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Department of Anesthesiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, PO Box 67031, Cincinnati, OH 45267-0531, USA Drug therapy is the mainstay of management for acute, chronic, and cancer pain in all age groups, including neonates, infants, and children. Theanalgesics include opioids, nonopioid analgesics, and adjuvants or coanalge-sics. In this article we will overview various nonopioid analgesics includingsalicylates, acetaminophen, traditional nonselective nonsteroidal anti-inflam-matory drugs (NSAIDs), and cyclooxygenase-2 (COX-2) inhibitors. Unlesscontraindicated, any analgesic regimen should include a nonopioid drug,even when pain is severe enough to require the addition of an opioid .
Acetaminophen and NSAIDs are useful for acute and chronic pain resulting from a variety of disease processes including trauma, arthritis, sur-gery, and cancer NSAIDs are indicated for pain that involves inflam-mation as an underlying pathologic process because of their ability tosuppress production of inflammatory prostaglandins. NSAIDs are both an-algesic and anti-inflammatory, and may be useful for the treatment of painnot involving inflammation as well Nonopioid analgesics differ from opioid analgesics in certain important regards. These differences should be realized to provide the most effectivecare to acute pain patients and include the following: 1. There is a ceiling effect to the dose response curve of NSAIDs, therefore after achieving an analgesic ceiling, increasing the dose increases the sideeffects but additional analgesia does not result.
A version of this article originally appeared in the 91:1 issue of Medical Clinics of North This work was partly supported by Grant No. NS45594 from the National Institutes of * Corresponding author.
E-mail address: (M.A. Munir).
1932-2275/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.anclin.2007.07.007 2. NSAIDs don’t produce physical or psychological dependence and there- fore sudden interruption in treatment doesn’t cause drug withdrawals.
Nonopioid analgesics are underrated for the treatment of chronic pain and unnecessarily omitted for patients with chronic pain and patients unableto take oral medications. Parenteral, topical, and rectal dosage forms areavailable for some NSAIDs that are often underused.
All NSAIDs, including the subclass of selective COX-2 inhibitors, are anti-inflammatory, analgesic, and antipyretic. NSAIDs are a chemically het-erogeneous group of compounds, often chemically unrelated, which never-theless share certain therapeutic actions and adverse effects. Aspirin alsoinhibits the COX enzymes but in a manner molecularly distinct from thecompetitive, reversible, active site inhibitors and is often distinguishedfrom the NSAIDs. Similarly, acetaminophen, which is antipyretic and anal-gesic but largely devoid of anti-inflammatory activity, also is conventionallysegregated from the group despite its sharing NSAID activity with otheractions relevant to its clinical action in vivo.
All NSAIDs inhibit the enzyme cyclooxygenase (COX), thereby inhibit- ing prostaglandin synthesis In addition to peripheral effects, NSAIDsexert a central action at the brain or spinal cord level that could be impor-tant for their analgesic effects . More than 30 years ago, multiple isoformsof COX were hypothesized. In 1990s, the second form (COX-2) was iso-lated. COX-1, the originally identified isoform, is found in platelets, the gas-trointestinal (GI) tract, kidneys, and most other human tissues. COX-2 isfound predominantly in the kidneys and central nervous system (CNS),and is induced in peripheral tissues by noxious stimuli that cause inflamma-tion and pain. The inhibition of COX-1 is associated with the well-knowngastrointestinal bleeding and renal side effects that can occur with NSAIDuse. The anti-inflammatory therapeutic effects of NSAIDs are largely dueto COX-2 and not the COX-1 inhibition. Until recently all availableNSAIDs nonselectively inhibited the COX-1 and COX-2 isoforms. Drugsthat do so are termed nonselective or traditional NSAIDs. Most NSAIDsinhibit both COX-1 and COX-2 with little selectivity, although some con-ventionally thought of as nonselective NSAIDs, diclofenac, etodolac, me-loxicam, and nimesulide, exhibit selectivity for COX-2 in vitro. Indeed,meloxicam acts as a preferential inhibitor of COX-2 at relatively low doses(eg, 7.5 mg daily).
