r i0003-3006-57-2-67 th 2010

Pain Management: Part 1: Managing Acute andPostoperative Dental Pain

Daniel E. Becker, DDSAssociate Director of Education, General Dental Practice Residency, Miami Valley Hospital, Dayton, Ohio

Safe and effective management of acute dental pain can be accomplished withnonopioid and opioid analgesics. To formulate regimens properly, it is essentialto appreciate basic pharmacological principles and appropriate dosage strategiesfor each of the available analgesic classes. This article will review the basic phar-macology of analgesic drug classes, including their relative efficacy for dentalpain, and will suggest appropriate regimens based on pain intensity. Managementof chronic pain will be addressed in the second part of this series.

Key Words: Pain management; Analgesics; Postoperative pain; Dental pain.

Pain is a complex experience consisting of a specif-ic sensation and the reactions evoked by that

sensation. Conventional analgesics either interrupt as-cending nociceptive impulses or depress their inter-pretation within the central nervous system (CNS). Avariety of so-called ‘‘analgesic adjuncts’’ have provenefficacy for managing chronic pain but will not be ad-dressed in this article. They include various antide-pressants and anticonvulsants that either enhance de-scending inhibitory pathways or modulate excitatoryneural traffic that amplifies pain interpretation. Theseagents have marginal benefit in the management ofacute pain, and they are not regarded as ‘‘analgesics’’in the conventional sense. Management of chronicpain will be the topic of a subsequent continuing edu-cation article in this journal.

Analgesics are classified as opioids and nonopioids,but dated terms like narcotic and non-narcotic are usedinterchangeably. Formerly, it was believed that opioidsacted only within the brain and spinal cord, but theaction of nonopioids was confined to the periphery( ie, the site of injury). This explanation is no longertenable, however; both are known to act centrally andperipherally.1,2 In fact, the feature that best distin-guishes these analgesic classes is their mechanism ofaction. Opioids activate specific receptors in a manneridentical to opiates, such as morphine. Nonopioids in-terrupt prostaglandin synthesis, thereby resemblingaspirin in action.

NONOPIOID ANALGESICS

The nonopioid analgesics include acetaminophen(APAP) and the nonsteroidal anti- inflammatory drugs(NSAIDs). The analgesic efficacy of these agents istypically underestimated. This is unfortunate becausethey generally are equivalent or superior to opioidsfor managing musculoskeletal pain, and they producea lower incidence of side effects, including the poten-tial for abuse. Dental pain is included in the musculo-skeletal category, and for decades studies have repeat-edly found that NSAIDs are generally superior toopioids at conventional dosages.3^5 This principle willbe revisited during the final portion of this article, butat this time it is important to review essential pharma-cological features of the nonopioids.

NSAIDS

Actions and Effects. Ibuprofen is conventionallyregarded as the prototype of this large group of syn-thetic compounds known for their analgesic, antipy-retic, and anti-inflammatory efficacy. These therapeu-tic effects and their most notable side effects can beexplained almost entirely by their ability to inhibit thecyclooxygenase (COX) required for synthesis of vari-ous families of prostanoids.6 This action is illustratedand further explained in Figure 1.

Precautions and Side Effects. Clinical use ofNSAIDs is predicated on their ability to reduce theAddress correspondence to Dr Becker at [email protected].

CONTINUING EDUCATION

Anesth Prog 57:67^79 2010

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synthesis of prostaglandins implicated in pain, fever,and inflammation. However, these agents are hardlyselective in this goal and also inhibit the productionof additional prostanoids that perform useful physio-logical functions. This accounts for potential side ef-fects and contraindications.

The most frequent side effects of NSAIDs are relat-ed to their gastrointestinal (GI ) toxicity. Prostaglandinsstimulate the production of a mucous lining that pro-tects the stomach and small intestine. The erosive andulcerative side effects common to NSAIDs are attribut-ed to their inhibiting the synthesis of these particularprostaglandins. This action not only occurs locally asorally administered drug lies in contact with gastricmucosa but also follows absorption and systemic dis-tribution to the GI mucosa. Parenteral administrationdoes not preclude a risk for GI erosions and ulcera-tions. It is important to distinguish dyspepsia (upset

stomach) from GI toxicity, which reflects actual muco-sal damage. The incidence of dyspepsia attributed toNSAIDs does not correlate with mucosal injury. Al-though less likely to produce gastric upset, bufferedaspirin carries similar risk for mucosal damage as reg-ular aspirin.7

The ability of NSAIDs to inhibit cyclooxygenases inplatelets reduces the synthesis of thromboxane A2,which normally contributes to platelet aggregation.This accounts for the so-called antiplatelet effect ofthese agents and is a consideration following surgicalprocedures. However, aspirin is the only NSAID thathas proven effective in preventing thrombotic eventssuch as acute coronary syndromes or stroke. This isso because the antiplatelet action of aspirin is irrevers-ible, lasting the life span of the platelet (10^14 days).Other NSAIDs bind weakly and reversibly to plateletcyclooxygenases, which results in loss of their mild an-tiplatelet influence after drug elimination.8 Althoughnonaspirin NSAIDs all prolong bleeding times to somedegree, this does not correlate with significant clinicalbleeding following minor surgical procedures. Howev-er, nonaspirin NSAIDs generally are withheld beforemajor thoracic, abdominal, or orthopedic procedures.If aspirin is medically necessary for patients, such asthose with endovascular stents who are at risk for life-threatening clot formation, it should not be withdrawn.

