Cochrane for Clinicians

Putting Evidence into Practice

Glucosamine Treatment for Osteoarthritis

Jasmine Chen Gatti, M.D., Holy Cross Hospital Home Care and Hospice, Silver Spring, Maryland

The Cochrane Abstract on the next page is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Jasmine Chen Gatti, M.D., presents a clinical scenario and question based on the Cochrane Abstract, followed by an evidence-based answer and a full critique of the review.

This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). EB CME is clinical content presented with practice recommendations supported by evidence that has been reviewed systematically by an AAFP-approved source. The practice recommendations in this activity are available online at http://www.cochrane.org/reviews/en/ab002946.html.

Clinical Scenario

A 75-year-old obese woman presents with chronic, severe knee pain from osteoarthritis. She would like to know whether glucosamine sulfate therapy is beneficial.

Clinical Question

Is glucosamine sulfate safe and effective for osteoarthritis?

Evidence-Based Answer

This review1 shows that, compared with placebo, glucosamine sulfate produces a moderate, clinically significant reduction in pain and improvement in function for patients with osteoarthritis. However, study results were not consistent. Most studies in the review used preparations of glucosamine sulfate marketed in Europe by Rotta pharmaceutical company. Subgroup analysis showed that the Rotta preparation had benefit over placebo, whereas non-Rotta preparations did not. Glucosamine does not cause more side effects than placebo.1

Practice Pointers

Osteoarthritis is the most common arthritis, affecting an estimated 12.1 percent of Americans 25 years and older.1 Therapy includes nonpharmacologic interventions such as weight loss, physical and occupational therapy, and surgery. Medication options include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular injections, opiates, and glucosamine sulfate.2 Glucosamine exists naturally in the body as a building block of cartilage.

This review1 is an update of a Cochrane review published in 2000.3 That review of 16 studies (with a total of 2,029 patients) demonstrated that patients who took 1,500 mg of glucosamine sulfate per day for six weeks had a 60 percent improvement from baseline in pain and a 33 percent improvement in function.3 The update,1 which included only the higher quality studies and eight new studies (2,570 patients), showed less consistent and somewhat less favorable results regarding improvement in pain and function with use of glucosamine sulfate for two to three months.1

The Rotta pharmaceutical company sponsored 65 percent of the studies in the updated review. Studies of the Rotta prescription preparation revealed significant improvements over placebo in pain and in the Lequesne function index, but not in the WOMAC pain, stiffness, and function indices. Non-Rotta preparations showed no benefit over placebo in any of the three outcome measures. Because glucosamine sulfate is not a prescription drug in North America, it is not regulated; therefore, the purity and content can vary greatly.4,5 One study4 of glucosamine and chondroitin supplements showed that label claims differed from the actual content by up to 115 percent. The Rotta pharmaceutical company brand is available in the United States and by prescription in European countries.

Two studies of the radiologic progression of osteoarthritis found that this was slowed by glucosamine over a three-year period. However, the clinical significance of this finding remains uncertain. The authors did not compare the effects of glucosamine on patients with osteoarthritis of different levels of severity and duration, two factors that might affect response to glucosamine.

The safety profile of glucosamine is superior to that of NSAIDs and similar to placebo. In one study,6 88 percent of patients had no adverse effects; in the remaining patients, the majority of side effects were gastrointestinal and resolved on discontinuation of glucosamine. Concerns have been raised about whether glucosamine causes abnormal glucose metabolism, asthma, hypersensitivity, or arteriosclerosis; there is no evidence to support these concerns.

The Author

Jasmine Chen Gatti, M.D., is inpatient hospice medical director at Holy Cross Hospital Home Care and Hospice in Silver Spring, Md., where she is also a family practitioner and geriatrician. She completed a combined fellowship in Australasian Cochrane Collaboration and Medical Education at the Australasian Cochrane Centre, Adelaide, Australia.

Address correspondence to Jasmine Chen Gatti, M.D., Holy Cross Hospital Home Care and Hospice, 11800 Tech Rd., #240, Silver Spring, MD 20910 (e-mail: jgatti@md.net). Reprints are not available from the author.

REFERENCES

1. Towheed TE, Maxwell L, Anastassiades TP, Shea B, Houpt J, Robinson V, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev 2005;(2):CD002946.

2. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum 2000;43:1905-15.

3. Towheed TE, Anastassiades TP, Shea B, Houpt J, Welch V, Hochberg MC. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev 2000;(2):CD002946.

4. Adebowale AO, Cox DS, Liang Z, Eddington ND. Analysis of glucosamine and chondroitin sulfate content in marketed products and the caco-2 permeability of chondroitin sulfate raw materials. J Am Nutraceutical Assoc 2000;3:37-44.

5. Russell AS, Aghazadeh-Habashi A, Jamali F. Active ingredient consistency of commercially available glucosamine sulfate products. J Rheumatol 2002;29:2407-9.

6. Tapadinhas MJ, Rivera IC, Bignamini AA. Oral glucosamine sulphate in the management of arthrosis: report on a multi-centre open investigation in Portugal. Pharmatherapeutica 1982;3:157-68.

Cochrane Briefs

Mark H. Ebell, M.D., M.S.

Benzodiazepines for Alcohol Withdrawal

Clinical Question

Are benzodiazepines safe and effective for the treatment of alcohol withdrawal?

