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OBJECTIVE: We assessed the efficacy of S-adenosylmethionine (SAMe), a dietary supplement now available in the United States, compared with that of placebo or nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of osteoarthritis (OA).
STUDY DESIGN: This was a meta-analysis of randomized controlled trials.
DATA SOURCES: We identified randomized controlled trials of SAMe versus placebo or NSAIDS for the treatment of OA through computerized database searches and reference lists.
OUTCOMES MEASURED: The outcomes considered were pain, functional limitation, and adverse effects.
RESULTS: Eleven studies that met the inclusion criteria were weighted on the basis of precision and were combined for each outcome variable. When compared with placebo, SAMe is more effective in reducing functional limitation in patients with OA (effect size [ES] = .31; 95% confidence interval [CI], .098 - .519), but not in reducing pain (ES = .22; 95% CI, -.247 to .693). This result, however, is based on only 2 studies. SAMe seems to be comparable with NSAIDs (pain: ES = .12; 95% CI, -.029 to .273; functional limitation: ES = .025; 95% CI, -.127 to .176). However, those treated with SAMe were less likely to report adverse effects than those receiving NSAIDs.
CONCLUSIONS: SAMe appears to be as effective as NSAIDs in reducing pain and improving functional limitation in patients with OA without the adverse effects often associated with NSAID therapies.
- S-adenosylmethionine (SAMe) is as effective as NSAIDs in offering pain relief and improving functional limitation with less risk of side effects.
- When compared with placebo, SAMe improved functional limitations of osteoarthritis, but there was no improvement in pain.
- The tolerability of SAMe was similar to that of placebo and greater than that of NSAIDs.
One alternative therapy for osteoarthritis (OA) is Sadenosylmethionine (SAMe), a naturally occurring sulphur-containing physiologic compound synthesized from amino acid L-methionine and adenosine triphosphate (ATP).1,2 Although scientists are not certain how it works to control pain, SAMe plays a key role in 3 major pathways: transmethylation, transsulfuration, and aminopropylation.2 SAMe was introduced in the United States in 1999 as a dietary supplement to promote joint health, mobility, and joint comfort. On the basis of a 1987 review of 12 clinical studies involving more than 20,000 patients, SAMe has been touted as “the prototype of a new class of safe drugs for the treatment of osteoarthritis.”3 However, the majority of the patients in those studies (97%) were enrolled in a single open field trial.
Although systematic reviews have demonstrated the benefit of other alternative strategies for OA, such as glucosamine and chondroitin,4,5 there has been no systematic review of SAMe for OA. Because individual studies of SAMe vary in their sample sizes and report conflicting results, we conducted a meta-analysis to assess the efficacy of SAMe for OA as compared with that of placebo or NSAIDs. We also examined whether study quality, drug dosage, or length of treatment is associated with the effect, and we identified needs for future research.
Methods
Literature search and data sources
We conducted computerized searches using the term “arthritis” and all synonyms for SAMe: “S-Adenosylmethionine,” “Ademetionine,” “S-adenosyl-L-methionine,” “Adenosyl-l-methionine,” “Samyr,” “Gumbaral,” “Sammy,” and “SAM-e.” Results were then combined into the optimally sensitive search strategy for retrieving all clinical trials.6,7 All languages were included. Our database search included MEDLINE (1966- September 2000), EMBASE (1987-2000), CAMPAIN (Complementary and Alternative Medicine and Pain), Science Citation Index, International Pharmaceutical Abstracts, The Cochrane Complementary Medicine Field Registry, National Institutes of Health Office of Dietary Supplements Database, and Micromedix. We also hand searched the 3 journals with the highest impact factors for rheumatology (Arthritis and Rheumatism, British Journal of Rheumatology, and Journal of Rheumatology, 1985-1999),8 English-language journals from which we had already retrieved articles, and complementary medicine journals (inception to 1999). In addition, we examined bibliographies from retrieved articles, books, and Web sites related to SAMe and contacted manufacturers of SAMe for previously unidentified research studies.
Inclusion criteria
Criteria for inclusion were established a priori. Studies had to include a sample of patients with a diagnosis of OA; be a randomized controlled trial; compare SAMe with placebo or NSAID; and report data for at least 1 of the outcome variables: pain, functional limitation, and adverse effects. Two raters independently screened studies to determine whether they met the inclusion criteria and agreed in their assessments.
Quality assessment and data extraction
Two raters independently rated study quality of the English studies using the 5-point Jadad scale9 that assesses random allocation, double-blinding, and the reporting of withdrawals and dropouts. An additional rating item concerned concealed allocation. Only 1 of the 2 raters assessed the quality of the 4 non-English articles. Two reviewers also independently extracted descriptive information and outcomes that reflected pain, functional impairment, and adverse effects. Any differences in ratings and data extraction were discussed and a consensus was reached.
For pain and functional impairment we computed the difference in the average response between treatment groups and control groups, standardized to account for differences in the measurement scale across studies. The result is a difference effect size (ES) with a positive ES favoring SAMe. We also applied a correction factor10 that adjusts for the positive bias in the ES estimate for small samples. For the binary outcome of adverse effects, we computed the odds ratio (OR) for the individual trials.11 An OR of less than 1 indicated that treatment with SAMe was more effective than the control.
Heterogeneity in the strategy to measure pain was expected. Either individual studies pooled several pain items (eg, day pain and resting pain) that were rated using a 4- or 5-point rating scale or Visual Analog Scale (VAS), or studies used a single-item VAS. Functional limitation reflects stiffness, swelling, and joint mobility as rated by the physician according to the degree of joint movement (eg, flexion, extension, abduction, adduction, and rotation). In some studies, this score also included a pain item. Adverse effects refer to patient reports of nonspecific gastrointestinal complaints, mucocutaneous symptoms, and central nervous systems disturbances. Finally, a pooled dropout rate because of side effects was computed across studies as a measure of the tolerability of SAMe.
Statistical analysis
Outcomes for each subject measured at multiple time points tend to be correlated, which introduces dependency between corresponding ESs. To avoid this dependency, we computed the ES for the end-of-treatment only, rather than for all time points. Although dependency is also a concern when results are reported for more than one outcome within a study,12-14 we did not control for this. Following the test for homogeneity or consistency within the set of ESs using the Q statistic with α = .10,11we computed the weighted mean ES with 95% confidence intervals (CI) across studies for each outcome, weighting for sample size (the inverse of the variance). The choice of a fixed-effects model was dependent on the finding of homogeneity of results.
To assess sensitivity of the results, we examined the relationship of the ES to the dosage of SAMe, length of treatment, and study quality rating. Subgroup analyses examined differences related to the location of the OA to estimate the robustness of results. Finally, we assessed potential publication bias informally by using the funnel plot of ES by precision, and statistically through the rank correlation between the standardized ES and standardized study variance.15
Results
Description of studies
Twenty studies were identified through our search and 11 of them16-26 met the inclusion criteria (Table). We excluded one duplicate study27and one study whose sample included persons with rheumatoid arthritis.28 Other excluded studies compared the routes of administration of SAMe,29 compared SAMe plus ketoprofen with ketoprofen alone,30 or were not randomized controlled trials.31-34 Four of the included studies18,20,21,25 were published in Italian; the others were published in English. The majority of studies (7 of 11) were conducted in Italy.
Quality assessment
Percent agreement between raters for the items on the Jadad scale averaged 87.5%. Following discussion, the raters reached consensus for all items. Using Jadad’s criteria, all studies were rated of high quality (score 3), although only 2 studies16,23 included a description of the method of randomization. None of the studies addressed allocation concealment.
Study characteristics
Ten of the 11 studies used a parallel groups design including one with 3 arms19; the 11th one25 used a crossover design (Table W1).* The SAMe dosage in 6 studies was 1200 mg per day orally18,19,22-24,26; 3 studies used 600 mg per day orally17,21,25; and one used 400 mg per day intravenously.20 In one study16 the dosage varied. Duration of treatment ranged from 10 days to 84 days; a duration of 28 or 30 days was used in 8 of the studies. A variety of NSAIDs served as active comparators and 2 studies16,19 used placebo. The studies involved 1442 subjects with a mean age of 60.3 years, of whom 70.1% were women. Mean duration of OA was 5.7 years, ranging from 2.6 years to 9.1 years. In 5 studies, the majority of subjects had OA of the knee; across all studies 54.2% of the subjects had OA of the knee.
