years was associated with reduced knee pain over the same time period (r = 0.24, P = 0.007), reduced medial tibial cartilage loss from 2 to 4.5 years (B coefficient −16.8 [95% CI −28.9, −4.6]), and reduced risk of knee replacement over 4 years (odds ratio 0.61 [95% CI 0.40, 0.94]).

Conclusion

In a population of patients with symptomatic knee OA, increased vastus medialis size was associated with reduced knee pain and beneficial structural changes at the knee, suggesting that management of knee pain and optimizing vastus medialis size are important in reducing OA progression and subsequent knee replacement.

     

Use of 3H‐glucosamine and 35S‐sulfate with cultured human chondrocytes to determine the effect of glucosamine concentration on formation of chondroitin sulfate

Objective

To determine whether addition of glucosamine will stimulate synthesis of chondroitin sulfate by cultures of human chondrocytes, and to compare the relative contribution of endogenous glucosamine to exogenous glucosamine in forming chondroitin sulfate.

Methods

Cultured human chondrocytes were incubated with ³⁵S‐sulfate and various amounts of glucosamine to determine whether any incremental formation of chondroitin ³⁵S‐sulfate occurred. Similarly, chondrocytes incubated with variable concentrations of ³H‐glucosamine were examined to determine how much the incorporation into ³H‐chondroitin sulfate was diluted by provision of endogenous glucosamine that was derived by metabolism from glucose.

Results

No stimulation of chondroitin ³⁵S‐sulfate synthesis was found at concentrations of glucosamine up to 1 mM, a concentration of ³H‐glucosamine well above the concentrations that could be presented to cartilage after ingestion of advertised amounts of glucosamine. Furthermore, there was significant dilution of exogenous glucosamine by endogenous glucosamine provided by metabolism from glucose.

Conclusion

The results indicate that exogenous glucosamine does not stimulate chondroitin sulfate synthesis by human chondrocytes. Furthermore, the cells have the capacity to form amounts of glucosamine from glucose far in excess of that provided from exogenous sources, except at concentrations greater than could possibly be achieved with oral administration of glucosamine.

     

Efficacy of celecoxib,a cyclooxygenase 2–specific inhibitor,in the treatment of ankylosing spondylitis: A six‐week controlled study with comparison against placebo and against a conventional nonsteroidal antiinflammatory drug

Objective

To evaluate the short‐term efficacy of celecoxib, a cyclooxygenase 2–specific inhibitor, in the treatment of ankylosing spondylitis (AS).

Methods

The study was a 6‐week randomized, double‐blind, placebo‐controlled trial with 3 treatment arms: placebo, ketoprofen 100 mg twice daily, and celecoxib 100 mg twice daily. Patients who had AS according to the modified New York criteria, without peripheral synovitis and with active disease (pain ≥40 mm on a 100‐mm visual analog scale [VAS] and an increase in pain of at least 30% after nonsteroidal antiinflammatory drug withdrawal) were eligible for study. Primary outcome measures were change in pain intensity (VAS) and change in functional impairment (Bath Ankylosing Spondylitis Functional Index [BASFI]).

Results

Of the 246 randomized patients, 76 were allocated to receive placebo, 90 ketoprofen, and 80 celecoxib. There were no statistically significant differences between treatment groups at study entry. During the 6 weeks of the study, the decrease in pain and functional impairment was greater in the active treatment groups than in the placebo group, with a trend in favor of celecoxib when the 2 active treatments were compared. The mean changes were −13 mm, −21 mm, and −27 mm (P = 0.006) for pain and 1, −6, and −12 (P = 0.0008) for BASFI score in the placebo, ketoprofen, and celecoxib groups, respectively. During treatment, the number of patients reporting epigastric pain was 6 (8%), 13 (14%), and 10 (13%) in the placebo, ketoprofen, and celecoxib groups, respectively.

Conclusion

The results of this study confirm the clinically relevant antiinflammatory effect of celecoxib at a 200‐mg daily dosage, with significant improvement of both pain and function in patients with AS.

     

Comparing the efficacy of cyclooxygenase 2–specific inhibitors in treating osteoarthritis: Appropriate trial design considerations and results of a randomized,placebo‐controlled trial

Objective

To compare the efficacy of the cyclooxygenase 2 (COX‐2)–specific inhibitors celecoxib and rofecoxib in treating the signs and symptoms of osteoarthritis (OA).

Methods

In this randomized, placebo‐controlled, double‐blind, multicenter study, 475 patients with OA of the knee received either celecoxib 200 mg/day (n = 189), rofecoxib 25 mg/day (n = 190), or placebo (n = 96) for 6 weeks. Arthritis assessments were performed at baseline, week 3, and week 6 (or at the time of early termination).

