Systemic Nonsteroidal Anti-inflammatory Drugs Research Articles

BMP‐7–induced ectopic bone formation and fracture healing is impaired by systemic NSAID application in C57BL/6‐mice

Nonsteroidal antiinflammatory drugs (NSAIDs) are known to potentially impair the fracture healing process. The aim of the present study was to determine if the impairment of bone healing by systemic NSAID application is, at least in part, due to an interaction of NSAIDs with the bone anabolic BMP-7 pathway. Therefore, we first analyzed fracture healing in control and diclofenac-treated mice, where we not only found a significant impairment of fracture healing due to diclofenac treatment as assessed by biomechanical testing and microCT imaging, but also found high coexpression of bone morphogenetic protein-7 (BMP-7) and cyclooxygenase-2 (COX-2) within the fracture callus of both groups. To experimentally address the possible interaction between BMP-7 and COX-2, we then induced ectopic bone formation in control (n = 10) and diclofenac-treated mice (n = 10) by application of BMP-7 (recombinant human OP-1, rhOP-1) into the hamstring muscles. After 20 days of treatment, each ectopic bone nodule was analyzed by contact-radiography, microCT, histology, and histomorphometry. Diclofenac application decreased the trabecular number and bone mass in the ectopic bone nodules significantly due to reduced osteoblast number and activity. These data demonstrate that the bone anabolic effect of BMP-7 and fracture healing is impaired by diclofenac application, and suggest that the potential negative impact of NSAIDs on fracture healing is, at least in part, due to interference with BMP-7 signaling.

Safety of diclofenac sodium 1% gel for knee osteoarthritis in patients with comorbidities

Osteoarthritis (OA) is associated with elevated risk of cardiovascular disease (CVD), relative risk increasing with younger age.1 Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a risk of cardiovascular adverse events (AEs), increasing with dose and duration of use. 2 Topical NSAIDs reduce systemic NSAID exposure, offering potential benefits. The safety and efficacy of topical diclofenac sodium 1% gel (DSG) in patients with knee OA pain were established in 3 double-blind randomized trials, wherein 721 patients (aged ≥35 y) with radiographically mild to moderate knee OA applied DSG 4 grams 4 times daily per knee to 1 or both knees for 12 weeks.

Nonsteroidal Anti-inflammatory Therapy and Recurrent Acute Anterior Uveitis

Objective: To investigate oral nonsteroidal anti-inflammatory drug (NSAID) therapy in the prevention of recurrences of uveitis in patients with recurrent nongranulomatous, idiopathic, or HLA-B27-associated acute anterior uveitis (AAU).Methods: Retrospective case series of 59 patients with recurrent AAU treated with celecoxib or diflunisal.Results: The average duration of NSAID therapy was 21.2 ± 5.7 months. The average number of relapses for all patients prior to systemic NSAID therapy was 2.84 per person-year follow-up. These relapses declined to 0.53 per person-year follow-up with NSAID therapy (p < .001). The relapse rates prior to and after treatment in the HLA-B27-positive group (n = 21) were compared with the relapse rates prior to and after treatment in the HLA-B27-negative group (n = 38) and were also statistically significant (p < .001).Conclusion: Morbid attacks and the cumulative exposure to corticosteroids can be prevented with systemic NSAID therapy in patients with recurrent AAU.

Safety and efficacy of diclofenac sodium 1% gel in unilateral and bilateral osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial

Topical nonsteroidal anti-inflammatory drugs (NSAIDs) have demonstrated effectiveness in patients with osteoarthritis (OA) while minimizing systemic NSAID exposure. This randomized double-blind trial examined the efficacy and safety of diclofenac sodium topical gel 1% (DSG) in patients with mild to moderate knee OA. 420 adults aged ≥35 years with symptomatic Kellgren-Lawrence Grade 1–3 OA of ≥6 months' duration in 1 or both knees were randomized to apply DSG 4 g (n = 208) or vehicle (n = 212) 4 times daily to each symptomatic knee for 12 weeks.

