Long-acting Non-steroidal Anti-inflammatory Drug Research Articles

Pharmacokinetics of carprofen in anaesthetized pigs: a preliminary study

ObjectiveTo investigate the pharmacokinetics of carprofen after a single intravenous (IV) dose and multiple oral doses administered to pigs undergoing electroporation of the pancreas. Study designProspective experimental study. AnimalsA group of eight female pigs weighing 31.74 ± 2.24 kg (mean ± standard deviation). MethodsCarprofen 4 mg kg−1 was administered IV after placement of a central venous catheter during general anaesthesia with isoflurane. Blood samples were collected 30 seconds before and 5, 10, 20, 30 and 60 minutes and 2, 4, 6, 8, 12 and 24 hours after carprofen administration. Subsequently, the same dose of carprofen was administered orally, daily, for 6 consecutive days and blood collected at 36, 48, 60, 72, 96, 120, 144 and 168 hours after initial carprofen administration. Plasma was analysed using liquid chromatography with mass spectrometry. Standard pharmacokinetic parameters were calculated by compartmental analysis of plasma concentration–time curves. Data are presented as mean ± standard error. ResultsThe initial plasma concentration of IV carprofen was estimated at 54.57 ± 3.92 μg mL−1 and decreased to 8.26 ± 1.07 μg mL−1 24 hours later. The plasma elimination curve showed a bi-exponential decline: a rapid distribution phase with a distribution half-life of 0.21 ± 0.03 hours and a slower elimination phase with an elimination half-life of 17.31 ± 3.78 hours. The calculated pharmacokinetic parameters were as follows: the area under the plasma concentration–time curve was 357.3 ± 16.73 μg mL−1 hour, volume of distribution was 0.28 ± 0.07 L kg−1 and plasma clearance rate was 0.19 ± 0.009 mL minute−1 kg−1. The plasma concentration of carprofen, administered orally from days 2 to 7, varied from 9.03 ± 1.87 to 11.49 ± 2.15 μg mL−1. Conclusions and clinical relevanceCarprofen can be regarded as a long-acting non-steroidal anti-inflammatory drug in pigs.

Determination of piroxicam from rat articular tissue and plasma based on LC-MS/MS.

Osteoarthritis (OA) is the most common type of arthritis. To manage OA, in general, oral administration of non-steroidal anti-inflammatory drugs (NSAIDs) is used. Recently, the analgesic and anti-inflammatory efficacy of piroxicam (PX), a long-acting NSAID, by intra-articular (IA) administration in OA was reported, and the possibility that PX is distributed in articular tissues at a certain concentration was raised. Thus, herein, novel LC-MS/MS methods to detect PX in rat articular tissue and plasma are presented. For articular tissue, solvent extraction with acetonitrile for 12h was employed and a protein precipitation method was used for the preparation of a plasma sample. The developed methods were validated by following the FDA guidelines, and the validated methods were successfully applied to a PK study of IA PX. The present study presents, to our knowledge, the first method of determining a drug in articular tissue. Additionally, the level of PX in articular tissue after IA PX administration was experimentally confirmed for the first time using the present methods. Therefore, the present methods provide a new direction for in vivo evaluation for IA PX formulations and contribute to the development of alternative IA PX formulations with better effects for the treatment of OA.

IMPACT OF THE SELECTIVITY AND HALF-LIFE OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS ON THE DEVELOPMENT OF SUBCLINICAL KIDNEY INJURY

