Multicenter, randomized, double-blind, active-controlled, parallel-group trial of the long-term (6-12 months) safety of acetaminophen in adult patients with osteoarthritis.

OBJECTIVE: This study evaluated the safety of acetaminophen 4 g/d administered for up to 12 months to adult patients with osteoarthritis pain, using naproxen 750 mg/d as an active comparator. METHODS: This multicenter, multidose, single-dummy, randomized, double-blind, active-controlled, parallel-group study enrolled patients with mild to moderate osteoarthritis pain of the hip or knee. Patients received acetaminophen 4 g/d or naproxen 750 mg/d for 12 months (group 1) or 6 months (group 2). Patients in both groups had follow-up visits at months 1, 3, and 6 of treatment (or at the time of study withdrawal). Patients in group 1 also had follow-up visits at months 9 and 12 (or at the time of study withdrawal). Tolerability evaluations consisted of determinations of hepatic (aminotransferase activities) and renal (serum creatinine) function, adverse events, and physical examinations. Adverse events reported by the patient or observed by the investigator during clinical evaluation were recorded. In addition, patients were questioned at each visit regarding the occurrence of adverse events using a nonspecific question. Investigators rated the intensity of adverse events and their subjective assessment of the relationship to study medication while blinded to the treatment group. At all visits, patients completed the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), in visual analog scale format, to assess pain, stiffness, and physical function over the previous 2 weeks. The primary efficacy end point was the mean change from baseline in the WOMAC pain subscale score at 6 months. Data from the 6- and 12-month groups were combined for analysis. RESULTS: Of 581 randomized patients, the safety population included 571 patients who received > or = 1 dose of study medication. The 571 patients had a mean (SD) age of 59.3 (8.6) years, 395 (69.2%) were female, and 480 (84.1%) were white. Of 290 patients randomized to receive acetaminophen, 134 completed 3 months of treatment, 96 completed 6 months, 60 completed 9 months, and 55 completed a full 12 months. The median dose adherence ranged from 95.5% to 98.6% during the trial. The completion and adherence patterns were similar for patients receiving naproxen. Of 291 patients randomized to receive naproxen, 151 completed 3 months, 124 completed 6 months, 85 completed 9 months, and 80 completed 12 months. The median dose adherence ranged from 96.4% to 98.4% during the trial. No patient in either treatment group experienced hepatic failure, hepatic dysfunction, aminotransferase levels > or = 2x the upper limit of the reference range, renal failure, or serum creatinine levels > or = 1.5x the upper limit of the reference range. No statistically significant differences were observed between the 2 treatment groups in the proportion of patients who reported > or = 1 adverse event (206 [71.8%] acetaminophen, 209 [73.6%] naproxen) or in the proportion of patients who discontinued treatment because of adverse events (71 [24.7%] acetaminophen, 63 [22.2%] naproxen). Among adverse events considered to be drug related and reported by > or = 1% of patients, constipation and peripheral edema were reported more frequently in the naproxen group than in the acetaminophen group (9.9% vs 3.1% [P<0.002] and 3.9% vs 1.0% [P<0.033], respectively). No adverse event reported in the acetaminophen group was considered both serious and related to study medication. One subject in the naproxen group had an event that was considered serious and related to study drug: gastrointestinal bleeding. No statistically significant differences were observed between the 2 treatment groups for the primary efficacy end point. CONCLUSION: With physician supervision, acetaminophen was found to be generally well tolerated in these patients for the treatment of osteoarthritis pain of the hip or knee for periods of up to 12 months.

The therapeutic use of acetaminophen in patients with liver disease.

Acetaminophen has been used safely and effectively for many years to manage pain and/or fever in patients of all ages. It is commonly recommended as first-line therapy for a variety of patients and conditions, including the elderly, children with viral illnesses, and patients with osteoarthritis, gastrointestinal conditions, bleeding disorders, cardiovascular disease, or renal disease. However, its use is often avoided in patients with chronic liver disease. The perception that acetaminophen should be avoided in such patients arose from awareness of the association between massive acetaminophen overdose and hepatotoxicity, combined with a lack of understanding of the metabolism of acetaminophen in patients with liver disease. There are various theoretical mechanisms of acetaminophen hepatotoxicity in chronic liver disease including: altered metabolism and depleted glutathione stores that would be expected to increase accumulation of the hepatotoxic intermediate, N-acetyl-p-benzoquinone imine (NAPQI). Available studies in patients with chronic liver disease, however, have shown that although the half-life of acetaminophen may be prolonged, cytochrome P-450 activity is not increased and glutathione stores are not depleted to critical levels in those taking recommended doses. Furthermore, acetaminophen has been studied in a variety of liver diseases without evidence of increased risk of hepatotoxicity at currently recommended doses. Therefore, acetaminophen can be used safely in patients with liver disease and is a preferred analgesic/antipyretic because of the absence of the platelet impairment, gastrointestinal toxicity, and nephrotoxicity associated with nonsteroidal antiinflammatory drugs.