Pharmacist intervention reduces gastropathy risk in patients using NSAIDs

To establish a detection and intervention strategy in order to reduce the number of non-steroidal anti-inflammatory drug (NSAIDs) users at risk of gastropathy from receiving either inadequate or no gastroprotection. Community Pharmacies in Valencia, Spain. Prospective longitudinal intervention study without control group carried out by 79 Community Pharmacies. Patients over 18 who asked for any systemic NSAID were interviewed according to standard procedure. Pharmacist intervention was carried out when a patient at risk of serious NSAID-induced gastrointestinal complications due to inadequate or no gastric protection was identified. The doctor responsible was informed in order to then be able to assess the need to prescribe gastroprotection or change it if inadequate. In the case of over-the-counter (OTC) drugs, pharmacist intervention mainly involved replacing NSAIDs for safer medications. Firstly, the number of patients who had no prescribed gastroprotection or inadequate gastroprotection was determined. Pharmacist intervention then brought about changes in pharmacotherapy in this situation. Of the 6,965 patients who asked for NSAIDs during the study period, 3,054 (43.9%) presented NSAID gastropathy risk factors. 35.6% of the latter (1,089) were not prescribed gastroprotection or were prescribed inadequate gastroprotection. Pharmacist intervention was carried out in 1,075 of these cases. On 391 occasions such risk situations were reported to doctors, who accepted pharmacist intervention on 309 occasions (79.0%) and then either prescribed gastroprotection (77% of cases); changed it (13.9%); withdrew the NSAID (5.8%) or substituted it (3.2%). 235 Pharmacist interventions took place when dispensing OTC NSAIDs. Our strategy allowed us to identify a large number of patients who asked for NSAIDs in Community Pharmacies and who were at risk of NSAID gastropathy, as they received either inadequate gastroprotection or no gastroprotection whatsoever. Moreover, the pharmacist intervention carried out has reduced the number of these risk situations.

An alternative topical treatment of osteoarthritis of the knee with cutaneous diclofenac solution

Background: Osteoarthritis (OA) is the most common chronic degenerative disease, which is characterised by the destruction of the articular cartilage and subchondral bone. The current treatment of OA is based primarily on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics. There are disadvantages to routinely using NSAIDs in OA. Topical NSAIDs represent a potentially important advance in this regard as they may be significantly safer than oral NSAIDs. Cutaneous diclofenac solution (Pennsaid®) was developed for the treatment of symptomatic OA of the knee and contains diclofenac sodium as an active ingredient and dimethyl sulfoxide (DMSO), a penetration enhancer. Objective: To review: i) dermal drug application; ii) the treatment of OA with systemic and topical NSAID therapies; and iii) the clinical efficiency of Pennsaid on the topical treatment of OA of the knee. Methods: A literature search was carried out on skin, topical drug delivery, treatment of OA and assessment of published clinical studies with Pennsaid. Results and discussion: The clinical studies showed that applying the topical diclofenac solution (Pennsaid) to a painful knee with primary OA could provide symptom relief equivalent to oral diclofenac with minimal systemic side effects; however, studies are needed that compare the effectiveness of Pennsaid with different topical forms of diclofenac.

Current strategies for preventing or ameliorating postoperative ileus: A multimodal approach

Internal and external factors that contribute to postoperative ileus (POI), the efficacy and safety of various nonpharmacologic and pharmacologic interventions that have been evaluated for the prevention or amelioration of POI, and the current multimodal approach used in patients undergoing major abdominal surgery are described. Catecholamine and cytokine release associated with the stress response to surgery and the use of certain antiemetic medications, opioid analgesics, and inhaled anesthetics are among the factors that contribute to POI. Early ambulation does not affect the duration of POI, although it has other benefits for patients undergoing abdominal surgery. Clinical experience supports the use of laparoscopy instead of laparotomy if possible, removal of nasogastric tubes shortly after surgery, restriction of intravenous fluids, and initiation of clear oral liquids and ambulation on the first postoperative day. The recommended therapeutic approach for patients undergoing major abdominal surgery involves thoracic epidural analgesia using a local anesthetic with or without an epidural opioid analgesic, and systemic nonsteroidal anti-inflammatory drugs for their opioid-sparing effect if systemic opioid analgesics are used. Buprenorphine may be preferred if a systemic opioid analgesic is used, because it has little effect on gastrointestinal smooth muscle. Metoclopramide, erythromycin, beta blockers, laxatives, neostigmine, naloxone, and gum chewing are not useful for treating POI. Most pharmacologic interventions that have been tried in an effort to prevent or ameliorate POI are ineffective or cause intolerable adverse effects. Research is needed to identify and develop new drug therapies for POI.