NSAIDs should be avoided in patients who sufferbleeding disorders and in those taking anticoagulantssuch as warfarin and powerful antiplatelet drugs suchas clopidogrel (Plavix). Patients receiving monothera-py with low-dose aspirin are not as great a concernbut should be considered. The issue with NSAIDs isdue not so much to their antiplatelet action but toNSAID-induced injury of GI mucosa that may bleedfar more profusely in this patient population. Aspirinprovides a maximum antiplatelet influence at a verylow dose?80 mg daily?and frequently is prescribedin combination with warfarin without consequence be-cause such doses have a lower potential to producegastric insult. In contrast, other NSAIDs increase therisk for GI bleeding twofold to threefold in patientsmedicated with clopidogrel (Plavix) and fourfold tofivefold in those taking warfarin.9 All concerns relatedto NSAID-induced mucosal injury are particularly im-portant for older patients, especially those taking anti-thrombotic medications, including low-dose aspirin.

Prostaglandins play an essential role in renal perfu-sion, and diminished levels of these are believed to ac-count for reported cases of nephrotoxicity after long-term NSAID use. In the healthy patient, nephrotoxici-ty attributed to NSAIDs requires high doses for extend-ed periods (eg, a year or longer).10 However, a patientwith compromised renal function relies more heavily

Figure1. Synthesis and function of prostanoids. Perturbationof cell membranes can be mediated by diverse endogenousand exogenous stimuli. This triggers activity of phospholipaseA2, releasing arachidonic acid from the phospholipids makingup the membrane. Two families of cyclooxygenases (COX-1and COX-2) convert this fatty acid to a variety of so-calledprostanoids that are unique to the particular cell or tissue andinclude prostaglandins, thromboxanes, and prostacyclin. Eachof these prostanoids has specific physiological functions, someof which are listed in the table within this figure. Most nonste-roidal anti-inflammatory drugs (NSAIDs) are nonselective andinhibit both COX-1 and COX-2 families. Celecoxib (Celebrex)is representative of agents that selectively inhibit COX-2; it re-duces pain and inflammation with little or no influence on gas-tric mucosa. However, this selective inhibition may promotegreater synthesis of prostanoids derived from COX-1, includingthromboxane-mediated effects leading to possible thromboticevents (eg, myocardial infarction, stroke). Arachidonic acid isalso a substrate for lipoxygenase that catalyzes the formationof leukotrienes known for their anaphylactoid effects, includ-ing bronchospasm and upper airway edema. As NSAIDs inhib-it the activity of cyclooxygenases, a greater portion of arachido-nic acid can be converted to leukotrienes by lipoxygenase.Thismay not be tolerated by patients with atopy because they expe-rience pseudoallergic syndromes.

68 Pain Management Anesth Prog 57:67^79 2010

on prostaglandins for adequate function, and acute re-nal failure can occur within 24 hours of NSAID ad-ministration. NSAIDs must never be prescribed for pa-tients who have known or questionable renal function.The ability of NSAIDs to alter renal function has re-sulted in concern regarding their long-term use in pa-tients with hypertension and heart failure.11,12 Alteredrenal function accompanies the pathogenesis of thesedisorders, and any further renal decline may exacer-bate their condition. This concern has not been foundrelevant with short-term NSAID use (eg, 5^7 days).

By inhibiting cyclooxygenase, NSAIDs shunt thearachidonic pathway toward leukotriene synthesis(Figure 1). Leukotrienes mediate a variety of tissue re-sponses, including those associated with broncho-spasm and anaphylaxis.13 Certain individuals may beextremely sensitive to even subtle elevation in leukotri-ene synthesis, which may result in signs and symp-toms of allergic response. It is recommended that theterm aspirin or NSAID intolerance should be used todistinguish this reaction from true hypersensitivity re-sponses mediated by immunoglobulin ( Ig)E. Acet-aminophen is the conventional alternative for patientsreporting an allergic reaction to any NSAID, unless thepatient can identify a particular product that he or shehas tolerated without problem in the past.

In summary, NSAIDs are contraindicated for pa-tients who have a current history of nephropathy, ero-sive or ulcerative conditions of the GI mucosa, antico-agulant therapy, hemorrhagic disorders, or intoleranceor allergy to any NSAID. They also should be avoidedduring pregnancy because prostaglandins maintainpatency of the ductus arteriosus during fetal develop-ment. Although this concern is most relevant duringthe third trimester, NSAIDs generally should be avoid-ed throughout pregnancy. In all cases where NSAIDsare contraindicated, acetaminophen is the convention-al nonopioid alternative.

Drug Interactions. After prolonged use, NSAIDsmay interfere with the effectiveness of most classes ofantihypertensive medications; calcium channel block-ers are a notable exception. The precise mechanismfor this interaction is unknown but is believed to be re-lated to diminished vasodilator actions attributed to re-nal prostaglandins. In the rare event that postoperativeanalgesics must be continued for longer than 5 days,hypertensive patients should return to the office forblood pressure assessment. If pressure has elevatedmore than 10% above baseline, it would be wise to re-place the NSAID with acetaminophen.

Ibuprofen has been found to competitively inhibitthe antiplatelet influence of aspirin.14,15 It is the onlyNSAID implicated in this interaction, but diclofenac

and the selective COX-2 inhibitors are the only agentsthat have been confirmed not to interact.15 An empiricsolution to this problem is predicated on the fact thatthe antiplatelet influence of low-dose aspirin occurswhen it contacts platelets within the hepatic portalsystem after absorption.16 Simply advise the patientto take daily aspirin upon arising and to delay the firstdose of ibuprofen for 1^2 hours. By this time, the anti-platelet influence of aspirin will have been estab-lished.17 This entire issue may eventually prove mootbecause its actual clinical relevance has been chal-lenged impressively. Cryer et al18 found that throm-boxane inhibition by aspirin was reduced by only 1%after 10 days of concurrent ibuprofen use, and Patel19

found no increase in incidence of myocardial infarc-tion over a 10-year period in patients with coronarydisease taking ibuprofen with low-dose aspirin.