Objective: to investigate the impact of the selectivity and half-life of nonsteroidal anti-inflammatory drugs (NSAIDs) on the development of subclinical kidney injury (SKI). A standard physical examination was made. Patients and methods. The study included 80 patients with a verified rheumatoid arthritis (RA) diagnosis. The patients filled in a specially designed questionnaire to explore a history of drug use. As markers of SKI, the investigators determined the concentrations of albumin, α1-microglobulin (α1-MG), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) in urine. A control group consisted of 20 apparently healthy individuals matched for age and gender. Results. 80 patients suffering from RA received drug therapy. Of them, 82.5% and 87.5% took NSAIDs and disease-modifying antirheumatic drugs, respectively. The levels of SKI markers were compared in three groups of the examinees: 1) NSAID-treated patients; 2) NSAID-untreated patients; 3) a control group. There were statistically significant differences between all the groups (p < 0.05). Comparison of the levels of SKI markers revealed no statistically significant difference in the groups receiving selective cyclooxygenase-2 (COX-2) inhibitors (n=18.6%), in those taking nonselective ones (n=68.6%), and the control group. Comparison of the levels of SKI markers demonstrated significantly higher α1-MG levels in the long-acting NSAID groups (n=8.6%) than in the short-acting NSAID group (n=80%). ALT, ALP, and microalbuminuria showed a similar trend that failed to reach statistical significance. Conclusion: NSAIDs remain a group of medications with a certain nephrotoxic effect. At the same time, the design of selective COX-2 inhibitors has failed to solve the problem of nephrotoxicity. NSAIDs with long half-lives are characterized by greater nephrotoxicity. The available data provide preconditions for the more differentiated use of NSAIDs, particularly in patients with RA.

A Prodrug Approach Involving In Situ Depot Formation to Achieve Localized and Sustained Action of Diclofenac After Joint Injection

Long-acting nonsteroidal anti-inflammatory drug formulations for intra-articular injection might be effective in the management of joint pain and inflammation associated sports injuries and osteoarthritis. In this study, a prodrug-based delivery system was evaluated. The synthesized diclofenac ester prodrug, a weak base (pKa 7.52), has relatively high solubility at low pH (6.5 mg mL(-1) at pH 4) and much lower solubility at physiological pH (4.5 μg mL(-1) at pH 7.4) at 37°C. In biological media including 80% (v/v) human synovial fluid (SF), the prodrug was cleaved to diclofenac mediated by esterases. In situ precipitation of the prodrug was observed upon addition of a concentrated slightly acidic prodrug solution to phosphate buffer or SF at pH 7.4. The degree of supersaturation accompanying the precipitation process was more pronounced in SF than in phosphate buffer. In the rotating dialysis cell model, a slightly acidic prodrug solution was added to the donor cell containing 80% SF resulting in a continuous appearance of diclofenac in the acceptor phase for more than 43 h after an initial lag period of 8 h. Detectable amounts of prodrug were found in the rat joint up to 8 days after knee injection of the acidic prodrug solution.

Day case and short stay surgery: 2

Day case and short stay surgery: 2

Interventions for pain during fixed orthodontic appliance therapy

To compare the different methods of pain control intervention during fixed orthodontic appliance therapy. A computerized literature search was performed in MEDLINE (1966-2009), The Cochrane Library (Issue 4, 2009), EMBASE (1984-2009), and CNKI (1994-2009) to collect randomized controlled trials (RCTs) for pain reduction during orthodontic treatment. Data were independently extracted by two reviewers and a quality assessment was carried out. The Cochrane Collaboration's RevMan5 software was used for data analysis. The Cochrane Oral Health Group's statistical guidelines were followed. Twenty-six RCTs were identified and six trials including 388 subjects were included. Meta-analysis showed that ibuprofen had a pain control effect at 6 hours and at 24 hours after archwire placement compared with the placebo group. The standard mean difference was -0.47 and -0.48, respectively. There was no difference in pain control between ibuprofen, acetaminophen, and aspirin. Other analgesics such as tenoxicam and valdecoxib had relatively lower visual analog scale (VAS) scores in pain perception. Low-level laser therapy (LLLT) was also an effective approach for pain relief with VAS scores of 3.30 in the LLLT group and 7.25 in the control group. Analgesics are still the main treatment modality to reduce orthodontic pain despite their side effects. Some long-acting nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase enzyme (COX-2) inhibitors are recommended for their comparatively lesser side effects. Their preemptive use is promising. Other approaches such as LLLT have aroused researchers' attention.