Results

In primary measures of efficacy (OA pain score on a 100‐mm visual analog scale [VAS] and total domain score on the Western Ontario and McMaster Universities Osteoarthritis Index), celecoxib 200 mg/day and rofecoxib 25 mg/day demonstrated similar efficacy. At week 6, celecoxib was associated with a 34‐mm mean improvement on the VAS for OA pain, compared with 31.6 mm for rofecoxib and 21.2 mm for placebo. The difference between celecoxib and rofecoxib was −2.5 mm, with an upper limit of the 95% confidence interval of 2.7 mm and within the prespecified definition of noninferiority. Secondary measures of efficacy showed similar results. All differences in primary and secondary measures of efficacy between the 2 active treatments and placebo were statistically significant (P < 0.02), whereas all of the comparisons of efficacy between celecoxib and rofecoxib met the predefined criteria for noninferiority. All treatments were well tolerated throughout the study, with similar proportions of patients withdrawing due to adverse events.

Conclusion

Celecoxib 200 mg/day and rofecoxib 25 mg/day are equally efficacious in treating the signs and symptoms of OA.

     

The effectiveness of pulsed electrical stimulation in the management of osteoarthritis of the knee: Results of a double‐blind,randomized, placebo‐controlled,repeated‐measures trial

Objective

To determine the effectiveness of subsensory, pulsed electrical stimulation (PES) in the symptomatic management of osteoarthritis (OA) of the knee.

Methods

This was a double‐blind, randomized, placebo‐controlled, repeated‐measures trial in 70 participants with clinical and radiographically diagnosed OA of the knee who were randomized to either PES or placebo. The primary outcome was change in pain score over 26 weeks measured on a 100‐mm visual analog scale (VAS). Other measures included pain on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), function on the WOMAC, patient's global assessment of disease activity (on a 100‐mm VAS), joint stiffness on the WOMAC, quality of life on the Medical Outcomes Study Short‐Form 36 (SF‐36) health survey, physical activity (using the Human Activity Profile and an accelerometer), and global perceived effect (on an 11‐point scale).

Results

Thirty‐four participants were randomized to PES and 36 to placebo. Intent‐to‐treat analysis showed a statistically significant improvement in VAS pain score over 26 weeks in both groups, but no difference between groups (mean change difference 0.9 mm [95% confidence interval −11.7, 13.4]). Similarly, there were no differences between groups for changes in WOMAC pain, function, and stiffness scores (−5.6 [95% confidence interval −14.9, 3.6], −1.9 [95% confidence interval −9.7, 5.9], and 3.7 [95% confidence interval −6.0, 13.5], respectively), SF‐36 physical and mental component summary scores (1.7 [95% confidence interval −1.5, 4.8] and 1.2 [95% confidence interval −2.9, 5.4], respectively), patient's global assessment of disease activity (−2.8 [95% confidence interval −13.9, 8.4]), or activity measures. Fifty‐six percent of the PES‐treated group achieved a clinically relevant 20‐mm improvement in VAS pain score at 26 weeks compared with 44% of controls (12% [95% confidence interval −11%, 33%]).

Conclusion

In this sample of subjects with mild‐to‐moderate symptoms and moderate‐to‐severe radiographic OA of the knee, 26 weeks of PES was no more effective than placebo.

     

The effect of estrogen plus progestin on knee symptoms and related disability in postmenopausal women: The heart and estrogen/progestin replacement study,a randomized,double‐blind,placebo‐controlled trial

Objective

Most observational studies suggest that postmenopausal women taking hormone replacement therapy have a reduced risk of radiographic knee and hip osteoarthritis (OA). There are no randomized trial data on the association of hormone treatment with knee or hip OA, and no studies have been published regarding the relationship of hormone treatment to knee or hip symptoms. This study examined the association of hormone treatment with prevalent knee symptoms and disability related to knee pain as assessed at the final visit of the Heart and Estrogen/Progestin Replacement Study (HERS).

Methods

The HERS was a 4‐year randomized, double‐blind, placebo‐controlled trial of estrogen plus medroxy progesterone acetate for prevention of coronary heart disease in postmenopausal women with documented coronary disease. Participants in this substudy on knee pain were 969 postmenopausal women, with a mean age of 66 years and mean body mass index of 28.6 kg/m², attending the final visit at 9 clinical centers. Frequent knee symptoms were assessed by interview and the severity of knee pain and disability related to knee pain were determined using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Knee symptoms and disability were compared between women assigned to receive hormones and those assigned to receive placebo.

Results

Frequent knee pain was reported in 24.1% of women assigned to receive hormone therapy versus 26.1% of those assigned to the placebo group, a difference of −2.0% (95% confidence interval [95% CI] −7.4% to 3.5%). Among women with knee pain, there were no differences in the severity of pain (score difference −0.2, 95% CI −1.2 to 0.8) or disability (score difference −0.7, 95% CI −3.8 to 2.4) as assessed on the WOMAC. All results were similar for women whose body mass index was either above or below the median.

