40 Musculoskeletal Disorders FAMILY P RACTICE N EWS • July 1, 2008 Novel Agent Targets Osteoarthritic Knee Pain

BY BRUCE JANCIN Tanezumab is a humanized monoclonal antibody es. These localized areas of numbness or reduced ap- Denver Bureau against nerve growth factor (NGF). NGF, which is up- preciation of pain are consistent with the inhibition of regulated in locally inflamed tissue and pain states, stim- NGF, as NGF is a sensitizer to pain, Dr. Lane explained. PARIS — Tanezumab, a novel inhibitor of nerve growth ulates the growth of sensory nerve cells peripherally and In the phase III trials to come, it’s likely that weight- factor, significantly eased knee pain in patients with increases the response to pain. adjusted dosing will be replaced by three non–weight-de- moderately severe osteoarthritis, according to the find- The subjects had moderately severe osteoarthritis knee pendent doses, perhaps 2.5 mg, 5 mg, and 10 mg. This ings of a large, phase II, double-blind randomized trial. pain, with average baseline walking knee pain VAS scores dosing format allows for titration, which is attractive in Within 3 days after a first dose of tanezumab, many par- of slightly more than 70 mm on a 0- to 100-mm scale. All treating chronic pain, the physician continued. ticipants in the 440-patient trial experienced a greater-than- were unresponsive to nonopiate pain medications or were There is a pressing need for better pharmacologic ther- 50% improvement in walking knee pain, as assessed by the candidates for total joint replacement or other surgical in- apies for osteoarthritis pain. Many patients can’t tolerate, Visual Analog Scale (VAS), Dr. Nancy E. Lane reported at terventions. After a washout period, they were randomized or don’t obtain, adequate pain relief with NSAIDs. In ad- the annual European Congress of Rheumatology. to intravenous placebo or tanezumab at 10, 25, 50, 100, or dition, cardiovascular issues limit the usefulness of NSAIDs “At higher doses, they had a 70%-80% reduction in knee 200 mcg/kg. Two doses were administered 8 weeks apart. in many older patients. Narcotic analgesics are efficacious pain that was maintained over 8 weeks. We’ve never seen Patients in the placebo arm averaged an 18-mm de- for the management of pain related to knee osteoarthri- that before, short of a joint replacement,” she said in an crease in walking knee pain from baseline to week 16, as tis and other chronic diseases, but these drugs entail prob- interview. The trial was sponsored by Pfizer Inc., where assessed by VAS. Those on 10-50 mcg/kg of tanezumab lems with addiction and various toxicities. Inhibition of Dr. Lane serves as a consultant. averaged 29- to 34-mm reductions. And those on 100 or NGF may offer an effective alternative option. Other possible applications for tanezumab include can- 200 mcg/kg of the NGF inhibitor averaged 46- and 48- “For patients with moderately severe osteoarthritis of the cer pain, degenerative disk disease pain, and fibromyal- mm reductions, respectively, in VAS pain scores. knee who [don’t want] a joint replacement or who want to gia, said Dr. Lane, professor of internal medicine and di- The most common adverse events related to tanezum- put it off, a treatment that lasts for 2 months gives them a rector of the center for healthy aging at the University ab were transient episodes of hypoesthesia, which oc- ‘pain holiday’ to rest and restore their energy so they can of California, Davis. curred in nearly 11% of patients at the two highest dos- better deal with their disease,” Dr. Lane said. ■ Fructose in Sugary Soft Drinks Allopurinol, Benzbromarone Are Is Implicated in Rise in Gout Equally Effective in High Doses