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The use of mitomycin C as an adjunctive treatment for equine ocular squamous cell carcinoma

To assess the effectiveness of topical mitomycin C application as an alternative adjunctive therapy to CO2 laser ablation in the treatment of equine ocular squamous cell carcinoma. A retrospective clinical study of eight client owned horses in which 10 affected eyes were treated for ocular squamous cell carcinoma over a 17 month period. (March 2003 to August 2004). Each horse was given a general anaesthetic to allow CO2 laser ablation of the lesion(s). Mitomycin C at a concentration of 0.4 mg/mL was then applied intraoperatively to the affected areas for 1 or 5 minutes. Postoperatively a triple antibiotic eye ointment was applied to the eye twice daily and each horse was treated with systemic non-steroidal anti-inflammatory drugs for 7 days. Recurrence following treatment was noted in three eyes. Two of these were retreated and no further signs developed. The remaining eye was enucleated at the request of the owner. Overall 90% of treated eyes appeared free of tumour a minimum of 11 months post treatment. In this case series mitomycin C appeared to offer a valid alternative to other adjunctive therapies currently employed in the treatment of equine ocular squamous cell carcinoma.

The Effect of Non-steroidal Anti-inflammatory Drugs on Inflammatory Cystoid Macular Edema

To assess the role of systemic non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of inflammatory cystoid macular edema (iCME). Pilot study. We included 66 patients with iCME and treated them with naproxen (2 x 250 mg daily; n = 28) or rofecoxib (1 x 25 mg daily; n = 38). After 4 months of therapy, visual acuity and inflammation activity were measured. We evaluated the grade of CME, retinal vasculitis, and papillary leakage with fluorescein angiography. No clear effect of NSAIDs on iCME, visual acuity, and intraocular inflammation was observed. A beneficial effect was noted in less than 8% of the affected eyes. The drop-out rate after 4 months of treatment was 52%, because of adverse effects or inefficacy of the treatment. Improvement of visual acuity was slightly better in patients who were treated with naproxen compared with rofecoxib (P < or = .05). Systemic NSAIDs have a limited role (if any) in the treatment of iCME.

Cyclooxygenase-2 inhibitors: A new therapeutic option in the treatment of macular edema after cataract surgery

Two patients had uneventful phacoemulsification. After initial improvement, vision deteriorated because of cystoid macular edema (CME). In 1 patient, treatment with systemic nonsteroidal antiinflammatory drugs showed significant improvement in visual acuity but had to be discontinued because of side effects and a relapse of the disease. In the other patient, this therapy was not sufficient. Both patients were given valdecoxib, a cyclooxygenase-2 inhibitor. The new therapy was tolerated well and led to significant and stable improvement in visual acuity in both patients. To our knowledge, this is the first report of using a cyclooxygenase-2 inhibitor in the treatment of clinically significant CME.

Acne fulminans with synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome treated with infliximab

Acne fulminans is a syndrome of sudden onset hemorrhagic and ulcerative acne involving the back, chest, and face combined with systemic symptoms. It can be the dermatologic manifestation of the synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome. Current therapy for acne fulminans consists of wound care, topical and systemic corticosteroids, isotretinoin, and nonsteroidal anti-inflammatory drugs (NSAIDs). Infliximab, a recently developed monoclonal antibody against tumor necrosis factor-alfa, has shown efficacy in the treatment of psoriatic arthritis and ankylosing spondylitis both of which share clinical similarities to the SAPHO syndrome. We report the case of a patient with the SAPHO syndrome and acne fulminans who was treated with infliximab. Ten months after initiating therapy with infliximab, the area of the patient's ulcerative lesions was reduced by 70%. Infliximab might be considered as a treatment option for patients with acne fulminans unresponsive to conventional therapies.