Evidence-Based Answer

Benzodiazepines are safe and effective for the treatment of alcohol withdrawal, particularly for the prevention of withdrawal seizures, although their superiority to anticonvulsants has not been demonstrated convincingly. There is no clear benefit of one benzodiazepine over another or of symptom-triggered versus fixed-dose scheduling.

Practice Pointers

Benzodiazepines are used widely for the treatment of alcohol withdrawal, with the goals of reducing the severity of withdrawal, preventing delirium, and reducing the incidence of seizures. This systematic review identified 57 relevant randomized controlled trials with a total of 4,275 participants. The quality of the included studies, many of which date from the 1970s and 1980s, was fair, and most were small. Only nine studies clearly concealed allocation of patients to treatment or control groups, and only 21 adequately described the randomization procedures, although all but three were double-blinded.

Not surprisingly, the authors found that benzodiazepines were much more effective than placebo at preventing alcohol withdrawal seizures (relative risk 0.16; 95% confidence interval, 0.04 to 0.69). However, there was no significant difference in prevention of seizure between benzodiazepines and antiseizure drugs. There also was no difference in control of symptoms (as measured by standard scales) among benzodiazepines and other drugs such as clonidine (Catapres) or carbamazepine (Tegretol). There were trends in favor of benzodiazepines, particularly longer-acting drugs, for prevention of delirium. Thirteen studies, with a total of 571 patients, compared different benzodiazepines but found no differences in effectiveness among them. Only three studies, with a total of 262 patients, compared fixed-dose with symptom-triggered dosing schedules, and no clear conclusions could be drawn.

An evidence-based guideline from the American Society of Addiction Medicine1 recommends benzodiazepines as a first-line agent for the treatment of alcohol withdrawal. The guideline notes that although agents with a longer duration of action may provide fewer breakthrough symptoms, those with a shorter duration of action, such as lorazepam (Ativan), may be preferred when there is concern about prolonged sedation (e.g., in patients with significant comorbidities or liver disease).1

REFERENCE

1. Mayo-Smith MF, Beecher LH, Fischer TL, Gorelick DA, Guillaume JL, Hill A, et al. Management of alcohol withdrawal delirium. An evidence-based practice guideline [published correction appears in Arch Intern Med 2004;164:2068]. Arch Intern Med 2004;164:1405-12.

Ntais C, et al. Benzodiazepines for alcohol withdrawal. Cochrane Database Syst Rev 2005;(3):CD005063.

Inhaled Beta Agonists for Chronic, Nonspecific Cough in Children?

Clinical Question

Are inhaled beta agonists effective for the treatment of chronic, nonspecific cough in children?

Evidence-Based Answer

The single clinical trial on this topic found that inhaled beta agonists do not reduce cough frequency or improve symptoms in children with chronic, nonspecific cough.

Practice Pointers

Cough lasting more than three weeks in children often is caused by asthma, post-nasal drip, gastroesophageal reflux disease, or chronic exposure to irritants such as tobacco smoke or allergens; it also may be attributed to overestimation of symptoms by parents. Rarely, it is caused by a serious problem such as cystic fibrosis or tuberculosis. When these causes have been excluded, chronic, nonspecific cough, sometimes called "cough variant asthma," often is diagnosed.

The authors of this systematic review identified only one study that compared an inhaled beta agonist with placebo in a randomized, double-blind trial. This study compared inhaled albuterol (Proventil) in a dosage of 200 mcg twice daily via metered dose inhaler with placebo in 42 children who had chronic, nonspecific cough.1 At the end of the one-week study, the researchers found no differences between groups regarding cough frequency, symptom score, airway responsiveness, or sensitivity of cough receptors to capsaicin. The study was small, and although it was powered to detect a 70 percent difference in cough frequency between groups, it might have missed a small but clinically significant benefit with inhaled beta agonists. The authors note that observational studies and examination of the symptoms of children in placebo groups suggest that cough tends to improve over time.

Another Cochrane review2 performed in 2005 by the same group of researchers found a possible benefit from high-dose inhaled corticosteroids in two studies with a total of 123 children; however, children in the placebo group also improved, and the clinical impact was of uncertain significance. An evidence-based guideline from the Finnish Medical Society3 recommends that treatment with inhaled corticosteroids be considered in children with cough-predominant asthma if pulmonary function testing is abnormal. For younger children who cannot cooperate adequately with pulmonary function testing, an empiric trial of inhaled corticosteroids should be considered.

REFERENCES

1. Chang AB, Phelan PD, Carlin JB, Sawyer SM, Robertson CF. A randomised, placebo controlled trial of inhaled salbutamol and beclomethasone for recurrent cough. Arch Dis Child 1998;79:6-11.

2. Tomerak AA, McGlashan JJ, Vyas HH, McKean MC. Inhaled corticosteroids for non-specific chronic cough in children. Cochrane Database Syst Rev 2005;(4):CD004231.

3. Finnish Medical Society Duodecim. Prolonged cough in children. In: EBM guidelines. Evidence-based medicine [CD-ROM]. Helsinki, Finland: Duodecim Medical Publications Ltd.; 2004.

4. Tomerak AA, et al. Inhaled beta2-agonists for treating non-specific chronic cough in children. Cochrane Database Syst Rev 2005;(3):CD005373.

The series coordinator for AFP is Clarissa Kripke, M.D., Department of Family and Community Medicine, University of California, San Francisco.

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