TABLE
Characteristics of studies included in meta-analysis
| Study, by first author | Sample size: treatment/control | Jadad score* | SAMe intervention† | Control group |
|---|---|---|---|---|
| Bradley16 | 24/24 (site A) | 5 (2+2+1) | (A) 400 mg/day IV for 5 days; | Placebo |
| 17/17 (site B) | (B) 600 mg/day for 23 days | |||
| Capretto17 | 53/58 | 4 (1+2+1) | 600 mg/day for 30 days | Ibuprofen 1200 mg/day |
| Caroli18 | 30/30 | 4 (1+2+1) | 1200 mg/day for 42 days | Aspirin 3000 mg/day |
| Caruso19 | (1) 248/241 | 4 (1+2+1) | 1200 mg/day for 30 days | (1) Placebo |
| (2) 248/245 | (2) Naproxen 750 mg/day | |||
| Ceccato20 | 48/47 | 4 (1+2+1) | 400 mg/day IV for 30 days | Ibuprofen 1200 mg/day |
| Cucinotta21 | 20/20 | 4 (1+2+1) | 600 mg/day for 30 days | Ibuprofen 1200 mg/day |
| Maccagno22 | 24/24 | 4 (1+2+1) | 1200 mg/day for 84 days | Piroxicam 20 mg/day |
| Marcolongo23 | 75/75 | 5 (2+2+1) | 1200 mg/day for 30 days | Ibuprofen 1200 mg/day |
| Müller-Fassbender24 | 18/18 | 3 (1+1+1) | 1200 mg/day for 28 days | Ibuprofen 1200 mg/day |
| Pelligrini25 | 50/50 | 3 (1+2+0) | 600 mg/day for10 days; 5-day washout | Sulindac 200 mg/day |
| Vetter26 | 18/18 | 3 (1+1+1) | 1200 mg/day for 28 days | Indomethacin 150 mg/day |
| IV denotes intravenously. | ||||
| *Numbers in parentheses are randomization + blinding + dropouts. | ||||
| †Interventions are oral, unless otherwise noted. | ||||
Analysis of outcomes
Pain. Twelve ESs from 7 studies16,18-20,22,23,25 were computed for pain, ranging from -.501 to +.794. Because of borderline heterogeneity of the results for SAMe versus placebo (Q[2] = 5.41; P= .067), a more conservative random effects model was used to compute the mean ES of .223 (P= .352; 95% CI, -.247 to .693). Homogeneity was present for SAMe versus NSAIDs (Q[8] = 9.31, P= .317) and on the basis of a fixed effects model, the weighted mean ES was .122 (P= .057; 95% CI, -.029 to .273). Among the studies of SAMe versus NSAIDs, effect size was not related to study quality (P= .32), length of intervention (P= .31), or dosage of SAMe (P= .97). Finally, there was no evidence of publication bias according to the funnel P lot (Figure W1)* or the rank order correlation (P= .297) for studies of SAMe versus NSAIDs.
Functional limitation. Six studies17-20,24,26 contributed 10 effect sizes for functional limitation. The length of the intervention phase was 28 days to 42 days for all 6 studies. Only one study19 compared SAMe with placebo (ES = .309; P= .002; 95% CI, .098 - .519). Among the studies comparing SAMe with NSAIDs, there was homogeneity of results (Q[8] = 2.53; P= .96) with a weighted mean ES of .025 (95% CI, -.127 to .176), indicating no difference between SAMe and NSAIDs with respect to functional limitation. There was no relationship of ES to study quality (P = .30), length of treatment (P= .71), or dosage of SAMe (P= .48). Both the funnel plot (Figure W2)** and the rank correlation of standardized ES and variance (P= .097) suggested no evidence of publication bias with respect to the functional limitation outcome for SAMe versus NSAIDs.
Adverse effects. Two studies16,19 reported adverse effects when comparing SAMe with placebo. Results were homogenous (Q[2] = 2.035; P= .362), with a pooled OR of 1.37 (95% CI, .81 - 2.32). Among the studies comparing SAMe with NSAIDs results also were homogeneous (Q[6] = 4.41; P =.622), with a pooled OR of .424 (95% CI, .294 - .611). Again, the effect size was not related to quality of study (P= .409), length of treatment (P= .367), or dosage of SAMe (P= .341). That is, those treated with SAMe were 58% less likely to experience side effects than those treated with NSAIDs. Further, this was independent of study quality, dosage of SAMe, or the length of the intervention.
As an additional indication of tolerability we compared the overall dropout rates due to side effects. The dropout rate was highest (6.9%) among those treated with NSAIDs, followed by those receiving placebo (5.0%). The dropout rate for SAMe users was lowest at 2.6%. The only significant difference was between those treated with SAMe and with NSAIDs (P= .001).
Discussion
Results of this meta-analysis indicate that SAMe has a comparable effect to that of NSAIDs in reducing pain and functional limitation. In addition, there was significantly less likelihood of patients reporting adverse effects with the use of SAMe. When SAMe is compared with placebo, however, there is no differential effect on pain according to 2 studies, although there is minimal improved functional limitation according to one study. This improvement corresponds to a 15% decrease in functional limitation in the SAMe group as compared with placebo. The likelihood of adverse effects was similar in the 2 groups. Given the combined sample sizes in this meta-analysis, there was a more than 90% power to detect a moderate difference between groups at a .05 level of significance.
Several reporting issues were noted during the extraction of study data. Some researchers did not adequately describe study dropouts and how they were handled. Sample characteristics may have been reported for the initial sample, but there was no mention of the characteristics of the final sample, so that bias in subject loss could not be assessed in any studies that did not use intention-to-treat analysis. Some authors reported intervention results on the basis of the location of the OA, but only reported characteristics (age, sex, duration of disease) for the full sample. This precluded examining the relationship of intervention effect size to demographic characteristics. Finally, because not all authors provided complete descriptive statistics, we based the computation of the ES for one study on post-test scores only, rather than on the change from baseline, a strategy that could underestimate the ES. This potential underestimation occurred in a study with one of the larger sample sizes that, in turn, would carry more weight in the analysis.
Limitations
Potential limitations must also be noted in our analysis. First, in 6 of the studies, the SAMe dosage of 1200 mg per day exceeded the dosing recommendations for SAMe. These recommendations include 800 mg per day for 2 weeks followed by 400 mg per day as a maintenance dose, or to increase from 200 mg per day to 1200 mg per day over a 19-day period followed by 400 mg per day thereafter.35 Dosage was not related to the ES, however, in studies comparing SAMe with NSAIDs. Second, most studies used a short intervention (28 to 30 days). It may be that NSAIDs are more effective in the long run, that a longer treatment period is needed for patients to realize the effect of SAMe, or that there are more adverse side effects with SAMe over time. It is not yet clear how effective SAMe is over time. Those studies that did have an intervention longer than 30 days18,22 did not compare SAMe with ibuprofen. In general, concomitant medications for treatment of OA were not permitted, but 3 studies24-26 failed to provide this information. Finally, most of the studies looked at OA of the knee and/or hip, so generalizability of the results to other locations of OA is limited. Although we included subgroup analyses by location of OA, statistical power for subgroup analysis was low because of the smaller number of subjects for whom data were available.
Conclusions
Although SAMe appears to offer pain relief and improve functional limitations associated with OA without the side effects of NSAIDs, it must be remembered that SAMe is not considered a drug in the United States and is therefore not subject to federal regulations. (In contrast, Samyr is a prescription drug in Italy and is available in 200 mg and 400 mg doses.) Recent testing by ConsumerLab.com of over-the-counter brands of SAMe in the United States found, on average, that for 6 of the 13 brands tested, less than half the amount of SAMe stated on the label was actually present.36 Patients who use SAMe in the United States may fail to experience relief because of this dose inconsistency.
We offer several suggestions for further research. First, the long-term effectiveness of SAMe for the treatment of OA has not been investigated in a randomized controlled trial. Since OA is the most prevalent form of arthritis, the long-term effectiveness of SAMe should be assessed in this manner. Second, given that SAMe has been shown to decrease depression,1 it seems prudent to use multivariate techniques to examine both depression and OA outcomes (pain and functional limitation) to determine whether the effect of SAMe is directly on the joint or indirectly mediated through depression. Perhaps in the short term SAMe does decrease pain through decreasing depressive symptoms, but in the long term the effectiveness related to pain may diminish. Third, whether SAMe treats the symptoms of the disease or alters the course of the disease by increasing the production of new cartilage, as suggested by animal models, has not been investigated. Finally, can use of SAMe enhance the effectiveness of other nonpharmacologic modalities? These questions should all be investigated before we can make a determination about the efficacy and safety of SAMe for the treatment of OA.
