Clinical Drug Development Challenges in Osteoarthritis Theodore Pincus, M.D. from Vanderbilt University Medical Center discussed Reassessing the Efficacy of Acetaminophen in Osteoarthritis.
Dr. Pincus stated the present approach to treatment of osteoarthritis of the hip and knee according to ACR guidelines includes both non-pharmacological therapy as well as pharmacological therapy. Specifically, pharmacological therapy included acetaminophen, intra-articular steroids, NSAIDS, opioids and topical analgesics. Two earlier randomized controlled studies found no statistically significant difference between acetaminophen (3000mg per day) and NSAIDS (ibuprofen at 1200mg, 2400mg per day and naproxen 750mg per day) for relief of pain at rest. Additionally, the number of patients with reported gastric mucosal damage associated with NSAIDS was greater than that associated with acetaminophen. As a result, acetaminophen became widely recommended although its efficacy was supported by few data.
However, in a recent survey of 300 OA patients, 80% reported that NSAIDS were more helpful in pain management than acetaminophen. Dr. Pincus stated that it was interesting to note that opioids were not generally named as a means of pain management. On the basis of the aforementioned results of the earlier trials, Dr. Pincus and associates conducted a clinical trial entitled "Arthrotec Compared to Acetaminophen" (ACTA). [Arthrotec is a combination of diclofenac and misoprostol.] This was a six week double blind, randomized, controlled unique crossover design of 200 patients with knee (78%) and hip (22%) OA. In the ACTA trial the primary outcome measures included the Western Ontario McMaster Osteoarthritis (WOMAC) index- joint specific and the Multidimensional Health Assessment Questionnaires (MDHAQ) -pain visual analog scale, as well as the generalized WOMAC, MDHAQ, and SF36. Other assessments included efficacy, adverse events and worsening of clinical status.
The results indicated significantly greater efficacy (p<0.01) of Arthrotec in comparison to acetaminophen for the WOMAC (composite, pain, function, stiffness), the SF36 (physical function, pain, physical role, vitality, social function), and the MDHAQ (pain, function, advanced ADL, fatigue, global status, helplessness index, satisfaction) scores. Adverse events were reported in 54% of the Arthrotec group versus 46% of the controls. Overall GI adverse events followed expected trends with 14% reported in the acetaminophen group and 20% in the Arthrotec group. 8% in the acetaminophen group reported dyspepsia, in comparison to 10% Arthrotec. 2% in acetaminophen group reported abdominal pain in comparison to 7% in Arthrotec group. Additionally, among 174 patients who completed both arms of the cross-over clinical trial, 58% rated Arthrotec as better or much better, 22% reported no difference, and 21% reported acetaminophen as better or much better.
Dr. Pincus surmised that there could be several reasons why this trial produced different results from earlier trials. Arthrotec (diclofenac) may be a more powerful analgesic/anti-inflammatory drug than either ibuprofen or naproxen. Secondly, inadequate doses of ibuprofen and naproxen may have been used previously. Thirdly, the ACTA trial may have selection bias for patients who have responded to acetaminophen in the past. Additionally, OA severity may influence response to specific drugs. In the ACTA study, the 20% of patients who preferred acetaminophen over Arthrotec tended to have milder disease.
In conclusion, the ACTA trial demonstrated greater efficacy of an NSAID over acetaminophen for treatment of knee and hip OA. These results are consistent with a previously published survey of patient preference of NSAIDs vs acetaminophen for treatment of OA (J. Rheumatol. 27:1020, 2000 by Pincus et al). According to Dr. Pincus, the crossover design of a clinical trial is superior because it allows the patient to take both treatments (in a blinded fashion) and the patient, rather than the health professional, makes the assessment regarding relative efficacy of each.
R. Moskowitz, M.D. from Case Western Reserve discussed Glucosamine.
Dr. Moskowitz discussed the current knowledge of glucosamine and of chondroitin sulfate and their efficacy in treating osteoarthritis (OA). Both belong to a group of currently popular non-FDA approved nutritional agents known as nutraceuticals. In 1999, approximately $500,000 was spent on the purchase of glucosamine in the U.S., which correlates with approximately $35 to $40 monthly per person. Concerns in the medical community regarding efficacy and safety of glucosamine have arisen due to its popularity, cost to the patient, and advertising claim as an "arthritis cure". These concerns have prompted several clinical trials to evaluate safety and efficacy of the two nutraceuticals.