Single dose oral diflunisal for acute postoperative pain in adults.

Diflunisal is a long-acting non-steroidal anti-inflammatory drug (NSAID) most commonly used to treat acute postoperative pain or chronic joint pain from osteoarthritis and rheumatoid arthritis. This review analyses the effectiveness and harm of different doses of diflunisal in the context of moderate to severe postoperative pain. To assess efficacy, duration of action, and associated adverse events of single dose oral diflunisal in acute postoperative pain in adults. We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to January 2010. Randomised, double blind, placebo-controlled trials of single dose orally administered diflunisal in adults with moderate to severe acute postoperative pain. 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 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. Nine studies in dental, orthopedic and gynaecological surgery met the inclusion criteria, testing doses of diflunisal from 125 mg to 1000 mg.For diflunisal 1000 mg, the NNT for at least 50% pain relief over 4 to 6 hours was 2.1 (1.8 to 2.6) (6 studies, 391 participants); the NNT to prevent remedication within 6 hours was 1.9 (1.7 to 2.3), and within 12 hours was 2.2 (1.9 to 2.7) (6 studies, 409 participants). More participants experienced adverse events with diflunisal 100 mg than with placebo, but none were serious or led to withdrawal.For diflunisal 500 mg, the NNT for at least 50% pain relief over 4 to 6 hours was 2.6 (2.1 to 3.3) (6 studies, 357 participants); the NNT to prevent remedication within 6 hours was 2.6 (2.1 to 3.4) (6 studies, 390 participants), and within 12 hours was 2.9 (2.3 to 4.0) (5 studies, 329 participants). Adverse events did not differ significantly from placebo. Diflunisal has an analgesic effect similar to other NSAIDs in single dose, but benefits from providing significant analgesia for about twelve hours. This property may be useful when regular dosing is needed, or when taking several doses of a shorter acting analgesic is impractical.

Analgesic and Anti-Inflammatory Effects of Oxaprozin and Naproxen Sodium After Removal of Impacted Lower Third Molars: A Randomized, Double-Blind, Placebo-Controlled Crossover Study

In this study, oxaprozin, a long-acting nonsteroidal anti-inflammatory drug, and naproxen sodium were compared in terms of their effects on edema, pain, and trismus after surgery for impacted mandibular third molars. Thirty healthy patients with bilaterally impacted mandibular third molars were included in this randomized, cross-over, double-blind, placebo-controlled study. Patients were assigned randomly to 1 of 3 surgery groups and received postoperatively 1,200 mg oxaprozin, 550 mg naproxen sodium, or a placebo. Postoperative edema was measured with ultrasonography performed before and after surgery. Trismus was measured by comparison of preoperative and postoperative maximum interincisal mouth opening measurements by caliper. Pain was assessed by a visual analog scale (VAS) and by recording the number of rescue analgesic pills taken. After removal of impacted third molars, the patients administered oxaprozin and naproxen showed superior results over those given placebo in terms of pain parameters (P < .05), but these treatments had no statistically significant effect on facial swelling. Comparing the oxaprozin and naproxen groups, there were no differences in the mouth opening measurements, but naproxen showed a statistically superior effect over the placebo (P < .05). Although not statistically significant, oxaprozin showed a more pronounced effect in reducing trismus than did the placebo (P = .07). Administration of either oxaprozin or naproxen sodium during the postoperative period is effective and has similar effects in reducing pain but questionable benefit for the management of trismus. However, neither agent has clinical benefit in terms of reducing edema.

