Glucosamine and the Ongoing Enigma of Chronic Low Back Pain

Nonspecific chronic low back pain (LBP) remains one the most prevalent, expensive, and poorly treated conditions seen by primary care clinicians.¹ The etiology of most chronic LBP is unknown; therefore, treatment approaches are often empiric and usually based on a relatively thin foundation of evidence. Most interventions have not been rigorously tested and many back pain studies are limited by poor design and research practice, so little is known about what treatments are or are not effective for patients with chronic LBP. Because patient-specific diagnosis and treatment plans cannot be rationally formulated in most cases,² patients frequently experiment with a variety of interventions, often turning to complementary and alternative therapies.^{3 - 4}

Glucosamine is a precursor of the proteoglycans that make up articular cartilage, and it is widely used orally by patients for treating peripheral joint osteoarthritis based on the theory that degenerative cartilage lesions can be treated by taking high doses of a precursor molecule.⁵ However, the evidence regarding glucosamine for hip and knee osteoarthritis is inconsistent with great variation depending on the quality of the study design, the glucosamine preparation used, and the funding source.^{6 - 7} Similar arthritic changes often occur in the synovial facet joints of the spine, and more than 25% of patients with chronic LBP have tried glucosamine supplements, seeking to gain relief for their back pain.⁸

In this issue of JAMA, Wilkens et al⁹ report the results of a randomized, double-blind clinical trial of oral glucosamine for the treatment of patients with chronic LBP and imaging evidence of facet joint osteoarthritis. The investigators randomized 250 participants to 6 months of treatment with 1.5 g of glucosamine sulfate daily or an identical-appearing placebo. Overall, this was a well-designed and well-conducted trial with clear eligibility criteria, adequate allocation concealment, good baseline comparability, acceptable medication adherence, few withdrawals, well-accepted outcome measures, adequate sample size specified a priori, and an appropriate intention-to-treat analysis. The use of the sulfate salt of glucosamine was also a wise choice given the issues surrounding the bioavailability of this dietary supplement and the role of sulfate in its potential efficacy.⁵

The results of the trial were negative: on no outcome measure was there a statistically significant benefit of glucosamine over placebo. The 95% confidence intervals generally excluded any effect considered clinically meaningful, suggesting the results were probably not due to insufficient statistical power. Given the high quality of the trial methods and execution, the most likely explanation for the outcome is simply that glucosamine probably offers little benefit for chronic LBP with osteoarthritis beyond whatever placebo effect it may provide. Importantly, there were few adverse effects associated with the use of glucosamine in this study, consistent with other literature, indicating that glucosamine is well tolerated and causes minimal toxicity, at least in the short term.⁶ Thus, the data presented by Wilkens et al⁹ provide no incentive for clinicians to recommend glucosamine for patients with chronic LBP.

It would be easy for clinicians and patients to become discouraged as increasing numbers of potential chronic LBP treatments fail to survive the test of clinical trials. However, the public health burden of chronic LBP cannot afford cynicism, and high-quality negative trials such as that reported by Wilkens et al⁹ should be viewed positively as important contributions. Indeed, some important progress has been made as patients with back pain are no longer advised to try prolonged, counterproductive bed rest and there is much greater appreciation for the complex interactions between the psychosocial and physical aspects of chronic LBP.¹⁰ Overall, however, care for patients with LBP remains insufficient for far too many patients. Why has such an enormous public health problem remained so stubbornly resistant to the identification of effective treatment?

Some challenges are unique to back pain. Unlike other common chronic illnesses, there is no dominant organization that represents the chronic LBP community, advocating for greater attention and funding for LBP research. It is ironic that in the United States orders of magnitude more resources are spent on treatments for chronic LBP of limited or unknown value than on research to study existing and promising new approaches that could provide more hope for patients. Moreover, the fragmented clinical silos in which chronic LBP treatments are often delivered (eg, primary care, physical therapy, surgery, interventional procedures, behavioral therapy, complementary and alternative medicine practice) rarely align to force an objective appraisal of efficacy and collaborate to identify optimal treatment approaches. In the competition for federal research dollars, back pain has not been allocated funding commensurate with its societal cost and quality-of-life burden. For example, as of June 2010, the National Institutes of Health’s clinical trials registry (http://clinicaltrials.gov) includes only 69 federally funded intervention studies in back pain, of which only 20 are currently recruiting patients. Fortunately, funding agencies are beginning to recognize the compelling public health imperative of chronic LBP as evidenced by the increasing numbers of federally funded studies related to back pain over the past 25 years.

The great need for more and more efficient clinical research in chronic LBP highlights an overall clinical research environment in the United States that operates well below its potential. Similar to other clinical conditions, LBP research is limited by insufficient funding, misguided regulations,¹¹ a heavy reliance on funding from for-profit entities,¹² and a lack of consensus about outcome measures and clinically meaningful goals of therapy.

Perhaps most important is that the clinical research community has failed to create the strong partnerships with the public that are required to build and sustain a robust clinical research agenda.¹³ Without a fundamental change in the relationship between the clinical research community and the public, clinical and translational research will continue to struggle with recruitment problems, inadequate financial and public support, and insufficient appreciation for its societal value.

The results of the high-quality clinical trial by Wilkens et al⁹ carefully evaluating a widely used treatment for chronic LBP were disappointing but should not be discouraging. Clearly, much more work remains before realizing the kinds of success in the treatment of chronic LBP that other conditions have experienced. With an objective and determined focus, sufficient support, greater collaboration, and a working partnership with patients, there is every reason for optimism, however cautious. The real test will be whether the environment for this success can be created and sustained.