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Pharmacotherapy of acute orofacial painYair Sharav and Rafael Benoliel

Introduction 349

Modes of Action of NSAIDs 351

Adverse Effects of NSAIDs 351

Efficacy of NSAIDs 356

Paracetamol (Acetaminophen) 363

Dipyrone 365

Omega-3 Fatty Acids 365

Opioids 365

Analgesic Drug Combinations 367

Strategy of Pharmacotherapy of Acute Orofacial Pain 370

1. Introduction

The aim of drug therapy for acute orofacial pain is torelieve pain with maximum efficacy and minimum sideeffects. Ideally an analgesic drug provides significantrelief across all pain severities, has minimal side effects,has few drug interactions and is convenient to administer(e.g. single daily oral dose, pleasant tasting and rapidabsorption). However, ideal drugs do not exist and whenadministering an analgesic consideration should be givento pain severity, the patient’s medical background,susceptibility to the various side effects (e.g. gastrointesti-nal, cardiac, renal) and the fact that patients may differgenetically in their response to analgesics (Lotsch andGeisslinger 2006). The orofacial pain practitioner needsto thoroughly understand the different classes of analge-sics and their mechanisms of actions and appreciate thatdrug actions and interactions change with the patient’sage and medical status (Kim et al 2004). Analgesics alsohave gender-specific adverse events and complex phar-macological interactions with other medications that thepatient may be taking. This chapter reviews the clinicalpharmacology of drugs usually employed in the treat-ment of acute orofacial pain. Since long-term nonsteroidalanti-inflammatory drugs (NSAIDs) and opioids are some-times employed in the management of persistent or recur-ring orofacial pain conditions, relevant ‘chronic’ adverseeffects are also discussed.

The pathogenesis of acute and chronic pain involvesperipheral as well as central mechanisms of sensitizationthat are associated with plasticity in primary sensoryand dorsal horn neurons (Woolf and Salter 2000). Thelocal inflammatory response leads to heightened sen-sitivity and activity of local nociceptors and to distanteffects at the level of the central nervous system (CNS).A mechanism-based strategy for pain control with

analgesics should have, at least, three major aims (Camuet al 2003):

a. Prevention of sensitization of peripheral nociceptors;

b. Interruption of the neuronal transmission of

nociceptive signals; and

c. Attenuation of the nociceptive message in the spinal

cord and other parts of the CNS.

Acute pain is usually activated by an inflammatoryprocess, so the initial strategy to attain analgesia normallyinvolves the use of anti-inflammatory drugs. However,the sole inhibition of inflammation may not be sufficientto obtain adequate analgesia. NSAIDs, including selectivecyclo-oxygenase enzyme (COX)-2 inhibitors, combineanti-inflammatory effects with analgesic actions on periph-eral and central neural targets (Cashman 1996). The clinicalsuccess of NSAIDs has resulted in their widespread use,and it is estimated that over 30million patients ingest thesefor the treatment of pain and inflammation on a daily basis(Singh and Triadafilopoulos 1999).

1.1. The Inflammatory ‘Soup’

The ‘inflammatory soup’ is a mixture of bioactive mole-cules (bradykinin, histamine, prostaglandins, neurotro-phins and interleukins) produced in response to a varietyof stimuli and tissue injury. These molecules may act per-ipherally on primary afferents by direct and/or indirecteffects. Direct effects include activation of primary afferentnociceptors and sensitization of nociceptors that result inincreasing responses to various stimuli. Indirect effectsare mediated by leukocytes and the sympathetic nervoussystem. These effects may involve increased excitabilityof dorsal horn neurons (DHNs), leading to altered des-cending pain control mechanisms and adaptive changesin the thalamus, cortex and higher centres (Millan 1999).

Phospholipids

Arachidonic acid

Prostaglandin:PGG2

Prostaglandins: PGE2,PGI2 (prostacyclin)

Thromboxanes:TXA2

PGH2

Cell-specificenzymes

5-HPETE

Leukotrienes:LTB4, LTD4

Endoperoxides

Lipo oxygenases

Phospholipase

Cyclo oxygenases

Fig. 15.1 • A simplified diagram of the metabolic pathway fromarachidonic acid to prostaglandins, thromboxanes, and leukotrienes.The mechanisms of analgesia-associated adverse effects occurthrough the regulation of prostaglandin synthesis by anti-inflammatory drugs. Blocking the effect of cyclooxygenases (COX1and COX-2), by aspirin or traditional NSAIDs, inhibits the productionof prostaglandins, in particular PGE2, and causes analgesia. However,prostaglandins are needed for protection of the gastric mucosa, andkidney blood perfusion, hence the deleterious effect on these organsas a possible side effect of NSAID administration. Blocking COX-1activity also inhibits production of thromboxanes, needed for plateletaggregation and normal blood clotting. By blocking the COX pathwaymore arachidonic acid is available for the lipo-oxygenase pathwayand more leukotrienes such as leukotriene B4 (LTB4) and LTD4 areproduced. LTB4 induces neutrophil-dependent hyperalgesia; LTD4 isassociated with sensitivity reactions. Selective inhibition of COX-2 minimally blocks the production of PGE2, but selectively suppressesprostacyclin (PGI2) production (that has antithrombotic andantihypertensive effects) without affecting TXA2, and could thereforepredispose the patient (especially the elderly, or with other CV riskfactors) to thromboembolic adverse effects and hypertension.Additionally some leukotrienes increase gastric acid production that isunbalanced by the protective prostaglandins, leading to increased GIside effects.

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The concomitant presence of mediators such as nervegrowth factor (NGF), 5HT, interleukin (IL)-1 and bradyki-nin at sites of inflammation has led to the collective terminflammatory soup (Mamet et al 2002). This soup synergis-tically activates peripheral nociceptors (Kessler et al 1992).An important characteristic of inflammation is acidosis,and protons will directly and indirectly cause pain andhyperalgesia (Steen et al 1995). Protons directly activatesensory neurons, mainly through acid-sensing ion chan-nels (ASICs) (Sutherland et al 2000; Julius and Basbaum2001; Ichikawa and Sugimoto 2002; Kido et al 2003). Theinflammatory soup also induces ASIC upregulation,increases ASIC-expressing neurons and activates sensoryneurons leading to increased excitability (Mamet et al

2002, 2003). An additional receptor, the dorsal-root ASIC(DRASIC or ASIC3), is both proton and mechanosensitive(Price et al 2001). Further synergism is observed via aninteraction between mediators in the inflammatory soupand an acidic pH; enhanced effects are mutual and atwo-way intensification of experimental human pain hasbeen reported (Steen et al 1996). Protons also induce adecrease in the activation threshold for other receptorsand therefore increase pain.

1.2. Prostaglandins

Prostaglandins (PG) are synthesized by the constitutiveenzyme COX-1 and its inducible isoform COX-2, which isinduced in peripheral tissues by a number of inflammatorymediators including cytokines and growth factors (Ballouet al 2000). Neuronal effects of PG are mediated by a directaction on the nociceptor (Taiwo and Levine 1989; Noda et al1997) and are not under the control of NGF (Southall andVasko 2000). PGs are prime examples of sensitizing agents,and specific subtypes (PGE2 and PGI2) have been found tomediate the hyperalgesia induced by bradykinin and nor-adrenaline (Taiwo et al 1990). Experimentally, PGE2 willinduce sensitization of multiple classes of cutaneousafferents including C-polymodal nociceptors and Adhigh-threshold mechanonociceptors (Martin et al 1987).

COX-2 is upregulated in the spinal cord during periph-eral inflammation and COX-2 products contribute to theincreased excitability of spinal cord neurons duringpersistent peripheral inflammation (Samad et al 2001;Seybold et al 2003). This suggests that PGs are involvedat various sites and anatomical levels of the inflamma-tory-nociceptive pathway (Rueff and Dray 1993). It isnot surprising therefore that drugs acting on PGs suchas nonselective NSAIDs and selective COX-2 inhibitorsare effective analgesic and anti-inflammatory drugs.

The diagram presented in Fig. 15.1 is a highly simpli-fied version of the metabolic pathway from arachidonicacid to PGs, thromboxanes (TX) and leukotrienes (LT)(Funk 2001). Arachidonic acid is a product of cell mem-brane phospholipids, and its formation may be enhancedby tissue injury. After the release of arachidonic acid(AA), COX catalyzes a complex reaction that converts

AA to PGG2. In a second step a peroxidase-catalyzedreaction converts PGG2 to PGH2 (Funk 2001), which thenreacts with other enzymes, determined by the host tis-sue/cell, into different PGs or TX. For example, PGH2 inplatelets is converted into TXA2, whilst in endothelialcells it will be converted into PGE2 and PGI2 (Smith andMarnett 1991; Smith et al 1994). TXA2 is a powerful vaso-constrictor that stimulates platelet aggregation. PGE2 andPGI2 are vasodilators that affect renal glomerular filtra-tion rate and possess gastroprotective properties (Brune2004). Specific leukotrienes lead to vasoconstriction andincreased acid secretion in gastric mucosa whilst otherslead to hypersensitivity reactions such as oedema andbronchospasm (Brune 2004). Additionally, leukotrieneB4 is known to induce a number of proinflammatoryeffects and has been implicated in chronic inflammationand tissue destruction in inflammatory joint disease(Bertolini et al 2001).

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2. Modes of Action of NSAIDs

The blockade of the enzymatic effects of COX by aspirinor other NSAIDs inhibits the production of PGs asso-ciated with nociception (in particular PGE2), hence theanalgesic effect of these drugs (Vane 1971). However, aswe later describe in detail, prostaglandins are essentialfor the normal function of many organs (e.g. gastrointes-tinal, kidney) and their disruption is associated with seri-ous side effects. Additionally, the production of TXs isalso blocked. TXA2 is associated with platelet aggrega-tion, and blocking the production of TXA2 interferes withnormal blood clotting. In addition, the blockade of theCOX pathway increases the amount of AA substrateavailable for the lipo-oxygenase pathway, therebyenhancing the production of LTs. An excess of LT is asso-ciated with asthmatic attacks, urticaria and other sensitiv-ity reactions (see Fig. 15.1) (Israel et al 1993). There isevidence that some NSAIDs such as ibuprofen and indo-methacin exert part of their effect by COX-independentmechanisms (Tegeder et al 2001). These mechanisms prob-ably involve inhibition of transcription factors mediatedby alterations in the activity of cellular kinases.

2.1. COX Isoforms

An important advance in prostaglandin research was thediscovery that COX exists in various isoforms: primarilyCOX-1 and COX-2 (Fu et al 1990), and recent evidencepoints to the existence of COX-3. The level of COX-1 incells varies relatively over a narrow range (two- to four-fold), and is considered a constitutive or housekeepingenzyme, largely unrelated to inflammation. COX-1 main-tains PG and TX synthesis in the stomach, the kidney,endothelial cells, blood platelets and other tissues. COX-2,however, is mostly an inducible enzyme and is consideredpart of the inflammatory process (Robinson 1997). COX-2 isproduced in monocytes, synovial cells and fibroblastsafter stimulation by cytokines and growth factors, andits expression is augmented 10- to 80-fold when cells areactivated (Smith et al 1994). Less is known about COX-3,which is found in the cerebral cortex and cardiac tissueand appears to be involved in centrally mediated pain.The kinetics of COX-2 inhibition is different from that ofCOX-1. COX-1 inhibition is instantaneous and competi-tively reversible. COX-2 inhibition is time-dependent, withselectivity developing over 15–30minutes, and is thereafteressentially irreversible (Hawkey 1999). Different genesencode these two enzymes, and separate experiments inmice have used stem cell technology to knock out the genesfor COX-1 and COX-2 to provide evidence of each of theseenzymes’ role (Dinchuk et al 1995; Langenbach et al 1995).However, some of the results were quite unexpected, stres-sing a possible constitutive role for COX-2. Thus, deletionof the COX-2 gene was associated with a shortened lifespan, infertility due to failure of ovarian development

and incomplete maturation of nephrons resulting in renalfailure (Dinchuk et al 1995). Also the results of experimen-tal inflammation were similar in mice lacking the COX-2 gene and control mice, stressing the important role ofCOX-1 in inflammation (Dinchuk et al 1995). Anothersurprising find was that even though mice lacking COX-1had gastric PGE levels that were only 1% of controls, theyhad no gastric pathology, and were less susceptible toindomethacin-induced gastropathy than controls (Langen-bach et al 1995).

Indeed, it was first assumed that drugs with COX-2selectivity would spare physiological PG synthesis, andpossess anti-inflammatory action with fewer or none ofthe typical adverse effects of NSAIDs on the gastrointesti-nal tract, kidneys, platelets and lungs (Vane 1994). How-ever, it became obvious that COX-1 has an importantrole in the inflammatory response whilst COX-2 has fun-damental constitutive roles. Animal experiments andclinical trials with specific COX-2 inhibitors have revealedthat COX-2 is important for the normal function of manysystems (Crofford et al 2000; Katori and Majima 2000).This is particularly true for the kidney, central nervous,cardiovascular and reproductive systems.

Novel coxibs (e.g. etoricoxib, valdecoxib, parecoxib,lumiracoxib) have been recently developed withenhanced biochemical COX-2 selectivity over that ofolder ones such as rofecoxib and celecoxib. They havethe potential advantage to spare COX-1 activity, thusreducing gastrointestinal toxicity, even when adminis-tered at high doses to improve efficacy. However, severalrandomized clinical studies suggest that the novel coxibshave comparable efficacy to nonselective NSAIDs in thetreatment of osteoarthritis, rheumatoid arthritis and acutepain, but they share similar renal side effects.

