Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0344307 (analgesia)
28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay of therapy for the management of acute pain and rheumatoid arthritis, toxicity associated with chronic administration limits their benefit-to-risk relationship in many patients. A series of studies is reviewed that assesses the relationship between cytokines released at the site of tissue injury and NSAID analgesia, and the in vivo selectivity of a selective cyclooxygenase (COX)-2 inhibitor (celecoxib) in comparison to a dual COX-1/COX-2 inhibitor (ketorolac). Three replicate studies in the oral surgery model of acute pain used submucosal microdialysis sample collection for the measurement of prostaglandin E2 (PGE2; a product of both COX-1 and COX-2) and thromboxane B2 (as a biomarker for COX-1 activity) with parallel assessments of pain. The time course of PGE2 production was consistent with early release due to COX-1 activity followed by increased production 2-3 hours after surgery, consistent with COX-2 expression. Ketorolac 30 mg at pain onset suppressed both pain and peripheral PGE2 levels. Ketorolac 1 mg either at the site of injury or intramuscularly also produced analgesia but without any effect on peripheral PGE2 levels. Celecoxib selectively suppressed PGE2 but not TxB2 at time points consistent with COX-2 activity, while producing analgesia. These studies demonstrate the ability to assess the time course and selective effects of COX-2 inhibitors in vivo and suggest that suppression of COX-2 mediated PGE2 is temporally related to NSAID analgesia.
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PMID:Analgesia and COX-2 inhibition. 1169 55

Postsurgical pain is often undertreated. Opioids are frequently used in perioperative analgesia, but concern about side effects can result in administration of an inadequate dose for pain relief. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used increasingly for postoperative analgesia. The use of balanced analgesia-a combination of opioids, NSAIDs, and local anesthesia utilizing agents from other classes (eg, ketamine, clonidine)-improves the efficacy of pain relief and decreases risk of side effects. While lacking some of the troublesome side effects of opioids, nonselective NSAIDs may cause bleeding as a result of their inhibitory effects on COX-1. For this reason, COX-2-selective inhibitors (coxibs) are attractive opioid-sparing analgesic options in the perioperative setting. Factors in addition to side effects such as time to onset of action, duration of action, maximum pain relief, use of rescue medication, and other factors relevant to a given pain model are important in determining overall analgesic efficacy. Clinical studies show that COX-2-selective inhibitors are effective for the treatment of preoperative and postoperative pain and reduce postsurgical requirements for opioids. This evidence supports a role for COX-2-derived prostaglandins as key mediators of nociceptive pain and peripheral sensitization (hyperalgesia). Pain management in the perioperative setting and the role of COX-2-selective inhibitors in acute and postoperative pain are reviewed here.
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PMID:Cyclooxygenase-2-selective inhibitors in the management of acute and perioperative pain. 1208 97

The role of the coxibs in the management of osteoarthritis and rheumatoid arthritis has been widely discussed, but there are other potential applications for the coxibs that have received less attention. Here we consider the use of the coxibs in acute pain syndromes such as primary dysmenorrhea and the pain associated with dental extraction, as well as considering their application in chronic low back pain and cancer pain. Another area where the coxibs may prove particularly beneficial is in the management of post-surgical pain. Traditional post-surgical analgesia has involved the use of non-selective NSAIDs and opioids, but these agents can be associated with side effects such as post-operative bleeding, gastrointestinal problems, nausea, and constipation. Because the coxibs do not inhibit COX-1 dependent platelet aggregation like traditional NSAIDs, the risk of post-surgical bleeding is reduced. The careful application of coxibs as part of a multi-modal approach to pain management in the perioperative period can reduce the requirement for opioid medications and thus reduce the risk of post-operative complications such as ileus. In the future, coxibs are likely to play an important role in multi-modal perioperative analgesic regimens with the aim of reducing post-operative periods of convalescence.
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PMID:Strategies in pain management: new and potential indications for COX-2 specific inhibitors. 1260 54