COX-2 selective NSAIDs that first became available in the late 1990s provide all of the beneficial effects of nonselective NSAIDs but fewer ad-verse effects on bleeding and the GI tract. COX-2 selective NSAIDs are no safer to the kidneys than nonselective NSAIDs. As of mid-2003, threemembers of the initial class of COX-2 inhibitors, the coxibs, were approvedfor use in the United States and Europe. Both rofecoxib and valdecoxibhave now been withdrawn from the market in view of their potential cardio-vascular adverse event profile. None of the coxibs have established greaterclinical efficacy over NSAIDs.
Aspirin covalently modifies COX-1 and COX-2, irreversibly inhibiting cyclooxygenase activity. This is an important distinction from all theNSAIDs because the duration of aspirin’s effects is related to the turnoverrate of cyclooxygenases in different target tissues. The duration of effectof nonaspirin NSAIDs, which competitively inhibit the active sites of theCOX enzymes, relates more directly to the time course of drug disposition.
The importance of enzyme turnover in relief from aspirin action is most no-table in platelets, which, being anucleate, have a markedly limited capacityfor protein synthesis. Thus, the consequences of inhibition of platelet COX-1 last for the lifetime of the platelet. Inhibition of platelet COX-1-dependentthromboxane (TX)A2 formation therefore is cumulative with repeated dosesof aspirin (at least as low as 30 mg/day) and takes roughly 8 to 12 days, theplatelet turnover time, to recover once therapy has been stopped.
Acetaminophen is a nonsalicylate that may produce similar analgesic and antipyretic potency as aspirin, but has no antiplatelet effects, lacks clinicallyuseful peripheral anti-inflammatory effects, and does not damage the gastricmucosa. A proposed mechanism of acetaminophen is inhibition of a thirdisoform of cyclooxygenase (COX-3) that was identified recently COX-3 is only found within the CNS, which would account for the analgesicand antipyretic, but not anti-inflammatory, action of acetaminophen. How-ever, the significance of COX-3 remains uncertain, and the mechanism(s) ofaction of acetaminophen has yet to be defined.
All NSAIDs, including selective COX-2 inhibitors, are antipyretic, anal- gesic, and anti-inflammatory, with the exception of acetaminophen, whichis antipyretic and analgesic but is largely devoid of anti-inflammatoryactivity.
When employed as analgesics, these drugs usually are effective only against pain of low-to-moderate intensity, such as dental pain. Althoughtheir maximal efficacy is generally much less than the opioids, NSAIDslack the unwanted adverse effects of opiates in the CNS, including respira-tory depression and the development of physical dependence. NSAIDs donot change the perception of sensory modalities other than pain. Chronicpostoperative pain or pain arising from inflammation (eg, somatic pain) iscontrolled particularly well by NSAIDs.
NSAIDs reduce fever in most situations, but not the circadian variation in temperature or the rise in response to exercise or increased ambient tem-perature. It is important to select an NSAID with rapid onset for the man-agement of fever associated with minor illness in adults. Due to theassociation with Reye’s syndrome, aspirin and other salicylates are contra-indicated in children and young adults less than 12 years old with feverassociated with viral illness.
NSAIDs have their key application as anti-inflammatory agents in the treatment of musculoskeletal disorders, such as rheumatoid arthritis andosteoarthritis. In general, NSAIDs provide only symptomatic relief frompain and inflammation associated with the disease, and do not arrest theprogression of pathological injury to tissue.
In addition to analgesic, antipyretic and anti-inflammatory effects, NSAIDs are also used for closure of patent ductus arteriosus in neonates,to treat severe episodes of vasodilatation and hypotension in systemic mas-tocytosis, treatment of biochemical derangement of Bartter’s syndrome, che-moprevention of certain cancers such as colon cancer, and prevention offlushing associated with use of niacin.