3. Adverse Effects of NSAIDs

NSAIDs interfere with the production of prostaglandinsand thromboxanes, and enhance the amount of leuko-trienes. The main adverse effects of NSAID administrationassociated with inhibition of PG are gastrointestinal toxic-ity and renal failure. Inhibition of TX is associated withcoagulation problems, and the surplus production of LTis mainly associated with hypersensitive reactions such asasthma and urticaria. The selective COX-2 inhibitorsgained widespread popularity, having equivalent analge-sic and anti-inflammatory effects as the conventionalNSAIDs, yet with reduced gastrointestinal (GI) side effects(Bombardier et al 2000; Silverstein et al 2000; Schnitzer et al2004). A recent review discusses the clinical implications ofCOX-2 inhibitors for acute dental pain management andits benefits and risks (Spink et al 2005).

Recently COX-2 inhibitors have been shown to increasethe risk of cardiovascular (CV) events such as myocardialinfarction and ischaemic stroke (Wong et al 2005). They

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are also intimately involved in prostaglandin-dependentrenal homeostatic processes, and therefore do not offerrenal safety over that of NSAIDs (Brater et al 2001). In avery short time, COX-2 inhibitors have gone from thedarlings to the pariahs of the pharmaceutical industry(Brophy 2005). The risks and adverse effects of traditionalNSAIDs and of the newer more selective COX-2 inhibitorsare detailed below.

3.1. Gastrointestinal

3.1.1. Pathophysiology

Gastroduodenal mucosal injury develops when the dele-terious effect of gastric acid overwhelms the normaldefensive properties of the mucosa. Concepts aboutNSAID-induced gastroduodenal mucosal injury haveevolved from a simple notion of topical injury to theoriesinvolving multiple mechanisms with both local andsystemic effects. Topical injury caused by NSAIDs contri-butes to the development of gastroduodenal mucosalinjury but the systemic effects of these agents appear tohave the predominant role (Schoen and Vender 1989),largely through the decreased synthesis of mucosal pros-taglandins (Lanza et al 1980). Aspirin, at a dose as low as30mg, is sufficient to suppress prostaglandin synthesis inthe gastric mucosa (Lee et al 1994). Prostaglandin inhibi-tion, in turn, leads to decreases in epithelial mucus pro-duction, secretion of bicarbonate, mucosal blood flow,epithelial proliferation and mucosal resistance to injury(Wolfe and Soll 1988). The impairment in mucosal resis-tance permits injury by endogenous factors, includingacid, pepsin and bile salts, as well as by exogenousnoxious agents.

Selective COX-2 inhibitors hold the promise of feweradverse effects as far as the gastrointestinal tract and pla-telets are concerned (Silverstein et al 2000; FitzGerald andPatrono 2001; Schnitzer et al 2004). However, despite the50% reduction of symptomatic ulcers, perforations andbleeding observed for rofecoxib (Bombardier et al 2000),the risk for serious GI toxicity by selective COX-2 inhibi-tors is still within the 2–4% range for COX-nonselectiveNSAIDs. Furthermore, there is increasing evidence ofthe importance of COX-2 in resolution of mucosalinflammation and in ulcer healing (Wallace and Dev-chand 2005). COX-2 inhibitors are therefore contraindi-cated for use in patients with diagnosed and activelytreated GI ulcers (Stichtenoth and Frolich 2003).

3.1.2. Epidemiology

According to prospective data 13 of every 1000 patientswith rheumatoid arthritis who take NSAIDs for one yearhave a serious GI complication. The risk in patients withosteoarthritis is somewhat lower (7.3 per 1000 patientsper year) (Singh and Triadafilopoulos 1999). Mortalityattributed to NSAID-related GI toxic effects is 0.22% per

year, with an annual relative risk of 4.21 as comparedwith the risk for persons not using NSAIDs (Singh andTriadafilopoulos 1999). However, these figures are truefor 1999, before the wide introduction of COX-2 inhibitorssuch as celecoxib or rofecoxib. The severity of the NSAID-associated GI injury is not to be underestimated; onaverage 1 in 1200 patients taking NSAIDs for at least2 months, who would not have died had they not takenNSAIDs, will die from gastroduodenal complications. Thisextrapolates to about 2000 deaths each year in the UK alone(Tramer et al 2000).

3.1.3. Risk Factors

The risk for adverse GI events increases linearly with age(Longstreth 1995). Other risk factors that have been identi-fied in multiple studies are higher doses of NSAIDs(including the use of two or more NSAIDs), a history ofgastroduodenal ulcer or gastrointestinal bleeding, concom-itant use of corticosteroids, serious coexisting conditions,alcohol abuse and concomitant use of anticoagulants (Her-nandez-Diaz andGarcia-Rodriguez 2001). However, manyof these studies are based on univariate analysis and do notconsider the interactions among multiple factors and coex-isting conditions so for medically complex patients the riskmay be even higher (Wolfe et al 1999).

3.1.4. Clinical Spectrum of Injury

In the majority of patients, NSAID-induced gastroduode-nal mucosal injury is superficial and self-limiting. How-ever, peptic ulcers develop in some patients, and theymay lead to gastroduodenal haemorrhage, perforation,and death. After ingestion of an NSAID, ultrastructuraldamage to the gastric surface epithelium occurs withinminutes, and gross, endoscopically detectable haemor-rhages and erosions in the gastroduodenal epitheliumoccur within several hours (Graham and Smith 1986).

3.1.5. Prevention and Management

At least 10–20% of patients have dyspeptic symptomsduring NSAID therapy (Singh et al 1996). However, suchsymptoms are poorly correlated with the endoscopicappearance and severity of mucosal injury. Up to 40%of persons with endoscopic evidence of erosive gastritisare asymptomatic (Larkai et al 1987; Pounder 1989) andas many as 50% of patients with dyspepsia havenormal-appearing mucosa (Larkai et al 1987). HistamineH2-receptor antagonists improve dyspeptic symptoms,but still permit a high risk of GI complications (Wolfeet al 1999).

The concomitant use of antacid medication in suscepti-ble individuals or for long-term therapy is commonpractice. The proton-pump inhibitor omeprazole andmisoprostol, a prostaglandin E1 analogue, are commonlyused for the treatment and prevention of NSAID-relatedgastroduodenal ulcers. However, omeprazole provided

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greater symptomatic relief, and also better healingof gastroduodenal ulcers in patients receiving ongoingNSAIDs (Hawkey et al 1998). A quality-of-life evaluationshowed that patients receiving omeprazole had signifi-cantly greater improvement in scores on the Gastrointesti-nal Symptom Rating Scale than the patients receivingmisoprostol (Hawkey et al 1998). Additionally, based on acost-effectiveness analysis omeprazole is preferable tomisoprostol (Eccles et al 1998). Proton-pump inhibitors rep-resent a suitable means of preventing the development ofgastroduodenal ulcers associated with the use of NSAIDs;they appear to provide a safe and effective form of therapyfor NSAID-associated dyspepsia (Lanza 1998; Morgneret al 2007).

3.2. Renal

The kidney is the second most frequent target of seriousadverse effects of NSAIDs related to inhibition of COXand is estimated to affect 2 million patients annually inthe USA alone (Sandhu and Heyneman 2004). The renalside effects of NSAIDs comprise reduction in renal bloodflow (RBF) and glomerular filtration rate (GFR), sodium/water retention and hyperkalaemia (Sandhu and Heyne-man 2004). Animal experiments and clinical trials withpreferential and specific COX-2 inhibitors revealed thatCOX-2 is the critical enzyme for sodium excretion andrenin release and likely antagonism of antidiuretic hor-mone—a prime example of a constitutive role for COX-2.Additionally, a significant role of COX-2 in nephrogenesisis suggested. For renal haemodynamics the available evi-dence points to COX-1 as the predominant enzyme,but further investigations are required (Stichtenoth andFrolich 2000).

Furthermore, PGI2 significantly influences the renalsystem of medically compromised patients, especiallywith diabetes, peripheral vascular disease or other causesof renal insufficiency. COX-2 inhibition decreases PGE2

and PGI2, modifiers of glomerular filtration in compro-mised kidneys, and causes sodium retention, promotingperipheral oedema and hypertension, lower renal perfu-sion with renal ischaemia (Khan et al 2001). The dose-dependent consequences of standard NSAIDs andCOX-2 inhibitors on the kidney include elevated bloodpressure, oedema and congestive heart failure in some com-promised patients and in patients taking beta-adrenergicblocker drugs or angiotensin-converting enzyme (ACE)inhibitors (Whelton et al 2002).

The second generation of COX-2 inhibitors with higherCOX-2 selectivity (valdecoxib, parecoxib, and especiallyetoricoxib and lumaricoxib) possesses marginal, if any,gain in safety compared with the first generation (Sandhuand Heyneman 2004). The apparent dose dependence ofrenal toxicity also limits the use of higher dosages. Itcan be concluded at this stage that with regards to renaladverse events, selective COX-2 inhibitors do not offer aclinically relevant advantage over conventional NSAIDs

(Stichtenoth and Frolich 2003; Sandhu and Heyneman2004). It seems, however, that renal effects are related toindividual COX-2 inhibitors and are not a ‘class effect’(Sandhu and Heyneman 2004; Zhang et al 2006).

The epidemiological impact is substantial and currentusers of NSAIDs are estimated to be 2–4 times more atrisk for acute renal failure (Evans et al 1995; PerezGutthann et al 1996; Henry et al 1997). This risk is dosedependent and is highest (relative risk >8) during thefirst month of therapy (Perez Gutthann et al 1996; Henryet al 1997). Other risk factors for acute renal failure arelong drug half-life, male gender, increasing age, cardio-vascular comorbidity, renal diseases, concomitant use ofother nephrotoxic drugs and any recent hospitalization(Perez Gutthann et al 1996; Henry et al 1997). Of the specificCOX-2 inhibitors rofecoxib has been found to significantlyincrease the risk for peripheral oedema, hypertension,renal dysfunction and arrhythmias (Zhang et al 2006).Increased risk was associated with increased dose andduration of rofecoxib use (Zhang et al 2006). The NSAIDeffect on acute renal failure is stronger among subjectswitha previous history of renal disease and in those with a his-tory of gout or hyperuricaemia. Among these patients,NSAID exposure increases the risk of acute renal failureby a factor of 7 (Whelton et al 1990; Henry et al 1997). Onlyindomethacin presented a higher relative risk for acuterenal failure than the other conventional NSAIDs (PerezGutthann et al 1996).

3.3. Cardiovascular

Current users of any NSAIDs are estimated to have up toa twofold increase in risk of hospitalization for congestiveheart failure, even greater in patients with pre-existingheart disease (Hernandez-Diaz and Garcia-Rodriguez2001; Kearney et al 2006). The risk is dose dependent,and higher during the first month of therapy (Heerdinket al 1998; Page and Henry 2000; Kearney et al 2006).

While COX-2 inhibitors gained widespread popularityas effective anti-inflammatory and analgesic agents withreduced GI side effects (Bombardier et al 2000; Silversteinet al 2000; Schnitzer et al 2004), concerns over cardiovascu-lar risk of selective COX-2 inhibitors have been raised,which may outweigh any gain in GI safety (FitzGeraldand Patrono 2001). Increased risk was shown for certainvascular events: myocardial infarction (MI) and ischaemicstroke (Bresalier et al 2005; Kearney et al 2006). The cardio-vascular harm associated with COX-2 inhibitors becameapparent in trials conducted for other indications. There-fore, even with the evidence from these trials, we lackinformation to make confident statements about theexact levels of risk for each drug, the time course of therisk and the populations of patients (if any) in whomthe benefits might exceed the known risks (Psaty andFurberg 2005). Cardiovascular safety of all COX-2 inhibi-tors and traditional NSAIDs has since been under intenseinvestigation.

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Rofecoxib was withdrawn from the market followingthe findings of a doubling of risk of vascular events inthe rofecoxib group compared to placebo (relative risk,1.92; 95% CI: 1.19–3.11) (Bresalier et al 2005). Meta-analysisof controlled studies using rofecoxib had previouslyshown that the risk of MI was increased after a fewmonths of treatment (Juni et al 2004; Solomon et al 2004).Rofecoxib at all doses increases the risk by a factor of1.59 (95% CI: 1.1–2.3) and for rofecoxib >25mg/d by afactor of 3.58 (CI: 1.3–10.1). Rofecoxib is also associatedwith higher incidences of hypertension, peripheral oedemaand congestive heart failure compared with celecoxib andother NSAIDs (Bombardier et al 2000; Mamdani et al 2004;Solomon et al 2004). A significant elevation in the cardio-vascular event rate for rofecoxib has been confirmed inrecent studies (Solomon et al 2006). The increase rate forrofecoxib was seen in the first 60 days of use and thereafter.

Death from CV causes, MI, stroke, or heart failure washigher in a group taking celecoxib 200mg twice per dayand 400mg twice per day than in the placebo group (relativerisk 2.8; 95% CI: 1.3–6.3) (Solomon et al 2005). CV risk withcelecoxib became apparent only after 12 months of treat-ment and increased with higher doses but this has not beena consistent finding (ADAPT 2006).

MI, cardiac arrest, stroke and pulmonary embolismwere more frequent among the patients given the newercoxibs, valdecoxib and its prodrug parecoxib, thanamong those given placebo (2.0 vs. 0.5%; relative risk3.7) (Ott et al 2003; Nussmeier et al 2005). In one studythe risks of using COX-2 inhibitors in high CV riskpatients, who were excluded from previous randomizedcontrolled studies, were noted (Nussmeier et al 2005).A pooled analysis of these studies suggests that pare-coxib/valdecoxib elevate the combined incidence ofMI and stroke by threefold in these populations(Furberg et al 2005).

