What To Do About the Pain of No More Vioxx?

Source: Bruyere O, et al. Glucosamine sulfate reduces osteoarthritis progression in postmenopausal women with knee osteoarthritis: Evidence from two 3-year studies. Menopause 2004;11:138-143.

Abstract: This study was designed to investigate the effect of glucosamine sulfate on long-term symptoms and structure progression in postmenopausal women with knee osteoarthritis (OA). This study consisted of a preplanned combination of two 3-year, randomized, placebo-controlled, prospective, independent studies evaluating the effect of glucosamine sulfate on symptoms and structure modification in OA and post-hoc analysis of the results obtained in postmenopausal women with knee OA. Minimal joint space width was assessed at baseline and after three years from standing anteroposterior knee radiographs. Symptoms were scored by the algo-functional WOMAC index at baseline and after three years. All primary statistical analyses were performed in intention-to-treat, comparing joint space width and WOMAC changes between groups by ANOVA. Of 414 participants randomized in the two studies, 319 were postmenopausal women. At baseline, glucosamine sulfate and placebo groups were comparable for demographic and disease characteristics, both in the general population and in the postmenopausal women subset. After three years, postmenopausal participants in the glucosamine sulfate group showed no joint space narrowing (joint space change of +0.003 mm [95% confidence interval {CI} -0.09 to 0.11]), whereas participants in the placebo group experienced a narrowing of -0.33 mm (95% CI -0.44 to -0.22; P < 0.0001 between the two groups). Percent changes after three years in the WOMAC index showed an improvement in the glucosamine sulfate group (-14.1% [95% CI -22.2 to -5.9]) and a trend for worsening in the placebo group (5.4% [95% CI -4.9 to 15.7] [P = 0.003] between the two groups). This analysis, focusing on a large cohort of postmenopausal women, demonstrated for the first time that a pharmacological intervention for OA has a disease-modifying effect in this particular population, the most frequently affected by knee OA.

Source: Najm WI, et al. S-adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: A double-blind cross-over trial. BMC Musculoskelet Disord 2004;5:6.

Abstract: S-adenosylmethionine (SAMe) is a dietary supplement used in the management of OA symptoms. Studies evaluating SAMe in the management of OA have been limited to non-steroidal anti-inflammatory drugs (NSAIDs) for comparison. The present study compares the effectiveness of SAMe to a cyclooxygenase-2 (COX-2) inhibitor (celecoxib) for pain control and functional improvement, and to decrease side effects in people with OA of the knee. This randomized double-blind crossover study compared SAMe (1,200 mg) with celecoxib (Celebrex 200 mg) for 16 weeks to reduce pain associated with OA of the knee. Sixty-one adults diagnosed with OA of the knee were enrolled and 56 completed the study. Subjects were tested for pain, functional health, mood status, isometric joint function tests, and side effects. At the end of the first month of Phase 1, celecoxib showed significantly more reduction in pain than SAMe (P = 0.024). By the second month of Phase 1, there was no significant difference between both groups (P < 0.01). The duration of treatment and the interaction of duration with type of treatment were statistically significant (Ps < 0.029). On most functional health measures both groups showed a notable improvement from baseline; however, no significant difference between SAMe and celecoxib was observed. Isometric joint function tests appeared to be steadily improving over the entire study period regardless of treatment. SAMe has a slower onset of action but is as effective as celecoxib in the management of symptoms of knee OA. Longer studies are needed to evaluate the long-term effectiveness of SAMe and the optimal dose to be used.

Comments by Mary L Hardy, MD

In September of this year, Merck announced the voluntary withdrawal of refecoxib (Vioxx), the most common COX-2 selective non-steroidal anti-inflammatory (NSAID), from the market because of an increased risk of cardiovascular events.1 Experts have suggested that cardiovascular risk may be increased for all COX-2 inhibitors.2 Such concerns leave millions of osteoarthritis (OA) patients and their health care providers with a dilemma—how to get relief from the most common cause of musculoskeletal pain without risking cardiovascular complications or increasing the risk of gastrointestinal bleeding? Two commonly used dietary supplements may be part of the answer.

Glucosamine sulfate is the second most commonly used over-the-counter medication for OA.3 In this instance, the consumer-patients are onto something. A large meta-analysis has demonstrated significant relief of OA symptoms by glucosamine, either alone or in combination with chondroitin sulfate.4 Early data in these studies, intriguingly, suggested that glucosamine actually might reverse or ameliorate the basic disease process of OA—the destruction of intra-articular cartilage. The first study for consideration this month looks at the effect of oral glucosamine sulfate on disease progression in postmenopausal women.

