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An Evidence-Based Assessment of Glucosamine Sulfate, St. John's Wort, and Echinacea
Jack J. Chen, PharmD Disclosures
An Evidence-Based Assessment of Glucosamine Sulfate, St. John's Wort, and Echinacea
Jack J. Chen, PharmD, BCPS, FCPhA
Introduction
Dietary supplements and botanical preparations have become mainstream products in the management of several acute and chronic medical conditions, such as the common cold, depression, and osteoarthritis. For certain products, sufficient scientific evidence is now available to enable clinicians to perform systematic analyses on safety and efficacy and to provide recommendations based on levels of evidence. Evidence-based medicine principles should be applied when formulating clinical decisions on the use of dietary supplements and botanical products. For some products, such as Echinacea purpurea for management of the common cold, St. John's wort for depression, and glucosamine sulfate for osteoarthritis, the evidence is favorable and supportive.
The Evidence-Based Medicine Process for Dietary Supplements
The evidence-based medicine process is a focused, intense process that provides a systematic method for clinicians to ensure that decisions are based on the quality of results from clinical studies. The process is similar to that for decisions regarding allopathic medications and is consistent with the provision of quality pharmaceutical care. Cydney E. McQueen, PharmD, Assistant Director of the Drug Information Center at the University of Missouri-Kansas City School of Pharmacy, recommends a step-by-step approach when formulating an evidence-based recommendation on a dietary supplement. However, clinicians should be aware of certain caveats.
Step One: Retrieval of Scientific Information
A major caveat in the retrieval of scientific information on dietary supplements is that alternative indexing systems must be used to capture relevant literature. Otherwise, significant scientific citations may be overlooked. In addition to Medline or PubMed, bibliographic databases such as Embase, International Pharmaceutical Abstracts (IPA), Natural Medicines Comprehensive Database, AltMedDex (Micromedex Corporation), and the quarterly journal, Focus on Alternative and Complementary Therapies (FACT), are recommended. Other sources of bibliographic information include newsletters such as Natural Medicine News, a complimentary electronic newsletter; Bandolier.com, an evidence-based medicine Web site; and the Cochrane Collaboration. A second caveat in search strategy involves using appropriate and comprehensive search terminology. For dietary supplements and botanical preparations, bibliographic searches should be performed using the common name, Latin nomenclature, and alternative spellings. When possible, keywords recognized by the search system are also recommended. A third caveat is that scientific literature on dietary supplements may be in a non-English journal. Such information should not be automatically disregarded. The American Botanical Council offers selective literature translation services.
Step Two: Evaluation of the Scientific Literature
Once the relevant scientific literature has been identified and retrieved, the next step is to evaluate the information. A major caveat is to identify the specific dietary supplement or botanical product formulation used in the study. Attention should be given to product standardization and commercial availability. If the product is widely available in the commercial market, then the external validity of the study is strengthened. If the study used a special formulation that is not widely available on the market, then clinicians should be cautious when extrapolating the study results to other product formulations on the market, as this is not appropriate. Additionally, merit is given if the study was performed in a randomized, blinded, and placebo-controlled manner, if the researchers have expertise in the disease state under investigation, and if the outcome measures are clinically accepted and applicable.
Clinicians often have questions about the statistical power of the study. Studies with low false-negative errors (high power; eg, 80%) and low false-positive errors (eg, alpha = 0.05%) are desirable. In essence, anytime a statistically significant difference exists between the treatment groups, then the study was appropriately powered (whether or not a power analysis was provided by the investigators). If no statistically significant difference is reported, then the reader should examine the investigators' a priori power analysis. If a sufficient number of patients completed the study to fulfill the criteria for providing sufficient power, then the finding of no statistically significant difference can be accepted as valid. However, if a power analysis is not reported, then a finding of no statistical difference must be questioned since the study may not have enrolled enough patients to detect a statistically significant difference between treatment groups. Dr. McQueen presented a 10-item checklist that clinicians can use to aid in the evaluation of the evidence (Table 1). The checklist contains 10 major considerations that clinicians should examine when analyzing a study.
Table 1. Ten-Item Checklist for Evaluating a Clinical Study
Power is/is not met.
Length of study is/is not appropriate to show effect.
Doses used are/are not in therapeutic range.
Inclusion criteria are /are not adequate or not flawed/flawed.
