Letters to the Editor

Pharmacotherapy for Nonmalignant Pain

TO THE EDITOR: I was pleased to read the article¹ on management of nonmalignant pain. The undertreatment of pain is a widespread issue in the United States, and helping to educate practicing family physicians in the most current pain management techniques is an important, even critical, goal.

I was disappointed, however, by the relative lack of information in the article on the two newest classes of oral analgesics: (1) tramadol (Ultram) and (2) cyclooxygenase-2 (COX-2) inhibitors, which represent a new type of nonsteroidal anti-inflammatory drug (NSAID).

Tramadol has been available in the United States for five years. It is effective not only for an acute episode of neuropathic pain (as suggested in the article), but also for chronic neuropathic pain syndrome, fibromyalgia, osteoarthritis pain² and chronic low back pain.³ Tramadol may be most notable for what it is not--tramadol is not an NSAID, nor is it a typical opioid. Tramadol has a dual mechanism of action: it acts centrally at µ-opioid receptors and acts spinally, inhibiting the reuptake of monoamines (serotonin and norepinephrine). This may explain why tramadol and antidepressants are effective for some analgesic-resistant pain states.⁴

COX-2 inhibitors (rofecoxib [Vioxx] and celecoxib [Celebrex]) are used for a variety of indications: acute pain, dysmenorrhea and osteoarthritis. Further research is needed on the use of these drugs in the treatment of other painful states, but it is reasonable to assume, based on the available evidence, that COX-2 inhibitors are generally as effective as nonselective NSAIDs. Therefore, in cases of acute low back pain or chronic nonmalignant pain, COX-2 inhibitors should be especially useful for patients with inflammation and who are at high risk for gastrointestinal bleeding. Patients with such risk factors include those receiving treatment with "dual" NSAIDs, those receiving concomitant glucocorticoid treatment, those with a history of gastroduodenal ulcers or bleeding and those receiving anticoagulation therapy.^5,6

The use of COX-2 inhibitors may be appropriate in chronic and acute pain states; however, they may still be associated with nongastrointestinal adverse events (e.g., renal, hepatic, cardiovascular).^5,6

It is critically important that family physicians continue to be familiar with all aspects of pain management. I commend your efforts to call attention to the importance of this subject in primary care.

ROBERT L BARKIN, M.B.A., PHARM.D.
RUSH­Presbyterian-St. Luke's Medical Center
Chicago, IL 60612

Dr. Barkin is affiliated with the Speaker's Bureau for the following organizations: Abbott Laboratories, Astra USA, Athena Neurosciences Inc., Baxter Healthcare, Bristol-Myers Squibb, Eli Lilly and Co., Glaxo Wellcome Inc., Janssen Pharmaceuticals, Knoll Pharmaceutical Co., Merck & Co., Novartis Pharmaceutical Corp., Ortho-McNeil Pharmaceutical Corp., Organon, Inc., Parke-Davis, Purdue Frederick, Smithkline Beecham and Wyeth Laboratories.

REFERENCES

1. Marcus DA. Treatment of nonmalignant chronic pain. Am Fam Physician 2000;61:1331-8.
2. Schnitzer TJ, Kamin M, Olson WH. Tramadol allows reduction of naproxen dose among patients with naproxen-responsive osteoarthritis pain: a randomized, double-blind, placebo-controlled study. Arthritis Rheum 1999;42:1370-7.
3. Schnitzer TJ, Gray WL, Paster RZ, Kamin M. Efficacy of tramadol in treatment of chronic low back pain. J Rheumatol 2000;27:772-8.
4. Barkin RL, Fawcett J. The management challenges of chronic pain: the role of antidepressants. Amer J Ther 2000;7:31-47.
5. Venkat K, Brown MD, Barkin RL. Nonsteroidal anti-inflammatory drugs and gastroduodenal injury. Am J Ther 1998;5:263-72.
6. Barkin RL, Soble KS. Caution recommended for prescribing and administering COX 1/COX 2 and COX 2 specific NSAIDs. P&T 2000;4:196-201.