Adverse effects of aspirin and NSAIDs therapy are listed in and are considerably common in elderly patients and caution is warranted inchoosing an NSAID for pain management in the elderly.
The most common symptoms associated with these drugs are gastrointes- tinal, including anorexia, nausea, dyspepsia, abdominal pain, and diarrhea.
These symptoms may be related to the induction of gastric or intestinalulcers, which is estimated to occur in 15% to 30% of regular users. Therisk is further increased in those with Helicobacter pylori infection, heavyalcohol consumption, or other risk factors for mucosal injury, includingthe concurrent use of glucocorticoids. All of the selective COX-2 inhibitorshave been shown to be less prone than equally efficacious doses of tradi-tional NSAIDs to induce endoscopically visualized gastric ulcers .
Nausea, anorexia, abdominal pain, ulcers, anemia, gastrointestinal Hypertension, decreased effectiveness of anti-hypertensive medications, myocardial infarction, stroke, and thromboembolicevents (last three with selective COX-2 inhibitors); inhibitplatelet activation, propensity for bruising and hemorrhage Salt and water retention, edema, deterioration of kidney function, decreased effectiveness of diuretic medication, decreased urateexcretion, hyperkalemia, analgesic nephropathy Headache, dizziness, vertigo, confusion, depression, lowering of seizure threshold, hyperventilation (salicylates) Vasomotor rhinitis, asthma, urticaria, flushing, hypotension, shock Gastric damage by NSAIDs can be brought about by at least two distinct mechanisms. Inhibition of COX-1 in gastric epithelial cells depresses muco-sal cytoprotective prostaglandins, especially PGI2 and PGE2. These eicosa-noids inhibit acid secretion by the stomach, enhance mucosal blood flow,and promote the secretion of cytoprotective mucus in the intestine. Anothermechanism by which NSAIDs or aspirin may cause ulceration is by localirritation from contact of orally administered drug with the gastric mucosa.
Co-administration of the PGE1 analog, misoprostol, or proton pump inhibitors (PPIs) in conjunction with NSAIDs can be beneficial in the pre-vention of duodenal and gastric ulceration .
Selective inhibitors of COX-2 depress PGI2 formation by endothelial cells without concomitant inhibition of platelet thromboxane. Experiments inmice suggest that PGI2 restrains the cardiovascular effects of TXA2, afford-ing a mechanism by which selective inhibitors might increase the risk ofthrombosis This mechanism should pertain to individuals otherwiseat risk of thrombosis, such as those with rheumatoid arthritis, as the relativerisk of myocardial infarction is increased in these patients compared withpatients with osteoarthritis or no arthritis. The incidence of myocardial in-farction and stroke has diverged in such at-risk patients when COX-2 inhib-itors are compared with traditional NSAIDs . Placebo-controlled trialshave now revealed that there may be an increased incidence of myocardialinfarction and stroke in patients treated with rofecoxib valdecoxiband celecoxib , suggesting potential for a mechanism-based cardio-vascular hazard for the class, ie, selective COX-2 inhibitors (although notequal for all agents) Blood pressure, renal, and renovascular adverse events Traditional NSAIDs and COX-2 inhibitors have been associated with renal and renovascular adverse events NSAIDs have little effect on renal function or blood pressure in normal human subjects. However, inpatients with congestive heart failure, hepatic cirrhosis, chronic kidney dis-ease, hypovolemia, and other states of activation of the sympathoadrenal orrenin-angiotensin systems, prostaglandin formation and effects in renalblood flow/renal function becomes significant in both model systems andin humans Analgesic nephropathy is a condition of slowly progressive renal failure, decreased concentrating capacity of the renal tubule, and sterile pyuria. Riskfactors are the chronic use of high doses of combinations of NSAIDs andfrequent urinary tract infections. If recognized early, discontinuation ofNSAIDs permits recovery of renal function.