Recently concern has been introduced regarding in-creased risk for GI mucosal injury in patients takingselective serotonin reuptake inhibitor (SSRI ) antide-pressants and NSAIDs. This risk is most significant af-ter prolonged use of NSAIDs, but caution may be ad-vised during short-term use for patients who have aprevious history of mucosal injury.20,21 Finally, serumlevels of lithium and methotrexate are elevated duringconcurrent consumption of NSAIDs. To prevent toxici-ty, NSAIDs should be avoided in patients medicatedwith these agents, particularly those taking high-doseregimens.

Therapeutic Uses. In general, no convincing evi-dence indicates that a particular NSAID is more effec-tive or safer than other members of this drug class.22

Selective COX-2 inhibitors such as celecoxib produceless GI toxicity after short-term use, but this advantagewanes as consumption continues. Chou et al23 pub-lished an impressive evidence-based analysis ofNSAIDs for the Oregon Evidence-Based Practice Cen-ter that supports this generalization. Nevertheless, pa-tients vary considerably in their clinical response andGI tolerance to a particular agent. Given its unsur-passed efficacy and low side effect profile and cost,ibuprofen is generally a sound initial choice. Regard-less of the agent selected, however, an optimal dosingschedule should be maintained for 2^3 days before analternative agent is prescribed. It is reasonable to se-lect an alternative NSAID for initial therapy for pa-tients who appear to question the effectiveness of aproduct that is available over-the-counter. Regardlessof the NSAID selected, clinical considerations areidentical.

All NSAIDs have greater potency as analgesics andantipyretics than as anti- inflammatory agents; higherdoses are required to achieve anti- inflammatory than

Anesth Prog 57:67^79 2010 Becker 69

analgesic effects. This may reflect a different site of ac-tion for analgesic versus anti-inflammatory actions (eg,CNS vs periphery), but this has not been confirmed.For example, a single 200- to 400-mg dose of ibupro-fen may reduce pain and fever, but daily consumptionof 1600^2400 mg may be required to suppress in-flammation adequately. Nevertheless, if we consideronly their analgesic properties, the dose-responsecurves for nonopioids (NSAIDs and acetaminophen)exhibit a ceiling effect; additional increases in doseprovide no further benefit (Figure 2). The ceiling re-sponses for aspirin and acetaminophen occur at1000 mg, and the analgesic ceiling for ibuprofen isachieved at 400 mg.24,25 As the dose of an NSAID isincreased, anti- inflammatory effects improve untilmaximum safe doses preclude any further increase.Most NSAIDs have ranges in their recommended dos-ages, but precise doses for their analgesic ceilings havenot been determined. It is reasonable to presume thatthe lower doses, like those for ibuprofen, confer anal-gesia, and the higher range adds anti- inflammatory ef-ficacy. With this in mind, lower dosages should be se-lected for noninflammatory pain, and higher rangesare reserved for those situations in which inflamma-tion and swelling are significant cofactors. Of coursemost cases of dental pain have at least some degreeof contributing inflammation.

Preoperative use of NSAIDs has been demonstratedrepeatedly to decrease the intensity of postoperativepain and swelling.26,27 This is not surprising becauseNSAIDs inhibit the ‘‘formation’’ of prostaglandins;however, they do not destroy or inhibit those alreadyformed. More recent understanding of pain mecha-nisms reveals that benefits of this practice are evidentso long as prostaglandin synthesis is inhibited beforelocal anesthesia wanes. Otherwise, prostaglandinstrigger nociceptive impulses that travel to the brainand ‘‘wind up’’ the brain’s interpretation of pain inten-sity. When an extensive surgical procedure is planned,optimal serum levels of an NSAID should be estab-lished preoperatively or before patient discharge,while tissues remain anesthetized. This ‘‘preemptiveanalgesia’’ may be useful for endodontic and extensiverestorative procedures as well.

COX-2 Inhibitors

As was stated previously, clinical trials comparing theCOX-2 inhibitors (eg, celecoxib [Celebrex]) versusconventional NSAIDs have not identified substantivedifferences in their anti-inflammatory or analgesicefficacy.22,23 Clinical studies have found celecoxib lesseffective as an analgesic when comparedwith ibuprofenand naproxen.22 COX-2 agents offer the advantages ofno increase in bleeding time and minimal GI injury de-spite a comparable incidence of dyspepsia. However,controversy persists regarding their risk for thromboticevents in patients with atherosclerotic disease. As is il-lustrated in Figure 1, selective COX-2 inhibition tiltsprostanoid production toward platelet aggregation. In-deed several publications have suggested an increase inacute coronary events in patients with preexisting CADwho have beenmedicatedwithCOX-2 inhibitors. In fair-ness, this correlation has been found with most of thenonselective NSAIDs as well. Naproxen is the onlyNSAID that appears to lack this correlation. Neverthe-less, it is probably wise to avoid selective COX-2 inhibi-tors in patients with significant atherosclerotic disease.

Acetaminophen

Actions and Effects. Compared with NSAIDs, themechanism of action of acetaminophen is less clearbut is believed to involve an inhibition of prostaglandinsynthesis within the CNS.28 It has little influence onperipheral prostaglandin synthesis, especially withininflamed tissues.7 This is a likely explanation for itslacking anti-inflammatory efficacy and sharing none ofthe peripheral side effects attributed to NSAIDs. How-ever, it is an ideal analgesic for patients who present

Figure 2. Analgesic efficacy. This graph illustrates a typicaldose-response curve for orally administered (PO) analgesics.The dose-response curve for opioids such as morphine dem-onstrates unlimited efficacy in which greater doses providegreater analgesia. At equipotent doses, all opioids demon-strate a similar dose response. In contrast, nonopioids dem-onstrate a ‘‘ceiling’’ effect that generally is adequate for reliefof mild to moderate pain (pain relief rating of 4^5 in thisscale). For ibuprofen, doses greater than 400 mg do not pro-vide further analgesia. For aspirin (ASA) and acetaminophen(APAP ), this cei ling effect is achieved at 1000 mg and issomewhat lower than that provided by nonsteroidal anti-in-flammatory drugs (NSAIDs).


any contraindications to NSAIDs. As an analgesic andantipyretic, acetaminophen is equal in potency and ef-ficacy to aspirin29 and presumably may be somewhatinferior to ibuprofen and other NSAIDs as well.