Acknowledgments
This research was supported by grant #5-P50-AT00084-02 from the National Center for Complementary and Alternative Medicine, National Institutes of Health.
1. Gaster B. S-adenosylmethionine (SAMe) for treatment of depression. Altern Med Alert 1999;2:133-5.
2. Stramentinoli G. Pharmacologic aspects of S-adenosylmethionine. Am J Med 1987;83(suppl 5A):35-42.
3. DiPadova C. S-adenosylmethionine in the treatment of osteoarthritis: review of the clinical studies. Am J Med 1987;83(suppl 5A):60-5.
4. Leeb BF, Schweitzer H, Montag K, Smolen JS. A meta-analysis of chondroitin sulfate in the treatment of osteoarthritis. J Rheumatol 2000;27:205-11.
5. McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA 2000;28:1469-75.
6. Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies for systematic reviews. BMJ 1994;309:1286-91.
7. Jadad AR, Carrol D, Moore A, McQuay H. Developing a database of published reports of randomized controlled trials in pain research. Pain 1996;66:239-46.
8. Journal Citation Report Science Edition, Institute for Scientific Information, 1998.
9. Jadad AR, Carrol D, Moore A, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1-12.
10. Hedges LV. Estimation of effect size from a series of independent experiments. Psychol Bull 1982;92:490-9.
11. Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song J. Methods for meta-analysis in medical research. New York: John Wiley & Sons, Ltd, 2000.
12. Hedges LV, Olkin I. Statistical methods for meta-analysis. New York: Academic Press, 1985.
13. Rosenthal R. Meta-analytic procedures for social research (rev ed). Newbury Park, Calif: Sage Publications, 1991.
14. Glesser LJ, Olkin I. Stochastically dependent effect sizes. In: Cooper H, Hedges LV, eds. The handbook of research synthesis. New York: Russell Sage Foundation, 1994;339-56.
15. Begg CB. Publication bias. In: Cooper H, Hedges LV, eds. The handbook of research synthesis. New York: Russell Sage Foundation, 1994;399-409.
16. Bradley JD, Flusser D, Katz BP, et al. A randomized, double blind, placebo controlled trial of intravenous loading with S-adenosyl-methionine (SAM) followed by oral SAM therapy in patients with knee osteoarthritis. J Rheumatol 1994;21:905-11.
17. Capretto C, Cremona C, Canaparo L. A double-blind controlled study of S-adenosylmethionine (SAMe) v.ibuprofen in gonarthrosis, coxarthrosis and spondylarthrosis. Clin Trials J 1985;22:15-2-43.
18. Caroli A. Studio in doppio cieco SAMe (capsule) - Aspirina nell’osteoartrosi. G Clin Med 1980;61:844-57.
19. Caruso I, Pietrogrande V. Italian double-blind multicenter study comparing S-adenosylmethionine, naproxen, and placebo in the treatment of degenerative joint disease. Am J Med 1987;83(suppl 5A):66-71.
20. Ceccato S, Cucinotta D, Carapezzi C, Ferretti G, Passeri M. Stuio clinico in doppio cieco sull’effetto terapeutico della SAMe e del-l’ibuprofen nella patologia degenerativa articolare. G Clin Med 1980;61:148-62.
21. Cucinotta D, Mancini M, Ceccato S, Castino E. Studio clinico controllato sull’attivita della SAMe somministrata per via orale nella patologia degenerative osteo-articolare. G Clin Med 1980;61:553-65.
22. Maccagno A, DiGiorgio EE, Caston OL, Sagasta CL. Double-blind controlled clinical trial of oral S-adenosylmethionine versus piroxicam in knee osteoarthritis. Am J Med 1987;83 (suppl 5A):72-7.
23. Marcolongo R, Giordano N, Colombo B, et al. Double-blind multicentre study of the activity of S-adenosyl-methionine in hip and knee osteoarthritis. Curr Ther Res 1985;37:82-94.
24. Müller-Fassbender H. Double-blind clinical trial of S-adenosylme-thionine vesus ibuprofen in the treatment of osteoarthritis. Am J Med 1987;83 (suppl 5A):81-3.
25. Pellegrini P. La S-adenosil-metionina (SAMe) nell’osteoartrosi studio in doppio cieco crossover per via orale. G Clin Med 1980;61:616-27.
26. Vetter G. Double-blind comparative clinical trial with S-adenosyl-methionine and indomethacin in the treatment of osteoarthritis. Am J Med 1987;83 (suppl 5A):78-80.
27. Glorioso S, Todesco S, Mazzi A, et al. Double-blind multicentre study of the activity of S-adenosylmethionine in hip and knee osteoarthritis. Int J Clin Pharm Res 1985;1:39-49.
28. Polli E, Cortellaro M, Parrini L, Tessari L, Ligniere GC. Aspetti farmacologici e clinici della solfo-adenosil-metionina (SAMe) nella artropatia degnerativa primaria (osteoartrosi). Min Med 1975;66:4443-59.
29. Bach GL, Gmeiner G. Wochen-doppelblindstudie mit ademetionin (Gumbaral(r)) bei gonarthrose zur ermittlung der äquivalenz intravenöser und oraler dosen. In: Bach GL, Muller-Fassbender H, editors. Arthrose-workshop uber Gumbaral(r) (Ademetionin). Frankfurt am Main:Verlag GmbH. 1986;23-30.
30. Ceccato S, Cucinotta D, Carapezzi C, Passeri M. Indagine clinica aperta e comparativa sull’impiego della SAMe e del ketoprofen nell’osteoartrosi. Progr Med 1979;35:177-91.
31. Berger R, Nowak H. A new medication approach to the treatment of osteoarthritis: report of an open phase IV study with ademethionine (Gumbaral(r)). Am J Med 1987;83(suppl 5A):84-8.
32. Konig B. A long-term (two years) clinical trial with S-adenosylmethionine for the treatment of osteoarthritis. Am J Med 1987;83(suppl 5A):89-94.
33. Domljan Z, Vrhovac B, Dürrigl T, Pu_ar I. A double-blind trial of ademetionine vs naproxen in activated gonarthritis. Int J Clin Pharmacol Ther Toxicol 1989;27:329-33.
34. Montrone F, Fumagalli M, Sarzi Puttini P, et al. Double-blind study of S-adenosyl-methionine versus placebo in hip and knee arthrosis [letter]. Clin Rheumatol 1985;4:484-5.
35. Mitchell D. The SAMe solution. New York: Warner Books, Inc., 1999.
36. ConsumerLab.com. Product review: SAMe. [http://www.consumerlab.com]. Accessed March 11, 2002.
OBJECTIVE: We assessed the efficacy of S-adenosylmethionine (SAMe), a dietary supplement now available in the United States, compared with that of placebo or nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of osteoarthritis (OA).
STUDY DESIGN: This was a meta-analysis of randomized controlled trials.
DATA SOURCES: We identified randomized controlled trials of SAMe versus placebo or NSAIDS for the treatment of OA through computerized database searches and reference lists.
OUTCOMES MEASURED: The outcomes considered were pain, functional limitation, and adverse effects.
RESULTS: Eleven studies that met the inclusion criteria were weighted on the basis of precision and were combined for each outcome variable. When compared with placebo, SAMe is more effective in reducing functional limitation in patients with OA (effect size [ES] = .31; 95% confidence interval [CI], .098 - .519), but not in reducing pain (ES = .22; 95% CI, -.247 to .693). This result, however, is based on only 2 studies. SAMe seems to be comparable with NSAIDs (pain: ES = .12; 95% CI, -.029 to .273; functional limitation: ES = .025; 95% CI, -.127 to .176). However, those treated with SAMe were less likely to report adverse effects than those receiving NSAIDs.
CONCLUSIONS: SAMe appears to be as effective as NSAIDs in reducing pain and improving functional limitation in patients with OA without the adverse effects often associated with NSAID therapies.
- S-adenosylmethionine (SAMe) is as effective as NSAIDs in offering pain relief and improving functional limitation with less risk of side effects.
- When compared with placebo, SAMe improved functional limitations of osteoarthritis, but there was no improvement in pain.