The Efficacy of Preemptive Analgesia for Acute Postoperative Pain Management: A Meta-Analysis

Whether preemptive analgesic interventions are more effective than conventional regimens in managing acute postoperative pain remains controversial. We systematically searched for randomized controlled trials that specifically compared preoperative analgesic interventions with similar postoperative analgesic interventions via the same route. The retrieved reports were stratified according to five types of analgesic interventions: epidural analgesia, local anesthetic wound infiltration, systemic N-methyl-d-aspartic acid (NMDA) receptor antagonists, systemic nonsteroidal antiinflammatory drugs (NSAIDs), and systemic opioids. The primary outcome measures analyzed were the pain intensity scores, supplemental analgesic consumption, and time to first analgesic consumption. Sixty-six studies with data from 3261 patients were analyzed. Data were combined by using a fixed-effect model, and the effect size index (ES) used was the standardized mean difference. When the data from all three outcome measures were combined, the ES was most pronounced for preemptive administration of epidural analgesia (ES, 0.38; 95% confidence interval [CI], 0.28-0.47), local anesthetic wound infiltration (ES, 0.29; 95% CI, 0.17-0.40), and NSAID administration (ES, 0.39; 95% CI, 0.27-0.48). Whereas preemptive epidural analgesia resulted in consistent improvements in all three outcome variables, preemptive local anesthetic wound infiltration and NSAID administration improved analgesic consumption and time to first rescue analgesic request, but not postoperative pain scores. The least proof of efficacy was found in the case of systemic NMDA antagonist (ES, 0.09; 95% CI, -0.03 to 0.22) and opioid (ES, -0.10; 95% CI, -0.26 to 0.07) administration, and the results remain equivocal.

Intralesional Steroid Injection for Management of Acute Idiopathic Dacryoadenitis: A Preliminary Result

To evaluate the efficacy of intralesional injection of steroid as a new line of therapy in treatment of the acute form of an isolated idiopathic dacryoadenitis. Five patients with unilateral isolated acute idiopathic dacryoadenitis were included in the study. In 2 patients, the pathology was recurrent. Intralesional injection of 2 to 4 ml betamethasone suspension (1 ml contains 2 mg betamethasone sodium phosphate and 5 mg betamethasone dipropionate) was followed by cold compression for 6 hours. Systemic nonsteroidal anti-inflammatory drugs were given for 2 weeks after the injection. Dramatic response was achieved within 7 days after injection in all cases. No patient had recurrence during the follow-up period of 8 to 19 months. The excellent preliminary results make this new line of therapy highly promising. However, more study and long-term follow-up are recommended.

Medical treatment of osteoarthritis in the horse – A review

The medical treatment of osteoarthritis (OA) in the horse is one of the most utilized therapeutic regimens in the equine practice. It is important to understand the anatomy of synovial joints and the pathophysiology of the disease process to treat OA adequately. Once a thorough understanding of the disease process is comprehended the proper combination of systemic nonsteroidal anti-inflammatory drugs (NSAIDs), intraarticular steroids, viscosupplementation and chondroprotectants can be used to treat the disease and inhibit further progression of degenerative changes to the cartilage surface. The equine practitioner is faced with many choices for controlling inflammation in OA. This review presents the background and appropriate uses of various NSAIDs such as phenylbutazone, flunixin meglumine, ketoprofen, naproxen, and carprofen as well as their associated toxicities. Various steroid formulations exist for intraarticular (IA) administration and much has been learned in the past decade regarding correct dosage, frequency of administrations, indications and toxicity. This review presents IA steroids and their indications in addition to various chondroprotective drugs that also exist to control inflammation and provide viscosupplementation. Data are also given on disease modifying OA drugs such as glucosamine and chondroitin sulphate that have more recently become available to the equine practitioner.

Comparison of benzydamine hydrochloride and Salvia officinalis as an adjuvant local treatment to systemic nonsteroidal anti-inflammatory drug in controlling pain after tonsillectomy, adenoidectomy, or both: an open-label, single-blind, randomized clinical trial