Hepatotoxicity is the most significant adverse effectof acetaminophen. It is attributed to a toxic metabolitethat cannot be adequately conjugated when dosagesexceed 200^250 mg/kg in a 24-hour period.30 Thedose may be less for patients who are poorly nour-ished, who have liver dysfunction, or who are beingtreated with other hepatotoxic medications. For exam-ple, in contrast to the 4 g/d allowed healthy patients,those suspected of chronic alcoholism should limittheir maximum daily intake to 2 grams.

Summary of Nonopioids

Most cases of postoperative dental pain include an in-flammatory component. For this reason, NSAIDs arethemost rational first- line agents?often superior to con-ventional dosages of opioids. Should a patient present acontraindication to NSAIDs, acetaminophen is the onlyalternative. Nonopioids exhibit a ceiling to their analge-sic response, but optimal doses should be established be-fore it is assumed that the NSAID has failed. Further-more, the combination of an NSAID with acetamino-phen provides greater analgesic efficacy than doeseither agent alone,31 and this strategy may obviate theneed for opioids. Data relevant for prescribing the mostcommonly used nonopioids are summarized inTable 1.

OPIOID ANALGESICS

Actions and Effects

Opioids produce most of their therapeutic and adverseeffects by acting as agonists at opioid receptors. Scien-

tists have not entirely established the physiological sig-nificance of these receptors, but they are activated by avariety of endogenous ligands, collectively called en-dorphins. Opioid receptors germane to clinical prac-tice are located within the CNS, but peripheral recep-tors have also been characterized.2 Unlike nonopioids,which exhibit a ceiling analgesic response, opioidsdemonstrate greater efficacy as the dose is increased(Figure 2). Unfortunately, when pain is very severe,side effects may preclude the use of doses adequateto produce complete analgesia.

Only 2 of the 5 opioid receptors isolated thus farhave relevance for clinical practice. The effects mediat-ed by mu and kappa receptors are summarized in Ta-ble 2. Morphine produces its effects by acting as anagonist at both mu and kappa receptors, while nalox-one acts as an antagonist.32

The mu receptor is responsible for mediating anal-gesia and 2 of the most undesirable side effects attrib-uted to opioids: respiratory depression and depen-dence. Mu effects have unlimited intensity, increasingproportionately with dose. Therefore, a striking con-trast exists between the unlimited analgesic efficacyof mu agonists and the limited or ceiling effect de-scribed for the nonopioids.

Like mu receptors, the kappa receptor mediates anal-gesia and respiratory depression, but efficacy at this re-ceptor is limited.28 These 2 receptors provide compara-ble efficacy after doses equivalent to10mgmorphine IM,but the response from kappa receptors does not increasewith greater doses.When high doses of opioids are used,selective kappa agonists are viewed as safer, but less anal-gesic, comparedwith traditional mu agonists.

Knowledge regarding the kappa receptor spawnedthe synthesis of several novel compounds that act as

Table1. Nonopioid Analgesics*�

Product Dosage

Ibuprofen (Motrin) 400^800 mg tid/qidFlurbiprofen (Ansaid) 50^100 mg tidKetoprofen (Orudis) 25^75 mg tid/qidNaproxen sodium (Anaprox) 550 mg bidDiflunisal (Dolobid) 1000 mg STAT, then

500 mg q8^12hDiclofenac potassium (Cataflam) 50^100 mg STAT, then

50 mg tidCelecoxib (Celebrex) 200 mg qd/bidAcetaminophen (Tylenol) 500^1000 mg tid/qid

* Acetaminophen and those nonsteroidal anti-inflammato-ry drugs (NSAIDs) most often used as nonopioids for manage-ment of postoperative pain and inflammation.

� Adapted from Abramowicz.22

Table 2. Action of Opioids*�

Receptors mu (m) kappa (k)

Effects in Common Analgesia AnalgesiaRespiratory

depressionRespiratory

depressionSedation Sedation

Other Effects Euphoria,dependence

Dysphoria/Psychomimetic

Constipation

Morphine +++ +Nalbuphine 2 2 ++Naloxone 2 2 2 2 2

* The most significant opioid effects are mediated throughmu and kappa receptors. Effects generated by mu receptorsproduce an unlimited dose response, but those mediated bykappa receptors have a ceiling to their effects. Opioids act asagonists or antagonists at these receptors.

� + indicates relative affinity as an agonist; 2, relative affinityas an antagonist.


agonists at kappa receptors but act as antagonists atmu receptors. Nalbuphine (Nubain) is an example (Ta-ble 2). These so-called agonist-antagonists are notconstipating, produce less respiratory depression athigher doses, and have less potential for abuse, buttheir limited analgesic efficacy diminishes their valuewhen postoperative pain is severe. Higher doses areno more effective than conventional doses. Becausethey act as antagonists at mu receptors, agonist-antag-onists may precipitate a withdrawal syndrome in pa-tients dependent on opioids. They are good choicesfor patients who have a previous history of drug seek-ing, but they must never be given to a patient who iscurrently dependent. Dysphoric reactions producedby these agents were formerly believed to be mediatedby sigma receptors. However, this receptor is no longerconsidered an opioid receptor, and dysphoria is cred-ited as a kappa receptor phenomenon.32

Dependence,Tolerance, and Addiction

Fear of dependence and addiction often results in un-derprescribing of opioids for severe acute, chronic, andeven terminal pain. This unfortunate practice is due topoor understanding of dependence, tolerance, and ad-diction.