- The tolerability of SAMe was similar to that of placebo and greater than that of NSAIDs.
One alternative therapy for osteoarthritis (OA) is Sadenosylmethionine (SAMe), a naturally occurring sulphur-containing physiologic compound synthesized from amino acid L-methionine and adenosine triphosphate (ATP).1,2 Although scientists are not certain how it works to control pain, SAMe plays a key role in 3 major pathways: transmethylation, transsulfuration, and aminopropylation.2 SAMe was introduced in the United States in 1999 as a dietary supplement to promote joint health, mobility, and joint comfort. On the basis of a 1987 review of 12 clinical studies involving more than 20,000 patients, SAMe has been touted as “the prototype of a new class of safe drugs for the treatment of osteoarthritis.”3 However, the majority of the patients in those studies (97%) were enrolled in a single open field trial.
Although systematic reviews have demonstrated the benefit of other alternative strategies for OA, such as glucosamine and chondroitin,4,5 there has been no systematic review of SAMe for OA. Because individual studies of SAMe vary in their sample sizes and report conflicting results, we conducted a meta-analysis to assess the efficacy of SAMe for OA as compared with that of placebo or NSAIDs. We also examined whether study quality, drug dosage, or length of treatment is associated with the effect, and we identified needs for future research.
Methods
Literature search and data sources
We conducted computerized searches using the term “arthritis” and all synonyms for SAMe: “S-Adenosylmethionine,” “Ademetionine,” “S-adenosyl-L-methionine,” “Adenosyl-l-methionine,” “Samyr,” “Gumbaral,” “Sammy,” and “SAM-e.” Results were then combined into the optimally sensitive search strategy for retrieving all clinical trials.6,7 All languages were included. Our database search included MEDLINE (1966- September 2000), EMBASE (1987-2000), CAMPAIN (Complementary and Alternative Medicine and Pain), Science Citation Index, International Pharmaceutical Abstracts, The Cochrane Complementary Medicine Field Registry, National Institutes of Health Office of Dietary Supplements Database, and Micromedix. We also hand searched the 3 journals with the highest impact factors for rheumatology (Arthritis and Rheumatism, British Journal of Rheumatology, and Journal of Rheumatology, 1985-1999),8 English-language journals from which we had already retrieved articles, and complementary medicine journals (inception to 1999). In addition, we examined bibliographies from retrieved articles, books, and Web sites related to SAMe and contacted manufacturers of SAMe for previously unidentified research studies.
Inclusion criteria
Criteria for inclusion were established a priori. Studies had to include a sample of patients with a diagnosis of OA; be a randomized controlled trial; compare SAMe with placebo or NSAID; and report data for at least 1 of the outcome variables: pain, functional limitation, and adverse effects. Two raters independently screened studies to determine whether they met the inclusion criteria and agreed in their assessments.
Quality assessment and data extraction
Two raters independently rated study quality of the English studies using the 5-point Jadad scale9 that assesses random allocation, double-blinding, and the reporting of withdrawals and dropouts. An additional rating item concerned concealed allocation. Only 1 of the 2 raters assessed the quality of the 4 non-English articles. Two reviewers also independently extracted descriptive information and outcomes that reflected pain, functional impairment, and adverse effects. Any differences in ratings and data extraction were discussed and a consensus was reached.
For pain and functional impairment we computed the difference in the average response between treatment groups and control groups, standardized to account for differences in the measurement scale across studies. The result is a difference effect size (ES) with a positive ES favoring SAMe. We also applied a correction factor10 that adjusts for the positive bias in the ES estimate for small samples. For the binary outcome of adverse effects, we computed the odds ratio (OR) for the individual trials.11 An OR of less than 1 indicated that treatment with SAMe was more effective than the control.
Heterogeneity in the strategy to measure pain was expected. Either individual studies pooled several pain items (eg, day pain and resting pain) that were rated using a 4- or 5-point rating scale or Visual Analog Scale (VAS), or studies used a single-item VAS. Functional limitation reflects stiffness, swelling, and joint mobility as rated by the physician according to the degree of joint movement (eg, flexion, extension, abduction, adduction, and rotation). In some studies, this score also included a pain item. Adverse effects refer to patient reports of nonspecific gastrointestinal complaints, mucocutaneous symptoms, and central nervous systems disturbances. Finally, a pooled dropout rate because of side effects was computed across studies as a measure of the tolerability of SAMe.
Statistical analysis
Outcomes for each subject measured at multiple time points tend to be correlated, which introduces dependency between corresponding ESs. To avoid this dependency, we computed the ES for the end-of-treatment only, rather than for all time points. Although dependency is also a concern when results are reported for more than one outcome within a study,12-14 we did not control for this. Following the test for homogeneity or consistency within the set of ESs using the Q statistic with α = .10,11we computed the weighted mean ES with 95% confidence intervals (CI) across studies for each outcome, weighting for sample size (the inverse of the variance). The choice of a fixed-effects model was dependent on the finding of homogeneity of results.
To assess sensitivity of the results, we examined the relationship of the ES to the dosage of SAMe, length of treatment, and study quality rating. Subgroup analyses examined differences related to the location of the OA to estimate the robustness of results. Finally, we assessed potential publication bias informally by using the funnel plot of ES by precision, and statistically through the rank correlation between the standardized ES and standardized study variance.15
Results
Description of studies
Twenty studies were identified through our search and 11 of them16-26 met the inclusion criteria (Table). We excluded one duplicate study27and one study whose sample included persons with rheumatoid arthritis.28 Other excluded studies compared the routes of administration of SAMe,29 compared SAMe plus ketoprofen with ketoprofen alone,30 or were not randomized controlled trials.31-34 Four of the included studies18,20,21,25 were published in Italian; the others were published in English. The majority of studies (7 of 11) were conducted in Italy.
Quality assessment
Percent agreement between raters for the items on the Jadad scale averaged 87.5%. Following discussion, the raters reached consensus for all items. Using Jadad’s criteria, all studies were rated of high quality (score 3), although only 2 studies16,23 included a description of the method of randomization. None of the studies addressed allocation concealment.
Study characteristics
Ten of the 11 studies used a parallel groups design including one with 3 arms19; the 11th one25 used a crossover design (Table W1).* The SAMe dosage in 6 studies was 1200 mg per day orally18,19,22-24,26; 3 studies used 600 mg per day orally17,21,25; and one used 400 mg per day intravenously.20 In one study16 the dosage varied. Duration of treatment ranged from 10 days to 84 days; a duration of 28 or 30 days was used in 8 of the studies. A variety of NSAIDs served as active comparators and 2 studies16,19 used placebo. The studies involved 1442 subjects with a mean age of 60.3 years, of whom 70.1% were women. Mean duration of OA was 5.7 years, ranging from 2.6 years to 9.1 years. In 5 studies, the majority of subjects had OA of the knee; across all studies 54.2% of the subjects had OA of the knee.
TABLE
Characteristics of studies included in meta-analysis
| Study, by first author | Sample size: treatment/control | Jadad score* | SAMe intervention† | Control group |
|---|---|---|---|---|
| Bradley16 | 24/24 (site A) | 5 (2+2+1) | (A) 400 mg/day IV for 5 days; | Placebo |
| 17/17 (site B) | (B) 600 mg/day for 23 days | |||
| Capretto17 | 53/58 | 4 (1+2+1) | 600 mg/day for 30 days | Ibuprofen 1200 mg/day |
| Caroli18 | 30/30 | 4 (1+2+1) | 1200 mg/day for 42 days | Aspirin 3000 mg/day |
| Caruso19 | (1) 248/241 | 4 (1+2+1) | 1200 mg/day for 30 days | (1) Placebo |
| (2) 248/245 | (2) Naproxen 750 mg/day | |||
| Ceccato20 | 48/47 | 4 (1+2+1) | 400 mg/day IV for 30 days | Ibuprofen 1200 mg/day |
| Cucinotta21 | 20/20 | 4 (1+2+1) | 600 mg/day for 30 days | Ibuprofen 1200 mg/day |
| Maccagno22 | 24/24 | 4 (1+2+1) | 1200 mg/day for 84 days | Piroxicam 20 mg/day |
| Marcolongo23 | 75/75 | 5 (2+2+1) | 1200 mg/day for 30 days | Ibuprofen 1200 mg/day |
| Müller-Fassbender24 | 18/18 | 3 (1+1+1) | 1200 mg/day for 28 days | Ibuprofen 1200 mg/day |
| Pelligrini25 | 50/50 | 3 (1+2+0) | 600 mg/day for10 days; 5-day washout | Sulindac 200 mg/day |
| Vetter26 | 18/18 | 3 (1+1+1) | 1200 mg/day for 28 days | Indomethacin 150 mg/day |
| IV denotes intravenously. | ||||
| *Numbers in parentheses are randomization + blinding + dropouts. | ||||
| †Interventions are oral, unless otherwise noted. | ||||
Analysis of outcomes
Pain. Twelve ESs from 7 studies16,18-20,22,23,25 were computed for pain, ranging from -.501 to +.794. Because of borderline heterogeneity of the results for SAMe versus placebo (Q[2] = 5.41; P= .067), a more conservative random effects model was used to compute the mean ES of .223 (P= .352; 95% CI, -.247 to .693). Homogeneity was present for SAMe versus NSAIDs (Q[8] = 9.31, P= .317) and on the basis of a fixed effects model, the weighted mean ES was .122 (P= .057; 95% CI, -.029 to .273). Among the studies of SAMe versus NSAIDs, effect size was not related to study quality (P= .32), length of intervention (P= .31), or dosage of SAMe (P= .97). Finally, there was no evidence of publication bias according to the funnel P lot (Figure W1)* or the rank order correlation (P= .297) for studies of SAMe versus NSAIDs.