Glucosamine originates from crustacean shells such as crab, shrimp, and lobster and is largely supplied to the U.S. by China. However, chondroitin sulfate is derived from U.S. bovine tracheal or layrngeal cartilage. Glucosamine is available as N-acetyl-glucosamine, as well as two salt forms: hydrochloride (HCL) and sulfate. The former has been most widely used in clinical trials. Both salts are cleaved in the stomach and the replete sulfate form stimulates glycosaminoglygan (GAG) synthesis in vivo. [GAGs are a major structural component of human cartilage.] Variations in the purity of glucosamine may produce differences in results. For example, in most clinical trials 1500 mg of glucosamine sulfate is used and has a bioactive purity of 80% in comparison to 99% found in 1100 mg of glucosamine HCL. On average, the purity of chondroitin sulfate, which is often used in combination with glucosamine by consumers, is 10% of the concentration listed on the label.
In in vivo studies of rabbits with experimentally induced OA, glucosamine treated rabbits exhibited a decrease in OA severity, and a positive change in proteoglygan and GAG concentration in the cartilage suggesting a possible beneficial role in cartilage metabolism. In human trials, glucosamine is more effective than placebo in relieving pain but its analgesic effect is slow in onset and can persist for several months after discontinuation of the agent. As a result, Dr. Moskowitz advised that glucosamine be washed out for several months before enrolling patients in clinical trials.
A symptomatic response to glucosamine was also reported by Dr. McAlindon and colleagues in a metaanalysis of 15 glucosamine and chondroitin sulfate trials conducted in knee and hip OA lasting 4 weeks or more. In each of the studies there was an improvement from baseline in the pain scales for VAS, Likert, WOMAC, and Lequesne scale (pain and function). The effects were moderate for both glucosamine and chondroitin sulfate.
Furthermore, recent studies indicate that glucosamine may have some ability to modify articular structure. Reginster and colleagues investigated the effect of glucosamine on the progression of joint space narrowing, as measured by digital image analysis of plain standing knee x-rays (read news article). A decrease in joint space width of 0.06mm was observed in the glucosamine treated group, in comparison to 0.31mm decrease in the placebo group, over three years. Dr. Moskowitz cautioned that these results should be confirmed using state-of-the-art radiological technique - that is, flexed knee views with foot maps. However, Pavelka and colleagues also completed a 3-year placebo-controlled trial in which a highly significant difference between placebo and glucosamine sulfate in the loss of knee joint space width (30% and 15%, respectively), was observed. Given that two subjects with different baseline joint space width values could experience the same measurement of loss yet experience a variable percent of loss may signify differences in the rates of loss according to Dr. Moskowitz.
The efficacy of glucosamine is further supported by data suggesting that it decreases matrix breakdown, increases proteoglycan synthesis, has anti-inflammatory effects, and decreases generation of superoxide radicals. Also, glucosamine appears to be very safe and well tolerated with relatively minor adverse events reported such as nausea, bloating, seafood allergy, increased insulin resistance (not well defined), angioedema, and transaminitis. Hence, glucosamine shows a favorable therapeutic effect on the symptoms of OA.
Finally, Dr. Moskowitz reviewed a meta-analysis of multicenter clinical trials utilizing chondroitin sulfate (Leeb et al.) at doses from 800-2000mg for 1-3 month in which concomitant medications were not withdrawn. Consistent improvement in pain after 180 days, protective effect on cartilage matrix, and decrease in free radical production were observed. Reports of adverse events were minimal and included an anticoagulant effect, decreased platelet aggregation, and mild gastrointestinal intolerance.
In conclusion, glucosamine and chondroitin sulfate appear to have efficacy with minimal toxicity in the treatment of osteoarthritis and thus are reasonable to use. However, patients should be informed of both the pros and cons in the use of these agents, including content discrepancies due to product variation, and should also continue to follow a physician recommended regimen as these agents have not been FDA approved as standard treatments for osteoarthritis.
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