Traditional NSAIDs, such as diclofenac and ibuprofen,have also been implicated in increased MI risk (Hippis-ley-Cox and Coupland 2005; Kearney et al 2006; McGetti-gan and Henry 2006). These findings have not, however,been universally duplicated (Solomon et al 2006). Fornaproxen versus any NSAID, taken at least 60 dayspreviously, the adjusted odds ratio was not significant(1.14, CI: 1–1.3) (Graham et al 2005). A significant reduc-tion in CV events was noted for naproxen in one study(RR 0.75, CI: 0.62–0.92) (Solomon et al 2006), whilstin another naproxen significantly increased CV risk(ADAPT 2006). It may be concluded that naproxen maynot significantly protect against serious coronary heartdisease; however, it is not consistently associated withany increased risk (Graham et al 2005; Kearney et al

2006; McGettigan and Henry 2006). Hypertensive pati-ents on NSAIDs are more susceptible to blood pres-sure increases than normotensives (Johnson et al 1994)and demonstrate significantly increased rates of MIor CVA relative to normotensive patients (Spalding et al

2007).

Concomitant NSAID and antihypertensive treatmentmay induce clinically significant drug interactions. Indo-methacin andpiroxicam induce ahypertensive effect greaterthan that of alternative NSAIDs. There is also relativelygreater antagonism between NSAIDs and beta-blockerscomparedwith other antihypertensives (Johnson 1998). For-tunately, the CV risk of short-term use of most NSAIDs isminimal and most serious side effects occur only afterlong-term use. There are, however, three classes of antihy-pertensive agents that can interact with NSAIDs: ACE inhi-bitors, beta-blockers and diuretics. The action of all thesedrugs is aided by renal prostaglandins. With the principaleffect of NSAIDs being PG inhibition, the effectiveness ofthese agents may be diminished. This interaction usuallytakes approximately 7–8 days to occur. Therefore, NSAIDuse in a hypertensive patient on these medications shouldbe limited to 4–6 days (Haas 1999).

The American Heart Association released a scientificstatement to aid clinicians in selection of analgesics forpatients with increased CV risk (Antman et al 2007). Theirrecommendations reiterate our conclusions summarizedin detail at the end of this chapter. In brief, for patientswith increased CV risk acetaminophen or aspirin shouldinitially be tried. Naproxen remains the NSAID with themost data indicating no increased risk for CV eventsand is therefore a logical second option; the use of gastro-protective agents should be considered in at-risk indivi-duals. COX-2 inhibitors are contraindicated in patientswith recent bypass surgery, unstable angina, previousMI, ischaemic cerebrovascular events or any other activeatherosclerotic process as they are associated with signifi-cantly increased risk for adverse CV events (Antman et al

2007). Additionally COX-2 inhibitors may lead toimpaired renal perfusion, sodium retention and increasedblood pressure which contribute to increased CV risk.When NSAIDs, particularly COX-2 inhibitors, are indi-cated they should be used at the lowest dose for theshortest time (Antman et al 2007).

3.4. Platelet Effects and ConcomitantAspirin Use

Human platelets and vascular endothelial cells processPGH2 to produce TXA2 and prostacyclin (PGI2), respec-tively (Majerus 1983). COX-1 converts arachidonic acidto TXA2 (mostly from platelets), which induces plateletaggregation and vasoconstriction. COX-2 is responsiblefor the conversion of AA to PGI2, which inhibits plateletaggregation and induces vasodilatation. Selective inhibi-tion of COX-2 causes suppression of PGI2 productionwithout affecting TXA2, and predisposes to hypertensionand increased thromboembolic risks (Fitzgerald 2004;Grosser et al 2006).

The best characterized mechanism of action of aspirin isrelated to its capacity to irreversibly inactivate COX-1 andCOX-2. Since aspirin probably also inactivates COX-1

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in relatively mature megakaryocytes, and only 10% ofthe platelet pool is replenished each day, once-a-daydosing of aspirin is able to maintain virtually completeinhibition of platelet TXA2 production (Patrono et al

2001). Vascular PGI2 can be derived from both COX-1and COX-2 (McAdam et al 1999) and there is substantialresidual COX-2-dependent PGI2 biosynthesis in vivo atdaily doses of aspirin in the range of 30 to 100mg tomaintain vascular homeostasis (Clarke et al 1991). Exper-imental studies support the importance of PGI2 in theprevention of arterial thrombosis (Murata et al 1997). Ithas not been established that more profound suppres-sion of PGI2 formation by higher doses of aspirin is suf-ficient to initiate or to predispose to thrombosis.However, one trial showed a significantly lower rate ofvascular events in patients receiving 80 or 325mg aspi-rin than in patients receiving 650 or 1300mg daily, con-sistent with an important role for PGI2 in preventingthrombosis (Taylor et al 1999).

In contrast to the irreversible effects of aspirin, tradi-tional NSAIDs reversibly inhibit platelet aggregationand prolong bleeding time (Schafer 1999). The regularadministration of naproxen 500mg BID can mimic theantiplatelet COX-1 effect of low-dose aspirin but doesnot decrease prostacyclin biosynthesis in vivo (Caponeet al 2004). Rofecoxib and valdecoxib do not impair plate-let aggregation, and rofecoxib does not alter the antiplate-let effect of aspirin (Ouellet et al 2001; Leese et al 2002).Thus, in terms of bleeding COX-2 inhibitors may be givenmore safely than traditional NSAIDs in the dental periop-erative setting.

Aspirin is taken on a daily basis by a large number ofpatients, especially for cardioprotection (Gaziano andGibson 2006). Choosing an analgesic that does not inter-fere with aspirin’s action or increase adverse events isimportant. For example, the use of NSAIDs in conjunctionwith aspirin may increase the risk of GI complications.Moreover, ibuprofen and naproxen interfere withaspirin’s ability to irreversibly acetylate platelet COX-1,and theoretically may reduce aspirin’s protective antith-rombotic effect (Catella-Lawson et al 2001; Capone et al

2005). Data from epidemiological studies suggest that tak-ing any NSAID may cancel aspirin’s cardioprotectiveeffects (Gaziano and Gibson 2006). Treatment withNSAIDs, particularly ibuprofen or naproxen, should beavoided in patients taking concomitant low-dose aspirin(Antman et al 2007). Taking aspirin prior to ibuprofen ornaproxen ingestion does not seem to resolve this interac-tion (Capone et al 2005; Antman et al 2007). However,concomitant administration of rofecoxib, acetaminophenor diclofenac did not affect the pharmacodynamics of aspi-rin (Catella-Lawson et al 2001). The use of COX-2 inhibi-tors in patients taking aspirin a priori defeats the veryreason for prescribing COX-2 inhibitors: GI safety. Itwould therefore seem prudent to preferentially use acet-aminophen for these patients (Gaziano and Gibson2006).

3.5. Hypersensitivity Reaction

It is well known that aspirin and other NSAIDs can exac-erbate various forms of urticaria and asthma (Szczeklikand Stevenson 1999; Stevenson et al 2001). Aspirin sensi-tivity can be confirmed by drug challenge tests in20–41% of patients with urticaria (Juhlin 1981). In con-trast, the rate of aspirin sensitivity in the normal popula-tion is about 1% (Bigby 2001). Susceptible individualshave cross-sensitivity to the entire class of drugsregardless of their chemical structure.

The most common clinical presentation is urticaria andangioedema. Current theories regarding the mechanismsof NSAID sensitivity in chronic idiopathic urticaria (CIU)are largely inferred from studies of an analogous, well-defined clinical syndrome of aspirin-induced asthma(AIA), which affects about 10% of adult asthmatic patients(Szczeklik and Stevenson 1999). Both syndromes affect mid-dle-aged individuals, with a female preponderance. Sensi-tivity to NSAIDs is present in only a subset of patientswith asthma and CIU. Although some NSAID-inducedcutaneous eruptions are immunologic, in most cases themechanism involves inhibition of COX. It iswell establishedthat in AIA themechanism of sensitivity involves inhibitionof COX-1 (Szczeklik 1990). At the biochemical level, AIA ischaracterized by overproduction of leukotrienes andincreased urinary excretion of leukotriene E4 (LTE4) (Chris-tie et al 1991). The mechanism of sensitivity to NSAIDs inCIU is also associated with overproduction of leukotrienesand mast cell activation and most likely depends on inhibi-tion of COX-1 (Zembowicz et al 2003). COX-2 inhibitors(rofecoxib, up to 37.5mg, and celecoxib, up to 300mg) donot induce urticaria in patients with CIU sensitive toNSAIDs. Etoricoxib, a second-generation COX-2 inhibitor,at 120mg dosage was also found safe in patients withNSAID-induced urticaria and angioedema (Sanchez-Borgeset al 2005). The COX-2 inhibitor rofecoxib, up to 25mg, wasalso safe in AIA patients also sensitive to other NSAIDs(Martin-Garcia et al 2002; Perrone et al 2003; Nettis et al

2005; Micheletto et al 2006). Celecoxib 200mg was also safein AIA patients (Martin-Garcia et al 2003; Celik et al 2005).However, valdecoxib, one of the newer COX-2 inhibitors,is not recommended in patients with a history of asthma orurticaria. Valdecoxib is a benzene-sulphonamide and couldalso have cross reactivity in patients who are allergic to sul-pha-type drugs (Glasser and Burroughs 2003).

About 7% of AIA patients who had no adverse reactionto rofecoxib had experienced asthma induced by acet-aminophen (Martin-Garcia et al 2002). Cross reactivity ofpatients with AIA to acetaminophen is fairy prevalent,especially in doses >1000mg. Thus, 34% of AIA patientsreacted to acetaminophen in doses of 1000–1500mg (95%CI: 20–49%). By contrast, none of the non-AIA patientsreacted to acetaminophen (95% CI: 0–14%). This differ-ence was highly significant, supporting the hypothesisthat cross sensitivity between aspirin and acetaminophenis unique in AIA patients. Daily paracetamol use

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increases the risk of asthma by a factor of 2.38 (CI: 1.22–4.64). It is recommended that frequent (daily) or highdoses of acetaminophen (1000mg or greater) should beavoided in aspirin-sensitive asthmatic patients (Settipaneet al 1995).

Anaphylactic shock and urticaria/angio-oedema aftera single dose of dipyrone has been reported (Szczekliket al 1977). All patients had positive skin tests to thesedrugs but no cross reactivity with NSAIDs. Dipyrone-induced hypersensitivity reactions include skin rash withan intriguing geographical difference in frequency (Levy2000). Respiratory asthma-like reactions with cross reac-tivity in patients sensitive to aspirin have been morerarely reported (Levy 2000). Dipyrone has been clearlyshown to cause agranulocytosis, but there is insufficientuseful information to adequately quantify the risk. Moststudies are old, methodologically weak and small, anduse different definitions of agranulocytosis (Edwardsand McQuay 2002). It is absolute risks that are importantwhen determining harm. Absolute risks of rare events fol-lowing some drug treatments have been determined butit is not possible to determine the risk of agranulocytosiswith dipyrone and uncertainty is likely to remain (Trameret al 2000; Edwards and McQuay 2002).

The pathogenesis of agranulocytosis following the useof dipyrone (and other pyrazolones) is considered immu-nological (Levy 2000). Conflicting data and regulationsprevail worldwide as to the incidence of agranulocytosisfollowing the use of pyrazolones in general, and dipyronein particular (Levy 2000). A multinational study foundsignificant regional variability in the risk ratio for agranu-locytosis following the use of dipyrone (InternationalAgranulocytosis and Aplastic Anemia Study 1986). InUlm, Berlin and Barcelona the risk ratio was 23.7 andthe excess risk estimate connected with hospital admis-sion for agranulocytosis from any dipyrone use in aseven-day period amounted to 1.1 cases per million users.In Israel and Budapest there was no evidence of increasedrisk associated with dipyrone use (International Agranu-locytosis and Aplastic Anemia Study 1986). The reasonfor the geographical variation in the risk of dipyrone-induced agranulocytosis and rash is unclear (Levy 2000).

3.6. Effects on Bone Healing

Studies suggest that nonspecific NSAIDs, which inhibitboth COX-1 and COX-2 isoforms, delay bone healing.Recent studies investigating the effects of COX-2-selectiveinhibitors on bone healing have yielded similar results(Harder and An 2003). A recent animal study demon-strated that ketorolac significantly delays fracture healing(Gerstenfeld et al 2003). It was further demonstrated thata COX-2-selective NSAID, such as parecoxib (valdecoxib),has only a small effect on delaying fracture healing evenat doses known to fully inhibit prostaglandin production(Gerstenfeld et al 2003). Despite the understanding of thepotential mechanism through which NSAIDs and COX-2

inhibitors hamper bone healing in a laboratory setting,few studies exist that showwhether these inhibitory effectsare also evident clinically (Harder and An 2003).

3.7. Reproductive System andPregnancy Risk

COX-2 plays a prominent role at all stages of reproduction(Chan 2004). Thus prolonged use of COX-2 inhibitors inwomen may lead to pregnancy risks and infertility(Silverstein et al 2000; Nielsen et al 2001; Li et al 2003;Norman and Wu 2004). Both oestrogen and progesteroneare involved in the regulation of COX production in tissuesof the reproductive tract (Chan 2004). Therefore changes inoestrogen and progesterone levels during pregnancy con-tribute to the dramatic increase in COX-2 expressionalthough this effect seems to vary at different stages ofpregnancy. This further strengthens the earlier findingsthat COX-2 activities are necessary to support pregnancy.