Exclusion criteria are /are not adequate or not flawed/flawed.
Blinding is /is not flawed.
Randomization did/did not result in similar groups.
Evaluation measurements are standard/not standard or accepted/not accepted practice.
Statistical tests used are/are not appropriate.
Authors' conclusions are/are not supported by the results.
Step Three: Classification of Evidence and Grading of Recommendations
Once the study results have been reviewed, the next step is to classify the evidence, develop a recommendation, and grade the recommendation based on the level of evidence. The classification of evidence and grading of recommendations is performed in a manner similar to that applied to allopathic treatment interventions (Tables 2 and 3).[1,2] The recommendation should be stated with firmness and supported by the evidence. Dr. McQueen recommends that clinicians summarize the evidence in a tabular format (Table 4).
Table 2. Levels of Evidence
Level I RCT or meta-analysis with high power
Level II RCT or meta-analysis with low power
Level III Nonrandomized concurrent cohort studies
Level IV Nonrandomized historical cohort studies
Level V Case series
RCT = randomized controlled trial
Table 3. Grading of Recommendations
Grade Supported by
A Level I Evidence
B Level II Evidence
C Level III, IV, or V Evidence
Table 4. Tabular Format for Evidence
Study Subjects (N) Results* Control† LOE Limitations‡
Author A
Author B
Author C
* Results reported as positive or negative.
† Control reported as placebo or comparative intervention.
‡ Limitations reported as major or minor.
LOE = level of evidence
Case Study: Echinacea purpurea
Applying the evidence-based medicine process and the 10-item evaluation checklist, June McDermott, MSPharm, MBA, FASHP, Clinical Assistant Professor at the University of North Carolina-Chapel Hill School of Pharmacy, provided an overview of the clinical evidence for Echinacea purpurea in the treatment and prevention of the common cold.
The results of 3 randomized, double-blind, placebo-controlled studies investigating the efficacy of Echinacea purpurea preparations in the treatment of common cold symptoms (Table 5)[3-5] and 3 randomized, double-blind, placebo-controlled studies investigating the efficacy of Echinacea purpurea preparations in the prevention of the common cold (Table 6)[6-8] were presented.
Table 5. Evidence Table: Echinacea Preparations in the Treatment of the Common Cold
Study Subjects (N) Results Control LOE Limitations
Brinkeborn[3] 246 Positive Placebo and Echinacea root extract I Minor
Hoheisel[4] 120 Positive Placebo I Major
Lindenmuth[5] 95 Positive Placebo II Major
LOE = level of evidence
Table 6. Evidence Table: Echinacea Preparations in the Prevention of the Common Cold
Study Subjects (N) Results Control LOE Limitations
Melchart[6] 202 Negative Placebo II Major
Grimm[7] 108 Negative Placebo II Major
Turner[8] 92 Negative Placebo II Major
LOE = level of evidence
Based on the evidence, Dr. McDermott recommended that certain Echinacea purpurea preparations (eg, Echinaforce) are effective in reducing the duration of symptoms associated with the common cold (Grade B recommendation). The preparation should be administered as early as possible after the onset of symptoms. Side effects experienced by Echinacea purpurea-treated patients are similar to those of placebo-treated patients. For the prevention of the common cold, Echinacea purpurea preparations are not effective.
Case Study: St. John's Wort
C. W. Fetrow, PharmD, Clinical Pharmacy Specialist at the University of Pittsburgh Medical Center -- Passavant Hospital, Pittsburgh, Pennsylvania, provided an overview of the evidence from 3 randomized, double-blind, placebo-controlled trials on the use of St. John's wort for the management of depression (Table 7).[9-11] All 3 trials used a dosage of St. John's wort >= hypericum 900 mg/day with a treatment duration of at least 8 weeks. Although various outcomes measurements were used, all 3 trials included the Hamilton Rating Scale for Depression (HAM-D) as a primary outcome measurement. The HAM-D is a standardized tool that is commonly used in therapeutic trials for depression.
