Acute Liver Failure Due to Etodolac, a Selective Cycloxygenase- 2 (COX -2) Inhibitor Non-Steroidal Anti-Inflammatory Drug Established by RUCAM-Based Causality Assessment.

Drug induced liver injury is a common cause of acute liver failure (ALF). While most of these cases are due to dose dependent hepatotoxicity with acetaminophen, idiosyncratic drug-induced liver injury (DILI) is responsible for about 15% cases of ALF. Antibiotics are the most common cause of idiosyncratic DILI as well as DILI induced ALF. Etodolac is a selective cycloxygenase- 2 (COX -2) inhibitor non-steroidal anti-inflammatory drug used as an analgesic and anti-inflammatory in musculoskeletal diseases. Severe liver impairment is extremely rare. Till date, only 3 cases of ALF related to etodolac have been reported in the literature. Here we report two cases with a unique presentation of ALF occurring due to DILI caused by etodolac, as diagnosed by Roussel Uclaf Causality Assessment Method (RUCAM).

Increased gastric mucus secretion alleviates non-steroidal anti-inflammatory drug-induced abdominal pain.

Non-steroidal anti-inflammatory drugs (NSAIDs) can cause dyspeptic symptoms, including abdominal pain. Gastric mucus is important as the first line of defense against luminal irritants. In the present study, we investigated whether gastric mucus secretion could influence the severity of gastric mucosal injuries or NSAID-induced dyspeptic symptoms. Fifteen Helicobacter pylori-negative, healthy males were administered two types of NSAIDs, a non-selective cyclooxygenase inhibitor, naproxen (300 mg, twice a day), or a cyclooxygenase-2-selective inhibitor, etodolac (200 mg, twice a day), for 1 week in a crossover study, with an interval of ≥ 4 weeks. Study participants underwent endoscopic examinations before and after treatment. Pentagastrin-stimulated gastric secretions were collected for 10 min during endoscopic examinations, and were analyzed for gastric acid levels (mEq/10 min) and mucus output (mg hexose/10 min). The grade of gastric mucosal injury was assessed endoscopically. Among 29 subjects who completed the crossover study, 11 individuals reported abdominal pain following the administration of naproxen or etodolac for 1 week, as judged by elevated pain scores, while 18 individuals did not report abdominal pain. The occurrence of symptoms was not associated with the type of NSAIDs administered or the occurrence of erosive injury visualized by endoscopy. Gastric mucus secretion was significantly increased in subjects without drug-induced abdominal pain (P < 0.05), whereas it was significantly reduced in those with drug-induced abdominal pain (P < 0.05). In conclusion, the occurrence of NSAID-induced abdominal pain is associated with reduced levels of gastric mucus secretion rather than the occurrence of endoscopic mucosal injury.

Efficacy and safety of 400 and 800 mg etodolac vs. 1,000 mg paracetamol in acute treatment of migraine: a randomized, double-blind, crossover, multicenter, phase III clinical trial.

AIM: We aimed to determine the efficacy and safety of etodolac, in acute migraine attacks in comparison with paracetamol (acetaminophen). METHODS: We designed a randomized, double-blind, crossover phase III clinical trial for patients diagnosed with migraine for at least 1 year, according to ICHD-II criteria. Two hundred and twenty-nine adult patients having 2 to 8 attacks monthly from 17 centers were included. The patients were instructed to use 3 attack treatment packages consisting of 1,000 mg paracetamol, 400 mg etodolac, and 800 mg etodolac on 3 migraine attacks of moderate-severe intensity each in a 3-month treatment period, interchangeably. RESULTS: Any pain medication was used in 1,570 migraine attacks while study treatments were used in 1,047 attacks. The results for 1,000 mg paracetamol, 400 mg etodolac, and 800 mg etodolac were as follows: response of headache at 2 hours 44.9%, 48.3% and 46.1%; pain-free at 2 hours 19.2%, 19.3% and 24.1%; sustained pain-free from 2 to 24 hours 34.3%, 38.3% and 41.1%; relapse rates in 2 to 24 hours 7.3%, 14.3% and 9.7%. There were no statistically significant differences between the groups regarding the headache response, pain-free, sustained pain-free, and relapse rates. Nausea, vomiting, phonophobia, or photophobia decreased similarly in all groups within 24 hours of treatment administration. Drug-related adverse events were noted in 8 patients with 1,000 mg paracetamol, in 9 patients with 400 mg etodolac and in 9 patients for 800 mg etodolac during the study. COMMENT: Our study showed that etodolac is a safe and effective alternative in acute migraine treatment and showed comparable efficacy to paracetamol 1,000 mg. Etodolac may be considered as an alternative option for acute treatment of migraine.