Conclusion

In a group of older, postmenopausal women with cardiac disease, we found no significant effect of 4 years of estrogen plus progestin therapy compared with placebo on knee pain and related disability. Our findings may not apply to other groups of women or to the effect of hormone therapy on the structural changes of knee OA.

     

Transdermal fentanyl for improvement of pain and functioning in osteoarthritis: A randomized,placebo‐controlled trial

Objective

Although common treatments for osteoarthritis (OA) pain, such as nonsteroidal antiinflammatory drugs (NSAIDs), simple analgesics, and weak opioids, provide relief in some cases, they fail to control pain or are poorly tolerated in many cases. Strong opioids have been used to successfully treat several types of noncancer pain but have rarely been tested in controlled studies. Therefore, we tested the effects of transdermal fentanyl (TDF) in patients with moderate‐to‐severe OA pain, in a placebo‐controlled study.

Methods

The cohort comprised patients with radiologically confirmed OA of the hip or knee (meeting the American College of Rheumatology criteria) requiring joint replacement and with moderate‐to‐severe pain that had been inadequately controlled by weak opioids. The patients were randomized to receive TDF or placebo for 6 weeks after a 1‐week pretreatment run‐in phase. During study treatment, previously prescribed NSAIDs and simple analgesics were continued, but weak opioids were discontinued. All patients had access to paracetamol and metoclopramide. Pain was recorded on a visual analog scale (VAS), and function was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).

Results

Data were available for 399 patients (202 receiving TDF, 197 receiving placebo), of whom 199 (50%) completed the study. TDF provided significantly better pain relief than placebo, as demonstrated by the primary outcome measure (area under the curve for VAS scores −20 in the TDF group versus −14.6 in the placebo group; P = 0.007). TDF was also associated with significantly better overall WOMAC scores and pain scores. The most common adverse events were nausea, vomiting, and somnolence, and these occurred more often in the TDF group.

Conclusion

TDF can reduce pain and improve function in patients with knee or hip OA.

     

Gabapentin in the treatment of fibromyalgia: A randomized,double‐blind,placebo‐controlled,multicenter trial

Objective

To assess the efficacy and safety of gabapentin in patients with fibromyalgia.

Methods

A 12‐week, randomized, double‐blind study was designed to compare gabapentin (1,200–2,400 mg/day) (n = 75 patients) with placebo (n = 75 patients) for efficacy and safety in treating pain associated with fibromyalgia. The primary outcome measure was the Brief Pain Inventory (BPI) average pain severity score (range 0–10, where 0 = no pain and 10 = pain as bad as you can imagine). Response to treatment was defined as a reduction of ≥30% in this score. The primary analysis of efficacy for continuous variables was a longitudinal analysis of the intent‐to‐treat sample, with treatment‐by‐time interaction as the measure of effect.

Results

Gabapentin‐treated patients displayed a significantly greater improvement in the BPI average pain severity score (P = 0.015; estimated difference between groups at week 12 = −0.92 [95% confidence interval −1.75, −0.71]). A significantly greater proportion of gabapentin‐treated patients compared with placebo‐treated patients achieved response at end point (51% versus 31%; P = 0.014). Gabapentin compared with placebo also significantly improved the BPI average pain interference score, the Fibromyalgia Impact Questionnaire total score, the Clinical Global Impression of Severity, the Patient Global Impression of Improvement, the Medical Outcomes Study (MOS) Sleep Problems Index, and the MOS Short Form 36 vitality score, but not the mean tender point pain threshold or the Montgomery Asberg Depression Rating Scale. Gabapentin was generally well tolerated.

Conclusion

Gabapentin (1,200–2,400 mg/day) is safe and efficacious for the treatment of pain and other symptoms associated with fibromyalgia.

     

Efficacy and safety of four doses of lumiracoxib versus diclofenac in patients with knee or hip primary osteoarthritis: A phase II,four‐week,multicenter, randomized,double‐blind,placebo‐controlled trial

Objective

To compare the efficacy and tolerability of the novel cyclooxygenase 2‐selective inhibitor lumiracoxib with placebo and diclofenac in osteoarthritis (OA).

Methods

Adults (n = 583) with knee or hip OA were randomized to receive for 4 weeks lumiracoxib 50, 100, or 200 mg twice daily or 400 mg once daily; placebo; or diclofenac 75 mg twice daily. Efficacy assessments included overall joint pain intensity and Western Ontario and McMaster Universities Osteoarthritis Index subscales; tolerability was evaluated by adverse event and physician reporting.

Results

All lumiracoxib doses were superior to placebo in relieving pain, improving stiffness, and improving physical function after 4 weeks. At study endpoint, pain relief was comparable among all lumiracoxib dosages and similar to diclofenac. Lumiracoxib tolerability was superior to diclofenac and comparable to placebo.

