Effect of glucosamine hydrochloride in the treatment of pain of osteoarthritis of the knee. A randomized, double-blind, placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee. Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis. A 3-month, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a highly optimized, capacitively coupled, pulsed electrical stimulator in patients with osteoarthritis of the knee. Effect of glucosamine sulfate on hip osteoarthritis: a randomized trial. Effectiveness of glucosamine for symptoms of knee osteoarthritis: results from an internet-based randomized double-blind controlled trial. Glucosamine for pain in osteoarthritis: why do trial results differ? Randomised, Double-Blind, Parallel, Placebo-Controlled Study of Oral Glucosamine, Methylsulfonylmethane and their Combination in Osteoarthritis. Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study.
Glucosamine products have been used extensively for the management of pain in osteoarthritis (OA). We investigated the efficacy of the hydrochloride salt of glucosamine on pain and disability in knee OA.
                At Week -2, subjects were examined, randomized, and instructed to take only prescribed acetaminophen for pain. At Week 0 patients were examined, prescribed acetaminophen, and either placebo or glucosamine hydrochloride (glucosamine). At Week 4 the prescriptions for acetaminophen and placebo or glucosamine were renewed. At Weeks 4 and 8, patients returned diaries and unused medications, and were examined. The WOMAC questionnaire was administered at Weeks -2, 0, and 8. After completing the randomized 8 week trial, subjects were offered known glucosamine hydrochloride capsules in an 8 week open label trial, with followup telephone survey after the 8 week open label trial.
                The primary endpoint (statistically significant difference in WOMAC pain score between Week 0 and Week 8) was not met. However, positive trends were noted for the glucosamine group in 23 of 24 WOMAC questions. A significant difference was noted from Week 5 through Week 8 in the knee examination (p = 0.026) and in the response to a daily diary pain question (p = 0.018). However, responding to the question, "Are you better than at the start of the trial?", 40% of placebo and only 49% of glucosamine subjects answered in the affirmative (p = 0.58). At the end of the randomized trial, 34% of placebo and 47% of glucosamine subjects believed that they had been given glucosamine. After the end of the 8 week open label trial, 77% of the subjects were still taking glucosamine, although now obliged to pay for commercially available products.
                There was no significant difference in pain reduction between the glucosamine hydrochloride and placebo groups as measured by WOMAC. However, the secondary endpoints of cumulative pain reduction as measured by daily diary and knee examination were favorable, suggesting that glucosamine hydrochloride benefits some patients with knee OA. A randomized, placebo-controlled, double-blind trial of the relative effectiveness of glucosamine sulphate and placebo in managing pain in osteoarthritis (OA) of the knee.
                Eighty patients with OA of the knee were recruited from a rheumatology out-patient clinic and received either glucosamine sulphate 1500 mg daily for 6 months or dummy placebo. The primary outcome measure was patients' global assessment of pain in the affected knee.
                Area under the curve analysis for the primary outcome measure showed no difference between placebo and glucosamine [mean difference 0.15 mm, 95% confidence interval (CI) -8.78 to 9.07]. The placebo response was 33%. There was a statistically significant difference between groups in knee flexion (mean difference 13 degrees, 95% CI -23.13 to -1.97), but this difference was small and could have been due to measurement error.
                As a symptom modifier in OA patients with a wide range of pain severities, glucosamine sulphate was no more effective than placebo. To assess the efficacy of glucosamine sulfate in knee osteoarthritis (OA).
                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.
                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.
                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. To investigate the efficacy and safety of a capacitively coupled, pulsed electrical stimulation device in treating knee osteoarthritis (OA).
                Fifty-eight outpatients with moderate to severe OA of the knee entered a 3-month, double-blind, placebo-controlled trial, using either an active or placebo device at home for 6 to 14 h/day. Outcome measures included a patient global evaluation, a patient report of knee pain severity, and the Western Ontario and McMaster Universities (WOMAC) questionnaire.
                Active treatment provided superior outcomes between baseline and 3-month follow-up measurements: 50.6% greater improvement than placebo in patient global (P=0.03), 31.2% in patient pain (P=0.04), 25.1% in WOMAC stiffness (P=0.03), 29.5% in WOMAC function (P=0.01), 19.9% in WOMAC pain (P=0.11), and 27% in total WOMAC (P=0.01). The percent of patients who improved by more than 50% was 38.5 active vs 5.3 placebo in patient global (P=0.01), 43.6 vs 15.8 in patient pain (P=0.04), 38.5 vs 10.5 in WOMAC pain (P=0.03), 28.2 vs 5.3 in WOMAC stiffness (P=0.08), 23.1 vs 5.3 in WOMAC function (P=0.14), and 23.1 vs 5.3 in total WOMAC (P=0.14). Twenty-one percent of placebo and 18% of actively treated patients developed a transient rash at the electrode sites. No other adverse device effects were reported.