Use of NSAIDs during the first 20 weeks of pregnancyhas been associated with an 80% increased risk of miscar-riage over non-use (risk ratio 1.8, CI: 1–3.2). Risk of mis-carriage was highest when the drug was taken aroundthe time of conception (risk ratio 5.6, CI: 2.3–13.7) or usedfor more than a week (risk ratio 8.1, CI: 2.8–23.4). Abso-lute risk of NSAID-associated miscarriage was 10% forany use, 35% for use around time of conceptionand 52% for use longer than one week (Li et al 2003).However, prenatal use of paracetamol, pharmacologicallydifferent from NSAIDs and aspirin, was not associatedwith increased risk of miscarriage regardless of timingand duration of use (Li et al 2003). In view of the above,warnings of drug effects on reproduction have beenincluded in the product labelling of marketed NSAIDsand COX-2-specific inhibitors (Chan 2004).

Paracetamol is generally considered to be the analgesicof choice in pregnant patients. However, the use of para-cetamol, but not aspirin, was positively associated withasthma and persistent wheezing in infants of motherswho took paracetamol frequently (defined as most daysor daily use) in late pregnancy (Shaheen et al 2005).No association was found with hay fever, eczema orskin test positivity. The proportion of asthma attributableto paracetamol use in late pregnancy, assuming a causalrelation, was 7% (Shaheen et al 2005). The number ofpregnant women taking frequent doses was very smallso the authors recommend that infrequent paracetamolremain the analgesic of choice in pregnancy (Shaheenet al 2005).

4. Efficacy of NSAIDs

Prostaglandins represent one of the key chemicals involvedin the sensitization of peripheral nociceptors, therebycontributing to the development of both primary andsubsequent secondary hyperalgesia. PGs are synthesized

0 87654

NNT

321

Celecoxib 200 mg

Aspirin 600/650 mg

Paracetamol 500 mg

Naproxen sod. 550 mg

Aspirin 1200 mg

Ibuprofen 400 mg

Diclofenac 50 mg

Dipyrone 500 mg

Rofexocib 50 mg

Diclofenac 100 mg

Ibuprofen 800 mg

Fig. 15.2 • Number needed to treat (NNT) for one patient toachieve at least 50% pain relief, �95% confidence interval (CI), fornon-opioid analgesics at usual recommended doses.

Data from Collins et al (2000b), Barden et al (2003, 2004, 2005) and Mason et al (2004).

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rather rapidly following tissue injury and appear insignificant concentrations just one hour after trauma(Henman et al 1979). The PGE2 prostanoid is especiallyimportant in inflammatory pain and levels of PGE2

correlate with pain intensity levels following theextraction of impacted wisdom teeth (Roszkowski et al

1997). The dental model for analgesic efficacy examinesthe effect of analgesics after surgical extraction of thethird mandibular molar. This is a widely establishedmodel for inducing postsurgical inflammation-basedmoderate to severe pain and a useful tool for examin-ing the efficacy of analgesics (Norholt 1998). Thismodel is particularly relevant to our discussion onanalgesic efficacy for acute orofacial pain, since thereis evidence that NSAIDs may be more effective in den-tal surgery than in, for example, orthopaedic surgery(Hyllested et al 2002).Measuring analgesic efficacy. The number needed to treat

(NNT) represents the number of patients treated toachieve one patient with at least 50% pain relief; itdescribes the differences between active treatment andcontrol and provides a useful way of comparing the rela-tive efficacy of analgesics. The relative efficacy of non-opioid analgesics is presented in Fig. 15.2. Informationon dosing and side effects are shown in Table 15.1.

4.1. Conventional NSAIDs

The use of NSAIDs is advocated for the management ofpostoperative pain, and these drugs have been widelyused for pain relief in dentistry (Gobetti 1992). Conven-tional NSAIDs typically inhibit prostaglandin productionby both COX-1 and COX-2 enzyme systems. Even thoughsignificant advances in the understanding of cyclooxy-genases and prostaglandins and their involvement in painproduction have led to the development of the specificCOX-2 inhibitors, the nonselective NSAIDs have retainedtheir position as analgesics of choice for the general popu-lation (Gotzsche 2005). Important differences in adverseeffects exist between different NSAIDs; in contrast theirbeneficial effects seem similar (Gotzsche 2005). The differ-ences in side effects are most important in consideringwhich NSAID to choose, such as the relative risks of GIulceration compared with the potential increase in CV risk(Juni et al 2005). The evidence suggests that if one NSAIDis unsatisfactory, then switching to another NSAIDwill not provide better analgesia. Likewise doublingthe therapeutic dose of an NSAID leads to only asmall increase in effect, which may not be clinically rele-vant (Huskisson et al 1976). The dose–response curve satu-rates at high doses, and recommended dosages are close toproviding a ceiling effect (Eisenberg et al 1994). However,the incidence of adverse effects increases in an approxi-mately linear fashion with the dose (Henry et al 1996;Henry and McGettigan 2003). Thus, there is a ceiling effecton the analgesic efficacy but not on the adverse effects.Therefore, general principles of NSAID use include:

• Use the lowest effective dose for the shortest possible

duration; and

• After observing initial response and side effects,

titrate the dose and frequency so as to meet the needsof the individual patient.

4.1.1. Ibuprofen

Ibuprofen is a prototypical NSAID and represents thegold standard against which new analgesic agents areevaluated for efficacy in acute orofacial pain (Dionneand Berthold 2001; Zelenakas et al 2004). Ibuprofen isone of the most commonly prescribed NSAIDs for dentalpain and this drug is widely available over the counter(OTC, i.e. without prescription) around the world. It hasbeen shown that ibuprofen is an effective analgesic inthe control of postoperative dental pain in a number ofclinical trials (Winter et al 1978; Seymour et al 1996; Hershet al 2000). Ibuprofen 400mg is apparently the most suit-able dose after third molar surgery; 200mg did not differfrom placebo and there is little analgesic advantage inincreasing the dose to 600mg (Seymour et al 1996).Ibuprofen 800mg is, however, extremely effective in acutepain and may be indicated in moderate to severe cases(Fig. 15.2). Analgesic efficacy relative to placebo is similarfor ibuprofen 400mg (NNT 2.4, CI: 2.3–2.6), diclofenac50mg (NNT 2.3, CI: 2.0–2.7) and naproxen sodium 550mg (NNT 2.6, CI: 2.2–3.2) (Collins et al 2000a). Ibuprofen400mg is, however, superior to paracetamol 500mg(NNT 3.5, CI: 2.7–4.8) and aspirin 600/650mg (NNT 4.4,CI: 4.0–4.9) (Collins et al 2000a; Barden et al 2004; Masonet al 2004). Overall, ibuprofen was associated with thelowest relative GI risk, followed by diclofenac. Indeed,ibuprofen in dosages of 800–1200mg per day over 1–10days duration has an excellent GI safety profile not signif-icantly different from placebo (Kellstein et al 1999). OtherNSAIDs such as ketoprofen and piroxicam ranked

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Table 15.1 Doses and Medical Considerations of Common Analgesics

Drug

Dose

(mg)a

Maintenance Dose

(In mg � Dosages

per day)bMedical

Considerationsc

Pregnancyd

Breast

Feeding

Common Side

EffectseCategory Comment

Ibuprofen 400 400�4 RI, AIA, CIU

GI, Asthma

D DA

3rd

Minimal CSE, stomatitis

Naproxen Na 275–550 a. 275�3

b. 550�2

RI, Hep

GI, Asthma

B DA

3rd

Minimal

Naproxen 250–500 a. 250�3

b. 500�2

Etodolac 200

400

a. 200�3

b. 400�3

CV, GI, Neu,

Asthma

C DA Unclear CSE, malaise,

flatulence

Etodolac ERf 400–1000 once daily

Indomethacin 25–50 a. 25�3

b. 50�3

CV, GI, Asthma,

AIA

B DA

3rd

Minimal CSE, fatigue,

depression

Diclofenacg 25–50 a. 25�3 or 4

b. 50�2 or 3

CV, GI, Asthma,

AIA

C DA

3rd

Unclear CSE, flatulence

Diclofenac SRf 100 1 daily

Celecoxib 400 200�2 AIA, CIU, Sulfa C CI CI CSE, pharyngitis

Etoricoxib 120 a. 60�1

b. 120�1

Asthma, AIA, CIU,

CV, GI,

Prothrombotic

NS CI CI CSE, taste

disturbance,

flatulence,

fatigue

Lumiracoxib 400 a. 200�1

b. 400�1

GI, AIA, CIU, CV,

Prothrombotic

NS Unknown CSE

Acetaminophenh 500

1000

a. 500�4

b. 1000�4

RI, Derm, alcohol,

Hypothermia

A Avoid frequent

use in third

trimester

Minimal Rash,

hypothermia

Dipyrone 500

1000

a. 500�4

b. 1000�4

Haem, G6PD,

Hep

NS Unclear Rash, GI,

AGRAN, AN

a For moderate to severe pain.bAlternative regimens, when available, are shown as a, b.c RI, renal insufficiency; AIA, aspirin-induced asthma; CIU, chronic idiopathic urticaria; GI, gastrointestinal; Hep, liver disease; CV, cardiovascular; Neu, neurological; Derm,

dermatologic; Haem, haematologic; G6PD, glucose-6-phosphate dehydrogenase deficiency; alcohol, abusers (>3 drinks daily).dAccording to the American or Australian food and drug administrations and United Kingdom product labelling. DA, use in late pregnancy may induce premature

closure of the ductus arteriosus. 3rd, use in third trimester may delay birth.eCSE: Common side effects of all NSAIDs include oedema, gastrointestinal complaints (abdominal pain, diarrhoea, constipation, dyspepsia, heartburn, nausea, vomiting),

rashes or pruritus, tinnitus, dizziness, somnolence, headache and increased liver function tests. AGRAN, agranulocytosis; AN, anaemia.f Extended or modified release formulation.gDiclofenac is also available in 50 and 75 mg with 200 mg misoprostol—this formulation is contraindicated during pregnancy.hContraindicated in first and second trimesters unless the potential benefit to the patient outweighs the potential risk to the foetus.

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highest for risk and indomethacin, naproxen, sulindacand aspirin occupied intermediate positions. Higherdoses of ibuprofen (>1200mg/d) were associated withrelative risks similar to those with naproxen and indo-methacin (Henry et al 1996). In summary, extensive epide-miological data on efficacy and safety support the use of400 mg of ibuprofen first when choosing an NSAID(Henry et al 1996). Recent evidence points to an increasedrisk for serious CV events with ibuprofen particularly at

high doses (Juni et al 2005; Kearney et al 2006; McGettiganand Henry 2006).Clinical considerations. For mild to moderate pain 400mg

as an initial dose followed by 400 mg orally every 4 hoursor as needed is effective. Strong pain may be treated withan 800 mg initial dose. Analgesic onset occurs within 30minutes (Malmstrom et al 2004a).

Common side effects of ibuprofen include oedema, GIcomplaints (abdominal pain, diarrhoea, constipation,

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dyspepsia, heartburn, nausea, vomiting), rashes or pruri-tus, tinnitus, dizziness, somnolence, headache andincreased liver function tests. Rarer but serious sideeffects include CV events, GI ulceration, anaemia, agranu-locytosis, leukopenia, hepatitis and depression. Erythemamultiforme or Stevens-Johnson syndrome has also beenreported. Severe, even fatal, anaphylactic-like reactionshave been reported in patients who have experiencedasthma, urticaria or allergic-type reactions after takingaspirin or other nonsteroidal anti-inflammatory agents.Treatment of patients with renal impairment should becoordinated with the treating physician and initiated atthe lowest recommended dosage. The patient must bemonitored closely and dosage reduced if necessary. Ibu-profen should be avoided in late pregnancy particularlyas it may cause premature closure of the ductus arterio-sus (Pregnancy Category: D). As for all NSAIDS, ibupro-fen may delay the onset of childbirth. The danger forbreastfeeding infants is minimal.

4.1.2. Naproxen

Meta-analysis of six trials that compared naproxensodium 550mg with placebo gave an NNT of 2.6 (95%CI: 2.2–3.2) (Mason et al 2003, 2004). Naproxen sodiumis more suitable for treatment of acute pain thannaproxen due to an earlier onset of analgesia (30 minutesversus 1 hour, respectively). The analgesic efficacy andonset are similar to that of ibuprofen 400mg (Fig. 15.2)but naproxen produces a longer duration of analgesia.Weighted mean time to re-medication for naproxensodium 550mg was 7.6 hours compared with 2.6 hoursfor placebo, and the effects of one dose last, on average,up to 7 hours (Mason et al 2003, 2004). It was concludedthat naproxen sodium 440–550mg and naproxen 400mgadministered orally are effective analgesics for the treat-ment of acute postoperative pain in adults. A low inci-dence of adverse events was found with no significantdifference between treatment and placebo, but reportingwas inconsistent (Mason et al 2003).Clinical considerations. For mild to moderate pain an ini-

tial dose of naproxen sodium 550mg will provide effi-cient and rapid analgesia. Maintenance of relief may beobtained with 275mg of naproxen sodium orally every6–8 hours or 550mg every 12 hours as needed. Its longhalf-life may offer some advantages. There is evidencethat naproxen may also possess fewer CV complicationsfor both short- and long-term therapy (Juni et al 2005;Kearney et al 2006; McGettigan and Henry 2006). Thismay therefore lead to naproxen becoming the NSAID ofchoice, particularly in at-risk individuals (Antman et al

2007), but the evidence must be regularly reviewed byclinicians. Doses should not exceed 1350mg/d initially,then 1100mg/d. Alternatively, in order to reduce sodiumconsumption, maintenance may be performed withnaproxen 250mg orally every 6–8 hours or 500mg every12 hours as needed.