The enantiomers of etodolac, a racemic anti-inflammatory agent, play different roles in efficacy and gastrointestinal safety.

The anti-inflammatory agent etodolac is used worldwide and it has a good gastrointestinal safety profile. Etodolac consists of two enantiomers, S- and R-etodolac. Here, we investigated the beneficial activities of racemic etodolac and its enantiomers. First, we compared S- and R-etodolac in terms of their inhibition of cyclooxygenase (COX) activity in vitro and their suppression of paw swelling in adjuvant-induced arthritic rats. The COX-2 inhibitory and anti-inflammatory effects of etodolac were found to be due to the S-enantiomer. We previously reported that etodolac attenuates allodynia in a mouse model of neuropathic pain by a COX-2-independent mechanism [N. Inoue et al., J. Pharmacol. Sci., 109, 600-605 (2009)]. In the present study, we showed that the anti-allodynic effects of etodolac in mice were also due to the S-enantiomer. In addition, we investigated the ulcerogenic activity of racemic etodolac and its enantiomers. At high doses, racemic etodolac showed a lower gastric lesion index in rats than the equivalent dose of S-etodolac. In contrast, R-etodolac showed no ulcerogenic activity and even showed protection against HCl/ethanol-induced gastric damage in rats. In conclusion, S-etodolac exhibited anti-inflammatory effects mediated by COX-2 inhibition and anti-allodynic effects that were independent of COX-2 inhibition, while R-etodolac showed gastroprotective effects that may contribute to the low gastrointestinal toxicity of racemic etodolac. Our results show that each enantiomer plays a different role in the efficacy and gastrointestinal safety of etodolac.

A multicentric, randomized, comparative clinical trial to evaluate the efficacy and safety of S-etodolac in the treatment of osteoarthritis in Indian patients.

OBJECTIVE: To compare the efficacy and safety of S-etodolac with etodolac in the treatment of osteoarthritis in Indian patients. MATERIALS AND METHODS: This was a double-blind, multicentric, comparative clinical trial conducted in 108 Indian patients with osteoarthritis. All patients received either S-etodolac ER 300 mg or etodolac ER 600 mg tablets once daily. Assessment was done on the basis of WOMAC score and VAS pain score, patient's and physician's global assessment of the arthritic condition. All patients were evaluated after every 2 weeks for 4 weeks for efficacy and safety variables. RESULTS AND DISCUSSION: Total 49 patients in the test group and 52 patients in the reference group completed the study. There was significant improvement (p < 0.0001) in all WOMAC subscales (pain, stiffness and physical function), WOMAC total score and VAS pain score in both the groups. Patient's and physician's global assessment of the arthritic condition also improved significantly (p < 0.0001). All patients showed improvement in WOMAC and VAS pain score by (3) 20%. There was no significant difference between the groups for the efficacy parameters. The adverse events reported were few and no serious adverse events were reported. Total 5 patients in S-etodolac group and 2 patients in etodolac group dropped out of the study. Only 1 patient dropped out because of the side effects of burning sensation, palpitations and anxiety in the test group. CONCLUSION: The present study has established the efficacy, tolerability and safety of S-etodolac extended release tablets in the treatment of osteoarthritis in Indian patients.

Single dose oral etodolac for acute postoperative pain in adults.