Non-steroidal anti-inflammatory drugs (NSAIDs) suppress the activity of both isoforms of cyclo-oxygenase (COX). Inhibition of COX-1, the constitutive isoform, is primarily responsible for the adverse gastrointestinal effects of the NSAIDs whereas inhibition of COX-2, the inducible isoform, accounts for their therapeutic effects. COX-2 inhibitors such as celecoxib and rofecoxib appear to be as effective as non-selective NSAIDs in the treatment of chronic inflammatory disease but their analgesic efficacy and their safety at the higher doses required for analgesia are less certain. There is consistent evidence that COX-1 plays a major role in the early pain response following injury and that analgesia is increased when both COX-1 and COX-2 are inhibited simultaneously. Early postoperative nociception may cause hyperalgesia at a later time by a process of central plasticity. In an experimental model of pain, ibuprofen promptly suppresses prostaglandin E2 concentrations whereas celecoxib has no discernible effect until 90-120 minutes postoperatively, when COX-2 activity is induced. Both drugs significantly reduce pain compared with placebo but celecoxib appears to have a slower onset of action. The analgesic effect of ibuprofen is well characterised for acute pain and short-term treatment is well tolerated.
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PMID:Relative efficacy of selective COX-2 inhibitors compared with over-the-counter ibuprofen. 1272 42

COX-2 selective inhibitors provide analgesia and blunt inflammation while also sparing the gastrointestinal tract from classic NSAID toxicity. Therapeutic effects are thought to result from inhibition of the inflammatory COX-2 isoform. Organ sparing is considered the result of preservation of homeostatic COX-1 enzyme function. Similar roles of the COX isoforms in the kidney would reduce NSAID-associated nephrotoxicity. However, human kidney tissue expresses COX-2 enzyme, suggesting a role for this isoform in maintenance of physiological renal processes. Available clinical data on the renal effects of COX-2 selective inhibitors in humans also demonstrate nephrotoxic potential.
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PMID:COX-2 selective inhibitors: analysis of the renal effects. 1290 60

This article reviews the gastrointestinal manifestations of traditional nonsteroidal anti-inflammatory drugs (NSAIDs) and the improved gastrointestinal safety profile of cyclooxygenase selective (COX)-2 inhibitors. By inhibiting the COX enzyme, NSAIDs provide effective analgesia and suppress inflammation in a variety of conditions. Most NSAIDs (nonselective or traditional) not only inhibit prostaglandins at sites of inflammation but also inhibit prostaglandins that have important normal functions in other parts of the body. This may be harmful when normal gastrointestinal mucosal function is impaired and mucosal damage occurs. Although such damage is often trivial and usually not symptomatic, gastrointestinal ulceration may produce pain and, more ominously, lead to bleeding, perforation, or obstruction. A new approach to the gastrointestinal complications of NSAIDs became feasible with the discovery of two isoforms of COX, COX-1 and COX-2, with COX-1 expressed mainly in the gastrointestinal tract. The development of NSAIDs that preferentially inhibit COX-2 offers the promise of relieving pain and inflammation without the side effects attendant to COX-1 blockade. In prospective studies evaluating gastrointestinal ulceration with COX-2-specific NSAIDs, rates of endoscopic ulceration have been equivalent to those with placebo and much lower than those with nonselective NSAIDs. In the recently released studies of gastrointestinal outcomes (perforated, painful, or bleeding ulcers), incidence of clinically relevant ulceration with COX-2 NSAIDs is much lower than that of traditional NSAIDs.
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PMID:The role of cyclooxygenase selective inhibitors in the gastrointestinal tract. 1460 52

Several lines of evidence have accumulated that release of excitatory amino acids, nitric oxide and prostaglandin E2 (PGE2) play a critical role in the development of peripheral tactile and thermal hypersensitivity in chronic inflammatory pain models. Synthesis of PGE2 is controlled by cyclooxygenase (COX), either the COX-1 or COX-2 isoform. COX-2 plays a central role in the inflammatory reactions. The relationship between central sensitization of a complete Freund's adjuvant (CFA) induced inflammation and expressions of COX-2 were assessed in a rat model of CFA injection induced inflammation. Moreover, the time course of analgesia and spinal COX-2 expression following intrathecal (IT) injection with a nonspecific COX inhibitor (ketorolac) and COX-2 inhibitor (celecoxib) were determined using Western blot and immunohistochemistry. COX-2 protein was slightly increased in the lumbosacral spinal cord at 24 h following subcutaneous injection of CFA in the plantar surface of the left hindpaw (p > 0.05). COX-1 was not detected in normal and CFA injection rats. Surprisingly, IT ketorolac or celecoxib significantly increased spinal COX-2 levels at 1 h post-IT injection (p < 0.05) both in inflamed and non-inflamed rats. Then, spinal COX-2 levels declined at 3 and 6 h post-IT injection. These results provide strong in vivo evidence that COX-2 activity but not level may play a central role in the Freund's adjuvant-induced inflammation. However, spinal COX-2 level was upregulated following IT ketorolac and celecoxib injection. These data implies that suppression of PGE2 activity may induce the expression of spinal COX-2 in Freund's adjuvant-induced pain model. Our study concludes that IT administration of COX-2 inhibitor or nonspecific COX inhibitor is associated with significant short-term increase in spinal COX-2 expression.
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PMID:Nonsteroidal anti-inflammatory drugs increase expression of inducible COX-2 isoform of cyclooxygenase in spinal cord of rats with adjuvant induced inflammation. 1519 28