Conclusion

Lumiracoxib provides predictable and sustained relief from pain, stiffness, and impaired physical function in OA. Lumiracoxib shows clinically comparable efficacy and superior tolerability to diclofenac.

     

A randomized,placebo‐controlled,double‐masked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis

Objective

To investigate the safety and efficacy of etanercept in the treatment of uveitis associated with juvenile idiopathic arthritis (JIA).

Methods

Children who met the American College of Rheumatology diagnostic criteria for JIA with active uveitis, who had anterior chamber cells of ≥1+ or requiring topical corticosteroid ≥3 times daily, and who were on a stable regimen for arthritis treatment were eligible. Study participants received etanercept (0.4 mg/kg) or placebo administered subcutaneously twice weekly for 6 months. All participants received open‐label etanercept for an additional 6 months.

Results

Five patients received placebo and 7 received etanercept. Three of the 7 patients treated with etanercept and 2 of the 5 placebo‐treated patients were considered ophthalmic successes (P = 1.0). One patient in each treatment group was considered a treatment failure. Three of the 7 etanercept‐treated and 2 of the 5 placebo‐treated patients were neither successes nor failures by our definition. There were no serious adverse events for any patient during the entire study period. Reports of minor infections were comparable in each treatment group, 71% for etanercept and 60% for placebo (P = 0.58).

Conclusion

In this small pilot study there was no apparent difference in the anterior segment inflammation between patients treated with etanercept and placebo. The stringent criteria used to measure ophthalmic success of treatment and the small patient population limit the implications of our findings.

     

Dehydroepiandrosterone treatment of women with mild‐to‐moderate systemic lupus erythematosus: A multicenter randomized,double‐blind,placebo‐controlled trial

Objective

To evaluate the efficacy and tolerability of dehydroepiandrosterone (DHEA) at a dosage of 200 mg/day in adult women with active systemic lupus erythematosus (SLE).

Methods

In a multicenter randomized, double‐blind, placebo‐controlled trial, 120 adult women with active SLE received oral DHEA (200 mg/day; n = 61) or placebo (n = 59) for 24 weeks. The primary end point was the mean change from baseline in the Systemic Lupus Activity Measure (SLAM) score at 24 weeks of therapy. Secondary end points included time to first flare, change in SLE Disease Activity Index (SLEDAI) score, and physician's and patient's global assessment scores at week 24.

Results

The two groups were well balanced for baseline characteristics. Mean reductions in SLAM scores from baseline were similar and were not statistically significantly different between treatment groups (DHEA −2.6 ± 3.4 versus placebo −2.0 ± 3.8, mean ± SD). The number of patients with flares was decreased by 16% in the DHEA group (18.3% of DHEA‐treated patients versus 33.9% of placebo‐treated patients; P = 0.044, based on time to first flare). The mean change in the patient's global assessment was statistically significant between the two groups (DHEA −5.5 versus placebo 5.4; P = 0.005). The number of patients with serious adverse events, most of which were related to SLE flare, was significantly lower in DHEA‐treated patients compared with placebo‐treated patients (P = 0.010). Expected hormonal effects, including increased testosterone levels and increased incidence of acne, were observed. No life‐threatening reactions or serious safety issues were identified during this study.

Conclusion

The overall results confirm that DHEA treatment was well‐tolerated, significantly reduced the number of SLE flares, and improved patient's global assessment of disease activity.

     

Correlation of polymorphic variation in the promoter region of the interleukin‐1β gene with secretion of interleukin‐1β protein

Objective

Significant variation in interleukin‐1β (IL‐1β) protein secretion between subjects has been observed when using a lipopolysaccharide (LPS)/ATP–mediated ex vivo blood stimulation assay. To explore the potential relationships between genetic polymorphisms in the IL1B cytokine gene and cellular responses to inflammatory stimuli such as LPS, we investigated the hypothesis that polymorphisms within the promoter and exon 5 of the IL1B gene contribute to the observed differences in IL‐1β protein secretion.

Methods

The IL1B gene polymorphisms C−511T, T−31C, and C3954T were tested for association with LPS‐induced secretion of IL‐1β protein as measured by an ex vivo blood stimulation assay. Samples from 2 independent study populations (n = 31 and n = 25) were available for use in the ex vivo assay after consent was obtained to analyze the DNA.

Results

A specific haplotype, composed of the T allele at −511 and the C allele at −31, was significantly associated with a 2–3‐fold increase in LPS‐induced IL‐1β protein secretion. This association was observed in both of the independent study populations (P = 0.0084 and P = 0.0017).

Conclusion

These data suggest that polymorphisms within the promoter region of the IL1B gene contribute to observed differences in LPS‐induced IL‐1β protein secretion.