Functional limitation. Six studies17-20,24,26 contributed 10 effect sizes for functional limitation. The length of the intervention phase was 28 days to 42 days for all 6 studies. Only one study19 compared SAMe with placebo (ES = .309; P= .002; 95% CI, .098 - .519). Among the studies comparing SAMe with NSAIDs, there was homogeneity of results (Q[8] = 2.53; P= .96) with a weighted mean ES of .025 (95% CI, -.127 to .176), indicating no difference between SAMe and NSAIDs with respect to functional limitation. There was no relationship of ES to study quality (P = .30), length of treatment (P= .71), or dosage of SAMe (P= .48). Both the funnel plot (Figure W2)** and the rank correlation of standardized ES and variance (P= .097) suggested no evidence of publication bias with respect to the functional limitation outcome for SAMe versus NSAIDs.
Adverse effects. Two studies16,19 reported adverse effects when comparing SAMe with placebo. Results were homogenous (Q[2] = 2.035; P= .362), with a pooled OR of 1.37 (95% CI, .81 - 2.32). Among the studies comparing SAMe with NSAIDs results also were homogeneous (Q[6] = 4.41; P =.622), with a pooled OR of .424 (95% CI, .294 - .611). Again, the effect size was not related to quality of study (P= .409), length of treatment (P= .367), or dosage of SAMe (P= .341). That is, those treated with SAMe were 58% less likely to experience side effects than those treated with NSAIDs. Further, this was independent of study quality, dosage of SAMe, or the length of the intervention.
As an additional indication of tolerability we compared the overall dropout rates due to side effects. The dropout rate was highest (6.9%) among those treated with NSAIDs, followed by those receiving placebo (5.0%). The dropout rate for SAMe users was lowest at 2.6%. The only significant difference was between those treated with SAMe and with NSAIDs (P= .001).
Discussion
Results of this meta-analysis indicate that SAMe has a comparable effect to that of NSAIDs in reducing pain and functional limitation. In addition, there was significantly less likelihood of patients reporting adverse effects with the use of SAMe. When SAMe is compared with placebo, however, there is no differential effect on pain according to 2 studies, although there is minimal improved functional limitation according to one study. This improvement corresponds to a 15% decrease in functional limitation in the SAMe group as compared with placebo. The likelihood of adverse effects was similar in the 2 groups. Given the combined sample sizes in this meta-analysis, there was a more than 90% power to detect a moderate difference between groups at a .05 level of significance.
Several reporting issues were noted during the extraction of study data. Some researchers did not adequately describe study dropouts and how they were handled. Sample characteristics may have been reported for the initial sample, but there was no mention of the characteristics of the final sample, so that bias in subject loss could not be assessed in any studies that did not use intention-to-treat analysis. Some authors reported intervention results on the basis of the location of the OA, but only reported characteristics (age, sex, duration of disease) for the full sample. This precluded examining the relationship of intervention effect size to demographic characteristics. Finally, because not all authors provided complete descriptive statistics, we based the computation of the ES for one study on post-test scores only, rather than on the change from baseline, a strategy that could underestimate the ES. This potential underestimation occurred in a study with one of the larger sample sizes that, in turn, would carry more weight in the analysis.
Limitations
Potential limitations must also be noted in our analysis. First, in 6 of the studies, the SAMe dosage of 1200 mg per day exceeded the dosing recommendations for SAMe. These recommendations include 800 mg per day for 2 weeks followed by 400 mg per day as a maintenance dose, or to increase from 200 mg per day to 1200 mg per day over a 19-day period followed by 400 mg per day thereafter.35 Dosage was not related to the ES, however, in studies comparing SAMe with NSAIDs. Second, most studies used a short intervention (28 to 30 days). It may be that NSAIDs are more effective in the long run, that a longer treatment period is needed for patients to realize the effect of SAMe, or that there are more adverse side effects with SAMe over time. It is not yet clear how effective SAMe is over time. Those studies that did have an intervention longer than 30 days18,22 did not compare SAMe with ibuprofen. In general, concomitant medications for treatment of OA were not permitted, but 3 studies24-26 failed to provide this information. Finally, most of the studies looked at OA of the knee and/or hip, so generalizability of the results to other locations of OA is limited. Although we included subgroup analyses by location of OA, statistical power for subgroup analysis was low because of the smaller number of subjects for whom data were available.
Conclusions
Although SAMe appears to offer pain relief and improve functional limitations associated with OA without the side effects of NSAIDs, it must be remembered that SAMe is not considered a drug in the United States and is therefore not subject to federal regulations. (In contrast, Samyr is a prescription drug in Italy and is available in 200 mg and 400 mg doses.) Recent testing by ConsumerLab.com of over-the-counter brands of SAMe in the United States found, on average, that for 6 of the 13 brands tested, less than half the amount of SAMe stated on the label was actually present.36 Patients who use SAMe in the United States may fail to experience relief because of this dose inconsistency.
We offer several suggestions for further research. First, the long-term effectiveness of SAMe for the treatment of OA has not been investigated in a randomized controlled trial. Since OA is the most prevalent form of arthritis, the long-term effectiveness of SAMe should be assessed in this manner. Second, given that SAMe has been shown to decrease depression,1 it seems prudent to use multivariate techniques to examine both depression and OA outcomes (pain and functional limitation) to determine whether the effect of SAMe is directly on the joint or indirectly mediated through depression. Perhaps in the short term SAMe does decrease pain through decreasing depressive symptoms, but in the long term the effectiveness related to pain may diminish. Third, whether SAMe treats the symptoms of the disease or alters the course of the disease by increasing the production of new cartilage, as suggested by animal models, has not been investigated. Finally, can use of SAMe enhance the effectiveness of other nonpharmacologic modalities? These questions should all be investigated before we can make a determination about the efficacy and safety of SAMe for the treatment of OA.
Acknowledgments
This research was supported by grant #5-P50-AT00084-02 from the National Center for Complementary and Alternative Medicine, National Institutes of Health.
OBJECTIVE: We assessed the efficacy of S-adenosylmethionine (SAMe), a dietary supplement now available in the United States, compared with that of placebo or nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of osteoarthritis (OA).
STUDY DESIGN: This was a meta-analysis of randomized controlled trials.
DATA SOURCES: We identified randomized controlled trials of SAMe versus placebo or NSAIDS for the treatment of OA through computerized database searches and reference lists.
OUTCOMES MEASURED: The outcomes considered were pain, functional limitation, and adverse effects.
RESULTS: Eleven studies that met the inclusion criteria were weighted on the basis of precision and were combined for each outcome variable. When compared with placebo, SAMe is more effective in reducing functional limitation in patients with OA (effect size [ES] = .31; 95% confidence interval [CI], .098 - .519), but not in reducing pain (ES = .22; 95% CI, -.247 to .693). This result, however, is based on only 2 studies. SAMe seems to be comparable with NSAIDs (pain: ES = .12; 95% CI, -.029 to .273; functional limitation: ES = .025; 95% CI, -.127 to .176). However, those treated with SAMe were less likely to report adverse effects than those receiving NSAIDs.