                A highly optimized, capacitively coupled, pulsed electrical stimulus device significantly improved symptoms and function in knee OA without causing any serious side effects. The effectiveness of glucosamine sulfate as a symptom and disease modifier for osteoarthritis is still under debate.
                To assess whether glucosamine sulfate has an effect on the symptoms and structural progression of hip osteoarthritis during 2 years of treatment.
                Randomized, controlled trial.
                Primary care in the Netherlands.
                222 patients with hip osteoarthritis who were recruited by their general practitioner. Patients were eligible if they met the American College of Rheumatology clinical criteria for hip osteoarthritis.
                2 years of treatment with 1500 mg of oral glucosamine sulfate or placebo once daily.
                Primary outcome measures were Western Ontario and McMaster Universities (WOMAC) pain and function subscales over 24 months and joint space narrowing after 24 months. The main secondary outcome measures were WOMAC pain, function, and stiffness after 3, 12, and 24 months.
                At baseline, both groups were similar in demographic and clinical variables. Overall, WOMAC pain did not differ (mean difference [glucosamine sulfate minus placebo], -1.54 [95% CI, -5.43 to 2.36]), nor did WOMAC function (mean difference, -2.01 [CI, -5.38 to 1.36]). Joint space narrowing also did not differ after 24 months (mean difference, -0.029 [CI, -0.122 to 0.064]). Only 1 of the sensitivity analyses, based on extreme assumptions regarding missing assessments due to total hip replacement, provided results consistent with a glucosamine effect.
                Twenty patients had total hip replacement during the trial. Half of the patients had a Kellgren and Lawrence score of 1.
                Glucosamine sulfate was no better than placebo in reducing symptoms and progression of hip osteoarthritis. International Standard Randomised Controlled Trial Number: ISRCTN54513166. To present the safety and effectiveness results of a prototypical 12-week, double-blind, randomized placebo-controlled trial of glucosamine among subjects with knee osteoarthritis who were recruited and followed entirely over the Internet.
                The study comprised 205 subjects aged 45 years or older with symptomatic knee osteoarthritis who were recruited over the Internet; eligibility was authenticated through medical record review. Participants were assigned randomly to 1.5 g/d of glucosamine (n = 101) or placebo (n = 104), of whom 108 completed the intervention (93 in each arm). The primary outcome measure was the pain subscale of the Western Ontario and McMaster Universities Osteoarthritis Index (Likert version). Additional outcome measures included the physical function and stiffness subscales and overall score of the questionnaire, and analgesic use.
                There was no difference between treatment and control groups in terms of change in pain score (2.0 +/- 3.4 vs. 2.5 +/- 3.8, P = 0.41), stiffness (0.7 +/- 1.6 vs. 0.8 +/- 1.5, P = 0.52), physical function (5.2 +/- 9.5 vs. 4.6 +/- 9.6, P = 0.49), overall score (7.8 +/- 13.1 vs. 7.8 +/- 13.5, P = 0.81), and analgesic use (133 +/- 553 vs. -88 +/- 755, P = 0.12). Stratification by osteoarthritis severity, glucosamine product, and use of a nonsteroidal anti-inflammatory drug, as well as exclusion of opiate users, did not alter the results. The number and type of adverse events reported was similar between the groups.
                Our results suggest that although glucosamine appears to be safe, it is no more effective than placebo in treating the symptoms of knee osteoarthritis. Investigators in trials of glucosamine report a range of estimates for efficacy, making conclusions difficult. We undertook this study to identify factors that explain heterogeneity in trials of glucosamine.
                We searched for reports of trial results in Ovid Medline, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and proceedings of scientific conferences. We selected reports of randomized, double-blind, placebo-controlled trials of glucosamine for pain from osteoarthritis of the knee or hip. We extracted data regarding features of design, subjects, and markers of industry involvement, including industry funding, whether a drug was supplied by industry, industry participation, and industry-affiliated authorship. We examined which factors best accounted for differences in the effect sizes of studies grouped by these characteristics, and we examined changes in I(2), a measure of heterogeneity.
                Fifteen trials met our inclusion criteria. The summary effect size was 0.35 (95% confidence interval 0.14, 0.56). I(2) was 0.80. Except for allocation concealment, no feature of study design explained this substantial heterogeneity. Summary effect sizes ranged from 0.05 to 0.16 in trials without industry involvement, but the range was 0.47-0.55 in trials with industry involvement. The effect size was 0.06 for trials using glucosamine hydrochloride and 0.44 for trials using glucosamine sulfate. Trials using Rottapharm products had an effect size of 0.55, compared with 0.11 for the rest.