Effects of meloxicam or tolfenamic acid administration on the pain and stress responses of Merino lambs to mulesing

To determine the effectiveness of two long-acting non-steroidal anti-inflammatory drugs (NSAIDs) at reducing the pain and stress responses to mulesing in lambs. Merino lambs (n = 60) were allocated at 5 weeks of age to six treatment groups: (1) sham mules; (2) mules; (3) tolfenamic acid-sham mules; (4) tolfenamic acid administered 45 min before mulesing; (5) tolfenamic acid at the time of mulesing; (6) meloxicam at the time of mulesing. Plasma cortisol was measured at -0.75, -0.25, 0, 0.5, 1, 3, 6, 12, 24, 48 and 72 h relative to mulesing. Beta-endorphin concentrations in plasma were determined at 0, 0.5, 1, 6, 12, 24, and 48 h. Haematology was performed on blood samples taken at -0.75, 0, 24, 48 and 72 h. Plasma haptoglobin was measured at 0, 12, 24, 48 and 72 h. Rate of wound healing was determined 72 h post mulesing, and animal behaviour, including posture, was measured for 6 h after mulesing. The mulesed lambs exhibited large increases in plasma concentrations of cortisol, beta-endorphin and haptoglobin. All mulesed animals lost weight significantly in the week after mulesing, regardless of analgesic administration, but the difference in weight between mulesed and unmulesed lambs was less at the final measurement, 2 weeks after mulesing. Mulesed lambs spent significantly less time lying ventrally than control lambs. All lambs that were mulesed, including those administered NSAIDs, spent more time standing with a hunched posture and less time walking normally than control lambs. The NSAID treatments applied 45 min before or at the time of mulesing at the dose levels used in this study were not effective in reducing the acute response of lambs to mulesing.

Novel Depots of Ketorolac Esters Have Long-Acting Antinociceptive and Antiinflammatory Effects

No long-acting nonsteroidal antiinflammatory drug is clinically available for the treatment of pain. In this study, we evaluated the antinociceptive and antiinflammatory effects and duration of action of several novel depots of ketorolac esters, such as ketorolac propyl ester, pentyl ester, heptyl ester, and decyl ester, and observed whether they had a long-acting effect. Four studies in Sprague-Dawley rats were performed. In Studies 1-3, the antinociceptive and antiinflammatory effects of IM ketorolac tromethamine and its base and propyl ester were evaluated. In Study 4, the antinociceptive and antiinflammatory effects of several other ketorolac esters were evaluated. We found that ketorolac tromethamine 24, 80, and 240 micromol/kg (in saline) produced significant antinociceptive and antiinflammatory effects with duration of action of approximately 6-8 h. The four ketorolac esters at a dose of 240 micromol/kg (in oil) produced significant long-acting antinociceptive and antiinflammatory effects, with duration of action of approximately 52-76 h. We concluded that IM injection of novel depots of ketorolac esters in rats produce long-acting antinociceptive and antiinflammatory effects that are 6.5- to 9.5-fold longer than the traditional dosage form of ketorolac tromethamine.

Evaluation of Academic Detailing Within a Coordinated Care Trial

Background: Academic detailing has been identified as an intervention that modifies health professionals' practice, particularly prescribing.Aim: To assess the impact of academic detailing on general practitioners' (GPs) prescribing for heart failure, and chronic pain associated with osteoarthritis, in an elderly population.Method: This was a quasi‐experimental study embedded within a coordinated care trial, with a 12‐month follow‐up. 1151120 (96%) of GPs invited to participate received academic detailing visits by experienced teaching‐hospital clinical pharmacists between July 1998 and July 1999. The pharmacological management of two conditions was addressed: heart failure in Phase 1, and chronic pain associated with osteoarthritis in Phase 2. Data from the Pharmaceutical Benefits Scheme (PBS) were analysed for changes in prescribing. The perceptions of the GP and pharmacist were also assessed.Results: Consistent with key messages, non‐steroidal anti‐inflammatory drug (NSAID) use decreased in Phase I, and in Phase 2long‐acting NSAID use decreased and low‐dose tricyclic antidepressant use increased. Inconsistent with key messages of Phase 1, angiotensin converting enzyme inhibitor prescribing for heart failure did not change. GPs and pharmacists were highly satisfied with the project.Conclusion: Academic detailing visits to GPs were partly successful in changing prescribing practices for heart failure, and pain management of osteoarthritis. Initiatives such as this may strengthen professional links between pharmacists and GPs and benefit patients through enhanced quality use of medicines.