Table 7. Evidence Table: St. John's Wort in the Treatment of Depression
Study Subjects (N) Results Control LOE Limitations
Philipp[9] 263 Positive Placebo and imipramine II Major
Shelton[10] 200 Negative Placebo II Major
Laakmann[11] 147 Positive Placebo II Major
LOE = level of evidence
Based on the evidence, Dr. Fetrow recommended that St. John's wort preparations administered at a dosage >= hypericum 900 mg/day are effective for the treatment of mild to moderate depression (Grade B recommendation). Patients with severe depression or who are at high risk for suicide are not candidates for treatment with St. John's wort. Additionally, there is a paucity of data for the use of St. John's wort in patients suffering from depression that is refractory to conventional allopathic agents.
Case Study: Glucosamine Sulfate
Joseph Pepping, PharmD, Pain Management and Nutritional Medicine Consultant for the Kaiser Moanalua Medical Center, Honolulu, Hawaii, reviewed 4 double-blinded, randomized clinical trials on the effect of glucosamine sulfate for the management of knee osteoarthritis (Table 8).[12-15] Particular attention was focused on a well-designed, randomized, double-blind, placebo-controlled trial investigating the long-term effects of glucosamine sulfate.[12] In this study, patients with severe osteoarthritis or morbid obesity were excluded. Symptoms were scored by the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index, a well-validated tool for measuring osteoarthritis-related outcomes such as pain, stiffness, and disability. Long-term progression of osteoarthritis was evaluated by measuring the change in width of the medial tibiofemoral joint space using digitized radiographs over a period of 3 years. Treatment with crystalline glucosamine sulfate (Dona, Viartril-S, Xicil, Rotta Research Group, Monza, Italy) 1500 mg once daily for 3 years (normally glucosamine sulfate is administered 500 mg 3 times daily) was well tolerated and associated with beneficial structure- and symptom-modifying effects in patients with mild to moderate osteoarthritis of the knee. The treatment period of 3 years is the longest to date of all studies of glucosamine in the management of osteoarthritis. This study is also remarkable in that the results suggest that oral glucosamine sulfate may act as a disease-modifying agent in patients with mild to moderate osteoarthritis of the knee.
Based on the evidence, Dr. Pepping recommended that stabilized glucosamine sulfate administered at a dosage of 1500 mg/day has beneficial effects on osteoarthritis symptoms (Grade A recommendation) and that long-term treatment is well tolerated (with superior safety over nonsteroidal anti-inflammatory agents) and may slow the progression of cartilage degeneration. Glucosamine sulfate "can be responsibly offered as either a first-line or adjunctive agent in the treatment of osteoarthritis," Pepping said. A caveat is that these studies used the sulfate salt of glucosamine (stabilized with potassium chloride or sodium chloride), and other forms of glucosamine may not be as effective. When counseling patients on glucosamine sulfate, clinicians should emphasize that the product should be taken with meals and routinely (not as needed). Additionally, a trial of at least 4 weeks is necessary to assess benefits. Diabetic patients should be informed that there are case reports of glucosamine sulfate causing an increase in blood glucose levels and that blood glucose levels should be monitored. However, in the 4 large clinical trials that were reviewed, significant changes in blood glucose levels were not noted.
Table 8. Evidence Table: Glucosamine Sulfate in the Long-term Treatment of Osteoarthritis
Study Subjects (N) Results Control LOE Limitations
Reginster[12] 212 Positive Placebo I Minor
Noack[13] 252 Positive Placebo I Minor
Muller-Fassbender[14] 200 Equivalent Ibuprofen I Minor
Qiu[15] 178 Equivalent Ibuprofen II Major
LOE = level of evidence
Conclusions
As scientific evidence on dietary supplements and botanical products become increasingly available, clinicians should use the evidence-based medicine process to objectively evaluate the data and to formulate appropriate recommendations. Based on the available evidence to date, the following recommendations can be made: Echinacea purpurea is effective for reducing the duration of symptoms of the common cold (but not for prevention), St. John's wort is effective for treating mild to moderate depression, and glucosamine sulfate is beneficial for treating osteoarthritis of the knee.
References
Cook DJ, Guyatt GH, Laupacis A, et al. Rule of evidence and clinical recommendations on the use of antithrombotic agents. Chest. 1992;104(suppl):305S-311S.
Guyatt GH, Cook DJ, Sackett DL, et al. Grades of recommendation for antithrombotic agents. Chest. 1998;114(suppl):441S-444S.
Brinkeborn RM, Shah DV, Degenring FH. Echinaforce and other Echinacea fresh plant preparations in the treatment of the common cold. Phytomedicine. 1999;6:1-6.