BACKGROUND: Etodolac is a selective cyclo-oxygenase-2 (COX-2) inhibitor, with evidence of efficacy in osteoarthritis and rheumatoid arthritis. Its analgesic efficacy in postoperative pain has not been clearly established. There are no systematic reviews on Etodolac's use in this condition. OBJECTIVES: To assess the analgesic efficacy of etodolac in single oral doses for moderate and severe postoperative pain. SEARCH STRATEGY: We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to May 2009. SELECTION CRITERIA: Randomised, double blind, placebo-controlled trials of single dose orally administered etodolac (any formulation) in adults with moderate to severe acute postoperative pain. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Pain relief or pain intensity data were extracted and converted into the dichotomous outcome of number of participants with at least 50% pain relief over 4 to 6 hours, from which relative risk (RR) and number needed to treat to benefit (NNT) were calculated. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected. MAIN RESULTS: Nine studies (1459 participants) compared etodolac and placebo. Studies were of adequate reporting quality, and the majority of participants had pain following dental extractions. The dose of etodolac used was 25 mg to 1200 mg, with most of the information for 100 mg and 200 mg. For at least 50% pain relief over 4 to 6 hours compared with placebo the NNT for etodolac 100 mg (498 participants) was 4.8 (3.5 to 7.8) and for etodolac 200 mg (670 participants) it was 3.3 (2.7 to 4.2). Very limited information with the extended release formulation did not suggest improved benefit for this outcome.The proportion of participants with at least 50% pain relief was 41% with 100 mg and 44% with 200 mg. Remedication was needed by about 60% with etodolac 200 mg or 400 mg over 6 to 8 hours, compared with almost 80% with placebo.Adverse events were uncommon, and not significantly different form placebo. AUTHORS' CONCLUSIONS: Etodolac 200 mg may be a useful analgesic in postoperative pain, with efficacy similar to paracetamol 1000 mg and celecoxib 200 mg. Higher doses may provide analgesia equivalent to more commonly used drugs, such as ibuprofen 400 mg, naproxen 500 mg and diclofenac 50 mg.

In vitro and in vivo characteristics of a thermogelling rectal delivery system of etodolac.

Rectal etodolac-Poloxamer gel systems composed of Poloxamer and bioadhesive polymers were developed and evaluated. Hydroxypropylmethyl cellulose, poly)vinyl) pyrrolidone, methyl cellulose, hydroxyethylcellulose, and carbopol were examined as mucoadhesive polymers. The characteristics of the rectal gels differed according to the properties of mucoadhesive polymers. The physicochemical properties such as gelation temperature, gel strength, and bioadhesive force of various formulations were investigated. The analysis of release mechanism showed that the release of etodolac was proportional to the square root of time, indicating that etodolac might be released from the suppositories by Fickian diffusion. The anti-inflammatory effect of etodolac-Poloxamer gel system was also studied in rats. Moreover, liquid suppository of etodolac did not cause any morphological damage to the rectal tissues. These results suggested that in situ gelling liquid suppository with etodolac and mucoadhesive polymer was a physically safe, convenient, and effective rectal dosage form for etodolac.

The risk of acute myocardial infarction with etodolac is not increased compared to naproxen: a historical cohort analysis of a generic COX-2 selective inhibitor.

BACKGROUND: This study compares the risk of acute myocardial infarction among patients exposed to etodolac, naproxen, celecoxib, and rofecoxib. METHODS: A retrospective cohort study in 38 258 veteran patients (26 376 patient-years) measured the adjusted odds ratios of acute myocardial infarction during exposure to etodolac, naproxen, celecoxib, or rofecoxib. RESULTS: Diagnosis of acute myocardial infarction was confirmed in 100 patients who were exposed to a study nonsteroidal anti-inflammatory drug. Compared to naproxen, the increased risk of acute myocardial infarction was not significant for etodolac (OR = 1.32, P = .27), whereas celecoxib (OR = 2.18, 95% CI 1.09-4.35, P = .03) and rofecoxib (OR = 2.16, 95 CI 1.04-4.46, P = .04) were significant. A post hoc analysis indicates that patients with a prior history of acute myocardial infarction had a significant, 4.26-fold risk for another acute myocardial infarction if taking celecoxib or rofecoxib. CONCLUSION: Etodolac is not associated with a statistically increased risk of acute myocardial infarction compared to naproxen.