Differential Analgesic Effect of Tenoxicam on the Wound Pain and Uterine Cramping Pain After Cesarean Section

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to enhance opioid analgesia in the acute pain service. The question, however, of whether NSAIDs produce a similar extent of potentiation among different types of pain, has not been thoroughly investigated. A randomized, placebo-controlled, double-blind study was performed to characterize the analgesic effect of tenoxicam, a long-acting NSAID, on resting wound pain, evoked wound pain, and uterine cramping pain after cesarean section. Saline (n = 48) or 20 mg tenoxicam (n = 45) was intravenously injected immediately after clamping the umbilical cord. All patients were instructed to obtain maximal postoperative analgesia by intravenous patient-controlled morphine. RESULTS Tenoxicam profoundly reduced the intensity of uterine cramping pain (3.6 [2.0-5.6] versus 5.5 [3.4-6.6]; p < 0.01) but had no additional effect on wound pain at rest, with movement, changing position, sitting, and walking. Intraoperative injection of 20 mg tenoxicam decreased the demand ratio for patient-controlled analgesia (PCA) and 24-hour morphine consumption by approximately 30%. The data show that tenoxicam potentiates opioid analgesic effect on the somatic and visceral types of pain to different extents, and they suggest that intraoperative injection of 20 mg tenoxicam is sufficient to enhance intravenous PCA morphine on uterine cramping pain for the first 24 hours after cesarean section.

Low-dose tizanidine with nonsteroidal anti-inflammatory drugs for detoxification from analgesic rebound headache.

To describe an outpatient regimen for analgesic detoxification and resolution of analgesic rebound headache. Frequent analgesic use is believed to promote the transformation of episodic migraine into a chronic, pervasive headache syndrome. Management of pain precipitated by analgesic withdrawal is crucial to treatment success. Outpatient treatment protocols designed to achieve successful withdrawal will reduce costs and potentially lead to more widespread implementation of therapy. Patients with appropriate histories were managed on an outpatient basis for detoxification by discontinuation of the offending analgesic and initiation of treatment with tizanidine and a long-acting nonsteroidal anti-inflammatory drug. Patients kept diaries of pain and medication use. Results were evaluated at 6 and 12 weeks. Patients able to tolerate no or trivial analgesic use (ie, 4 or fewer doses in each 2-week period) were considered responders. At 6 weeks, 36 patients (65%) were responders. At 12 weeks, 38 patients (69%) were responders. The chronic daily headache pattern had resolved at 12 weeks in 34 patients (62%). This treatment protocol was well tolerated and yielded a high degree of efficacy, demonstrating that outpatient management can be effective for achieving analgesic withdrawal and resolution of analgesic rebound headache.

Requirement of Analgesia for Extracorporeal Shock Wave Lithotripsy and Efficacy of a Nonsteroidal Antiinflammatory Drug: Piroxicam

Objective: In this study, the requirement of analgesia and the analgesic efficacy of a long-acting nonsteroidal antiinflammatory drug (NSAID), piroxicam, were investigated in patients with renal stone disease treated with extracorporeal shock wave lithotripsy (ESWL). Methods: This randomized, placebo-controlled study included 60 patients. Patients were divided into two groups randomly. A single dose of saline (2 ml) was given to the patients in group 1 (n = 20) and 2 ml of 40 mg piroxicam to the patients in group 2 (n = 40). All injections were administered into the gluteal muscle 45 min before ESWL. A verbal rating scale (VRS) was used to evaluate the pain. Groups were compared according to age, sex, weight, height, stone size, number of shock waves, duration of ESWL and VRS scores. Results: There was no statistically significant difference between both groups in demographic data, stone size, number of shock waves and duration of ESWL procedure (p > 0.05). However mean VRS scores were significantly lower in group 2 than in group 1 during and after the ESWL procedure. Conclusion: We considered that analgesic agents should be used to control the pain in second-generation lithotriptors. Piroxicam has clinically significant effects on the pain and also antiinflammatory effects, inhibits ureteric activity, and helps in stone passage.