Hoheisel O, Sandberg M, Bertram S, et al. Echinagard treatment shortens the course of the common cold: a double-blind, placebo-controlled clinical trial. Eur J Clin Res. 1997;9:261-268.
Lindenmuth GF, Lindenmuth EB. The efficacy of Echinacea compound herbal tea preparation on the severity and duration of upper respiratory and flu symptoms: a randomized, double-blind placebo-controlled study. J Altern Complement Med. 2000;6:327-334.
Melchart D, Walther E, Linde K, et al. Echinacea root extracts for the prevention of upper respiratory tract infections: a double-blind, placebo-controlled randomized trial. Arch Fam Med. 1998;7:541-545.
Grimm W, Muller HH. A randomized controlled trial of the effect of fluid extract of Echinacea purpurea on the incidence and severity of colds and respiratory infections. Am J Med. 1999;106:138-143.
Turner RB, Riker DK, Gangemi JD. Ineffectiveness of echinacea for prevention of experimental rhinovirus colds. Antimicrob Agents Chemother. 2000;44:1708-1709.
Philipp M, Kohnen R, Hiller KO. Hypericum extract versus imipramine or placebo in patients with moderate depression: randomized multicentre study of treatment for eight weeks. BMJ. 1999;319:1534-1538.
Shelton RC, Keller MB, Gelenberg A, et al. Effectiveness of St John's wort in major depression: a randomized controlled trial. JAMA. 2001;285:1978-1986.
Laakmann G, Schule C, Baghai T, et al. St. John's wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry. 1998;31(suppl 1):54-59.
Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomized, placebo-controlled clinical trial. Lancet. 2001;357:251-256.
Noack W, Fischer M, Forster KK, et al. Glucosamine sulfate in osteoarthritis of the knee. Osteoarthritis Cartilage. 1994;2:51-59.
Muller-Fassbender H, Bach GL, Haase W, et al. Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee. Osteoarthritis Cartilage. 1994;2:61-69.
Qiu GX, Gao SN, Giacovelli G, et al. Efficacy and safety of glucosamine sulfate versus ibuprofen in patients with knee osteoarthritis. Arzneimittelforschung. 1998;48:469-474.
An Evidence-Based Assessment of Glucosamine Sulfate, St. John's Wort, and Echinacea
Jack J. Chen, PharmD Disclosures
An Evidence-Based Assessment of Glucosamine Sulfate, St. John's Wort, and Echinacea
Jack J. Chen, PharmD, BCPS, FCPhA
Introduction
Dietary supplements and botanical preparations have become mainstream products in the management of several acute and chronic medical conditions, such as the common cold, depression, and osteoarthritis. For certain products, sufficient scientific evidence is now available to enable clinicians to perform systematic analyses on safety and efficacy and to provide recommendations based on levels of evidence. Evidence-based medicine principles should be applied when formulating clinical decisions on the use of dietary supplements and botanical products. For some products, such as Echinacea purpurea for management of the common cold, St. John's wort for depression, and glucosamine sulfate for osteoarthritis, the evidence is favorable and supportive.
The Evidence-Based Medicine Process for Dietary Supplements
The evidence-based medicine process is a focused, intense process that provides a systematic method for clinicians to ensure that decisions are based on the quality of results from clinical studies. The process is similar to that for decisions regarding allopathic medications and is consistent with the provision of quality pharmaceutical care. Cydney E. McQueen, PharmD, Assistant Director of the Drug Information Center at the University of Missouri-Kansas City School of Pharmacy, recommends a step-by-step approach when formulating an evidence-based recommendation on a dietary supplement. However, clinicians should be aware of certain caveats.
Step One: Retrieval of Scientific Information
A major caveat in the retrieval of scientific information on dietary supplements is that alternative indexing systems must be used to capture relevant literature. Otherwise, significant scientific citations may be overlooked. In addition to Medline or PubMed, bibliographic databases such as Embase, International Pharmaceutical Abstracts (IPA), Natural Medicines Comprehensive Database, AltMedDex (Micromedex Corporation), and the quarterly journal, Focus on Alternative and Complementary Therapies (FACT), are recommended. Other sources of bibliographic information include newsletters such as Natural Medicine News, a complimentary electronic newsletter; Bandolier.com, an evidence-based medicine Web site; and the Cochrane Collaboration. A second caveat in search strategy involves using appropriate and comprehensive search terminology. For dietary supplements and botanical preparations, bibliographic searches should be performed using the common name, Latin nomenclature, and alternative spellings. When possible, keywords recognized by the search system are also recommended. A third caveat is that scientific literature on dietary supplements may be in a non-English journal. Such information should not be automatically disregarded. The American Botanical Council offers selective literature translation services.