Certain individuals display hypersensitivity to aspirin and NSAIDs, as manifested by symptoms that range from vasomotor rhinitis with profusewatery secretions, angioedema, generalized urticaria, and bronchial asthmato laryngeal edema, bronchoconstriction, flushing, hypotension, and shock.
Aspirin intolerance is a contraindication to therapy with any other NSAIDbecause cross-sensitivity can provoke a life-threatening reaction reminiscentof anaphylactic shock. Despite the resemblance to anaphylaxis, this reactiondoes not appear to be immunological in nature.
Although less common in children, this syndrome may occur in 10% to 25% of patients with asthma, nasal polyps, or chronic urticaria, and in1% of apparently healthy individuals.
Most of the NSAIDs are rapidly and completely absorbed from the gastro- intestinal tract, with peak concentrations occurring within 1 to 4 hours. Aspi-rin begins to acetylate platelets within minutes of reaching the presystemiccirculation. The presence of food tends to delay absorption without affectingpeak concentration. Most NSAIDs are extensively protein-bound (95% to99%) and undergo hepatic metabolism and renal excretion. In general,NSAIDs are not recommended in the setting of advanced hepatic or renal dis-ease due to their adverse pharmacodynamic effects ().
Selected nonopioid analgesics: clinical pearls Salicylates include acetylated aspirin (acetylsalicylic acid) and the modi- fied salicylate diflunisal, which is a diflurophenyl derivative of salicylic acid. Aspirin was invented in 1897; it is one of the oldest nonopioid oralanalgesics. Gastric disturbances and bleeding are common adverse effectswith therapeutic doses of aspirin. Because of the possible association withReye’s syndrome, aspirin should not be used for children younger thanthe age of 12 with viral illness, particularly influenza.
Salicylate salts such as choline magnesium trisalicylate and salsalate are effective analgesics and produce fewer GI side effects than aspirin Unlike aspirin and other nonselective NSAIDs, therapeutic doses do notgreatly affect bleeding time or platelet aggregation tests in patients withoutprior clotting abnormalities Acetaminophen is a nonsalicylate that may produce similar analgesic and antipyretic potency as aspirin, but has no antiplatelet effects, lacks clinicallyuseful peripheral anti-inflammatory effects, and does not damage the gastricmucosa. Although acetaminophen is well tolerated at recommended dosesof up to 4000 mg/day, acute overdoses can cause potentially fatal hepaticnecrosis. Patients with chronic alcoholism and liver disease and patientswho are fasting can develop severe hepatotoxicity, even at usual therapeuticdoses . The Food and Drug Administration (FDA) now requires alcoholwarnings for acetaminophen as well as all other nonprescription analgesicsAcetaminophen overdoses are common because acetaminophen is a fre-quent ingredient in many nonprescription and prescription analgesic formu-lations. Acetaminophen has a reduced risk of ulcers and ulcer complicationswhen compared with nonselective NSAIDs and is rarely associated withrenal toxicity. Acetaminophen is an underrecognized cause of over-anticoa-gulation with warfarin in the outpatient setting Ketorolac is a pyrrolacetic acid, which is available in injection form. An initial dose of 30 mg followed by 10 to 15 mg intravenously (IV) every6 hours is equianalgesic to 6 to 12 mg of IV morphine. Ketorolac mayprecipitate renal failure especially in elderly and hypovolemic patients. Itis therefore recommended to limit use of Ketorolac to 5 days only. Also,clinicians should try to use the lowest dose felt to be needed.
Diclofenac potassium has been shown to be superior in efficacy and an- algesic duration to aspirin and also inhibits selectively more COX-2 thenCOX-1.
Table 2Nonopioid analgesics: comparative pharmacology children and adults.