CONCLUSIONS: SAMe appears to be as effective as NSAIDs in reducing pain and improving functional limitation in patients with OA without the adverse effects often associated with NSAID therapies.
- S-adenosylmethionine (SAMe) is as effective as NSAIDs in offering pain relief and improving functional limitation with less risk of side effects.
- When compared with placebo, SAMe improved functional limitations of osteoarthritis, but there was no improvement in pain.
- The tolerability of SAMe was similar to that of placebo and greater than that of NSAIDs.
One alternative therapy for osteoarthritis (OA) is Sadenosylmethionine (SAMe), a naturally occurring sulphur-containing physiologic compound synthesized from amino acid L-methionine and adenosine triphosphate (ATP).1,2 Although scientists are not certain how it works to control pain, SAMe plays a key role in 3 major pathways: transmethylation, transsulfuration, and aminopropylation.2 SAMe was introduced in the United States in 1999 as a dietary supplement to promote joint health, mobility, and joint comfort. On the basis of a 1987 review of 12 clinical studies involving more than 20,000 patients, SAMe has been touted as “the prototype of a new class of safe drugs for the treatment of osteoarthritis.”3 However, the majority of the patients in those studies (97%) were enrolled in a single open field trial.
Although systematic reviews have demonstrated the benefit of other alternative strategies for OA, such as glucosamine and chondroitin,4,5 there has been no systematic review of SAMe for OA. Because individual studies of SAMe vary in their sample sizes and report conflicting results, we conducted a meta-analysis to assess the efficacy of SAMe for OA as compared with that of placebo or NSAIDs. We also examined whether study quality, drug dosage, or length of treatment is associated with the effect, and we identified needs for future research.
Methods
Literature search and data sources
We conducted computerized searches using the term “arthritis” and all synonyms for SAMe: “S-Adenosylmethionine,” “Ademetionine,” “S-adenosyl-L-methionine,” “Adenosyl-l-methionine,” “Samyr,” “Gumbaral,” “Sammy,” and “SAM-e.” Results were then combined into the optimally sensitive search strategy for retrieving all clinical trials.6,7 All languages were included. Our database search included MEDLINE (1966- September 2000), EMBASE (1987-2000), CAMPAIN (Complementary and Alternative Medicine and Pain), Science Citation Index, International Pharmaceutical Abstracts, The Cochrane Complementary Medicine Field Registry, National Institutes of Health Office of Dietary Supplements Database, and Micromedix. We also hand searched the 3 journals with the highest impact factors for rheumatology (Arthritis and Rheumatism, British Journal of Rheumatology, and Journal of Rheumatology, 1985-1999),8 English-language journals from which we had already retrieved articles, and complementary medicine journals (inception to 1999). In addition, we examined bibliographies from retrieved articles, books, and Web sites related to SAMe and contacted manufacturers of SAMe for previously unidentified research studies.
Inclusion criteria
Criteria for inclusion were established a priori. Studies had to include a sample of patients with a diagnosis of OA; be a randomized controlled trial; compare SAMe with placebo or NSAID; and report data for at least 1 of the outcome variables: pain, functional limitation, and adverse effects. Two raters independently screened studies to determine whether they met the inclusion criteria and agreed in their assessments.
Quality assessment and data extraction
Two raters independently rated study quality of the English studies using the 5-point Jadad scale9 that assesses random allocation, double-blinding, and the reporting of withdrawals and dropouts. An additional rating item concerned concealed allocation. Only 1 of the 2 raters assessed the quality of the 4 non-English articles. Two reviewers also independently extracted descriptive information and outcomes that reflected pain, functional impairment, and adverse effects. Any differences in ratings and data extraction were discussed and a consensus was reached.
For pain and functional impairment we computed the difference in the average response between treatment groups and control groups, standardized to account for differences in the measurement scale across studies. The result is a difference effect size (ES) with a positive ES favoring SAMe. We also applied a correction factor10 that adjusts for the positive bias in the ES estimate for small samples. For the binary outcome of adverse effects, we computed the odds ratio (OR) for the individual trials.11 An OR of less than 1 indicated that treatment with SAMe was more effective than the control.
Heterogeneity in the strategy to measure pain was expected. Either individual studies pooled several pain items (eg, day pain and resting pain) that were rated using a 4- or 5-point rating scale or Visual Analog Scale (VAS), or studies used a single-item VAS. Functional limitation reflects stiffness, swelling, and joint mobility as rated by the physician according to the degree of joint movement (eg, flexion, extension, abduction, adduction, and rotation). In some studies, this score also included a pain item. Adverse effects refer to patient reports of nonspecific gastrointestinal complaints, mucocutaneous symptoms, and central nervous systems disturbances. Finally, a pooled dropout rate because of side effects was computed across studies as a measure of the tolerability of SAMe.
Statistical analysis
Outcomes for each subject measured at multiple time points tend to be correlated, which introduces dependency between corresponding ESs. To avoid this dependency, we computed the ES for the end-of-treatment only, rather than for all time points. Although dependency is also a concern when results are reported for more than one outcome within a study,12-14 we did not control for this. Following the test for homogeneity or consistency within the set of ESs using the Q statistic with α = .10,11we computed the weighted mean ES with 95% confidence intervals (CI) across studies for each outcome, weighting for sample size (the inverse of the variance). The choice of a fixed-effects model was dependent on the finding of homogeneity of results.
To assess sensitivity of the results, we examined the relationship of the ES to the dosage of SAMe, length of treatment, and study quality rating. Subgroup analyses examined differences related to the location of the OA to estimate the robustness of results. Finally, we assessed potential publication bias informally by using the funnel plot of ES by precision, and statistically through the rank correlation between the standardized ES and standardized study variance.15
Results
Description of studies
Twenty studies were identified through our search and 11 of them16-26 met the inclusion criteria (Table). We excluded one duplicate study27and one study whose sample included persons with rheumatoid arthritis.28 Other excluded studies compared the routes of administration of SAMe,29 compared SAMe plus ketoprofen with ketoprofen alone,30 or were not randomized controlled trials.31-34 Four of the included studies18,20,21,25 were published in Italian; the others were published in English. The majority of studies (7 of 11) were conducted in Italy.
Quality assessment
Percent agreement between raters for the items on the Jadad scale averaged 87.5%. Following discussion, the raters reached consensus for all items. Using Jadad’s criteria, all studies were rated of high quality (score 3), although only 2 studies16,23 included a description of the method of randomization. None of the studies addressed allocation concealment.
Study characteristics
Ten of the 11 studies used a parallel groups design including one with 3 arms19; the 11th one25 used a crossover design (Table W1).* The SAMe dosage in 6 studies was 1200 mg per day orally18,19,22-24,26; 3 studies used 600 mg per day orally17,21,25; and one used 400 mg per day intravenously.20 In one study16 the dosage varied. Duration of treatment ranged from 10 days to 84 days; a duration of 28 or 30 days was used in 8 of the studies. A variety of NSAIDs served as active comparators and 2 studies16,19 used placebo. The studies involved 1442 subjects with a mean age of 60.3 years, of whom 70.1% were women. Mean duration of OA was 5.7 years, ranging from 2.6 years to 9.1 years. In 5 studies, the majority of subjects had OA of the knee; across all studies 54.2% of the subjects had OA of the knee.