Step Two: Evaluation of the Scientific Literature
Once the relevant scientific literature has been identified and retrieved, the next step is to evaluate the information. A major caveat is to identify the specific dietary supplement or botanical product formulation used in the study. Attention should be given to product standardization and commercial availability. If the product is widely available in the commercial market, then the external validity of the study is strengthened. If the study used a special formulation that is not widely available on the market, then clinicians should be cautious when extrapolating the study results to other product formulations on the market, as this is not appropriate. Additionally, merit is given if the study was performed in a randomized, blinded, and placebo-controlled manner, if the researchers have expertise in the disease state under investigation, and if the outcome measures are clinically accepted and applicable.
Clinicians often have questions about the statistical power of the study. Studies with low false-negative errors (high power; eg, 80%) and low false-positive errors (eg, alpha = 0.05%) are desirable. In essence, anytime a statistically significant difference exists between the treatment groups, then the study was appropriately powered (whether or not a power analysis was provided by the investigators). If no statistically significant difference is reported, then the reader should examine the investigators' a priori power analysis. If a sufficient number of patients completed the study to fulfill the criteria for providing sufficient power, then the finding of no statistically significant difference can be accepted as valid. However, if a power analysis is not reported, then a finding of no statistical difference must be questioned since the study may not have enrolled enough patients to detect a statistically significant difference between treatment groups. Dr. McQueen presented a 10-item checklist that clinicians can use to aid in the evaluation of the evidence (Table 1). The checklist contains 10 major considerations that clinicians should examine when analyzing a study.
Table 1. Ten-Item Checklist for Evaluating a Clinical Study
Power is/is not met.
Length of study is/is not appropriate to show effect.
Doses used are/are not in therapeutic range.
Inclusion criteria are /are not adequate or not flawed/flawed.
Exclusion criteria are /are not adequate or not flawed/flawed.
Blinding is /is not flawed.
Randomization did/did not result in similar groups.
Evaluation measurements are standard/not standard or accepted/not accepted practice.
Statistical tests used are/are not appropriate.
Authors' conclusions are/are not supported by the results.
Step Three: Classification of Evidence and Grading of Recommendations
Once the study results have been reviewed, the next step is to classify the evidence, develop a recommendation, and grade the recommendation based on the level of evidence. The classification of evidence and grading of recommendations is performed in a manner similar to that applied to allopathic treatment interventions (Tables 2 and 3).[1,2] The recommendation should be stated with firmness and supported by the evidence. Dr. McQueen recommends that clinicians summarize the evidence in a tabular format (Table 4).
Table 2. Levels of Evidence
Level I RCT or meta-analysis with high power
Level II RCT or meta-analysis with low power
Level III Nonrandomized concurrent cohort studies
Level IV Nonrandomized historical cohort studies
Level V Case series
RCT = randomized controlled trial
Table 3. Grading of Recommendations
Grade Supported by
A Level I Evidence
B Level II Evidence
C Level III, IV, or V Evidence
Table 4. Tabular Format for Evidence
Study Subjects (N) Results* Control† LOE Limitations‡
Author A
Author B
Author C
* Results reported as positive or negative.
† Control reported as placebo or comparative intervention.
‡ Limitations reported as major or minor.
LOE = level of evidence
Case Study: Echinacea purpurea
Applying the evidence-based medicine process and the 10-item evaluation checklist, June McDermott, MSPharm, MBA, FASHP, Clinical Assistant Professor at the University of North Carolina-Chapel Hill School of Pharmacy, provided an overview of the clinical evidence for Echinacea purpurea in the treatment and prevention of the common cold.
The results of 3 randomized, double-blind, placebo-controlled studies investigating the efficacy of Echinacea purpurea preparations in the treatment of common cold symptoms (Table 5)[3-5] and 3 randomized, double-blind, placebo-controlled studies investigating the efficacy of Echinacea purpurea preparations in the prevention of the common cold (Table 6)[6-8] were presented.