BY NANCY WALSH In another study that includes 14,761 BY JEFF EVANS adequate in previous research, Mr. Rein- New York Bureau participants aged 20 years and older from Senior Writer ders said in an interview. the third National Health and Nutrition EULAR’s evidence-based recommenda- L IVERPOOL, ENGLAND — Con- Examination Survey (NHANES-III), out patients have equal rates of success tions for gout advise titrating the allopuri- sumption of soft drinks containing fruc- serum uric-acid levels increased signifi- Gin attaining a serum urate concentra- nol dosage according to the level of serum tose may underlie the sharp increase in cantly with increasing sugary soft-drink tion of 0.30 mmol/L or less—a value urate that is attained. There is a lack of in- gout in American adults that has oc- consumption, with multivariate odds ra- thought to predict good control of flares formation about this approach and the ef- curred in recent decades, Dr. Hyon K. tios for hyperuricemia being 1.82 in those and a reduction of tophi—with either al- fects of the higher dosages of serum Choi said at the annual meeting of the who consumed four or more servings a lopurinol or benzbromarone, as long as the urate–lowering drugs that will be required British Society for Rheumatology. day (Arthritis Rheum. 2008;59:109-16). doses are slightly higher than normal and to decrease serum urate in patients who Since 1967, when high-fructose corn In both of these studies, the associa- based on serum are not reaching syrup became commercially available tions were independent of risk factors for urate values, ac- ‘Allopurinol must target levels. Many and began to be used for sweetening soft gout including alcohol use, hyperten- cording to the re- be dosed higher clinicians also are drinks, there has been a 61% increase in sion, and body mass index. sults of a random- than usually done prescribing only a the consumption of these beverages and Data from NHANES-III, which is con- ized, open-label in trials and in fixed dosage of al- a doubling of the incidence and preva- sidered a nationally representative sam- trial. The data were clinical practice lopurinol 300 lence of gout, particularly in men. ple, also suggest that coffee may be pro- presented at the an- to reach target mg/day, he said. Conventional strategies for the preven- tective, but only if it is drunk in large nual meeting of the serum levels.’ Therefore, Mr. tion of gout have emphasized limiting quantities, he said. After adjustment for European League Reinders and his consumption of purine-rich foods because age and sex, serum uric-acid levels in Against Rheuma- MR. REINDERS coinvestigators ran- uric acid is a breakdown product of those drinking six cups of coffee a day tism in Paris. domized 55 pa- purine. But fructose also can increase uric were significantly lower by 0.43 mg/dL “Tolerability is not affected by doubling tients with newly diagnosed gout in an acid. The process involves the breakdown than in those who did not drink coffee the dosage in patients not reaching target open-label trial comparing the efficacy of adenosine triphosphate to adenosine (Arthritis Rheum. 2007;57:816-21). levels,” said Mattheus Reinders, a hospital and tolerability of allopurinol and monophosphate, a uric acid precursor, The effect was not related to caffeine in- pharmacist at the Atrium Medisch Cen- benzbromarone. Allopurinol began at a said Dr. Choi, a rheumatologist at the Uni- take, as modest effects were seen with de- trum, Heerlen, the Netherlands. dosage of 300 mg/day and was increased versity of British Columbia, Vancouver. caffeinated coffee, and none were seen in The results of the study make it clear to 600 mg/day if necessary, while Fructose also contributes to impaired tea drinkers. “It could derive from other that there is no difference in efficacy be- benzbromarone started at 100 mg/day glucose tolerance and increases insulin components in coffee such as chlorogenic tween allopurinol and benzbromarone, and could be increased to 200 mg/day. resistance and hyperinsulinemia, which acid or noncaffeine xanthines,” he said. when given in adequate doses, despite After 2 months of treatment, a signifi- could elevate serum uric acid levels. In conclusion, patients at risk for gout their different mechanisms of action. It cantly greater percentage of patients who Prospective studies have shown that should continue to emphasize limitations also shows “allopurinol must be dosed took benzbromarone 100 mg/day reached sugary soft drinks contribute significant- on purine-rich foods such as beer and cer- higher than usually done in trials and in the target serum urate concentration of ly to gout—as well as obesity, type 2 dia- tain meats. Purine-rich vegetables such as clinical practice [300 mg/day] to reach 0.30 mmol/L (13 of 25 patients, or 52%) betes, and metabolic syndrome, he said. spinach and beans do not seem to elevate target serum levels,” Mr. Reinders said. than did patients who took allopurinol 300 In the large, ongoing health-profes- uric-acid levels, and need not be avoided. Gout flares and tophi mostly occur in mg/day (8 of 30 patients, or 27%). After sionals follow-up study of more than Sugary soft drinks and other processed those body parts with the lowest temper- the investigators doubled the daily dosage 51,000 men aged 40-75 years who an- foods containing fructose should be avoid- ature: the extremities. It is often said that of each drug in patients who had not met swered dietary questionnaires and have ed, not only for gout prevention but for serum urate (uric acid) concentration—a the treatment target, there was no signifi- been followed since 1986, a total of 755 prevention of the common comorbidities well-accepted biomarker for evaluation of cant difference in the total percentage of new cases of gout have been diagnosed. such as hypertension and obesity, he said. gout treatment—must be lower than the patients who had successful treatment with The multivariate relative risk of gout for Dr. Choi’s work has been funded by solubility at 37 °C (0.42 mmol/L) for allopurinol (21 of 27, or 78%), compared five to six servings of sugary soft drinks the National Institutes of Health and the good treatment. But solubility drops dra- with benzbromarone (18 of 23, or 78%). a week was 1.29; this rose to 1.85 for two Arthritis Society of Canada. He said he matically with lower temperature, and so Mr. Reinders conducted the research or more servings a day, representing an has served on the advisory boards for lower serum urate values are needed. A when he was in training at the Medisch 85% increase in incident gout in the high- TAP Pharmaceutical Products Inc. and serum urate concentration of 0.30 Centrum Leeuwarden, also in the Nether- est consumers (BMJ 2008;336:309-12). Savient Pharmaceuticals Inc. ■ mmol/L or lower has been shown to be lands, which funded the study. ■

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