Common side effects of naproxen include oedema, GIcomplaints (abdominal pain, diarrhoea, constipation, dys-pepsia, heartburn, nausea, vomiting), stomatitis, rashes orpruritus, tinnitus, dizziness, somnolence, headache andincreased liver function tests. Rarer but serious sideeffects include CV events, GI ulceration, anaemia, agranu-locytosis, leukopenia, hepatitis and depression. Stevens-Johnson syndrome as well as severe, even fatal, anaphy-lactic-like reactions have been reported in patients whohad experienced asthma, urticaria or allergic-type reac-tions after taking aspirin or other nonsteroidal anti-inflammatory agents. Naproxen should be used only ifabsolutely necessary and with caution in patients with ahistory of asthma. Geriatric patients should not exceed200mg every 12 hours. Patients with liver disease or renalimpairment may require dosage reduction and need to bemonitored closely; such cases should be treated in con-junction with the treating physician. Naproxen shouldbe avoided in late pregnancy particularly as it may causepremature closure of the ductus arteriosus (PregnancyCategory: B). As for all NSAIDs, naproxen may delay theonset of childbirth. The danger for breastfeeding infantsis minimal.

4.1.3. Etodolac

Etodolac, a pyrano-indoleacetic acid derivative, is a mem-ber of a new class of NSAIDs that preferentially inhibitCOX-2 (Riendeau et al 2001). Etodolac is approved bythe US Food and Drug Administration (FDA) for treatingacute pain, in adults but not children. Some studies haveindicated a more rapid onset of analgesic action with eto-dolac 200mg and significantly better analgesic efficacycompared to aspirin 650mg (Gaston et al 1986); however,other studies have not confirmed these findings (Hutton1983). The analgesic efficacy of etodolac 200mg is compa-rable to paracetamol 600mg plus codeine 60mg, andetodolac 400mg is significantly superior to the latter com-bination (Mizraji 1990). Etodolac possesses a more favour-able therapeutic index between anti-inflammatory effectsand gastric irritation than other NSAIDs (Martel andKlicius 1982).Clinical considerations. Etodolac is also available in an

extended (modified) release formulation. For mild tomoderate acute pain it is advisable to use the immediaterelease formulation: 200–400mg orally every 6–8 hoursas needed up to a maximum of 1200mg/d. Maintenancecan also be performed with the extended release formula-tion: for adults over 50 kg in weight 800–1200mg every 24hours.

Common side effects of etodolac include GI complaints(abdominal pain, diarrhoea, dyspepsia, flatulence, nau-sea) and malaise. Oedema has been reported with theuse of etodolac so it should be avoided in patientswith CV disease. Rarer but serious side effects includebronchospasm, CV events, GI ulceration, anaemia,agranulocytosis, leukopenia, hepatitis and depression.

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Stevens-Johnson syndrome and toxic epidermal necro-lysis have also been reported. As for other NSAIDsetodolac is to be avoided in late pregnancy since it maycause premature closure of the ductus arteriosus (Preg-nancy Category: C). The danger for breastfeeding infantsis minimal.

4.1.4. Diclofenac

Diclofenac is a preferential COX-2 inhibitor that has beenextensively used for the treatment of acute and chronicinflammatory pain. Diclofenac is FDA approved for rheu-matoid and osteoarthritis, ankylosing spondylitis, inflam-matory disorder of the eye and refractive keratoplasty. Inaddition to standard (12.5, 25, 50, 75mg) and slow release(100mg) formulations, diclofenac is available as supposi-tories and a 1% topical gel (seeChapter 16). For patientswithGI discomfort diclofenac is available as 50 or 75mg with200 mg of misoprostol, a gastroprotective prostaglandinanalogue.Clinical considerations. Diclofenac is efficacious in acute

pain; the analgesic efficacy of diclofenac 50mg (NNT2.3, CI: 2.0–2.7) is similar to that of ibuprofen 400mg ornaproxen sodium 550mg (Collins et al 2000a). It may beprescribed as 25–50mg three times daily or as once-dailydosage of 100mg of its slow release formulation.

Diclofenac is usually well tolerated with relatively fewGI side effects but may cause dyspepsia, nausea, abdomi-nal pain and constipation. However, GI bleeding and per-foration have been reported. Headache, dizziness anddrowsiness are common side effects. It is contraindicatedin patientswhohave experienced asthma, urticaria or aller-gic-type reactions after taking aspirin or other nonsteroidalanti-inflammatory agents; severe, even fatal, anaphylactic-like reactions have been reported. Recently diclofenac hasbeen shown to significantly increase the risk of seriousCV events (Andersohn et al 2006; Helin-Salmivaara et al

2006; Kearney et al 2006; McGettigan and Henry 2006)and has also been associated with fluid retention andoedema. Increased liver function tests are commonlyobserved but hepatitis is relatively uncommon. Stevens-Johnson syndrome and toxic epidermal necrolysis havealso been reported.

Diclofenac should be avoided in late pregnancy partic-ularly as it may cause premature closure of the ductusarteriosus (Pregnancy Category: B). As for all NSAIDs, itmay delay the onset of childbirth. The diclofenac/miso-prostol combination is contraindicated in pregnancy.The risks of diclofenac for lactating infants are unclear.

4.1.5. Indomethacin

Currently indomethacin is largely unused in routine den-tistry or indeed for the control of any acute pain due tocommonly occurring and significant side effects. However,its important diagnostic and therapeutic role in paroxys-mal hemicrania and hemicrania continua mandates a brief

review. Indomethacin is FDA-approved for rheumatoidand osteoarthritis, gout, ankylosing spondylitis, patentductus arteriosus and acute shoulder pain.

Indomethacin has been shown to experimentally blockneurogenic inflammation (Buzzi et al 1989). Data fromanimal and human experiments have shown that IVindomethacin produces rapid, significant reductions(26–40%) in cerebral blood flow (Wennmalm et al 1984;Slavik and Rhoney 1999; Speziale et al 1999). Indometha-cin also possesses non-cyclooxygenase-based modes ofaction that may differentially modulate blood vessels(Feigen et al 1981; Quintana et al 1983, 1988). An interac-tion between indomethacin and nitric oxide (NO),involved in headache pathogenesis, has been proposed(Castellano et al 1998). Findings from an experimentalpain model suggest that an interaction between indo-methacin and local NO synthesis is involved in the anti-nociceptive effects of indomethacin (Ventura-Martinezet al 2004).Clinical considerations. Indomethacin is available in stan-

dard and slow release formulations (75mg) and addition-ally as suppositories. Standard dosages are 25–50mgtwice or three times daily. In paroxysmal hemicrania(see Chapter 10) most cases will respond to 25mg threetimes daily within 24 hours; however, therapy should becontinued for 3 days at 75mg followed, if needed, by150mg for a further 3 days (Pareja and Sjaastad 1996).

Adverse effects are probably more frequent with indo-methacin than with most other NSAIDs. The most com-mon are GI disturbances (abdominal pain, constipation,diarrhoea, dyspepsia, nausea, vomiting), headache, ver-tigo, dizziness and lightheadedness. More serious butrarer events include GI perforation, ulceration and bleed-ing. Rectal irritation and bleeding have been reportedoccasionally in patients who have received indomethacinsuppositories. Other adverse effects include depression,drowsiness, tinnitus, confusion, insomnia, oedema andweight gain, hypertension, haematuria and stomatitis.Indomethacin may increase the risk of serious CV eventsand is to be avoided in at-risk patients (Helin-Salmivaaraet al 2006; McGettigan and Henry 2006). Indomethacin iscontraindicated in patients who have experiencedasthma, urticaria or allergic-type reactions after takingaspirin or other nonsteroidal anti-inflammatory agents;severe, even fatal, anaphylactic-like reactions have beenreported. Serious skin reactions such as Stevens-Johnsonsyndrome and toxic epidermal necrolysis are rare. Nodose adjustment is needed in renal disease but indometh-acin should be used with caution in hepatic disease; theelderly require a 25% dose reduction. A complaint ofblurred vision may be an early symptom of indometha-cin-related corneal deposits and warrants evaluation byan ophthalmologist; these effects are reversible.

Indomethacin should be avoided in late pregnancyparticularly as it may cause premature closure of the duc-tus arteriosus (Pregnancy Category: B). As for allNSAIDs, indomethacin may delay the onset of childbirth.

P15

Maternal indomethacin is considered compatible withbreastfeeding.

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4.2. Selective COX-2 Inhibitors (Coxibs)

The documentation of significantly increased cardiovascu-lar and renal risks with COX-2 inhibitors has raised impor-tant issues relating to their continued use, particularly forchronic pain (McGettigan and Henry 2006; Zhang et al

2006). Moreover the lack of any significant increase in anal-gesic efficacy of COX-2 inhibitors over the classicalNSAIDs suggests that we should probably stay with thewell-researched older NSAIDs such as ibuprofen andnaproxen. Recent meta-analyses also show that adverseCV events associated with COX-2 inhibitors actually occurquite quickly after initiation of therapy and not monthsafterwards aswas initially claimed (McGettigan andHenry2006). This raises the important question whether COX-2inhibitors should be used at all for pain control (Graham2006). Our approach has been to first employ conventionalNSAIDs particularly ibuprofen and naproxen. Emergingevidence of CV safetywould suggest that naproxen is pres-ently the drug of choice. However, theCOX-2 inhibitors arestill widely available and are extensively used particularlyin patients with GI problems.

4.2.1. Rofecoxib

Rofecoxib was voluntarily withdrawn by the manufac-turer in 2004 due to safety concerns of an increased riskfor CV events, including heart attack and stroke. How-ever, rofecoxib’s effectiveness for acute pain is excellentand as one of the first selective COX-2 inhibitors itdeserves brief review.

The NNT for rofecoxib 50mg versus placebo wasfound to be 2.2 (95% CI: 1.9–2.4) (Barden et al 2005) witha median time to onset of analgesia of 34 minutes (Desjar-dins et al 2005). After surgical extraction of third molarsrofecoxib 50mg demonstrated significantly better analge-sic efficacy and duration than celecoxib 400mg(Malmstrom et al 2002), enteric-coated diclofenac sodium(as a single 50-mg dose and 3�50mg doses) (Changet al 2002) and codeine/acetaminophen 60/600mg(Chang et al 2005). The overall analgesic efficacy of rofe-coxib 50mg was similar to that of ibuprofen 400mg butlasted significantly longer (up to 24 hours). A furtherstudy showed that 50mg rofecoxib was the lowest dosethat reproducibly demonstrated an analgesic effect com-parable to that of naproxen sodium 550mg or ibuprofen400mg (Morrison et al 2000).

4.2.2. Celecoxib

Ibuprofen 1200mg per day (‘liquigel’) was compared to asingle dose of celecoxib (200mg) and placebo in patientswith moderate or severe pain following surgical extrac-tion of impacted third molars (Doyle et al 2002). Time to

meaningful relief was significantly shorter, and the mean4-, 8-, and 12-hour summed pain relief combined withpain intensity difference scores were significantly higherfor ibuprofen liquigel than for celecoxib. Both active treat-ments were significantly more effective than placebo, welltolerated with no differences in incidence or severity ofadverse events. Ibuprofen 400–600mg has been shownsuperior to celecoxib 200–400mg, respectively (Khanet al 2002; Malmstrom et al 2002). Similarly, rofecoxib50mg has greater overall analgesic efficacy than celecoxib400mg, as well as a significantly longer duration of anal-gesic effect (Malmstrom et al 2002).

A recent systematic review concluded that celecoxib200mg is an effective means of postoperative pain relief,similar in efficacy to aspirin 600/650mg, and paracetamol1000mg. The NNT for celecoxib 200mg was 4.5 (CI: 3.3–7.2). However, the trials included used celecoxib 200mg,half the recommended dose for acute pain. More trialsare needed to estimate efficacy for 400mg and providedata for pooled quantitative estimates of adverse effects(Barden et al 2003). Importantly it seems that although200mg celecoxib is safe in terms of CV events, 400mg sig-nificantly increases the risk for serious CV events (McGet-tigan and Henry 2006). Celecoxib is therefore inferiorto first-line NSAIDs, such as naproxen or ibuprofen, bothin analgesic efficacy and safety profile so it is rarelyemployed for pain control.Clinical considerations. For mild to moderate acute pain

an initial dose of 400mg orally once plus 1 additional 200mg dose as needed on the first day is recommended.Main-tenance may be achieved by 200mg twice a day as needed.

Common side effects of celecoxib include oedema, GIcomplaints (abdominal pain, diarrhoea, dyspepsia, flatu-lence, nausea), rash, dizziness, headache, insomnia andrespiratory problems (pharyngitis, sinusitis, rhinitis). Rarerbut serious side effects include CV events, GI ulceration,anaemia, increased liver function tests and hepatitis. Severe,even fatal, anaphylactic-like reactions have been reported inpatients who have experienced asthma, urticaria or allergic-type reactions after taking aspirin or other nonsteroidal anti-inflammatory agents. Erythema multiforme or Stevens-Johnson syndrome has also been reported. Celecoxib is con-traindicated in patients with hypersensitivity to sulphona-mides and in asthmatics. Patients with a history ofurticaria or allergic-type reactions after taking aspirin orother nonsteroidal anti-inflammatory agents are at risk ofsevere, even fatal, anaphylactic-like reactions. Celecoxib isin pregnancy category C but many consider all COX-2 con-traindicated during pregnancy. Use during breastfeedingis contraindicated.

4.2.3. Valdecoxib

Valdecoxib was voluntarily withdrawn in 2005 due tosafety concerns of increased risk of CV events, andreports of serious and potentially life-threatening skinreactions, including death. Valdecoxib is a new highly

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selective COX-2 inhibitor with a rapid onset of action andsignificant analgesic properties. In patients with rheuma-toid arthritis, valdecoxib 10, 20 or 40mg/d was signifi-cantly more effective than placebo, and similar inefficacy to naproxen 500mg twice daily; there were nosignificant differences in efficacy between the threedosages of valdecoxib (Ormrod et al 2002).