                Heterogeneity among trials of glucosamine is larger than would be expected by chance. Glucosamine hydrochloride is not effective. Among trials with industry involvement, effect sizes were consistently higher. Potential explanations include different glucosamine preparations, inadequate allocation concealment, and industry bias. Glucosamine, classified as a slow-acting drug in osteoarthritis (SADOA), is an efficacious chondroprotective agent. Methylsulfonylmethane (MSM), the isoxidised form of dimethyl-sulfoxide (DSMO), is an effective natural analgesic and anti-inflammatory agent. The aim of this study was to compare the efficacy and safety of oral glucosamine (Glu), methylsulfonylmethane (MSM), their combination and placebo in osteoarthritis of the knee.
                A total of 118 patients of either sex with mild to moderate osteoarthritis were included in the study and randomised to receive either Glu 500mg, MSM 500mg, Glu and MSM or placebo capsules three times daily for 12 weeks. Patients were evaluated at 0 (before drug administration), 2, 4, 8 and 12 weeks post-treatment for efficacy and safety. The efficacy parameters studied were the pain index, the swelling index, visual analogue scale pain intensity, 15m walking time, the Lequesne index, and consumption of rescue medicine.
                Glu, MSM and their combination significantly improved signs and symptoms of osteoarthritis compared with placebo. There was a statistically significant decrease in mean (+/- SD) pain index from 1.74 +/- 0.47 at baseline to 0.65 +/- 0.71 at week 12 with Glu (p < 0.001). MSM significantly decreased the mean pain index from 1.53 +/- 0.51 to 0.74 +/- 0.65, and combination treatment resulted in a more significant decrease in the mean pain index (1.7 +/- 0.47 to 0.36 +/- 0.33; p < 0.001). After 12 weeks, the mean swelling index significantly decreased with Glu and MSM, while the decrease in swelling index with combination therapy was greater (1.43 +/- 0.63 to 0.14 +/- 0.35; p < 0.05) after 12 weeks. The combination produced a statistically significant decrease in the Lequesne index. All treatments were well tolerated.
                Glu, MSM and their combination produced an analgesic and anti-inflammatory effect in osteoarthritis. Combination therapy showed better efficacy in reducing pain and swelling and in improving the functional ability of joints than the individual agents. All the treatments were well tolerated. The onset of analgesic and anti-inflammatory activity was found to be more rapid with the combination than with Glu. It can be concluded that the combination of MSM with Glu provides better and more rapid improvement in patients with osteoarthritis. Conventional symptomatic treatments for osteoarthritis do not favorably affect disease progression. The aim of this randomized, placebo-controlled trial was to determine whether long-term (3-year) treatment with glucosamine sulfate can modify the progression of joint structure and symptom changes in knee osteoarthritis, as previously suggested.
                Two hundred two patients with knee osteoarthritis (using American College of Rheumatology criteria) were randomized to receive oral glucosamine sulfate, 1500 mg once a day, or placebo. Changes in radiographic minimum joint space width were measured in the medial compartment of the tibiofemoral joint, and symptoms were assessed using the algo-functional indexes of Lequesne and WOMAC (Western Ontario and McMaster Universities).
                Osteoarthritis was of mild to moderate severity at enrollment, with average joint space widths of slightly less than 4 mm and a Lequesne index score of less than 9 points. Progressive joint space narrowing with placebo use was -0.19 mm (95% confidence interval, -0.29 to -0.09 mm) after 3 years. Conversely, there was no average change with glucosamine sulfate use (0.04 mm; 95% confidence interval, -0.06 to 0.14 mm), with a significant difference between groups (P =.001). Fewer patients treated with glucosamine sulfate experienced predefined severe narrowings (>0.5 mm): 5% vs 14% (P =.05). Symptoms improved modestly with placebo use but as much as 20% to 25% with glucosamine sulfate use, with significant final differences on the Lequesne index and the WOMAC total index and pain, function, and stiffness subscales. Safety was good and without differences between groups.
                Long-term treatment with glucosamine sulfate retarded the progression of knee osteoarthritis, possibly determining disease modification.
Pooled results from studies using a non-Rotta preparation or adequate allocation concealment failed to show benefit in pain and WOMAC function while those studies evaluating the Rotta preparation showed that glucosamine was superior to placebo in the treatment of pain and functional impairment resulting from symptomatic OA.