The effects of etodolac, nimesulid and naproxen sodium on the frequency of sister chromatid exchange after enclused third molars surgery.

PURPOSE: Non-steroidal anti-inflammatory drugs (NSAID) are frequently used in oral surgical procedures in dentistry. The evaluation of the frequency of sister chromatid exchange (SCE) is accepted as a reliable cytogenetic method to assess the genotoxic effects of environmental factors. MATERIALS AND METHODS: In this study, the genotoxic effects of various NSAIDs were assessed in 30 patients to who they were administered following encluosed third molar surgery using SCE analysis before and after the operation. The frequency of SCE was evaluated before the operation and after 3 days of etodolac, nimesulid and naproxen use. RESULTS: There was no statistically significant difference in the frequency of SCE between the preoperative and postoperative states in patients given etodolac, nimesulid or naproxen sodium. CONCLUSION: Short term use of selective and non-selective NSAIDs was not associated with a significant genotoxic effect that could be detected using the SCE method in peripheric lymphocytes.

Safety of selective cyclooxygenase-2 inhibitors and a basic non-steroidal anti-inflammatory drug (NSAID) in Japanese patients with NSAID-induced urticaria and/or angioedema: Comparison of meloxicam, etodolac and tiaramide.

The identification of a safe and reliable alternative for patients with non-steroidal anti-inflammatory drug (NSAID)-induced urticaria/angioedema is a frequent problem for dermatologists and other practitioners. Cyclooxygenase-2 (COX-2) inhibitors have been reported to be safe for NSAID-intolerant patients from the US and Europe but not all of them have yet been approved for use in Japan. It was our objective to investigate the clinical manifestations of oral NSAID challenges in Japanese patients with histories of urticaria and/or angioedema after the intake of NSAIDs and to find safe alternative drugs, including COX-2 inhibitors and a basic anti-inflammatory drug. Twenty subjects suspected NSAID-induced urticaria/angioedema from histories were included in a double-blind or single-blind, placebo-controlled oral challenge protocol using NSAIDs. Skin prick tests using NSAIDs, which were dissolved in saline, were conducted. The mean age of the patients was 37.3 years; 14 patients were female. The results of other challenge tests showed that the most frequently intolerated drugs was loxoprofen (100%), followed by acetyl salicylic (94.4%), etodolac (53.3%), dicrofenac (50%), acetaminophen (38.5%), meloxicam (33%), and tiaramide (21.4%). Urticaria and angioedema were induced after aspirin intake in 83.3% and 22.2% of patients, respectively, whereas an asthmatic response was seen in 5.6%. Skin prick tests with NSAIDs were 100% negative. This study showed that among the NSAIDs that are available in Japan and that were investigated in this study, tiaramide, which does not inhibit COX, is the relatively safe alternative drug for Japanese patients with NSAID-induced urtiacaria and/or angioedema. Furthermore, meloxicam seems to be better tolerated than etodolac between two selective COX-2 inhibitors.

Evaluation of adverse effects of long-term oral administration of carprofen, etodolac, flunixin meglumine, ketoprofen, and meloxicam in dogs.