TABLE
Characteristics of studies included in meta-analysis
| Study, by first author | Sample size: treatment/control | Jadad score* | SAMe intervention† | Control group |
|---|---|---|---|---|
| Bradley16 | 24/24 (site A) | 5 (2+2+1) | (A) 400 mg/day IV for 5 days; | Placebo |
| 17/17 (site B) | (B) 600 mg/day for 23 days | |||
| Capretto17 | 53/58 | 4 (1+2+1) | 600 mg/day for 30 days | Ibuprofen 1200 mg/day |
| Caroli18 | 30/30 | 4 (1+2+1) | 1200 mg/day for 42 days | Aspirin 3000 mg/day |
| Caruso19 | (1) 248/241 | 4 (1+2+1) | 1200 mg/day for 30 days | (1) Placebo |
| (2) 248/245 | (2) Naproxen 750 mg/day | |||
| Ceccato20 | 48/47 | 4 (1+2+1) | 400 mg/day IV for 30 days | Ibuprofen 1200 mg/day |
| Cucinotta21 | 20/20 | 4 (1+2+1) | 600 mg/day for 30 days | Ibuprofen 1200 mg/day |
| Maccagno22 | 24/24 | 4 (1+2+1) | 1200 mg/day for 84 days | Piroxicam 20 mg/day |
| Marcolongo23 | 75/75 | 5 (2+2+1) | 1200 mg/day for 30 days | Ibuprofen 1200 mg/day |
| Müller-Fassbender24 | 18/18 | 3 (1+1+1) | 1200 mg/day for 28 days | Ibuprofen 1200 mg/day |
| Pelligrini25 | 50/50 | 3 (1+2+0) | 600 mg/day for10 days; 5-day washout | Sulindac 200 mg/day |
| Vetter26 | 18/18 | 3 (1+1+1) | 1200 mg/day for 28 days | Indomethacin 150 mg/day |
| IV denotes intravenously. | ||||
| *Numbers in parentheses are randomization + blinding + dropouts. | ||||
| †Interventions are oral, unless otherwise noted. | ||||
Analysis of outcomes
Pain. Twelve ESs from 7 studies16,18-20,22,23,25 were computed for pain, ranging from -.501 to +.794. Because of borderline heterogeneity of the results for SAMe versus placebo (Q[2] = 5.41; P= .067), a more conservative random effects model was used to compute the mean ES of .223 (P= .352; 95% CI, -.247 to .693). Homogeneity was present for SAMe versus NSAIDs (Q[8] = 9.31, P= .317) and on the basis of a fixed effects model, the weighted mean ES was .122 (P= .057; 95% CI, -.029 to .273). Among the studies of SAMe versus NSAIDs, effect size was not related to study quality (P= .32), length of intervention (P= .31), or dosage of SAMe (P= .97). Finally, there was no evidence of publication bias according to the funnel P lot (Figure W1)* or the rank order correlation (P= .297) for studies of SAMe versus NSAIDs.
Functional limitation. Six studies17-20,24,26 contributed 10 effect sizes for functional limitation. The length of the intervention phase was 28 days to 42 days for all 6 studies. Only one study19 compared SAMe with placebo (ES = .309; P= .002; 95% CI, .098 - .519). Among the studies comparing SAMe with NSAIDs, there was homogeneity of results (Q[8] = 2.53; P= .96) with a weighted mean ES of .025 (95% CI, -.127 to .176), indicating no difference between SAMe and NSAIDs with respect to functional limitation. There was no relationship of ES to study quality (P = .30), length of treatment (P= .71), or dosage of SAMe (P= .48). Both the funnel plot (Figure W2)** and the rank correlation of standardized ES and variance (P= .097) suggested no evidence of publication bias with respect to the functional limitation outcome for SAMe versus NSAIDs.
Adverse effects. Two studies16,19 reported adverse effects when comparing SAMe with placebo. Results were homogenous (Q[2] = 2.035; P= .362), with a pooled OR of 1.37 (95% CI, .81 - 2.32). Among the studies comparing SAMe with NSAIDs results also were homogeneous (Q[6] = 4.41; P =.622), with a pooled OR of .424 (95% CI, .294 - .611). Again, the effect size was not related to quality of study (P= .409), length of treatment (P= .367), or dosage of SAMe (P= .341). That is, those treated with SAMe were 58% less likely to experience side effects than those treated with NSAIDs. Further, this was independent of study quality, dosage of SAMe, or the length of the intervention.
As an additional indication of tolerability we compared the overall dropout rates due to side effects. The dropout rate was highest (6.9%) among those treated with NSAIDs, followed by those receiving placebo (5.0%). The dropout rate for SAMe users was lowest at 2.6%. The only significant difference was between those treated with SAMe and with NSAIDs (P= .001).
Discussion
Results of this meta-analysis indicate that SAMe has a comparable effect to that of NSAIDs in reducing pain and functional limitation. In addition, there was significantly less likelihood of patients reporting adverse effects with the use of SAMe. When SAMe is compared with placebo, however, there is no differential effect on pain according to 2 studies, although there is minimal improved functional limitation according to one study. This improvement corresponds to a 15% decrease in functional limitation in the SAMe group as compared with placebo. The likelihood of adverse effects was similar in the 2 groups. Given the combined sample sizes in this meta-analysis, there was a more than 90% power to detect a moderate difference between groups at a .05 level of significance.
Several reporting issues were noted during the extraction of study data. Some researchers did not adequately describe study dropouts and how they were handled. Sample characteristics may have been reported for the initial sample, but there was no mention of the characteristics of the final sample, so that bias in subject loss could not be assessed in any studies that did not use intention-to-treat analysis. Some authors reported intervention results on the basis of the location of the OA, but only reported characteristics (age, sex, duration of disease) for the full sample. This precluded examining the relationship of intervention effect size to demographic characteristics. Finally, because not all authors provided complete descriptive statistics, we based the computation of the ES for one study on post-test scores only, rather than on the change from baseline, a strategy that could underestimate the ES. This potential underestimation occurred in a study with one of the larger sample sizes that, in turn, would carry more weight in the analysis.
Limitations
Potential limitations must also be noted in our analysis. First, in 6 of the studies, the SAMe dosage of 1200 mg per day exceeded the dosing recommendations for SAMe. These recommendations include 800 mg per day for 2 weeks followed by 400 mg per day as a maintenance dose, or to increase from 200 mg per day to 1200 mg per day over a 19-day period followed by 400 mg per day thereafter.35 Dosage was not related to the ES, however, in studies comparing SAMe with NSAIDs. Second, most studies used a short intervention (28 to 30 days). It may be that NSAIDs are more effective in the long run, that a longer treatment period is needed for patients to realize the effect of SAMe, or that there are more adverse side effects with SAMe over time. It is not yet clear how effective SAMe is over time. Those studies that did have an intervention longer than 30 days18,22 did not compare SAMe with ibuprofen. In general, concomitant medications for treatment of OA were not permitted, but 3 studies24-26 failed to provide this information. Finally, most of the studies looked at OA of the knee and/or hip, so generalizability of the results to other locations of OA is limited. Although we included subgroup analyses by location of OA, statistical power for subgroup analysis was low because of the smaller number of subjects for whom data were available.
Conclusions
Although SAMe appears to offer pain relief and improve functional limitations associated with OA without the side effects of NSAIDs, it must be remembered that SAMe is not considered a drug in the United States and is therefore not subject to federal regulations. (In contrast, Samyr is a prescription drug in Italy and is available in 200 mg and 400 mg doses.) Recent testing by ConsumerLab.com of over-the-counter brands of SAMe in the United States found, on average, that for 6 of the 13 brands tested, less than half the amount of SAMe stated on the label was actually present.36 Patients who use SAMe in the United States may fail to experience relief because of this dose inconsistency.
We offer several suggestions for further research. First, the long-term effectiveness of SAMe for the treatment of OA has not been investigated in a randomized controlled trial. Since OA is the most prevalent form of arthritis, the long-term effectiveness of SAMe should be assessed in this manner. Second, given that SAMe has been shown to decrease depression,1 it seems prudent to use multivariate techniques to examine both depression and OA outcomes (pain and functional limitation) to determine whether the effect of SAMe is directly on the joint or indirectly mediated through depression. Perhaps in the short term SAMe does decrease pain through decreasing depressive symptoms, but in the long term the effectiveness related to pain may diminish. Third, whether SAMe treats the symptoms of the disease or alters the course of the disease by increasing the production of new cartilage, as suggested by animal models, has not been investigated. Finally, can use of SAMe enhance the effectiveness of other nonpharmacologic modalities? These questions should all be investigated before we can make a determination about the efficacy and safety of SAMe for the treatment of OA.
Acknowledgments
This research was supported by grant #5-P50-AT00084-02 from the National Center for Complementary and Alternative Medicine, National Institutes of Health.
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16. Bradley JD, Flusser D, Katz BP, et al. A randomized, double blind, placebo controlled trial of intravenous loading with S-adenosyl-methionine (SAM) followed by oral SAM therapy in patients with knee osteoarthritis. J Rheumatol 1994;21:905-11.
17. Capretto C, Cremona C, Canaparo L. A double-blind controlled study of S-adenosylmethionine (SAMe) v.ibuprofen in gonarthrosis, coxarthrosis and spondylarthrosis. Clin Trials J 1985;22:15-2-43.
18. Caroli A. Studio in doppio cieco SAMe (capsule) - Aspirina nell’osteoartrosi. G Clin Med 1980;61:844-57.
19. Caruso I, Pietrogrande V. Italian double-blind multicenter study comparing S-adenosylmethionine, naproxen, and placebo in the treatment of degenerative joint disease. Am J Med 1987;83(suppl 5A):66-71.