Patients undergoing oral surgery and receiving valde-coxib 40mg experienced a significantly quicker onset ofanalgesia, significantly improved pain relief and lowerpain intensity than did patients receiving rofecoxib 50mg (Fricke et al 2002). Valdecoxib, rofecoxib and placebowere equally well tolerated.

Following oral surgery, subjects receiving valdecoxib(20 or 40mg) experienced a rapid onset of analgesia and,at valdecoxib 40mg, a level of pain relief comparable withthat of those who received oxycodone/acetaminophen(10mg/1000mg) (Daniels et al 2002). Both valdecoxibdoses had a significantly longer duration of analgesiceffect than did oxycodone/acetaminophen. Pooled safetydata demonstrated that each valdecoxib dose had a toler-ability profile superior to that of oxycodone/acetamino-phen and similar to that of placebo.

4.2.4. Etoricoxib

Etoricoxib is a novel COX-2 inhibitor with high selectivityfor COX-2 (106 COX-2/COX-1 ratio, as compared to 35for rofecoxib or 1.78 for ibuprofen), and is as effective asibuprofen and naproxen and more effective than acet-aminophen for arthritic pain (Cochrane et al 2002).

In patients, after extraction of two or more third molarsetoricoxib 120mg and oxycodone/acetaminophen 10/650mg achieved significant analgesia with a rapid onset,although the time was slightly faster for oxycodone/acet-aminophen (Chang et al 2004). The peak effect was similarfor both drugs. Oxycodone/acetaminophen treatmentresulted in more frequent drug-related nausea and vomit-ing compared with etoricoxib treatment (Chang et al

2004).The duration of analgesic effect after third molar

extractions, defined as median time to rescue medicationuse, was >24 hours for etoricoxib 120mg, 20.8 hours fornaproxen sodium 550mg, 3.6 hours for acetaminophen/codeine 600/60mg and 1.6 hours for placebo. All threeactive treatments had rapid onset of analgesia (Mal-mstrom et al 2004a). The median time to onset of analge-sia for etoricoxib 120–240mg is about 25–30 minutes(Malmstrom et al 2004a,b). There were no significant dif-ferences in the onset of analgesia between etoricoxib andibuprofen. The duration of analgesic effect was >24 hoursfor etoricoxib 120–240mg, and 12.1 hours for etoricoxib 60mg. The duration of effect was significantly longer withall four etoricoxib doses than with ibuprofen (Malmstromet al 2004b). Etoricoxib 120mg provided superior overallanalgesic effect with a smaller percentage of patientsexperiencing nausea compared to both oxycodone/

acetaminophen 10/650mg and codeine/acetaminophen60/600mg (Malmstrom et al 2005). Based on these pla-cebo-controlled studies we calculated a mean NNT of1.6 for good to excellent pain relief at 8 hours using 120mg etoricoxib and an NNT of 1.4 using 180mg etoricoxib(Malmstrom et al 2004a,b, 2005). These attractive NNTsmust, however, be taken together with NNTs for theactive controls in these studies that were similarly low:1.4 for 550mg naproxen sodium, 1.7 for 400mg ibuprofenand 1.6 for an oxycodone/paracetamol 10/650mgcombination.Clinical considerations. The optimal doses of etoricoxib

have not been clearly established. An oral dose of 120mg has been effective in acute post-dental surgery witha rapid onset (25–30 minutes) with no significant benefitobtained at higher doses (180 or 240mg). Its long half-lifeoffers the possibility of once-daily dosing.

GI effects (nausea, vomiting, diarrhoea, flatulence,taste disturbances, decreased appetite), headache, dizzi-ness and fatigue have been reported but are relativelyrare. Whether etoricoxib is as problematic in terms ofCV safety as the earlier COX-2 drugs is unclear. Earlydata suggest that etoricoxib is indeed associated withthromboembolic events and an increased CV risk andwe advise great caution until further data accumulate(Andersohn et al 2006; Helin-Salmivaara et al 2006). Etor-icoxib is contraindicated in patients with a history ofbronchospasm, rhinoconjunctivitis or urticaria/angioe-dema associated with aspirin or other NSAIDs due to arisk of anaphylactic-like reactions. A history of adult-onset asthma, chronic rhinitis, nasal polyps and chronicurticaria/angioedema predispose to these reactions. It isalso contraindicated in patients with hypertension, recentMI, angina or other CV disease due to a potential for fluidretention and the possibility of prothrombotic activity.Etoricoxib has not been categorized for use in pregnancy;however, many consider all COX-2 contraindicatedduring pregnancy. Similarly, use during breastfeeding iscontraindicated.

4.2.5. Lumiracoxib

Lumiracoxib is a new coxib with even higher COX-2 selec-tivity (COX-2/COX-1 ratio¼700) (Stichtenoth and Frolich2003). In patients with postoperative dental pain lumira-coxib 100mg was comparable to ibuprofen 400mg butlumiracoxib 400mg was superior to both (Zelenakas et al

2004). Lumiracoxib 400mg demonstrated the fastest timeto analgesic onset (37.4 min) followed by ibuprofen thenlumiracoxib 100mg (Zelenakas et al 2004).

Following third molar extraction a single oral dose oflumiracoxib 400mg was superior to rofecoxib 50mg, cel-ecoxib 200mg or placebo at 8 hours post dose (Kellsteinet al 2004). Lumiracoxib demonstrated the fastest onsetof analgesia and the longest time to rescue medicationuse. Patient global evaluation of lumiracoxib was compa-rable to rofecoxib and superior to celecoxib and placebo.

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All treatments were well tolerated. A recent review(Bannwarth and Berenbaum 2005) found that in patientswith acute pain related to primary dysmenorrhoea ordental or orthopaedic surgery, lumiracoxib 400mg/dwas at least as effective as standard doses of traditionalNSAIDs and other coxibs.

Endoscopic studies have indicated that lumiracoxib isassociated with a rate of gastroduodenal ulcer formationsignificantly lower than that with ibuprofen and doesnot differ from celecoxib. The cumulative 1-year inci-dence of ulcer complications (primary endpoint) was sig-nificantly reduced by approximately threefold onlumiracoxib 400mg/d compared with naproxen 1000mg/d or ibuprofen 2400mg/d. Regarding CV eventsthere was no significant difference between lumiracoxiband combined NSAIDs.Clinical considerations. A single dose of lumiracoxib

400mg is an effective analgesic for mild to moderate pain(extraction of impacted third molars). Analgesic onsetoccurs in about 35 minutes with about 12 hours duration.If needed, maintenance may be obtained with 200–400mgdaily. Lumiracoxib is contraindicated in acute pepticulcer or GI bleeding as it may delay healing. As withother NSAIDs a history of bronchospasm with rhinocon-junctivitis or urticaria/angioedema associated with aspi-rin or other nonsteroidal anti-inflammatory agents carriesa high risk of anaphylactic-like reactions.

Side effects of lumiracoxib include abdominal pain thatmay rarely reflect GI ulceration. Because of its potential toinduce fluid retention and prothrombotic activity lumira-coxib is contraindicated in patients with hypertension,recent MI, angina or other CV disease. There is no avail-able data on the use of lumiracoxib in pregnancy andbreastfeeding. However, in view of the contraindicationsto other selective COX-2 inhibitors we suggest not touse these drugs in pregnant or lactating mothers till fur-ther data are collected. It should be noted that the lasttwo drugs (etoricoxib and lumiracoxib) have yet to beapproved by the US FDA (Huber and Terezhalmy 2006).

4.3. Dual-Acting NSAIDs

As discussed earlier the standard NSAIDs and the newerselective COX-2 inhibitors are associated with a numberof severe GI, CV and renal side effects. This is due tothe inhibition of protective prostaglandins and theunchecked effects of specific leukotrienes on the gastricmucosa. Additionally the proalgesic and proinflamma-tory effects of the leukotrienes are largely unaffectedby these drugs. Drugs acting on both COX and lipo-oxy-genase enzymes are an attractive option and are collec-tively referred to as dual-acting NSAIDs (Bertolini et al2001; Charlier and Michaux 2003). The dual-actingNSAIDs are still in the experimental stage but showpromising results in animal models of pain and osteoar-thritis (Hinz and Brune 2004; Moreau et al 2006; Singhet al 2006).

4.4. Conclusions

Significant advances in the understanding of COXs andprostaglandins have led to the development of the spe-cific COX-2 inhibitors. Yet the nonselective NSAIDsremain a reliable class of analgesics due to their predict-ability and tolerability (Gotzsche 2005). Important differ-ences in adverse effects exist between different NSAIDsand depend amongst other factors on their selectivityfor the different COXs. As reviewed earlier, however,the analgesic efficacy of NSAIDs and the newer COX-2 inhibitors seems similar. These differences have a majoreffect on our considerations; for example, reduction inulcers with COX-2 inhibitors should be weighed againsttheir potential increase in CV risk compared with theolder NSAIDs (Juni et al 2005). The medical history ofthe patient is therefore mandatory, and provides the mostimportant consideration for selection of the proper anal-gesic (Antman et al 2007).

Ibuprofen remains the gold ‘analgesic’ standard againstwhich new pain relieving drugs are evaluated (Dionneand Berthold 2001; Zelenakas et al 2004). However,naproxen has been shown in most studies not to increaseCV risk and is thus the NSAID of choice, particularly inat-risk individuals (Graham et al 2005; Kearney et al 2006;McGettigan and Henry 2006). Unless there is a specificcontraindication to their use, short-term NSAIDs are effec-tive for treating acute dental pain in ambulatory patientswho generally experience a higher incidence of adverseeffects after ingesting an opioid analgesic (Dionne andBerthold 2001; Savage and Henry 2004). COX-2 inhibitorsdo not posses any additional efficacy over traditionalNSAIDs, except for a longer duration of analgesia insingle-dose studies (Romsing and Moiniche 2004). Ibupro-fen 400mg is considered the first-line NSAID based on itsgood safety profile, high efficacy and low cost (Sachs2005). The evidence to date fails to demonstrateany therapeutic advantage of COX-2 inhibitors over ibu-profen in the treatment of acute dental pain (Huber andTerezhalmy 2006). Accumulating evidence continues tosupport that naproxen is not cardioprotective as oncethought. In most studies naproxen does not increase therisk for serious CV events, suggesting that it may be saferthan other NSAIDs (Graham 2006). However, recent dataindicate that naproxen does have potentially serious CVcomplications (ADAPT 2006).

5. Paracetamol (Acetaminophen)

Single doses of paracetamol are effective analgesics foracute postoperative pain and with few adverse effects.Paracetamol is generally considered to be a weak inhibi-tor of the synthesis of prostaglandins. Indeed, paraceta-mol fails to inhibit the formation of PGs in peripheraltissues and does not suppress the inflammation ofrheumatoid arthritis (Flower et al 1972). It does, however,

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decrease postoperative swelling in humans and sup-presses inflammation in rats and mice (Graham and Scott2005). Paracetamol depresses nociceptive activity evokedin thalamic neurons by electrical stimulation of nocicep-tive afferents, and presents evidence for a central analgesiceffect independent of endogenous opioids (Carlsson andJurna 1987). COX-3, a splice variant of COX-1, has beensuggested to be the target of paracetamol’s action(Chandrasekharan et al 2002), but genomic and kineticanalysis indicates that this selective interaction is unlikelyto be clinically relevant (Graham and Scott 2005). There isconsiderable evidence that the analgesic effect of paraceta-mol is central and is due to activation of descending sero-tonergic pathways, but its primary site of action may stillbe inhibition of PG synthesis (Libert et al 2004; Grahamand Scott 2005).

Forty-seven reportswere included in a recent systematicreview of paracetamol (Barden et al 2004). The NNT over4–6 hours following a single dose of paracetamol 500mgwas 3.5 (2.7–4.8) and increasing doses up to 1500mg didnot result in better NNTs. Studies report a variable inci-dence of adverse effects that are generally mild and tran-sient and there were no statistically significant differencesbetween paracetamol 975/1000mg and placebo. Otherreviews demonstrate similar ranges of efficacy with NNTsof 3.5–5.0 for 600–1000mg of paracetamol (Moore et al 1997,2000).

Paracetamol 975/1000mg is as effective as aspirin 600/650mg (NNT4.4, CI: 4.0–4.9), but less effective than ibupro-fen 400mg (NNT 2.4, CI: 2.3–2.6), and diclofenac 50mg(NNT 2.3, CI: 2.0–2.7); see Fig. 15.2 (Barden et al 2004). Para-cetamol is known to have fewer long-term GI adverseeffects than other NSAID treatment options, though long-term use is associated with renal and hepatic problems.Ibuprofen liquigel 200/400mg provided greater overalland peak analgesic effects with a more rapid onset to

Table 15.2 Pharmacotherapeutic Strategy for the Management of Acute O

Pain

Intensity Options Healthy Patient

Gastrointestinal

Limitations

Mild to

moderate

1st Paracetamol 500 mg Paracetamol 500 mg

2nd Ibuprofen 400 mg COX-2 inhibitor

3rd Naproxen 500 mg Naproxen/ibuprofen with

proton pump inhibitor

Moderate

to severe

1st Ibuprofen 800 mg Oxycodone 5 mg

paracetamol 500 g

2nd Oxycodone 5 mg

paracetamol 500 mg

Dipyrone 500–1000 mg

a There is a standard warning against use of COX-2 inhibitors in cases of asthma and

controlled studies that found rofecoxib, celecoxib and etoricoxib safe in these cases

Sanchez-Borges et al 2005).b Paracetamol demonstrates cross reactivity in aspirin-induced asthma but usually at

analgesia than did acetaminophen 1000mg following sur-gical removal of impacted third molars (Hersh et al 2000).