Table 5. Evidence Table: Echinacea Preparations in the Treatment of the Common Cold
Study Subjects (N) Results Control LOE Limitations
Brinkeborn[3] 246 Positive Placebo and Echinacea root extract I Minor
Hoheisel[4] 120 Positive Placebo I Major
Lindenmuth[5] 95 Positive Placebo II Major
LOE = level of evidence
Table 6. Evidence Table: Echinacea Preparations in the Prevention of the Common Cold
Study Subjects (N) Results Control LOE Limitations
Melchart[6] 202 Negative Placebo II Major
Grimm[7] 108 Negative Placebo II Major
Turner[8] 92 Negative Placebo II Major
LOE = level of evidence
Based on the evidence, Dr. McDermott recommended that certain Echinacea purpurea preparations (eg, Echinaforce) are effective in reducing the duration of symptoms associated with the common cold (Grade B recommendation). The preparation should be administered as early as possible after the onset of symptoms. Side effects experienced by Echinacea purpurea-treated patients are similar to those of placebo-treated patients. For the prevention of the common cold, Echinacea purpurea preparations are not effective.
Case Study: St. John's Wort
C. W. Fetrow, PharmD, Clinical Pharmacy Specialist at the University of Pittsburgh Medical Center -- Passavant Hospital, Pittsburgh, Pennsylvania, provided an overview of the evidence from 3 randomized, double-blind, placebo-controlled trials on the use of St. John's wort for the management of depression (Table 7).[9-11] All 3 trials used a dosage of St. John's wort >= hypericum 900 mg/day with a treatment duration of at least 8 weeks. Although various outcomes measurements were used, all 3 trials included the Hamilton Rating Scale for Depression (HAM-D) as a primary outcome measurement. The HAM-D is a standardized tool that is commonly used in therapeutic trials for depression.
Table 7. Evidence Table: St. John's Wort in the Treatment of Depression
Study Subjects (N) Results Control LOE Limitations
Philipp[9] 263 Positive Placebo and imipramine II Major
Shelton[10] 200 Negative Placebo II Major
Laakmann[11] 147 Positive Placebo II Major
LOE = level of evidence
Based on the evidence, Dr. Fetrow recommended that St. John's wort preparations administered at a dosage >= hypericum 900 mg/day are effective for the treatment of mild to moderate depression (Grade B recommendation). Patients with severe depression or who are at high risk for suicide are not candidates for treatment with St. John's wort. Additionally, there is a paucity of data for the use of St. John's wort in patients suffering from depression that is refractory to conventional allopathic agents.
Case Study: Glucosamine Sulfate
Joseph Pepping, PharmD, Pain Management and Nutritional Medicine Consultant for the Kaiser Moanalua Medical Center, Honolulu, Hawaii, reviewed 4 double-blinded, randomized clinical trials on the effect of glucosamine sulfate for the management of knee osteoarthritis (Table 8).[12-15] Particular attention was focused on a well-designed, randomized, double-blind, placebo-controlled trial investigating the long-term effects of glucosamine sulfate.[12] In this study, patients with severe osteoarthritis or morbid obesity were excluded. Symptoms were scored by the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index, a well-validated tool for measuring osteoarthritis-related outcomes such as pain, stiffness, and disability. Long-term progression of osteoarthritis was evaluated by measuring the change in width of the medial tibiofemoral joint space using digitized radiographs over a period of 3 years. Treatment with crystalline glucosamine sulfate (Dona, Viartril-S, Xicil, Rotta Research Group, Monza, Italy) 1500 mg once daily for 3 years (normally glucosamine sulfate is administered 500 mg 3 times daily) was well tolerated and associated with beneficial structure- and symptom-modifying effects in patients with mild to moderate osteoarthritis of the knee. The treatment period of 3 years is the longest to date of all studies of glucosamine in the management of osteoarthritis. This study is also remarkable in that the results suggest that oral glucosamine sulfate may act as a disease-modifying agent in patients with mild to moderate osteoarthritis of the knee.