Serial analysis of antimitochondrial antibody in patients with primary biliary cirrhosis.

Antimitochondrial antibodies (AMAs) are the classic serologic marker in primary biliary cirrhosis (PBC). However, there have been only limited attempts to study changes in titer or isotype analysis of such AMAs in patients followed for long periods of time. We took advantage of stored sera from well-characterized patients with PBC followed for a period of 7-28 years (mean duration of 13.5 years). Immunoblot and enzyme-linked immunosorbant assays were performed against PDC-E2, BCOADC-E2 and OGDC-E2 as well as isotype analysis of antigen-specific IgG, IgA and IgM antibodies against each of these mitochondrial autoantigens. Sera were analyzed for total IgG, IgA and IgM by radial immunodiffusion. The sera titer of AMAs was significantly higher in younger patients with PBC. Indeed, age of onset of clinical PBC was a significant predictor for the highest values of sera AMAs. In contrast, the AMA titer did not significantly change over time in this prolonged longitudinal study. The total sera levels of the individual immunoglobulins did not show a time-dependent change, when based on age of onset of the disease. Higher titers of AMAs were noted in the younger patients. Furthermore, despite this long follow-up, there was no evidence for a significant change in AMA levels; also, levels were not influenced by drug therapy used during the period of observation.

Autoreactivity to lipoate and a conjugated form of lipoate in primary biliary cirrhosis.

BACKGROUND & AIMS: Although considerable effort has been directed toward the mapping of peptide epitopes by autoantibodies, the role of nonprotein molecules has been less well studied. The immunodominant autoantigen in primary biliary cirrhosis (PBC), E2 components of pyruvate dehydrogenase complexes (PDC-E2), has a lipoate molecule bonded to the domain to which autoantibodies are directed. METHODS: We examined sera from patients with PBC (n = 105), primary sclerosing cholangitis (n = 70), and rheumatoid arthritis (n = 28) as well as healthy volunteers (n = 43) for reactivity against lipoic acid. The lipoic acid hapten specificity of the reactive antibodies in PBC sera was determined following incubation of aliquots of the sera with human serum albumin (HSA), lipoylated HSA (HSA-LA), PDC-E2, lipoylated PDC-E2, polyethylene glycol (PEG), lipoylated PEG, free lipoic acid, and synthetic molecular mimics of lipoic acid. RESULTS: Anti-lipoic acid specific antibodies were detected in 81% (79 of 97) of antimitochondrial antibody (AMA)-positive patients with PBC but not in controls. Two previously unreported specificities in AMA-positive sera that recognize free lipoic acid and a carrier-conjugated form of lipoic acid were also identified. CONCLUSIONS: We hypothesize that conjugated form(s) of native or xenobiotic lipoic acid mimics contribute to the initiation and perpetuation of autoimmunity by at first breaking self-tolerance and participating in subsequent determinant spreading. The variability in the immunoreactive carrier/lipoate conjugates provides an experimental framework on which potential mechanisms for the breakdown of self-tolerance following exposure to xenobiotics can be investigated. The data have implications for patients taking lipoic acid as a dietary supplement.

Geographic clusters of primary biliary cirrhosis.

Genetic and environmental factors have been widely suggested to contribute to the pathogenesis of primary biliary cirrhosis (PBC), an autoimmune disease of unknown etiology leading to destruction of small bile ducts. Interestingly, epidemiologic data indicate a variable prevalence of the disease in different geographical areas. The study of clusters of PBC may provide clues as to possible triggers in the induction of immunopathology. We report herein four such unique PBC clusters that suggest the presence of both genetic and environmental factors in the induction of PBC. The first cluster is represented by a family of ten siblings of Palestinian origin that have an extraordinary frequency of PBC (with 5/8 sisters having the disease). Second, we describe the cases of a husband and wife, both having PBC. A family in which PBC was diagnosed in two genetically unrelated individuals, who lived in the same household, represents the third cluster. Fourth, we report a high prevalence of PBC cases in a very small area in Alaska. Although these data are anedoctal, the study of a large number of such clusters may provide a tool to estimate the roles of genetics and environment in the induction of autoimmunity.