Bruyere and colleagues combined and reanalyzed data on postmenopausal women from two previously conducted studies.5 Both studies were randomized, double-blind, placebo-controlled trials designed to test the effects of 1,500 mg/d of glucosamine sulfate given for three years on both symptom relief and progression of disease. Data were included for all postmenopausal women in both trials (n = 319 of 414 total patients). Prior to intervention, treatment and placebo groups were comparable for demographics and disease severity. Likewise, there were no differences between the postmenopausal women and the rest of the subjects not included in this analysis with respect to age or disease severity. Symptoms and functionality were assessed using a standardized scale (WOMAC). Joint space was measured using a standing anteroposterior X-ray; a wider joint space correlates with a larger amount of intra-articular cartilage. After three years, not only did the WOMAC scale results improve, but the disease progress in the treatment group was stabilized. The WOMAC scales improved 14% with treatment, while the placebo group worsened (P = 0.003). The joint space of treated women did not increase in these studies, but this was still significantly better than the placebo group where the joint space actually narrowed by 0.33 mm (P < 0.0001). These highly significant results demonstrate that not only did glucosamine relieve pain, but it stabilized the underlying disease process. This finding is exciting, because neither NSAIDs nor acetaminophen, the most popular treatments for OA, do anything to change disease progression.

A second dietary supplement of interest for the treatment of OA, S-adensylmethionine (SAMe), is better known as an antidepressant than an anti-inflammatory. However, SAMe has been shown in a recent meta-analysis to be effective at relieving symptoms of OA in both placebo controlled trials as well as in comparison to non-selective NSAIDs.7 Since we are looking for a reasonable substitute for COX-2 inhibitors, a more recent study by Najm et al, which compares SAMe to celecoxib (Celebrex), is appropriate to consider more closely.8

Sixty-one adults with OA of the knee were enrolled in a randomized, double-blind, crossover trial. Patients were given either 600 mg of SAMe or 100 mg of celecoxib twice daily for eight weeks. After a one-week washout period, subjects were crossed over to the alternate treatment. Pain, functionality, mood, and activity impairment were tested using standard scales. After the first four weeks of treatment, the COX-2 inhibitor was superior to SAMe for symptom relief, but after an additional four weeks of treatment, there was no difference in efficacy between groups. This difference also was noted for patients who crossed over from celecoxib to SAMe. Their pain was greater in the first month of treatment, but no different after that. Tests of function, mood, and general well-being were not different between treatments at any time. It is interesting to note that the pain relief from SAMe continued to increase throughout treatment and had not plateaued by the end of the trial period. So, it is possible that the benefit of SAMe would be even better than demonstrated in this trial given longer use.

A word about the safety profile of both of these medications is indicated, since that was what started us on this search. Glucosamine is very well-tolerated, with only mild gastrointestinal side effects reported. Concern had been raised that glucosamine might decrease glucose control in diabetics. A randomized controlled trial using 1,500 mg of glucosamine with 1,200 mg of chondroitin in Type 2 diabetics for 90 days showed no adverse effects on glucose control.9 SAMe is likewise well-tolerated with the exception of mild gastrointestinal symptoms and the uncommon possibility of triggering mania in a depressed patient, a possibility with any antidepressant.7 The greatest challenge to using adequate doses of SAMe is price. The dose of 1,200 mg/d may be out of the range of some consumers. Products that combine the full dose of glucosamine with a more modest dose of SAMe have been developed and should be considered for patients where cost of SAMe is an issue. Both of these products have been tested in multiple clinical trials involving large numbers of patients for significant time periods without serious problems. Both of these products are different from NSAIDs—they require a significant time period to work (at least 4-8 weeks) and require chronic use to maintain efficacy.

Therefore, when your patients ask you, "What can I use now that my Vioxx is taken off the market?" it would be appropriate to consider both glucosamine and SAMe, which have been shown to be safe and effective for the treatment of OA.

Dr. Hardy, Associate Director, UCLA Center for Dietary Supplement Research: Botanicals Medical Director, Cedars-Sinai Integrative Medicine Program Los Angeles CA, is on the Editorial Advisory Board for Alternative Therapies in Women’s Health.


1. Merck announces voluntary worldwide withdrawal of VIOXX. Available at: www.vioxx.com/rofecoxib/vioxx/consumer/index.jsp. Accessed Oct. 5, 2004.

2. Mukherjee D, et al. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001;286:954-959.

3. Jordan KM, et al. The use of conventional and complementary treatments for knee osteoarthritis in the community. Rheumatology (Oxford) 2004;43:381-384.

4. Richy F, et al. Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: A comprehensive meta-analysis. Arch Intern Med 2003;163:1514-1522.

5. Bruyere O, et al. Glucosamine sulfate reduces osteoarthritis progression in postmenopausal women with knee osteoarthritis: Evidence from two 3-year studies. Menopause 2004;11: 138-143.

6. Einhorn TA. If it feels good, do it: Use of glucosamine sulfate to prevent the progression of osteoarthritis in postmenopausal women. Menopause 2004;11:134-135.

7. Hardy M, et al. S-Adenosyl-L-Methionine for treatment of depression, osteoarthritis, and liver disease. Agency for Healthcare Research and Quality. AHRQ Publication No. 02-E034. Available at: www.ahrq.gov.

8. Najm WI, et al. S-adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: A double-blind cross-over trial. BMC Musculoskelet Disord 2004;5:6.

9. Scroggie DA,et al. The effect of glucosamine-chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: A placebo-controlled, double-blinded, randomized clinical trial. Arch Intern Med 2003;163:1587-1590.