BackgroundBenzydamine hydrochloride (BNZD) is a nonsteroidal anti-inflammatory drug (NSAID) used in an oral rinse formulation as an adjuvant to other NSAIDs in controlling postoperative pain after tonsillectomy, adenoidectomy, or both. Salvia officinalis (SO) is a topically applied herbal preparation frequently used for the same indication. Pain, bleeding, and infection are the most common postoperative complications of tonsillectomy. ObjectiveThe aim of this study was to compare the efficacy and tolerability of BNDZ with those of SO as adjuvant treatments in controlling postoperative pain. MethodsThis open-label, single-blind, randomized clinical trial was conducted at the Department of Otorhinolaryngology, Clinical Hospital Center “Dr. Dragiša Mišović—Dedinje” (Belgrade, Serbia and Montenegro). Pediatric and adult patients undergoing tonsillectomy, adenoidectomy, or both were enrolled. Patients were randomized to receive BNZD or SO, in addition to ibuprofen 20 mg/kg·d (children) or diclofenac 100 mg/d (adults). The primary end point was the proportion of patients with mild or no pain on postoperative days 1, 2, 4, and 7. Secondary end points were the incidences of infection, hemorrhage, and other adverse events. ResultsA total of 420 patients were enrolled (217 females, 203 males; 278 children, 142 adults; mean [SD] age, 6.2 [2.1] years [children] and 24.1 [9.8] years [adults] [range, 3–45 years]). One hundred thirty-eight children received BNZD; 140 received SO (both in addition to ibuprofen 20 mg/kg·d). Seventy-two adults received BNZD; 70 received SO (both in addition to diclofenac 100 mg/d). A significantly lower proportion of children treated with adjuvant BNZD experienced moderate or severe pain than those treated with SO at each time point (P ≤ 0.01 at days 1 and 4; P ≤ 0.001 at days 2 and 7). In children, the risk for postoperative infection was similar between BNZD and SO (absolute risk reduction [ARR], 6.9%; 95% CI, 6.4%–7.6%); however, the risk was reduced in adults (ARR, 19.0%; 95% CI, 16.5%–21.9%; P = 0.008). ConclusionsIn this clinical trial of children and adults who underwent tonsillectomy, adenoidectomy, or both, BNZD, as an adjuvant to an NSAID, was more effective than SO in controlling postoperative pain and infection. The pain-reducing effect of BNZD was of quick onset and persisted for 1 week after surgery. The safety profile of BNZD was comparable to that of SO, with the exception of postoperative infection in adults, for which BNZD was more efficacious. In particular, the use of BNZD was not associated with a high risk for early postoperative hemorrhage.

Isobolographic analysis of the antinociceptive interactions of clonidine with nonsteroidal anti-inflammatory drugs

The present study was undertaken to characterize the interactions between nonsteroidal anti-inflammatory drugs and the α 2-adrenoceptor agonist clonidine in an acute nociceptive test. The writhing test was selected as a model of acute visceral pain. Isobolograms were constructed to assess the interactions of clonidine and each nonsteroidal anti-inflammatory drugs, when coadministered intraperitoneally and intrathecally (i.t.). The simultaneous intraperitoneal administration of fixed ratios of ED 50 fractions of all nonsteroidal anti-inflammatory drugs (naproxen, piroxicam, paracetamol, dipyrone or metamizol and nimesulide) combined with clonidine resulted in synergistic interactions. The same combinations administered intrathecally were additive. The synergistic interactions between systemic nonsteroidal anti-inflammatory drugs and clonidine may involve supraspinal mechanisms.

Isobolographic analysis of the antinociceptive interactions of clonidine with nonsteroidal anti-inflammatory drugs

The present study was undertaken to characterize the interactions between nonsteroidal anti-inflammatory drugs and the α2-adrenoceptor agonist clonidine in an acute nociceptive test. The writhing test was selected as a model of acute visceral pain. Isobolograms were constructed to assess the interactions of clonidine and each nonsteroidal anti-inflammatory drugs, when coadministered intraperitoneally and intrathecally (i.t.). The simultaneous intraperitoneal administration of fixed ratios of ED50 fractions of all nonsteroidal anti-inflammatory drugs (naproxen, piroxicam, paracetamol, dipyrone or metamizol and nimesulide) combined with clonidine resulted in synergistic interactions. The same combinations administered intrathecally were additive. The synergistic interactions between systemic nonsteroidal anti-inflammatory drugs and clonidine may involve supraspinal mechanisms.

Association between concomitant use of several systemic NSAIDs and an excess risk of adverse drug reaction. A case/non-case study from the French Pharmacovigilance system database.