Sustained-release preparationavailable, O2g/day may increase INR in patientsreceiving Warfarin.
do not use in children under12 with possible viral illness. Rectalsuppository available for children and adults. Sustained-releasepreparation available.
aspirin 650 mg,with slower onsetand longerduration; an initialdose of 1000 mgsignificantlyshortens time toonset and longerduration; 550 mgsuperior to aspirin Ketoprofen OTC Actron, Orudis-Kþ 12.5–25 Table 3Selected nonopioid analgesics: analgesic dosage and comparative efficacy to standards faiure indehydratedpatients, averagedose in elderly10–15 mg IM/IVQ6 h Meloxicam has long half-life and roughly 10-fold COX-2 selectivity on average in ex vivo assays There is significantly less gastric injurycompared with piroxicam (20 mg/d) in subjects treated with 7.5 mg/d ofmeloxicam, but the advantage is lost with 15 mg/d Nabumetone is a prodrug; it is absorbed rapidly and is converted in the liver to one or more active metabolites, principally 6-methoxy-2-naphtylace-tic acid, a potent nonselective inhibitor of COX The incidence of gas-trointestinal ulceration appears to be lower than with other NSAIDs (perhaps because of its being a prodrug or the fact that there is essentiallyno enterohepatic circulation).
Ibuprofen and naproxen are the most commonly used NSAIDs in the United States. These are available without a prescription in the UnitedStates. The relative risk of myocardial infarction appears unaltered byibuprofen, but it is reduced by around 10% with naproxen, comparedwith a reduction of 20% to 25% by aspirin. Ibuprofen and naproxen arebetter tolerated than aspirin and indomethacin and have been used inpatients with a history of gastrointestinal intolerance to other NSAIDs.
Indomethacin is a more potent inhibitor of the cyclooxygenase than is as- pirin, but patient intolerance generally limits its use to short-term dosing.
A very high percentage (35% to 50%) of patients receiving usual therapeuticdoses of indomethacin experience untoward symptoms. CNS side effects, in-deed the most common side effects, include severe frontal headache, dizzi-ness, vertigo, and light-headedness; mental confusion and seizure mayalso occur, severe depression, psychosis, hallucinations, and suicide havealso been reported. Caution must be exercised when starting indomethacinin elderly patients, or patients with history of epilepsy, psychiatric disorders,or Parkinson’s disease, because they are greater risk of CNS adverse effects.
Three members of the initial class of COX-2 inhibitors, the coxibs, were approved for use in the United States. Both rofecoxib and valdecoxib havenow been withdrawn from the market in view of their adverse event profile.
Valdecoxib has been associated with a threefold increase in cardiovascularrisk in two studies of patients undergoing cardiovascular bypass graft surgery. Based on interim analysis of data from the Adenomatous Polyp Prevention on Vioxx (APPROVe) study, which showed a significant (two-fold) increase in the incidence of serious thromboembolic events in subjectsreceiving 25 mg of rofecoxib relative to placebo rofecoxib was with-drawn from the market worldwide . The FDA advisory panel agreedthat rofecoxib increased the risk of myocardial infarction and stroke andthat the evidence accumulated was more substantial than for valdecoxiband appeared more convincing than for celecoxib. Effects attributed to inhi-bition of prostaglandin production in the kidney (hypertension and edema)may occur with nonselective COX inhibitors and also with celecoxib. Studiesin mice and some epidemiological evidence suggest that the likelihood of hy-pertension on NSAIDs reflects the degree of inhibition of COX-2 and the se-lectivity with which it is attained. Thus, the risk of thrombosis, hypertension,and accelerated atherogenesis may be mechanistically integrated. The coxibsshould be avoided in patients prone to cardiovascular or cerebrovascular dis-ease. None of the coxibs has established clinical efficacy over NSAIDs. Whileselective COX-2 inhibitors do not interact to prevent the antiplatelet effect ofaspirin, it now is thought that they may lose some of their gastrointestinaladvantage over NSAIDs alone when used in conjunction with aspirin.
NSAIDs are useful analgesics for many pain states, especially those involving inflammation. Their use is frequently overlooked in patientswith postoperative and chronic pain. Unless there is a contraindication,the use of an NSAID should be routinely considered to manage acutepain, chronic cancer, and noncancer pain.
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