A recent qualitative review of head-to-head compari-sons of paracetamol with NSAIDs found that of 16 dentalstudies, 8 showed that NSAIDs were superior to paracet-amol, 5 showed equal results and 2 showed paracetamolwas superior to NSAIDs (Hyllested et al 2002). NSAIDstherefore seem to be superior to paracetamol in dentalsurgery, regarding both pain scores and re-medication(Hyllested et al 2002). On the other hand, a recent cross-over study of 36 patients subjected to surgical removalof bilateral third molars, and acting as their own controls,compared the effects of ibuprofen 600mg�4/d withthose of paracetamol 1000mg�4/d, and found no signif-icant differences in pain scores or swelling between thetwo drugs (Bjornsson et al 2003).

Paracetamol is therefore a viable alternative to theNSAIDs, especially because of the low incidence ofadverse effects, and should be the preferred choice inhigh-risk patients (Hyllested et al 2002); see alsoTable 15.2. For example, the sustained use of paracetamolduring oral anticoagulant therapy in itself does not pro-voke clinically relevant INR changes (Gadisseur et al

2003). Furthermore, based on the data available to date,it still seems prudent to use NSAIDs only in thosepatients in whom there is good evidence of improved effi-cacy over paracetamol (Nikles et al 2005). The use of high-dose paracetamol (4 g daily) for 4 or more days is,however, associated with increased levels of alanine ami-notransferase, suggesting significant liver toxicity (Wat-kins et al 2006).

The available evidence supports the use of acetamino-phen in doses up to 1000mg as the initial choice for mildto moderate acute pain. In some cases, modest improve-ments in analgesic efficacy can be achieved by addingor changing to an NSAID.

rofacial Pain

Cardiovascular

Limitations Anticoagulants

Asthma, Urticaria

or Angioedema

Paracetamol 500 mg Paracetamol 500 mg COX-2 inhibitora

Naproxen 500 mg COX-2 inhibitor Paracetamol 500 mgb

Oxycodone 5 mg

paracetamol 500 mg

Oxycodone 5 mg

paracetamol 500 mg

COX-2 inhibitora

Dipyrone

500–1000 mg

COX-2 inhibitor Oxycodone 5 mg

paracetamol 500 mgb

urticaria. However, this warning could not be validated by several

(Martin-Garcia et al 2002; Martin-Garcia et al 2003; Celik et al 2005;

doses higher than 500 mg (Settipane et al 1995).

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Clinical considerations. For mild to moderate pain 500–

1000mg orally every 4 hours as needed to a maximumof 4 g/d. Common adverse effects include rash and hypo-thermia. The use of paracetamol in alcohol abusers (>3alcoholic drinks per day) is contraindicated. Moreoverthe observation of elevated liver enzymes during high-dose therapy (4 g daily) is a significant concern inpatients with liver disease (Watkins et al 2006). Paraceta-mol is the analgesic of choice during pregnancy or breast-feeding (Pregnancy Category: A). However, frequent useof paracetamol during the last trimester of pregnancy iscontraindicated.

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6. Dipyrone

Dipyrone, the most widely used pyrazolone derivative, isa rapidly reversible inhibitor of cyclooxygenase (Brogden1986). Dipyrone possesses analgesic, antipyretic, anti-inflammatory and spasmolytic properties, and is oftenclassified as peripherally acting. For example, it was foundthat dipyrone inhibited platelet aggregation and markedlydecreased TXA2 synthesis, which is consistent with a com-petitive inhibitory effect of dipyrone on PG synthetaseactivity (Eldor et al 1984). It has been suggested that a cen-tral action is also involved in the analgesic effect of dipyr-one, and that this central action manifests itself by anactivation of inhibition originating in the periaqueductalgrey (Carlsson et al 1986). Dipyrone depresses pain-evokedpotentials in thalamic neurons but less effectively thanmor-phine (Carlsson et al 1988). Naloxone abolishes the depres-sant effects of morphine but not of dipyrone (Carlsson et al

1988). Thus it appears that several mechanisms contributeto the analgesic effect of dipyrone, including the possibilitythat the effects of dipyrone result from antagonism of thepharmacological effects of PGs rather than from inhibitionof their synthesis (Brogden 1986).

Dipyrone is relatively safe for the GI tract. Thus, admi-nistered for 2 weeks, dipyrone has effects on the gastricand duodenal mucosa comparable to those of paraceta-mol and placebo, though noticeable damage is detectableat a dosage of 3 g/d (Bianchi Porro et al 1996). Dipyrone iscomparable in this respect to paracetamol and much saferthan diclofenac (Sanchez et al 2002). Dipyrone inhibitsplatelet aggregation and markedly decreases TXA2 syn-thesis (Eldor et al 1984).

Pyrazolone hypersensitivity associated with chronicasthma is similar to aspirin-induced asthma and probablyinvolves PG inhibition and overproduction of cysteinylleukotrienes. Other patients may develop anaphylaxis,urticaria and other forms of rash and the hypersensitivityis due to immunological mechanisms (Czerniawska-Mysikand Szczeklik 1981). However, a mixed form is probablymore common. Thus, of patients with dipyrone intolerancewith and without asthma, 76% of asthmatics and 9% ofnon-asthmatics reacted with bronchospasm after ingestionof dipyrone, while urticaria developed in 26% of

asthmatics and 65% of non-asthmatics (Karakaya andKalyoncu 2002).

The use of dipyrone as an analgesic is controversial. Itis used most commonly to treat postoperative pain, colicpain, cancer pain and migraine, and in many countries,e.g. Russia, Spain, Brazil, and in many parts of South-America and Africa, it is the most popular non-opioidfirst-line analgesic. In others it has been banned (e.g.USA, UK) because of its association with potentially life-threatening blood dyscrasias such as agranulocytosis.This side effect is discussed in the section that deals withNSAID-related hypersensitivity reactions. Dipyrone iscurrently available in Austria, Belgium, France, Germany,Italy, The Netherlands, Spain, Switzerland, South Africa,Latin America, Russia, Israel and India (Edwards et al

2001).Clinical considerations. Dipyrone is effective for adults

with moderate to severe postoperative pain, and single-dose oral dipyrone 500mg was found to be of similar effi-cacy to ibuprofen 400mg. Adverse effects were poorlyreported but the commonest were drowsiness, gastric dis-comfort and nausea. For a single oral dose of oral dipyr-one 500mg, the NNT was 2.3 (95% CI: 1.8–3.0) (Edwardset al 2001). The risk in pregnant or lactating mothers isunclear.

7. Omega-3 Fatty Acids

Recently, the effect of omega-3 fatty acids as an anti-inflammatory agent has emerged, with the possibility thatthey may serve as an alternative to NSAIDs for long-termuse (Cleland and James 2006; Maroon and Bost 2006).They are not suitable for treatment of acute pain, but theiruse for chronic pain is further discussed in Chapter 17 oncomplementary medicine.

8. Opioids

Opiates are drugs derived from opium and include mor-phine, codeine and a wide variety of semisynthetic conge-ners derived from them and from thebaine, anothercomponent of opium. The term opioid is more inclusive,applying to all agonists and antagonists with morphine-like activity as well as to naturally occurring and syntheticopioid peptides. Endorphin is a generic term referring to thethree families of endogenous opioid peptides: the enkepha-lins, dynorphins and beta-endorphins.Multiple opioid receptors. There is convincing evidence

for three major classes of opioid receptors in the CNS,designated mu, kappa and delta, as well as indicationsof subtypes within each class. While the commonly pre-scribed opioids bind preferentially to the mu receptor,they do associate with all three receptor types (Gourlay2002). Morphine shows the greatest relative preferencefor the mu receptor. Codeine displays exceedingly poor

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binding to opioid receptors, which raises the possibilitythat it is a prodrug where the pharmacologically activespecies is morphine (Sindrup and Brosen 1995). A similarsituation probably applies to oxycodone, where themetabolite oxymorphone may be responsible for thepharmacological effect. Alternatively, the intrinsic anti-nociceptive effect of oxycodone may be mediated viakappa receptors (Ross and Smith 1997).Mechanisms and sites of opioid-induced analgesia. Opioid-

induced analgesia is due to action at several sites withinthe CNS; both spinal and multiple supraspinal sites havebeen identified. Peripherally, opioid receptors on theterminals of primary afferent nerves mediate inhibitionof the release of neurotransmitters, including substanceP. Morphine also antagonizes the effects of exogenouslyadministered substance P by exerting postsynaptic inhib-itory action on interneurons and on the output neuronsof the spinothalamic tract that conveys nociceptive infor-mation to higher centres in the brain. Morphine selec-tively inhibits various nociceptive reflexes and inducesprofound analgesia without affecting other sensory mod-alities. Intrathecal administration of opioids can produceprofound segmental analgesia without causing significantalteration of motor or sensory functions (Yaksh and Rudy1978).

Tramadol is a synthetic, centrally acting opioid analge-sic. However, it only binds weakly to mu opioid receptorsand with weak affinity to delta and kappa receptors.Tramadol-induced anti-nociception ismediated by the opi-oid mu receptor and additionally by non-opioid mechan-isms (Raffa 2001). Non-opioid mechanisms include theinhibition of norepinephrine and serotonin pathwayswithin the CNS (Scott and Perry 2000).

8.1. Efficacy for Acute Pain

Traditionally, opioids have been classified as weak andstrong opioids. Weak opioids include codeine, dihydroco-deine, dextropropoxyphene and tramadol. Morphine,fentanyl, methadone, oxycodone and buprenorphine areconsidered strong opioids (Schug and Gandham 2006).The weak opioids are relatively poor analgesics on theirown, e.g. codeine 30mg NNT 16.7; tramadol 75mg NNT9.9; dextropropoxyphene 65mg NNT 7.7 (Collins et al

2000b; Edwards et al 2002). In addition, codeine,a prodrug for morphine, is converted to morphine inthe liver but 8–10% of the population lacks the enzymefor this conversion, a further limitation of the analgesicactivity of codeine.

Morphine is the gold standard for opioid therapy andonly lately was replaced by oxycodone as the most utilizedopioid worldwide (Schug and Gandham 2006). While oralmorphine is fully absorbed, it has a limited and very vari-able oral bioavailability of between 10 and 45% due toextensive first-pass metabolism (Gourlay et al 1986). Oxy-codone, a synthetic derivative of thebaine, has a bioavail-ability higher than that of morphine (approx. 60%) and is

available in a wide range of oral (including controlledrelease preparations) and parenteral preparations. Oxyco-done analgesic efficacy is comparable with that of mor-phine, with a median oxycodone:morphine dose ratio of1:1.5, and controlled release oxycodone is as safe and aseffective as controlled release morphine (Bruera et al

1998). The data also suggest that oxycodone has a reducedrate of hallucinations and itch compared with morphine(Bruera et al 1998).

Although there was no benefit for oxycodone 5mg, asignificant effect for oxycodone 15mg relative to placebowas shown with an NNT of 2.4 (1.5–4.9) for moderate tosevere postoperative pain (Edwards et al 2000).

8.2. Adverse Effects

8.2.1. Administration for Acute Pain

For a patient to report an adverse effect with a single doseof oxycodone 15mg compared with placebo the NNHwas 3.1 (1.8–11), but no increased adverse effects wereshown for oxycodone 5mg over placebo (Edwards et al

2000). Use of any oral opioid produced higher rates ofadverse events than did placebo. Dry mouth (25%), nau-sea (21%) and constipation (15%) were the most com-monly reported. A substantial proportion of patientson opioids (22%) withdrew because of adverse events(Moore and McQuay 2005). As most side effects arereported at the initial stage of opioid use, and since theabove figures refer mostly to trials of opioids in chronicnon-malignant pain, it is assumed that even more sideeffects prevail in patients starting on opioids for acutepain (Moore and McQuay 2005).