To examine whether the risk of some selected adverse effects increases with the number of systemic non-steroidal anti-inflammatory (NSAID) drugs. The French Pharmacovigilance database was examined for an association between drug reaction reports and the exposure to one and two or more NSAIDs using a case/non-case study design. In the analysis, 54,583 spontaneous reports of adverse drug reactions were included, consisting of 2270 reports of hepatic injury, 994 reports of acute renal failure, 194 reports of gastrointestinal bleeding and 525 reports of angioedema, among others. Use of NSAIDs significantly increased the risk of hepatic injury, gastrointestinal bleeding, acute renal failure and angioedema. The odds ratios tended to increase with the number of NSAIDs for hepatic injury, gastrointestinal bleeding and acute renal failure but not for angioedema. In comparison with reports that did not mention any use of NSAIDs, the odds ratios associated with the use of a single NSAID and two or more NSAIDs were respectively 1.2 (95%CI: 0.9-1.5) and 2.2 (95%CI: 1.3-3.8) for hepatic injury, 7.3 (95%CI: 4.9-10.9) and 10.7 (95%CI: 2.9-40.2) for gastrointestinal bleeding, 3.2 (95%CI: 2.5-4.1) and 4.8 (95%CI: 2.6-8.8) for acute renal failure. For angioedema, the odds ratios were roughly similar when a single NSAID (OR=2.7; 95% CI: 2.2-3.4) or two or more NSAIDs (OR=2.0; 95%CI: 0.7-6.0) were used. The risk of severe ADRs (hepatic injury and acute renal failure) was six- to sevenfold higher in reports mentioning concomitant use of two NSAIDs or more than in those that did not. This study shows that concomitant use of two or more NSAIDs was associated with an excess risk of adverse effects such as hepatic injury, acute renal failure and gastrointestinal bleeding. Although simultaneous use of several systemic NSAIDs has no pharmacological justification, this may raise a serious public health problem with the increasing use of over-the-counter non-steroidal anti-inflammatory agents.

Pharmacokinetic–pharmacodynamic modeling considering spinal and peripheral actions of nonsteroidal antiinflammatory drugs to optimize the treatment of inflammation-induced pain

It has been documented that nonsteroidal antiinflammatory drugs (NSAIDs) exhibit pharmacological actions at both the peripheral and central levels. However, the actual participation of the mechanisms of action elicited at different anatomical sites after systemic NSAID administration is not clear. To gain further knowledge on this issue, the aim of the present work is to study the pharmacodynamics and pharmacokinetics of diclofenac, a NSAID prototype, using an integrative approach. We have previously documented that local diclofenac administration at the site of injury induces antinociception in the formalin test, as well as in the pain-induced functional impairment model in the rat. This effect is reduced by nitric oxide (NO) and cyclic GMP synthesis inhibitors, as well as by potassium channel blockers [1,2]. We therefore assayed the effect of oral (systemic) diclofenac in the formalin test after pretreatment with either NG-nitro-L-arginine Methyl ester (L-NAME), a NO synthesis blocker, or glibenclamide, a potassium channel blocker, given by two routes of administration: locally at the site of injury and intrathecally. L-NAME and glibenclamide given by these two routes significantly reduced oral diclofenac antinociception. These results suggest that, after systemic administration, effective diclofenac concentrations are achieved at the site of injury as well as at the spinal cord, and that in these two sites of action there is a participation of the L-arginine–NO–cyclic GMP–potassium channel pathway. In a second series of experiments, diclofenac was administered locally at the site of injury (peripheral location), intrathecally, and simultaneously at the site of injury, intrathecally. Isobolographic analysis showed that there is an additive interaction between the effects at the peripheral and spinal levels. It is then likely that, after systemic administration, the observed antinociceptive effect is the result of the sum of peripheral and central mechanisms. Thus, effective diclofenac concentrations at central sites achieved after systemic administration probably are considerably lower that those required to observe an antinociceptive effect after direct injection, due to the interaction of mechanisms elicited at different anatomical locations. Therefore, from a pharmacokinetic point of view, the various central and peripheral sites of action can be considered as the affected compartment. In a third experimental series, the pharmacokinetics and antinociceptive effect of diclofenac was assayed in the pain-induced functional impairment model in the rat, which allows a simultaneous determination of antinociception and blood drug concentration [3]. It appeared that there was no direct relationship between diclofenac in blood and antinociception. Antinociception, however, was significantly related to affect compartment concentrations estimated by pharmacokinetic–pharmacodynamic modeling, consistently with the earlier described pharmacodynamic results. Computer simulations using the derived pharmacokinetic–pharmacodynamic model showed that an oral formulation of diclofenac yielding a very fast absorption, and hence a high blood concentration peak, can optimize drug transfer to the affected compartment, resulting in a fast-onset, long-lasting antinociceptive response. Our results show that the study of NSAID pharmacodynamics and pharmacokinetics using an integrative approach is useful for the characterization of the mechanisms of action involved after systemic drug administration, yielding information that allows the optimization of dosing regimens.