Based on the evidence, Dr. Pepping recommended that stabilized glucosamine sulfate administered at a dosage of 1500 mg/day has beneficial effects on osteoarthritis symptoms (Grade A recommendation) and that long-term treatment is well tolerated (with superior safety over nonsteroidal anti-inflammatory agents) and may slow the progression of cartilage degeneration. Glucosamine sulfate "can be responsibly offered as either a first-line or adjunctive agent in the treatment of osteoarthritis," Pepping said. A caveat is that these studies used the sulfate salt of glucosamine (stabilized with potassium chloride or sodium chloride), and other forms of glucosamine may not be as effective. When counseling patients on glucosamine sulfate, clinicians should emphasize that the product should be taken with meals and routinely (not as needed). Additionally, a trial of at least 4 weeks is necessary to assess benefits. Diabetic patients should be informed that there are case reports of glucosamine sulfate causing an increase in blood glucose levels and that blood glucose levels should be monitored. However, in the 4 large clinical trials that were reviewed, significant changes in blood glucose levels were not noted.
Table 8. Evidence Table: Glucosamine Sulfate in the Long-term Treatment of Osteoarthritis
Study Subjects (N) Results Control LOE Limitations
Reginster[12] 212 Positive Placebo I Minor
Noack[13] 252 Positive Placebo I Minor
Muller-Fassbender[14] 200 Equivalent Ibuprofen I Minor
Qiu[15] 178 Equivalent Ibuprofen II Major
LOE = level of evidence
Conclusions
As scientific evidence on dietary supplements and botanical products become increasingly available, clinicians should use the evidence-based medicine process to objectively evaluate the data and to formulate appropriate recommendations. Based on the available evidence to date, the following recommendations can be made: Echinacea purpurea is effective for reducing the duration of symptoms of the common cold (but not for prevention), St. John's wort is effective for treating mild to moderate depression, and glucosamine sulfate is beneficial for treating osteoarthritis of the knee.
References
Cook DJ, Guyatt GH, Laupacis A, et al. Rule of evidence and clinical recommendations on the use of antithrombotic agents. Chest. 1992;104(suppl):305S-311S.
Guyatt GH, Cook DJ, Sackett DL, et al. Grades of recommendation for antithrombotic agents. Chest. 1998;114(suppl):441S-444S.
Brinkeborn RM, Shah DV, Degenring FH. Echinaforce and other Echinacea fresh plant preparations in the treatment of the common cold. Phytomedicine. 1999;6:1-6.
Hoheisel O, Sandberg M, Bertram S, et al. Echinagard treatment shortens the course of the common cold: a double-blind, placebo-controlled clinical trial. Eur J Clin Res. 1997;9:261-268.
Lindenmuth GF, Lindenmuth EB. The efficacy of Echinacea compound herbal tea preparation on the severity and duration of upper respiratory and flu symptoms: a randomized, double-blind placebo-controlled study. J Altern Complement Med. 2000;6:327-334.
Melchart D, Walther E, Linde K, et al. Echinacea root extracts for the prevention of upper respiratory tract infections: a double-blind, placebo-controlled randomized trial. Arch Fam Med. 1998;7:541-545.
Grimm W, Muller HH. A randomized controlled trial of the effect of fluid extract of Echinacea purpurea on the incidence and severity of colds and respiratory infections. Am J Med. 1999;106:138-143.
Turner RB, Riker DK, Gangemi JD. Ineffectiveness of echinacea for prevention of experimental rhinovirus colds. Antimicrob Agents Chemother. 2000;44:1708-1709.
Philipp M, Kohnen R, Hiller KO. Hypericum extract versus imipramine or placebo in patients with moderate depression: randomized multicentre study of treatment for eight weeks. BMJ. 1999;319:1534-1538.
Shelton RC, Keller MB, Gelenberg A, et al. Effectiveness of St John's wort in major depression: a randomized controlled trial. JAMA. 2001;285:1978-1986.
Laakmann G, Schule C, Baghai T, et al. St. John's wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry. 1998;31(suppl 1):54-59.
Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomized, placebo-controlled clinical trial. Lancet. 2001;357:251-256.
Noack W, Fischer M, Forster KK, et al. Glucosamine sulfate in osteoarthritis of the knee. Osteoarthritis Cartilage. 1994;2:51-59.
Muller-Fassbender H, Bach GL, Haase W, et al. Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee. Osteoarthritis Cartilage. 1994;2:61-69.
Qiu GX, Gao SN, Giacovelli G, et al. Efficacy and safety of glucosamine sulfate versus ibuprofen in patients with knee osteoarthritis. Arzneimittelforschung. 1998;48:469-474.