Non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are the most commonly used analgesics in the management of acute and chronic pain. Combined use of NSAIDs and opioids has been indicated for achieving better analgesia with reduced side effects. The present study was aimed at evaluating the combination of different NSAIDs, which inhibit cyclooxygenase (COX) enzymes and tramadol against acetic acid-induced writhing in mice. The expected beneficial effect of combination regimen was analyzed by isobolographic analysis. The oral and intrathecally administered tramadol, a mu-opioid and naproxen, a nonselective COX inhibitor produced dose-dependent antinociception, however, rofecoxib, a selective COX-2 inhibitor lacked analgesic efficacy in writhing test. Isobolographic analysis showed synergistic or supra-additive interactions for the combinations of naproxen and tramadol after oral and intrathecal administration. However, similar interaction was not observed when tramadol was combined with rofecoxib. Pretreatment with naloxone partially reversed the antinociceptive effect of tramadol per se and its combination with naproxen without modifying the per se effect of NSAID. The results demonstrated marked synergistic interaction between naproxen and tramadol and such interaction involved opioid as well as non-opioid mechanisms of tramadol and inhibition of COX-1 but not COX-2 by naproxen.
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PMID:Isobolographic analysis of interaction between cyclooxygenase inhibitors and tramadol in acetic acid-induced writhing in mice. 1527 89

To compare the efficacy and adverse effects of celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, with naproxen, a non-steroidal anti-inflammatory drug, and placebo in the treatment of painful temporomandibular joints (TMJs). In this randomized, double-blind, placebo-controlled trial, 68 subjects with painful TMJs secondary to disc-displacement with reduction, received celecoxib 100 mg twice a day; naproxen, 500 mg twice a day; or placebo for 6 weeks. Subjects were evaluated with standard measures of efficacy: pain intensity measured by visual analogue scale, maximal comfortable mandibular opening, and quality of life (SF-36), at baseline (1 week after discontinuing previous analgesic therapy) and again after 6 weeks of drug treatment. Naproxen significantly reduced the symptoms of painful temporomandibular joint disc-displacement (TMJ DD) with reduction as determined by most efficacy measures. Significant improvement in pain intensity occurred within 3 weeks of treatment, and was sustained throughout the 6-week study. Clinically significant improvement in mandibular range of motion was observed for naproxen compared to celecoxib and placebo. Celecoxib showed slightly better pain reduction than placebo, but was not significantly effective for temporomandibular disorder pain. Celecoxib and naproxen were well tolerated, with similar number of reported adverse effects. Dual COX-1 and COX-2 inhibition with naproxen was demonstrated to be effective for the treatment of painful TMJs, as seen by significant improvement in clinical signs and symptoms of TMJ DD with reduction compared to celecoxib and placebo. Inhibition of both COX isozymes is needed to achieve effective analgesia for this type of musculoskeletal pain.
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PMID:Treatment of painful temporomandibular joints with a cyclooxygenase-2 inhibitor: a randomized placebo-controlled comparison of celecoxib to naproxen. 1532 4

Paracetamol produces analgesia in the mouse writhing test through a central action which is paralleled by a reduction in brain PGE(2) concentrations. In contrast, diclofenac has a peripheral analgesic action in this test. Paracetamol-induced hypothermia is also accompanied by a reduction in brain PGE(2) concentrations in C57/Bl6 mice. This hypothermic effect of paracetamol was reduced in COX-1 but not in COX-2 gene-deleted mice. These results support the view that analgesia and hypothermia due to paracetamol are mediated by inhibition of a third COX isoenzyme (designated COX-3). In cultured mouse macrophages, COX-2 is induced by treatment with LPS or with high concentrations of diclofenac. Diclofenac-induced COX-2 is inhibited with low concentrations of paracetamol, whereas LPS-induced COX-2 is insensitive to paracetamol inhibition. The mechanisms of induction and possibly the functions of these two COX-2 enzymes are also different.
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PMID:COX-3 and the mechanism of action of paracetamol/acetaminophen. 1562 90


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