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Guidance on the Appropriate Use of NSAIDs
In this issue: NSAIDs in the elderly; managing GI and CVD risk with NSAIDs; low-dose naltrexone and fibromyalgia; treating glucocorticoid-induced bone loss; FDA Actions.
NSAIDs and dementia
Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the elderly may increase the risk of dementia and Alzheimer's disease according to a new study. This is in contrast to previous studies that suggested that NSAIDs may actually be neuroprotective. The current study from Seattle looked at members of Group Health who were age ≥ 65 years (median, 74.8 years) and free of dementia. Patients were followed for up to 12 years to identify dementia and Alzheimer's disease. Of the 2736 patients studied, 351 (12.8%) were heavy users of NSAIDs at enrollment and another 107 became heavy users during follow-up. Over the course of the study 476 individuals developed dementia including 356 who developed Alzheimer's disease. Those defined as heavy NSAID users showed an increased incidence of dementia (hazard ratio [HR], 1.66; 95% confidence interval [CI], 1.24-2.24) and Alzheimer's disease (HR, 1.57; 95% CI, 1.10-2.23). The authors suggest that this study looked at an older cohort than previous studies. Decreased rates of dementia seen in the previous studies may have reflected a delay in onset of dementia, which may explain the increased incidence seen in the older patients in this study (Neurology 2009 April 22; epub ahead of print).
GI and CVD risk with NSAIDs
In a related story, the Canadian Association of Gastroenterology Consensus Group has published guidelines on use of long-term NSAIDs in patients at risk for GI bleeding and cardiovascular disease. The guideline includes the recommendation that NSAIDs should always be used at the lowest effective dose for the shortest possible duration of treatment and that patients should be evaluated for the need for gastroprotective strategies and cardiovascular risk. For patients at low GI risk but high cardiovascular risk, the group recommends naproxen because of potentially lower cardiovascular risk than other NSAIDs or COX-2 inhibitors. For patients at high risk for GI side effects and low cardiovascular risk, a COX-2 inhibitor alone or traditional NSAIDs with a PPI offers similar protection. For patients at very high risk for GI bleeding, a COX-2 inhibitor plus a PPI is the safest option. In patients with both GI and cardiovascular risks, NSAIDs should be avoided if possible, but if anti-inflammatories are needed, and the patient is already on aspirin, the recommendations included naproxen plus a PPI if cardiovascular risk is the main concern or a COX-2 plus a PPI if GI side effects are the primary concern (Aliment Pharmacol Ther 2009;29:481-496).
Low-dose naltrexone and fibromyalgia
Perform a Google search of "low-dose naltrexone" and you will find a myriad of anecdotal testimonies to the benefits of the drug in a wide range of diseases including fibromyalgia. Now a small study suggests that naltrexone may be of some benefit in this difficult condition. Naltrexone (not to be confused with naloxone) is an opioid receptor antagonist used primarily for treatment of alcohol dependence and opioid dependence. Because of multiple internet reports of benefit in patients with fibromyalgia, researchers from Stanford performed a single-blind, placebo-controlled crossover study of 10 patients with moderately severe fibromyalgia who were not on opioids. The dose of naltrexone used was 4.5 mg per day, which is less than 10 times lower than the dose used for addiction (50 mg per day). Patients on active treatment reported a 32.5% reduction in fibromyalgia symptoms compared to baseline vs a 2.3% reduction for placebo (P = 0.003 vs placebo). Side effects, which included insomnia and vivid dreams, were rare. Interestingly, patients with higher sedimentation rates had the greatest reduction in symptoms and best response to low-dose naltrexone. The authors hypothesize that low-dose naltrexone may inhibit the activity of microglia and reverse central or peripheral inflammation, thus reducing symptoms of fibromyalgia, although more studies are needed. They also suggest that naltrexone can be used in addition to other medications commonly used for fibromyalgia (Pain Med 2009 April 22; epub ahead of print).
Treating glucocorticoid-induced osteoporosis
For patients with glucocorticoid-induced osteoporosis, a once-yearly infusion of zoledronic acid is as effective as daily risedronate for the prevention and treatment of bone loss according to a new study from Lancet. In a 1-year, international, randomized, double-blind, placebo-controlled, non-inferiority study, 833 patients with glucocorticoid-induced osteoporosis were randomized to receive zoledronic acid 5 mg as a 100 mL IV infusion over 15-20 minutes on day 1 plus oral placebo or 5 mg of risedronate daily and 100 mL IV placebo infusion on day 1. Patients were allocated to a prevention or treatment subgroup depending on the duration of glucocorticoid use preceding study. Zoledronic acid infusion was non-inferior and superior to risedronate for increase of lumbar spine bone mineral density in both the treatment (P = 0.001) and prevention groups (P < 0.0001), respectively. Adverse events were more frequent in patients given zoledronic acid primarily because of increased flu-like symptoms within the first 3 days after the infusion. The authors conclude that a single 5 mg intravenous infusion of zoledronic acid is non-inferior and possibly more effective and more acceptable to patients than 5 mg of oral risedronate daily for prevention and treatment of bone loss associated with glucocorticoid use (Lancet 2009;373:1253-1263). An accompanying editorial suggests that once-yearly zoledronic acid seems to have obvious advantages over an oral regimen but the long-term safety is still unknown and also raises the question of whether anabolic drugs, such as teriparatide, which stimulate bone formation by acting on osteoblasts and osteocytes, might eventually be a better option (Lancet 2009;373:1225-1226).
Plan B, the so-called "morning after pill" will soon be available to women age 17 and older without a prescription. Previously the FDA and the Bush administration had limited the access of the drug to women 18 and older but a U.S. district judge ruled in March that the older age limit was "arbitrary and capricious." The judge also directed the agency to evaluate clinical data to determine whether there should be any age restrictions on use of the drug. The FDA has no plans to appeal the court's decision. Duramed Pharmaceuticals must file paper work with the FDA, a process that is expected to take 30 days. Plan B is levonorgestrel in a 2-pill pack, the first to be taken within 72 hours of unprotected intercourse and the second pill 12 hours later.
The FDA has approved a new TNF-alpha blocker monoclonal antibody for the treatment of rheumatoid arthritis, active psoriatic arthritis, and active ankylosing spondylitis. Golimunab is given once a month as a subcutaneous injection in combination with methotrexate for rheumatoid arthritis. It may be used with or without methotrexate for psoriatic arthritis and as monotherapy for ankylosing spondylitis. As with all TNF-alpha blockers, the FDA is requiring a risk evaluation mitigation strategy (REMS), which includes a medication guide for patients and a communication plan for physicians regarding potential side effects. Also similar to other drugs in this class, golimumab will carry a boxed warning regarding the risk of tuberculosis and invasive fungal infections. Golimumab was developed by Centocor Ortho Biotech, a division of Johnson & Johnson. The drug will be marketed under the trade name Simponi™.
This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5468. E-mail: firstname.lastname@example.org.