OBJECTIVE: To evaluate adverse effects of long-term oral administration of carprofen, etodolac, flunixin meglumine, ketoprofen, and meloxicam in dogs. ANIMALS: 36 adult dogs. PROCEDURES: Values for CBC, urinalysis, serum biochemical urinalyses, and occult blood in feces were investigated before and 7, 30, 60, and 90 days after daily oral administration (n = 6 dogs/group) of lactose (1 mg/kg, control treatment), etodolac (15 mg/kg), meloxicam (0.1 mg/kg), carprofen (4 mg/kg), and ketoprofen (2 mg/kg for 4 days, followed by 1 mg/kg daily thereafter) or flunixin (1 mg/kg for 3 days, with 4-day intervals). Gastroscopy was performed before and after the end of treatment. RESULTS: For serum gamma-glutamyltransferase activity, values were significantly increased at day 30 in dogs treated with lactose, etodolac, and meloxicam within groups. Bleeding time was significantly increased in dogs treated with carprofen at 30 and 90 days, compared with baseline. At 7 days, bleeding time was significantly longer in dogs treated with meloxicam, ketoprofen, and flunixin, compared with control dogs. Clotting time increased significantly in all groups except those treated with etodolac. At day 90, clotting time was significantly shorter in flunixin-treated dogs, compared with lactose-treated dogs. Gastric lesions were detected in all dogs treated with etodolac, ketoprofen, and flunixin, and 1 of 6 treated with carprofen. CONCLUSIONS AND CLINICAL RELEVANCE: Carprofen induced the lowest frequency of gastrointestinal adverse effects, followed by meloxicam. Monitoring for adverse effects should be considered when nonsteroidal anti-inflammatory drugs are used to treat dogs with chronic pain.

Effects of cyclooxygenase inhibition on the gastrointestinal tract.

Cyclooxygenase (COX) is a rate-limiting enzyme that catalyzes the conversion of arachidonic acid, an essential fatty acid present in cell membrane phospholipids and liberated by phospholipase, into prostaglandins (PGs) and prostanoids. COX has two distinct membrane-anchored isoenzymes; COX-1 and COX-2. COX-1 is a constitutively expressed and found in most normal body tissues; COX-2 is expressed in normal tissues at low levels and is highly induced by pro-inflammatory mediators in the setting of inflammation, injury, and pain. Inhibitors of COX activity include: (1) conventional non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs); (2) selective COX-2 inhibitors (COXIBs); and (3) COX-1 inhibitors. Non-selective NSAIDs, at therapeutic doses, inhibit both COX-1 and COX-2. The anti-inflammatory benefits of these drugs are primarily derived from COX-2 inhibition, while inhibition of COX-1 often elicits gastrointestinal (GI) toxicity. Therefore, COXIBs were developed to provide a selective COX-2 agent, i.e., one, that at fully therapeutic doses demonstrated comparable therapeutic benefit to non-selective NSAIDs, without the attendant COX-1-mediated GI toxicities. In this review, we evaluate available literature describing the pathophysiologic role of cyclooxygenases and the effects of their inhibition in GI system in experimental and domestic animal species.

Efficacy and safety of preoperative etodolac and butorphanol administration in dogs undergoing ovariohysterectomy.

Eighteen dogs undergoing ovariohysterectomy were premedicated with etodolac, butorphanol, or their combination. Various parameters, such as blood pressure, isoflurane requirements, behavioral pain scores, plasma cortisol concentration, plasma glucose concentration, and mucosal bleeding time, were assessed. The integrated plasma cortisol values were significantly lower in the etodolac and etodolac with butorphanol groups. Dogs receiving etodolac and butorphanol had the lowest behavioral pain scores from extubation until the end of monitoring. Isoflurane concentration over time (area under the curve), buccal mucosal bleeding time, and indices of renal function were not significantly different among the treatment groups.

Efficacy and safety of firocoxib in the management of canine osteoarthritis under field conditions.

A total of 249 client-owned dogs with osteoarthritis were treated with firocoxib (5 mg/kg/day) or a positive control, etodolac (10-15 mg/kg/day), for 30 days. Veterinary examinations were performed on approximately days 0 (visit 1), 14 (visit 2), and 29 (visit 3). Based on defined noninferiority criteria, firocoxib and etodolac were comparable. Based on the magnitude of the change from baseline, improvement with firocoxib was significantly greater than with etodolac for lameness at a trot (visits 2 and 3) and for lameness at a walk, pain on manipulation, and range of motion (visit 3) (P < .05). In weekly owner evaluations, firocoxib provided significantly greater improvement than etodolac (P < .05) at each scoring.