EDITOR'S NOTE: A copy of this letter was sent to the author of "Treatment of Nonmalignant Chronic Pain," who declined to reply.

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Nutritional Supplements and Treatment of Osteoarthritis

TO THE EDITOR: I read the article on osteoarthritis by Drs. Manek and Lane¹ with great interest as it is commonly encountered in my practice. These authors detail a treatment algorithm ranging from patient education and acetaminophen treatment to joint replacement surgery, with a heavy emphasis on the use of nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX-2) enzyme inhibitors and co-therapy to protect against gastric and duodenal ulcers. Unfortunately, the full risks of NSAID therapy are not detailed, and minimal attention is given to the therapeutic use of glucosamine and chondroitin sulfates.

It is well accepted that NSAIDs can lead to gastrointestinal toxicity ranging from dyspepsia to serious gastrointestinal hemorrhage. It has been estimated that NSAID-induced gastrointestinal hemorrhage leads to at least 103,000 hospitalizations and 16,500 deaths each year, with direct costs of complications exceeding $2 billion annually.² Lesser known is the increased risk of gastrointestinal hemorrhage with concurrent use of selective serotonin reuptake inhibitors (SSRIs) and NSAIDs, giving an adjusted rate ratio of 3.0 (95 percent CI; range: 2.1 to 3.4).³ In addition, NSAIDs are associated with acute and chronic renal failure, although the actual incidence is unknown.²

Glucosamine and chondroitin sulfates are marketed as nutritional supplements in the United States and have been purported to be effective in the treatment of persons with osteoarthritis in various studies over the past three to four decades. In a recent meta-analysis,⁴ glucosamine and/or chondroitin demonstrated positive effects compared with placebo. Discrepancies in some of the study findings reported in the literature may relate to the composition and quality of the nutritional supplements used. A large number of preparations claiming certain doses of glucosamine or chondroitin sulfate have significantly less (or none) of the dosages described; however, some products have been independently tested for potency with the results posted on the following Web site: http://www.drtheo.com.

The cost of some nutritional supplements has decreased greatly with competition that is unavailable with patent-protected proprietary pharmaceuticals. For instance, the cost of supplementation with one product independently tested for potency (Sundown Osteo-Bi-Flex Maximum Strength) containing 1,500 mg of glucosamine sulfate and 1,200 mg of chondroitin sulfate has been quoted as less than $20 per month.⁵ For patients who pay medication costs out of pocket, this price compares favorably with the price of other prescription products, with the advantage of having a safer side effect profile without the risk of gastrointestinal hemorrhage.

A bias against nutritional supplements has been described elsewhere.⁶ They state there should be only three important questions when evaluating a potential treatment: "Does it work?" "What are the adverse effects?" and "How much does it cost?" Glucosamine and chondroitin sulfates appear to have answered these questions favorably and should be considered as a therapeutic option in the treatment of persons with osteoarthritis.

KENNETH N. WOLINER, M.D.
University of Connecticut
99 Woodland Street
Hartford, CT 06105

(E-mail: knw6@cornell.edu)

REFERENCES

1. Manek NJ, Lane NE. Osteoarthritis: current concepts in diagnosis and management. Am Fam Physician 2000;61:1795-804.
2. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N Engl J Med 1999;340:1888-99.
3. de Abajo FJ, Rodriguez LA, Monitor D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. BMJ 1999;319:1106-9.
4. McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA 2000;283:1469-75.
5. Price quote form Walgreen Pharmacy, Hartford, CT: $39.95/180 capsules (two month supply), quoted 4/15/00.
6. Goodwin JS, Tangum MR. Battling quackery: attitudes about micronutrient supplements in american academic medicine. Arch Intern Med 1998:158:2187-91.