Dependence occurs when the body accommodatesto the influences of a drug and, upon sudden discon-tinuation, the patient experiences a withdrawal syn-drome that generally includes reactions opposite thoseproduced by the particular drug. For example, opioidsproduce sedation, lethargy, and constipation. A pa-tient who is experiencing opioid withdrawal becomesexcited and experiences abdominal cramping and di-arrhea. If opioid doses are tapered gradually, a depen-dent patient will not experience withdrawal. Patientswho consume opioids regularly for longer than a weekcan develop some degree of dependence. This may re-quire gradual tapering of the dosage to avoid with-drawal symptoms, which can be confused as an exac-erbation of the painful condition. However, this doesnot mean that the patient has become addicted.22,32

After repeated administration, patients develop tol-erance to opioids. This is to say that greater doses arerequired to produce the same intensity of effect for-merly provided by a smaller dose. Tolerance to analge-sia, sedation, and respiratory depression occurs simul-taneously, but it is curious that no tolerance occurs tothe constipating or miotic effects of opioids. This isproblematic for the patient with chronic or terminalpain. Although staggering doses may be required tocontrol pain and generally will not jeopardize the pa-tient’s respiratory status, constipation can become ex-

tremely severe, and night vision becomes impaired.Similar doses, if administered to patients who havenot developed tolerance (ie, opioid-naive patients),would certainly be lethal. These identical issues mustbe considered when one is managing dental pain forpatients who are chronic opioid abusers.

Addiction is distinct from dependence or tolerance.It is a compulsive behavior centered on seeking a drugand its effects for nonmedical reasons?generally forpleasure. It is a complex psychiatric phenomenon,but it should not be attributed to the drug. Addictivebehavior can be reinforced by a particular drug, but itis not a pharmacodynamic property. A patient wholacks addictive behavior can be easily weaned fromopioid dosages without fear of precipitating addictivebehavior. In contrast, an addicted patient will seek thedrug despite having no remaining evidence of depen-dence or medical need for the drug. Opioids producedependence, even after as little as 5^7 days of therapy,and this may require institution of a tapering dosageschedule. However, opioids do not produce addiction;they should not be withheld on the presumption thatthe patient will become ‘‘addicted.’’32 Obviously,opioids must be prescribed cautiously for patientswho demonstrate addictive personality.

Therapeutic Considerations

Despite recent scientific literature to the contrary,many believe that certain opioids are more effectiveor more dangerous than others. This is simply not thecase; equipotent doses are equianalgesic. When ad-ministered subcutaneously or intramuscularly, 10 mgmorphine, 75 mg meperidine, and 120 mg codeineall produce equivalent analgesia and side effects.32

However, as will be explained below, issues regardingmetabolism and activity of metabolites have been not-ed with some of these agents.

After oral administration, gastric degradation andfirst-pass metabolism require that larger doses be usedif one is to achieve analgesia comparable with that fol-lowing parenteral administration. For example, theoral-to-parenteral dose ratio for morphine is generallyregarded as 3 : 1. If one is to duplicate the analgesicefficacy of a standard 10-mg IM injection of morphine,a 30-mg oral dose must be prescribed. Equianalgesicdoses of commonly used opioids are found in Table 3.

Effective pain control is predicated on selecting an op-timal dose, rather than selecting a particular agent. How-ever, individual differences in patient response and phar-macokinetic differences (eg, duration, elimination half-life) may favor the use of a particular agent. Morphine7.5^10 mg IM is a relatively safe and common standard


for inpatient analgesia. By using this as a reference point,one can select equianalgesic doses of other agents forboth parenteral and oral regimens.The opioid doses list-ed in Table 3 are equianalgesic and present equivalentrisks for serious side effects.

Considerations for Specific Opioids

Codeine has very little affinity for the mu receptor andmay be considered a prodrug because10% of the parentdrug is converted to morphine by cytochrome P450CYP2D6.The morphine metabolite accounts for its en-tire analgesic effect32 (Figure 3). Altered activity ofCYP2D6 offers one explanation for varied responses tocodeine and to its derivatives that will be addressed be-low. Roughly 5^10% of the Caucasian population me-tabolizes codeine poorly because these individuals haveinherited 2 nonfunctional alleles for synthesis ofCYP2D6. For them, analgesia resulting from codeinewill be less than expected with the general population. Ithas also been estimated that 1^7% of Caucasians haveelevated CYP2D6 activity, and this may account forheightened sensitivity.33 Likewise, a variety of drugs thata patient may be taking concurrently have the ability toinhibit or induce CYP2D6 activity. For example, theSSRI antidepressants are CYP2D6 inhibitors, makingcodeine less effective. This is established for fluoxetine(Prozac) and paroxetine (Paxil ) but appears less likelywith other agents of this class.34 In contrast, dexametha-

sone is a CYP2D6 inducer and will enhance the portionof codeine demethylated tomorphine.

Hydrocodone andOxycodone.Hydrocodone andoxycodone are more attractive analgesics than co-deine. They also are methylated, but these parentdrugs appear to have better affinity for opioid recep-tors than codeine. Hydrocodone is demethylated tohydromorphone in quantities sufficient to credit boththe parent drug and this active metabolite with its an-algesic influence. For this reason, hydrocodone sharesthe same considerations regarding demethylation ad-dressed previously for codeine.33 In contrast, the anal-gesic effect of oxycodone is almost entirely attributedto the parent drug because only scant amounts are de-methylated to oxymorphone.33 This makes it the bet-ter choice for patients taking medications known to in-hibit CYP2D6. Their potency allows for lower doses ofthese agents and reduces the incidence of nauseacompared with codeine.