20. Ceccato S, Cucinotta D, Carapezzi C, Ferretti G, Passeri M. Stuio clinico in doppio cieco sull’effetto terapeutico della SAMe e del-l’ibuprofen nella patologia degenerativa articolare. G Clin Med 1980;61:148-62.
21. Cucinotta D, Mancini M, Ceccato S, Castino E. Studio clinico controllato sull’attivita della SAMe somministrata per via orale nella patologia degenerative osteo-articolare. G Clin Med 1980;61:553-65.
22. Maccagno A, DiGiorgio EE, Caston OL, Sagasta CL. Double-blind controlled clinical trial of oral S-adenosylmethionine versus piroxicam in knee osteoarthritis. Am J Med 1987;83 (suppl 5A):72-7.
23. Marcolongo R, Giordano N, Colombo B, et al. Double-blind multicentre study of the activity of S-adenosyl-methionine in hip and knee osteoarthritis. Curr Ther Res 1985;37:82-94.
24. Müller-Fassbender H. Double-blind clinical trial of S-adenosylme-thionine vesus ibuprofen in the treatment of osteoarthritis. Am J Med 1987;83 (suppl 5A):81-3.
25. Pellegrini P. La S-adenosil-metionina (SAMe) nell’osteoartrosi studio in doppio cieco crossover per via orale. G Clin Med 1980;61:616-27.
26. Vetter G. Double-blind comparative clinical trial with S-adenosyl-methionine and indomethacin in the treatment of osteoarthritis. Am J Med 1987;83 (suppl 5A):78-80.
27. Glorioso S, Todesco S, Mazzi A, et al. Double-blind multicentre study of the activity of S-adenosylmethionine in hip and knee osteoarthritis. Int J Clin Pharm Res 1985;1:39-49.
28. Polli E, Cortellaro M, Parrini L, Tessari L, Ligniere GC. Aspetti farmacologici e clinici della solfo-adenosil-metionina (SAMe) nella artropatia degnerativa primaria (osteoartrosi). Min Med 1975;66:4443-59.
29. Bach GL, Gmeiner G. Wochen-doppelblindstudie mit ademetionin (Gumbaral(r)) bei gonarthrose zur ermittlung der äquivalenz intravenöser und oraler dosen. In: Bach GL, Muller-Fassbender H, editors. Arthrose-workshop uber Gumbaral(r) (Ademetionin). Frankfurt am Main:Verlag GmbH. 1986;23-30.
30. Ceccato S, Cucinotta D, Carapezzi C, Passeri M. Indagine clinica aperta e comparativa sull’impiego della SAMe e del ketoprofen nell’osteoartrosi. Progr Med 1979;35:177-91.
31. Berger R, Nowak H. A new medication approach to the treatment of osteoarthritis: report of an open phase IV study with ademethionine (Gumbaral(r)). Am J Med 1987;83(suppl 5A):84-8.
32. Konig B. A long-term (two years) clinical trial with S-adenosylmethionine for the treatment of osteoarthritis. Am J Med 1987;83(suppl 5A):89-94.
33. Domljan Z, Vrhovac B, Dürrigl T, Pu_ar I. A double-blind trial of ademetionine vs naproxen in activated gonarthritis. Int J Clin Pharmacol Ther Toxicol 1989;27:329-33.
34. Montrone F, Fumagalli M, Sarzi Puttini P, et al. Double-blind study of S-adenosyl-methionine versus placebo in hip and knee arthrosis [letter]. Clin Rheumatol 1985;4:484-5.
35. Mitchell D. The SAMe solution. New York: Warner Books, Inc., 1999.
36. ConsumerLab.com. Product review: SAMe. [http://www.consumerlab.com]. Accessed March 11, 2002.
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16. Bradley JD, Flusser D, Katz BP, et al. A randomized, double blind, placebo controlled trial of intravenous loading with S-adenosyl-methionine (SAM) followed by oral SAM therapy in patients with knee osteoarthritis. J Rheumatol 1994;21:905-11.
17. Capretto C, Cremona C, Canaparo L. A double-blind controlled study of S-adenosylmethionine (SAMe) v.ibuprofen in gonarthrosis, coxarthrosis and spondylarthrosis. Clin Trials J 1985;22:15-2-43.
18. Caroli A. Studio in doppio cieco SAMe (capsule) - Aspirina nell’osteoartrosi. G Clin Med 1980;61:844-57.
19. Caruso I, Pietrogrande V. Italian double-blind multicenter study comparing S-adenosylmethionine, naproxen, and placebo in the treatment of degenerative joint disease. Am J Med 1987;83(suppl 5A):66-71.
20. Ceccato S, Cucinotta D, Carapezzi C, Ferretti G, Passeri M. Stuio clinico in doppio cieco sull’effetto terapeutico della SAMe e del-l’ibuprofen nella patologia degenerativa articolare. G Clin Med 1980;61:148-62.
21. Cucinotta D, Mancini M, Ceccato S, Castino E. Studio clinico controllato sull’attivita della SAMe somministrata per via orale nella patologia degenerative osteo-articolare. G Clin Med 1980;61:553-65.
22. Maccagno A, DiGiorgio EE, Caston OL, Sagasta CL. Double-blind controlled clinical trial of oral S-adenosylmethionine versus piroxicam in knee osteoarthritis. Am J Med 1987;83 (suppl 5A):72-7.
23. Marcolongo R, Giordano N, Colombo B, et al. Double-blind multicentre study of the activity of S-adenosyl-methionine in hip and knee osteoarthritis. Curr Ther Res 1985;37:82-94.
24. Müller-Fassbender H. Double-blind clinical trial of S-adenosylme-thionine vesus ibuprofen in the treatment of osteoarthritis. Am J Med 1987;83 (suppl 5A):81-3.
25. Pellegrini P. La S-adenosil-metionina (SAMe) nell’osteoartrosi studio in doppio cieco crossover per via orale. G Clin Med 1980;61:616-27.
26. Vetter G. Double-blind comparative clinical trial with S-adenosyl-methionine and indomethacin in the treatment of osteoarthritis. Am J Med 1987;83 (suppl 5A):78-80.
27. Glorioso S, Todesco S, Mazzi A, et al. Double-blind multicentre study of the activity of S-adenosylmethionine in hip and knee osteoarthritis. Int J Clin Pharm Res 1985;1:39-49.
28. Polli E, Cortellaro M, Parrini L, Tessari L, Ligniere GC. Aspetti farmacologici e clinici della solfo-adenosil-metionina (SAMe) nella artropatia degnerativa primaria (osteoartrosi). Min Med 1975;66:4443-59.
29. Bach GL, Gmeiner G. Wochen-doppelblindstudie mit ademetionin (Gumbaral(r)) bei gonarthrose zur ermittlung der äquivalenz intravenöser und oraler dosen. In: Bach GL, Muller-Fassbender H, editors. Arthrose-workshop uber Gumbaral(r) (Ademetionin). Frankfurt am Main:Verlag GmbH. 1986;23-30.
30. Ceccato S, Cucinotta D, Carapezzi C, Passeri M. Indagine clinica aperta e comparativa sull’impiego della SAMe e del ketoprofen nell’osteoartrosi. Progr Med 1979;35:177-91.
31. Berger R, Nowak H. A new medication approach to the treatment of osteoarthritis: report of an open phase IV study with ademethionine (Gumbaral(r)). Am J Med 1987;83(suppl 5A):84-8.
32. Konig B. A long-term (two years) clinical trial with S-adenosylmethionine for the treatment of osteoarthritis. Am J Med 1987;83(suppl 5A):89-94.
33. Domljan Z, Vrhovac B, Dürrigl T, Pu_ar I. A double-blind trial of ademetionine vs naproxen in activated gonarthritis. Int J Clin Pharmacol Ther Toxicol 1989;27:329-33.
34. Montrone F, Fumagalli M, Sarzi Puttini P, et al. Double-blind study of S-adenosyl-methionine versus placebo in hip and knee arthrosis [letter]. Clin Rheumatol 1985;4:484-5.
35. Mitchell D. The SAMe solution. New York: Warner Books, Inc., 1999.
36. ConsumerLab.com. Product review: SAMe. [http://www.consumerlab.com]. Accessed March 11, 2002.