IN REPLY: We welcome Dr. Woliner's comments and concerns regarding the management of osteoarthritis. Nonsteroidal anti-inflammatory drugs (NSAIDs) are an accepted and appropriate part of treatment for patients with symptomatic osteoarthritis unless it is medically contraindicated. We kept in line with the state-of-the-art guidelines from the American College of Rheumatology.¹ Patients who require NSAID therapy should be carefully assessed for factors that increase their risk of gastrointestinal complications, including increased age, concomitant anticoagulant or corticosteroid use and a past history of NSAID-associated gastrointestinal events. If a patient is responsive to a standard NSAID therapy, then assessment should be made for the lowest possible effective dose and shortest duration of NSAID therapy on an individual basis. This would help to reduce the incidence of NSAID-induced ulcers.²

For patients who are unable to tolerate NSAID therapy, the newer cyclooxygenase-2 (COX-2) enzyme inhibitors are a good alternative. Celecoxib (Celebrex) and rofecoxib (Vioxx) are the first COX-2­specific inhibitors to receive FDA labeling for the treatment of patients with osteoarthritis and have been shown to significantly reduce the incidence of endoscopically identified gastroduodenal ulcers when compared to standard NSAID therapy.^3,4

Glucosamine and chondroitin sulfates have been studied in a number of short-term trials in Europe and Asia, with results suggesting efficacy in the treatment of patients with symptomatic osteoarthritis. A meta-analysis⁵ included 13 double-blind, placebo-controlled trials, of more than four weeks' duration, testing glucosamine sulfate or chondroitin sulfate for the treatment of patients with osteoarthritis of the hip or knee. The main finding of this meta-analysis is that glucosamine and chondroitin are likely to be effective therapies for the symptomatic management of patients with osteoarthritis. However, definitive analysis of the results was inconclusive because of study design and conduct.⁶ For example, a detailed description of the patients enrolled in the trials was not provided, making it difficult to generalize results from the meta-analysis to individual patients.

We should also emphasize that these agents are not FDA labeled for the treatment of patients with osteoarthritis. Because most of the published trials have been of a relatively short duration, the long-term efficacy and toxic effects of glucosamine and chondroitin have not been established. Large well designed, randomized, controlled trials are needed to determine whether these nutraceuticals can modify the radiologic progression of osteoarthritis.

The National Institutes of Health is sponsoring the first U.S. study evaluating glucosamine and chondroitin in patients with osteoarthritis of the knee. Until such high quality independent studies are completed and the results compared to existing trial data, the actual efficacy and utility of these preparations for the treatment of patients with osteoarthritis are still in question.

NANCY E. LANE, M.D.
NISHA MANEK, M.D.
San Francisco General Hospital
1001 Potrero, Bldg. 30, Room 3300
San Francisco, CA 94110

REFERENCES

1. Hochberg MC, Altman RD, Brandt KD, Clark BM, Dieppe PA, Griffin MR, et al. Guidelines for the medical management of osteoarthritis. Parts I and II. Osteoarthritis of the hip and knee. American College of Rheumatology. Arthritis Rheum 1995; 38:1535-4,1541-6.
2. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N Engl J Med 1999;340:1888-99.
3. Simon LS, Weaver AL, Graham DY, Kivitz AJ, Lipsky PE, Hubbard RC, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 1999;282:1921-8.
4. Langman MJ, Jensen DM, Watson DJ, Harper SE, Zhao PL, Quan H, et al. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA 1999;282:1929-33.
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;283:1469-75.
6. Towheed TE, Anastassiades TP. Glucosamine and chondroitin for treating symptoms of osteoarthritis: evidence is widely touted but incomplete. JAMA 2000;283:1483-4.

Send letters to Jay Siwek, M.D., Editor, American Family Physician, 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672; fax:913-906-6080; e-mail: afplet@aafp.org. Please include your complete address, telephone number and fax number. Letters should be double-spaced, fewer than 500 words and limited to one table or figure and six references. Please submit a word count. Letters submitted for publication in AFP must not be submitted to any other publication. Possible conflicts of interest must be disclosed at time of submission. Submission of a letter constitutes transfer of copyright to the American Academy of Family Physicians. The editors may edit letters to meet style and space requirements.

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