Unfortunately, equianalgesic doses for these codeinederivatives were poorly understood initially, whichspawned release of combination products that contain ir-rational dosage formulations. Equipotent doses listed intextbooks vary somewhat, but those provided inTable 3are well accepted and indicate that 200 mg codeine,30 mg hydrocodone, and 20 mg oxycodone are equipo-tent oral doses, and these are equianalgesic to the con-ventional opioid standard of morphine 10 mg IM or

Table 3. Opioid Analgesics*�`

Product Duration, h§ T1/2 beta (hr) Equianalgesic Doses, IM/POI

Hydromorphone 4^5 2^3 1.5/7.5 mgMorphine 3^7 1.5^2 10/30 mgIMethadone" 4^6 15^30 10/20 mgMeperidine 2^4 3^4 75^100/300 mg#Codeine 4^6 3 120/180^200 mg**Hydrocodone 4^8 3.3^4.5 ND/30 mgOxycodone 4^6 ND NA/20 mg��Propoxyphene 4^6 6^12 ND/200 mg``

* Pharmacokinetic data and equipotent doses of commonly used opioids are summarized in this table. Although10mgmorphineor 75mgmeperidine administered IM is a standard reference dose formoderate to severe postoperative pain, lower equivalent dosescan be used if combined with a nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen (APAP).

� NA indicates not available for IM use in the United States; ND, no data available.` Adapted from Facts and Comparisons 2009. (Olin BR, Hebel SK, Dombek CE, editors. Drug Facts and Comparisons. 2009

edition. St Louis: Facts and Comparisons, Inc 2009).§ Based on IV data. After oral use, duration may be longer.I Based on short-term use. Long-term use (eg, .2 days) may require reduction because of altered kinetics and reduction in the

oral-to-parenteral ratio." Duration and half- life increase with repeated doses because of drug accumulation. Do not exceed drug manufacturers’ recom-

mendations for dosage intervals.# Accumulation of toxic metabolite (normeperidine) precludes long-term use (.2 days).** Oral doses generally are limited to 90 mg to avoid excessive nausea and constipation from the prodrug.�� Derived from sources other than texts cited for other data. Most tables in traditional texts list 30 mg oxycodone as equipotent.

Empiric data and numerous journal articles suggest that this is excessive, and that 20 mg is more appropriate.`` 130 mg for HCl salt and 200 mg for Napsylate salt.These doses are the maximum recommended but may not be equipotent

with other opioids in this table.


30 mg PO. Codeine doses have been well studied, andfrom this table we find that the oral dose for codeine is ap-proximately 20 times the IMdoseofmorphine (200mgvs10 mg). Clinical studies that have attempted to addressequianalgesic doses of codeine derivatives are sparse,but they support this same ratio. Beaver et al35 found thatoxycodone10 mgwas comparable with codeine100 mg,and this would extrapolate to oxycodone 20 mg and co-deine 200 mg. Studies by Hopkinson36 and by Beaver37

have shown that hydrocodone10 mg was approximatelyequipotent to codeine 60 mg, and this would extrapolateto 33mghydrocodone and 200mg codeine.

It is not uncommon for patients to report previousepisodes of nausea as an ‘‘allergic reaction.’’ However,IgE antibodies have been detected that react with sev-eral opioids, including codeine,38 and nearly allopioids are capable of triggering degranulation of mastcells leading to the direct release of histamine.39 Untilissues regarding cross-reactivity among opioids are re-solved, a prudent approach would be to select alterna-tives that are molecularly dissimilar. For example,

when a patient reports clinical signs that are allergicin nature, one should select an agent that is not de-rived from morphine or codeine (eg, propoxyphene,pentazocine).40

Meperidine.Meperidine 75^100 mg is equianalge-sic to morphine 10 mg after IM administration. A sig-nificant portion of an IM dose of meperidine is con-verted to normeperidine, a metabolite that has no an-algesic properties but is a noted cardiovascular andCNS stimulant. Furthermore, this metabolite has a15- to 20-hour elimination half- life, compared with3 hours for the parent drug.32 For hospitalized pa-tients, meperidine is used for only a day or 2; other-wise, normeperidine will accumulate. In fact, manyhospitals have deleted it from their formularies. Thisissue becomes even more problematic after oral ad-ministration in outpatients. Oral bioavailability for me-peridine is approximately 25%, which requires a 300-mg dose to be equianalgesic to its IM dose of 75 mg.This introduces an even greater risk for accumulationof normeperidine. Poor oral absorption and accumula-tion of normeperidine make meperidine a very poorchoice as an oral analgesic.

Propoxyphene. Propoxyphene is available only fororal administration. The equianalgesic dose comparedwith morphine has not been established, but its poten-cy is low. By convention, 100 mg is considered equi-potent to oral codeine 60 mg. It is similar to meperi-dine in that it is converted to norpropoxyphene, astimulant that has an elimination half- life of30 hours.32 Its use should be limited to short-termmanagement of mild to moderate pain.

Pentazocine. Pentazocine is the only oral agonist-antagonist analgesic available in the United States. Itproduces its analgesic effect by acting as an agonist atkappa receptors but is an antagonist at mu receptors.Therefore it reverses all effects of traditional mu ago-nist opioids if taken concurrently. Unlike mu agonists,which provide unlimited analgesic efficacy, kappa ag-onists exhibit a ceiling to their analgesic effect, and nobenefit is derived by increasing doses beyond 50 mg.Pentazocine is available in the United States for oraluse compounded with naloxone to prevent parenteralinjection abuse issues. If injected, naloxone will blockall effects of pentazocine, rendering it useless. Whentaken by mouth, however, naloxone has no oral bio-availability and will not hinder pentazocine actions.Additionally, pentazocine is available compoundedwith APAP. It should not be used in the presence ofother opioids.When other opioids are present, pentaz-ocine will serve as an opioid antagonist, thus reducing