Acute and Chronic Effects of Nonsteroidal Antiinflammatory Drugs on Glomerular Filtration Rate in Elderly Patients

To assess the effects of nonsteroidal antiinflammatory drugs (NSAIDs) on glomerular filtration rate (GFR) in elderly patients with and without renal insufficiency, we conducted an open-label, randomized, prospective three-period cross-over study. Twenty-nine patients at least 65 years old were assigned to groups with preserved GFR (> 1.16 mL/s [70 mL/min]) or with renal insufficiency (GFR 0.50-1.16 mL/s [30-70 mL/min]). Patients received 800 mg ibuprofen three times daily, 20 mg piroxicam daily, or 200 mg sulindac twice daily for 1 month. Three-hour inulin and two-day creatinine clearances were measured before and after the first and last doses of NSAIDs. Ibuprofen, piroxicam, and sulindac decreased inulin clearance after single-doses in both groups of patients. In patients with renal insufficiency, creatinine clearance did not change after administration of ibuprofen for 1 month (0 +/- 0.06 mL/s, mean +/- standard error), but was decreased similarly with administration of either piroxicam or sulindac (-0.12 +/- 0.06 mL/s [-7.2 +/- 3.6 mL/min], P < 0.02). One patient with preserved GFR, but with other risk factors for NSAID-associated renal impairment, met our criteria for withdrawal by experiencing at least a 40 mumol/L (0.5 mg/dL) increase in serum creatinine above their baseline value. Our data indicate that NSAIDs do not adversely affect GFR in patients with preserved renal function unless they have another risk factor for NSAID-associated renal impairment. In contrast, patients with renal insufficiency may have significant chronic decrements in GFR with long-acting NSAIDs such as piroxicam and sulindac, but not with short-acting ibuprofen. Such patients should have renal function monitored while being treated with long-acting NSAIDs.

Diflunisal--a long-acting non-steroidal anti-inflammatory drug. A review of its pharmacology and effectiveness in management of postoperative dental pain.

Diflunisal is frequently used for management of postoperative dental pain as it has some advantages over other commonly used non-steroidal anti-inflammatory drugs including improved analgesia, a prolonged duration of action lasting up to 12 hours, and a low incidence of side effects. The aim of this paper is to review the relevant pharmacologic actions of the drug including its mechanism of action in suppressing the inflammatory response, and indications for its use in dentistry. Diflunisal can be safely recommended for the dental patient following oral surgery and exodontia, periodontal surgery and endodontic surgery.

Pharmacokinetic, biochemical and tolerance studies on carprofen in the horse

Carprofen, a non-steroidal anti-inflammatory drug (NSAID) was administered to three Thoroughbred geldings and three Shetland ponies to determine its plasma disposition and tolerance. The main pharmacokinetic characteristics of carprofen in horses and ponies were a volume of distribution of 0.08 to 0.32 litres/kg (mean +/- se = 0.23 +/- 0.04) a systemic clearance of 26.4 to 78.5 ml/min (mean +/- se = 44.9 +/- 8.0) and a plasma elimination half-life of 14.5 to 31.4 h (mean +/- se = 21.9 +/- 2.3). There was no evidence of any accumulation of carprofen in plasma when the drug was given orally at a dose rate of 0.7 mg/kg for 14 consecutive days. Carprofen was well tolerated following intravenous (iv) and oral administration. Intramuscular (im) administration resulted in elevated levels of plasma creatine kinase suggesting muscle cell damage. According to the results of this study carprofen can be regarded as a long-acting NSAID in horses from a pharmacokinetic point of view. Either iv, im or the oral route of administration could be used to achieve high carprofen plasma concentrations.