Figure 3. Molecular structures of morphine, codeine, andderivatives. The top row illustrates molecular structures formorphine and its two derivatives, hydromorphone and oxy-morphone. The subtle changes indicated by the asterisks en-hance affinity for the opioid receptors, which accounts forgreater potency. The bottom row illustrates codeine and itsderivatives, which differ from their morphine-derived coun-terparts only in a methyl substitution (circled). Approximate-ly 60% of an oral dose of codeine-related products is ab-sorbed and may be subjected to varying degrees of demethyl-ation by CYP2D6 to its active metabolite. Framed moleculesare those credited with the analgesic effect provided by vari-ous codeine-related products. Codeine has little affinity foropioid receptors. Roughly 10% of an absorbed dose is de-methylated to morphine, which is credited with its analgesiceffect. Hydrocodone and oxycodone have good receptor af-finity and provide an analgesic effect. The analgesic effect ofhydrocodone is credited to both the parent drug and its activemetabolite, hydromorphone, but analgesia provided by oxy-codone is almost entirely the result of the parent drug. Verylittle is demethylated to oxymorphone.


the patient’s analgesia. Additionally, it should not beprescribed for patients who are opioid dependent andat risk for withdrawal. It is an attractive choice for pa-tients who have a previous history of opioid abuse be-cause it does not provide euphoric effects mediated byconventional mu agonists. Because it is not a mu re-ceptor agonist, constipation is unlikely.

Tramadol. Tramadol is a centrally acting analgesicwith binary action. It is not classified as a controlledsubstance in the United States. The parent drug inhib-its the reuptake of norepinephrine and serotonin. Thisresembles the action of tricyclic antidepressants andpotentiates descending neural pathways that inhibitincoming nociceptive impulses. This action has provenefficacy in the management of chronic pain. However,any benefit for tramadol in acute postoperative painmanagement is not as well defined. The principal me-tabolite of tramadol, O-desmethyltramadol (M1), dem-onstrates agonist action on mu receptors, providinganalgesic efficacy approximating that of codeine60 mg. Formation of this metabolite is provided byCYP2D6 enzymes and introduces the identical riskfor drug interactions described earlier for codeine. Tra-madol is not recommended for patients with a tenden-cy toward opioid abuse or dependence.41 It is availablein combination with acetaminophen but is no more ef-fective than codeine-acetaminophen combinations.42

SELECTING ANALGESIC REGIMENS

Mild to moderate pain generally can be managed byusing optimal doses of nonopioids: ibuprofen 400^800 mg, acetaminophen 1000 mg, or a combinationof the two. Although it is unwise to combine NSAIDs,the addition of acetaminophen to an NSAID is reason-able because they have different sites for their analge-sic action.31,43,44 Regardless of pain severity, oneshould seek to optimize ‘‘around-the-clock’’ dosages ofthese agents and then, if necessary, add an opioid tothe regimen as needed for breakthrough pain. Thispractice generally will reduce the amount of opioid re-quired, sometimes to only a fraction of the maximumdoses listed in Table 3. It is irrational to prescribe opi-oid combinations routinely as ‘‘first- line’’ analgesics.

To further focus on the importance of nonopioid an-algesics, refer to the graph provided as Figure 4.Thesedata were derived from a clinical study funded by adrug company to promote a combination product con-taining ibuprofen and oxycodone.5 It is significant thatthe analgesia provided by single-entity agents recon-firms clinical studies published repeatedly over thepast 3 decades. NSAIDs are more effective for muscu-

loskeletal pain than are conventional doses of opioids.In fact, oxycodone 5 mg (the dose combined withAPAP in the most commonly prescribed Percocet tab-let ) is no more effective than placebo. Notice, however,that a small increment of opioid (oxycodone 5 mg)added to ibuprofen improves pain relief. This illus-trates the fact that opioids are synergistic, and analge-sia can be improved by titrating additional opioid in-crements to an optimally dosed nonopioid.

It is not surprising that such a large number of com-mercially compounded analgesics containing bothnonopioid and opioid ingredients have been pro-duced. The opioid contained in most of these productsis either hydrocodone or oxycodone. Some of thesecombinations appear to have been formulated with lit-tle consideration given to equianalgesic dosage strate-gies. Additionally, several products contain large quan-tities of acetaminophen that preclude the use of multi-ple tablets to achieve an adequate amount of opioidfor patients who experience severe pain. When pre-scribing combination products, the clinician must payparticular attention to the amount of acetaminophenused separately or compounded so that the maximumdaily dose of 4 grams is not exceeded. In many cases,it is better to write separate prescriptions for the opioidand the nonopioid at dosages that more precisely ad-dress the analgesic needs of the patient. Suggestedregimens are presented in Table 4.

The dentist must be cautious when prescribing forpatients managed over the long term with opioids bytheir physician. Ideally, these patients have contractedwith their physician to decline opioid prescriptionsfrom other health care providers.45 Regardless of theirarrangements, the dentist should avoid increasing thecurrent opioid dose or prescribing additional opioidsfor postoperative pain control. The patient’s daily non-opioid regimen should be optimized, and, if opioids

Figure 4. NSAID versus opioid analgesia. The following da-ta were derived from patients who underwent third molar im-paction surgery. See text for explanation. ( Ibu 400 5 ibupro-fen 400 mg; Oxy 5 5 oxycodone 5 mg)


are required, the physician should be asked to tempo-rarily increase the dosage. Pain experienced after den-tal surgery is additive to the patient’s normal chronicintensity of pain, and opioid tolerance may require atemporary increase in opioid dosage.

SUMMARY

Careful selection of an effective analgesic regimenshould be based on the type and amount of pain thepatient is expected to experience. This strategy canprevent the stress and anxiety associated with break-through pain.46^48 When analgesics fail, it is not un-usual for patients to make desperate attempts to seekrelief. The clinician should develop several safe and ef-fective analgesic regimens based on estimates of antic-ipated pain intensity. Following are key features for theproper management of acute postoperative pain:

1. Patients benefit from receiving optimal NSAID dos-es given at regular, ‘‘clock-based’’ time intervals.These agents are effective and relatively safe and re-

duce the need for opioids. In situations where paincan be anticipated, the analgesia may be optimizedby commencing administration before local anes-thesia wanes ( ie,‘‘preemptive analgesia’’).

2. Although NSAIDs achieve an analgesic ceiling attheir lower dose ranges, it is proper to prescribehigher doses for most cases of dental pain to derivebenefit from their anti-inflammatory properties.

3. The site of action of acetaminophen differs fromthat of NSAIDs. Therefore, the analgesic effect ofacetaminophen is considered synergistic whencombined with NSAIDs.

4. If the dose of an NSAID, acetaminophen, or theircombination has been optimized but pain persists,an opioid should be added. A commercially avail-able combination product containing opioid andacetaminophenmay be an option and is easy to pre-scribe. However, when prescribing these combina-tion products, the practitioner must be cautious notto exceed 4 grams of acetaminophen per day be-cause of concerns about hepatic injury.

5. Because opioids have no ceiling dose, opioid dos-ing is better accomplished by prescribing it sepa-rately in some situations.This allows opioid to be ti-trated to the analgesic dose required and decreasesconcern for acetaminophen toxicity.

6. Avoid prescribing any opioid product for patientsalready receiving opioids for chronic pain disordersand for those under treatment for opioid abuse. It isappropriate to request an increase in dosage fromthe prescribing physician if necessary.

REFERENCES

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Table 4. Stepped Approach for Managing PostoperativePain*�`

Suggested Regimens

Step1 Ibuprofen 400^800 mg tid/qid or equivalentNSAID

and/orAcetaminophen (APAP) 500^1000 mg qid

Step 2 Add any of the following to Step1regimen:Oxycodone 5^10 mg or Morphine15 mg1or 2tabs q4h PRN

orPentazocine/NX 50 mg orTramadol 50 mg1tabq4h PRN

orUse combinations, provided noAPAP included in

Step1HC/APAP 5^10/5001or 2 tabs q4h PRN

orOC/APAP 5^10/5001or 2 tabs q4h PRN

orPentazocine/APAP1or 2 tabs q4h PRN

orTramadol/APAP1or 2 tabs q4h PRN

* Step 1 regimens generally are adequate for mild and mostcases of moderate postoperative dental pain.They should beprescribed continuously,‘‘around-the-clock’’?not PRN. Effec-tive patient education is absolutely essential if this is to be ac-complished. ‘‘They must take the medicine even when theyare NOT having pain.’’ When this regimen proves inadequate,or when pain is anticipated to bemore severe, Step 2 regimenscan be added but should not replace those in Step1.

� APAP indicates acetaminophen; HC, hydrocodone; andOC, oxycodone.

` Adapted from Becker and Phero.48


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8. Goldenberg NA, Jacobson MT, Manco-Johnson MJ.Duration of platelet dysfunction after a 7-day course of ibu-profen. Ann Intern Med. 2005;142:506^509.

9. DelaneyJA,Opatrny L, BrophyJM, Suissa S. Drug-druginteractions between antithromboticmedications and the riskofgastrointestinal bleeding.CMAJ. 2007;177:347^351.

10. DeBroe ME, Elseviers MM. Analgesic nephropathy.N Engl J Med. 1998;338:446^452.

11. Gislason GH, Rasmussen JN, Abildstrom SZ, et al. In-creased mortality and cardiovascular morbidity associatedwith use of nonsteroidal anti-inflammatory drugs in chronicheart failure. Arch Intern Med. 2009;169:141^149.

12. White WB. Defining the problem of treating the pa-tient with hypertension and arthritis pain. Am J Med.2009;122(5 suppl):S3^S9.

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19. Patel TN, Goldberg KC. Use of aspirin and ibuprofencompared with aspirin alone and the risk of myocardial in-farction. Arch Intern Med. 2004;164:852^856.

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21. Pinto A, Farrar JT, Hersh EV. Prescribing NSAIDs topatients on SSRIs: possible adverse drug interaction of im-portance to dental practitioners. Compend Contin Educ Dent.2009;30:142^151; quiz 152, 154.

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24. Troullos ES, Freeman RD, Dionne RA. The scientificbasis for analgesic use in dentistry. Anesth Prog. 1986;33:123^138.

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CONTINUING EDUCATION QUESTIONS

1. All of the following statements are correct regardingnonsteroidal anti-inflammatory drugs EXCEPT:

A. Their antiplatelet action is the principal basisfor their contraindication in patients receiv-ing antithrombotic drugs.

B. Their analgesic ceiling is achieved at dosesbelow those required to effectively depressinflammation.

C. Gastrointestinal toxicity is their most com-mon side effect.

D. Their analgesic efficacy is somewhat greaterthan that for aspirin or acetaminophen.

2. All of the following are correct statements regardingopioids EXCEPT:

A. Conventional mu agonist opioids have an un-limited dose response.

B. Constipation is a mu receptor ^mediated ef-fect.

C. Patients managed on a long-term basis withopioids develop tolerance to analgesia and re-spiratory depression, but not to constipation.

D. An agonist-antagonist opioi d is i deal forpostoperative pain in patients who are re-ceiving opioids on a long-term basis fromtheir physician.

3. Which of the following statements regarding anal-gesics for postoperative pain is most correct?

A. Al l regimens shou ld commence with anNSAID and/or APAP prescribed on an asneeded (PRN) schedule.

B. Pentazocine is an acceptable Step 2 optionfor patients who are not currently takingopioi ds but who have a history of opioi dabuse.

C. Oxycodone has greater analgesic efficacythan hydrocodone.

D. Low-dose opioid ^APAP combinations areideal Step1agents and should be dosed on adesignated ‘‘around-the-clock’’schedule.

4. Drugs that inhibit CYP2D6 are least likely to reducethe analgesic efficacy of which of the following?

A. codeineB. hydrocodoneC. oxycodoneD. tramadol


r i0003-3006-57-2-67 th 2010

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