8.2.2. Administration for Chronic Pain

Opinions are divided about the chronic use of opioids.The development of the Analgesic Ladder by the WorldHealth Organization (WHO) in 1984 paved the way fora rational approach to the management of chronic cancerpain, and ‘legitimized’ the regular administration of oralopioids for these patients. However, opinions are evenmore divided about the use of opioids in non-cancerpain patients that have a normal expected life span(O’Callaghan 2001). The potential complications ofchronic opioids use may include organ toxicity, cognitiveimpairment, tolerance and physical and psychologicaldependence. These views have been balanced againstthe reports of improved pain relief in patients resistantto other therapies (Portenoy and Foley 1986), andimprovement in function (Zenz et al 1992). Moreover,studies on chronic non-cancer pain patients showed areduction in pain and disability and little effect on cogni-tive state (Arkinstall et al 1995; Moulin et al 1996). A con-trolled study in patients on stable doses of oral morphine(mean daily dose 209mg) considered them non-hazardous with regard to driving ability (Vainio et al

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1995). Many patients with postherpetic neuralgia reportthat they prefer opioids to other standard pharmacothera-pies (Raja et al 2002; Hempenstall et al 2005). A survey ofanalgesic use in the US burn units did not reveal any caseof iatrogenic dependence in more than 10000 patientsgiven opioid analgesics (Perry and Heidrich 1982). Toler-ance to analgesic effects seems to be irrelevant in clinicalpractice (Collett 1998). Therefore when the dose needsincreasing tolerance should not be considered automati-cally, and the following factors should be evaluated: dete-rioration of the underlying condition, new pathology,increased physical activity (e.g. walking, chewing) andpoor compliance. A 10-year follow-up study on opioidsin chronic pain revealed that dose escalation occurred inonly a few patients, suggesting that pain-related toleranceis rare (Jensen et al 2006). However, tolerance to respira-tory depression develops rapidly and is rapidly revers-ible. Tolerance to sedation, cognitive effects, nausea andvomiting develops more slowly. Unfortunately, constipa-tion and miosis are the two receptor-mediated effects towhich no tolerance develops (Schug et al 1992). Physicaldependence can be easily avoided by gradual reductionin dosage, and is not to be confused with psychologicaldependency. The risk of psychological dependence onopioids when used in the management of chronic painis low, unless there is a prior history of substance abuse,major personality disorder or social disruption (Moulin1999). Unfortunately, a significant number of patientsattending multidisciplinary pain clinics do suffer thesepsychological factors, thereby making detailed clinicalassessment prior to the commencement of opioid therapyessential (O’Callaghan 2001).Guidelines for the use of opioids in chronic pain. The

appropriate use of potent opioids is accepted medicalpractice for chronic recalcitrant pain in patients with nor-mal life expectancy (Breivik 2003). Following initial diag-nosis evidence-based pain therapies will reduce the needfor opioids and only a minority of patients referred to apain clinic will qualify for long-term treatment withpotent opioids (Maier et al 2002). When indicated opioidsshould be used according to published guidelines on theuse of opioids in chronic pain (Savage 1996; Kalso et al

2003).Ideally one physician should take responsibility for the

treatment and follow-up of patients. Strong opioids arenot recommended as monotherapy and should beincorporated into a comprehensive rehabilitationprogramme that includes the attainment of improvedphysical and social function. Other pharmacological treat-ments for pain or comorbid conditions (such as antide-pressants) and non-pharmacological treatments such ascognitive behavioural therapy and physiotherapy maybe indicated. These should be carefully coordinated withthe family physician. A written agreement with thepatient that outlines therapeutic aims, prescribing legisla-tion, dosages, side effects, risks of dependence and indi-cations for cessation of therapy is recommended (Breivik

2003). Baseline recordings of pain severity and frequency,quality of life and functional status must precede theinitiation of treatment. Only sustained-release strongopioids are recommended and these should be titratedover a trial period of 3–4 months. No rapidly actingopioids should be prescribed for breakthrough pain asthey are very difficult to control and may rapidly inducedependence. The maximum length of the trial periodmust be clearly defined for the patient. Additionallypatients must understand that opioids are not consideredlifelong treatments.Conclusions. It seems that for moderate to strong acute

orofacial pain when the use of opioids is indicated, espe-cially when NSAIDs are not recommended, the oraladministration of a combination of oxycodone plus para-cetamol is a good choice (see below). Opioid administra-tion for chronic pain is largely reserved for resistantneuropathic pain syndromes as discussed in Chapter 11(Eisenberg et al 2005; Finnerup et al 2005). Meta-analysisof published intermediate term trials (weeks–months)showed consistent and significant opioid analgesicefficacy in reducing spontaneous neuropathic pain(Eisenberg et al 2005). These trials are more clinically rel-evant than shorter ones because they assess the benefitsand risks associated with opioid treatment for weeks tomonths.

9. Analgesic Drug Combinations

Combination pharmacotherapy is not new in medicineand is commonly used in the management of hyperten-sion and other CV diseases. Clinical outcomes might beimproved under certain conditions with the use of a com-bination of analgesics, rather than reliance on a singleagent. Combination analgesic formulations are an impor-tant and effective means of pain relief, and could proveuseful in treating elderly and other groups of patientswho often cannot tolerate NSAIDs, including the newerCOX-2 inhibitors (McQuay and Edwards 2003). A combi-nation of systemic analgesics is most effective when theindividual agents act through different mechanisms andresult in synergistic pain control (Raffa 2001). Combina-tions aim at taking advantage of such complementarymodes and sites of action and additionally at providingreduced side effects. The combination of an NSAID withparacetamol is a good example (Miranda et al 2006).Moreover drug combinations may not necessarily be syn-ergistic in order to provide an improved risk–benefitratio; additive or even subadditive analgesic effects butwith reduced side effects may offer clinical benefits.NSAIDs clearly have an analgesic ‘ceiling’ (Forbes et al

1992; Eisenberg et al 1994), but the combination of twoNSAIDs with different toxicity profiles would be advan-tageous in terms of side effects without a significantincrease in analgesic potency. The combination of 75mgtramadol with 500mg paracetamol (described below)

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provides equivalent analgesia to tramadol 150mg butwith reduced side effects. Future work may analyze thecombinations of more than two analgesics with comple-mentary modes of action.

9.1. Paracetamol in Combinationwith Opioids

Paracetamol has been combined with several drugs,particularly of the opioid family (e.g. codeine, oxycodone,tramadol) as well as with other drugs, e.g. NSAIDs.

The weak opioids are relatively poor analgesics ontheir own (Collins et al 2000b; Edwards et al 2002). Allare more effective when combined with paracetamol

0 87654

NNT

321

Para (1000)/Cod (60)

Para (500)/Oxy (5)

Oxy 15 mg

Para (325)/Oxy (5)

Para (650)/Oxy (10)

Para (1000)/Oxy (10)

Para (650)/Cod (60)

Para 1000 mg

Para 600/650 mg

Fig. 15.3 • Number needed to treat (NNT), for one patient to achieveat least 50% pain relief, �95% confidence interval (CI), for paracetamol(Para) and for paracetamol combined with codeine (Cod) or withoxycodone (Oxy).

Data from Edwards et al (2000) and Moore et al (1997, 2000).

0 1816141210864

NNT

2

Ibuprofen 400 mg

Tramadol 150 mg

Para (500)/Tram (75)

Paracetamol 650 mg

Tramadol 100 mg

Tramadol 75 mg

Fig. 15.4 • Number needed to treat (NNT), for one patient to achieveat least 50% pain relief, �95% confidence interval (CI), forparacetamol (Para), tramadol (Tram) and paracetamol combined withtramadol compared to ibuprofen.

Data from Moore and McQuay (1997) and Edwards et al (2002).

(see Figs. 15.3, 15.4) and show synergistic efficacy; withlower opioid dosage there are significantly fewer sideeffects.

9.1.1. Codeine and Paracetamol

The analgesic efficacy of paracetamol 1000mg was com-pared to that of paracetamol 1000mg plus codeine 30mgin patients after extractions of impacted third molars.The average increase in pain intensity over 12 hourswas significantly less in patients receiving paracetamolplus codeine and there was no difference in adverseevents between the two groups (Macleod et al 2002). Intwo systematic reviews on postoperative pain, paraceta-mol 1000mg had an NNT of 4.6 (3.8–5.4) when comparedwith placebo, and paracetamol 600/650mg had an NNTof 5.3 (4.1–7.2). Paracetamol 600/650mg plus codeine60mg had an NNT of 3.6 (2.9–4.5). The combination of1000mg paracetamol with 60mg codeine improves theNNT to 2.2 (1.7–2.9) with no significant increase in sideeffect profile relative to lower paracetamol containingcombinations (Fig. 15.3).

Relative risk estimates for paracetamol 600/650mgplus codeine 60mg versus placebo showed a significantdifference for ‘drowsiness’/somnolence (NNH 11 (7.5–20)) and dizziness (NNH 27 (15–164)) but no significantdifference for nausea/vomiting (Moore et al 1997, 2000).Clinical considerations. For mild to moderate pain para-

cetamol 300–1000mg (¼4000mg/d) with codeine 15–60mg (¼360mg/d) orally every 4 hours as needed is veryeffective. Common adverse effects of these combinationsinclude lightheadedness, nausea, vomiting, dizziness,sedation and dyspnea that may be severe. Codeine is inpregnancy category A and is considered compatible withbreastfeeding although infant risk cannot be completelyruled out.

9.1.2. Oxycodone and Paracetamol

Oxycodone is a strong opioid and is similar to morphinein its effects, with the exception of hallucinations whichoccur rarely with morphine. The efficacies of oxycodone15mg, oxycodone 5mg plus paracetamol 325mg and oxy-codone 10mg plus paracetamol 650mg were similar; therelative benefit estimates and NNTs were about 2.5 foreach. This indicates that the dose of oxycodone may belowered when it is combined with paracetamol, with noloss of efficacy (Edwards et al 2000). The combination ofother NSAIDs with opioids seems less successful. Trialsof combinations of an NSAID with an opioid have dis-closed no difference (4 out of 14 papers), a statisticallyinsignificant trend towards superiority (1 out of 14papers) or at most a slight but statistically significantadvantage (9 out of 14 papers), compared with either sin-gle entity (McNicol et al 2005).

Oxycodone 5mg plus paracetamol (325, 500 and 1000mg) was significantly more effective than placebo; with

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NNTs of 2.5 (2.0–3.4), 2.2 (1.7–3.2) and 3.9 (2.1–20) respec-tively for moderate to severe postoperative pain over 4–6hours (Edwards et al 2000). For single-dose oxycodone10mg plus paracetamol (650 or 1000mg) NNTs were 2.5(2.0–3.3) and 2.7 (1.7–5.6) for moderate to severe postop-erative pain over 4–6 hours (Fig. 15.3). Since the combina-tion of oxycodone 10mg with paracetamol did not show abetter NNT than oxycodone 5mg plus paracetamol(Fig. 15.3), and oxycodone 10mg exhibited more adverseeffects than 5mg (whether on its own or combined withparacetamol) (Edwards et al 2000), it seems prudent touse the oxycodone 5mg/paracetamol 500mg combinationas first choice.Clinical considerations. This combination is indicated for

moderate to severe pain. Dosing is every 6 hours and thetotal daily dosage of paracetamol/oxycodone should notexceed 4000/60mg. Common adverse effects includelightheadedness, pruritus, rash, constipation, nausea andvomiting. Dizziness, sedation and a dysphoric mood havealso been reported. Headache and vomiting were alsoreported with oxycodone 10mg plus paracetamol 650mg, but no adverse effects were severe in nature(Edwards et al 2000). Oxycodone is in pregnancy categoryB but is associated with infant risk during breastfeedingand therefore contraindicated for lactating mothers.

9.1.3. Tramadol and Paracetamol

Tramadol is a synthetic, centrally acting analgesic thatbinds weakly to mu opioid receptors and also inhibits nor-epinephrine and serotonin pathwayswithin the CNS (Scottand Perry 2000). After third molar extraction a single oraldose of tramadol 75mg plus acetaminophen 650mg pro-duces effective analgesia in moderate to severe pain,NNT 2.6 (2.3–3.0) (Edwards et al 2002). For tramadol 75mg on its own, the equivalent NNT was 9.9 (6.0–17), andfor acetaminophen 650mg 3.6 (3.0–4.5) (Fig. 15.4; Edwardset al 2002).

In a meta-analysis of postsurgical pain tramadol 50,100 and 150mg had NNTs of 7.1 (4.6–18), 4.8 (3.4–8.2)and 2.4 (2.0–3.1), comparable with aspirin 650mg pluscodeine 60mg NNT 3.6 (2.5–6.3) and acetaminophen 650mg plus propoxyphene 100mg NNT 4.0 (3.0–5.7). How-ever, with the same doses of drug postsurgical patientsat large had more pain relief than those having dentalsurgery (Moore and McQuay 1997). Moore and McQuayconcluded that absolute ranking of analgesicperformance should be done separately for dental pain.Such a study recently examined the tramadol/paraceta-mol combination specifically for dental pain in 456patients after third molar extraction (Fricke et al 2004).This study established the superiority of tramadol/para-cetamol 75/650mg over tramadol 100mg in the treatmentof acute pain following oral surgery. Adverse eventsoccurred more frequently in the tramadol group thanin the tramadol/paracetamol group. Significantly morepatients reported adverse effects with tramadol 75mg or

tramadol 75mg plus acetaminophen 650mg than withplacebo; the NNH for a patient to report any adverseeffects was 5.0 (3.7–7.3) and 5.4 (4.0–8.2) respectively.No significant difference in reported incidence of adverseeffects was shown for acetaminophen 650mg or ibupro-fen 400mg compared with placebo. Almost all reportedadverse effects were of mild or moderate severity andall resolved (Edwards et al 2002).Clinical considerations. For acute pain paracetamol (500–

650mg)/tramadol (75mg) orally every 4–6 hours as neededfor 5 days or less is moderately effective. Maximum dailydoses should not exceed 3000mg of paracetamol and 300mg of tramadol. In patients with pulmonary disease, onhigher doses or prolonged treatment, regular monitoringof vital signs is indicated. Common adverse effects includenausea, dizziness, vomiting, excessive sweating, pruritus,rash and slight weight loss. Confusion, headache, somno-lence, tremor, anxiety and fatigue are also commonlyreported.

Withdrawal of tramadol, particularly if this is abrupt,may induce anxiety, insomnia, nausea, tremors, diaphoresisand hallucinations; slow tapering will minimize or alleviatethese withdrawal symptoms. Tramadol is in pregnancy cat-egory C and the risk to breastfeeding is unclear.

9.2. NSAIDs and Paracetamol

Several controlled clinical studies among patients withmusculoskeletal conditions, dental pain or postoperativepain have shown that combinations of acetaminophenand NSAIDs provide additive pain-relieving activity,thereby leading to dose-sparing effects and improvedsafety (Altman 2004).

Patients with moderate to strong pain after surgicalremoval ofwisdom teethwere given the following in singleoral doses: 100mg diclofenac; 1 g paracetamol; 1 g paracet-amol/60mg codeine; 100mg diclofenac/1 g paracetamol;or 100mg diclofenac/1 g paracetamol/60mg codeine.Diclofenac plus paracetamol with and without codeinehad superior analgesic effect compared with diclofenac,paracetamol, or paracetamol plus codeine. However, theaddition of 60mg codeine increased the degree of sideeffects. These results support the clinical practice ofcombining diclofenac with paracetamol for acute pain. Ofclinical importance is superior and prolonged analgesiawith fewer side effects after enteric-coated diclofenactablets plus paracetamol compared with paracetamol pluscodeine (Breivik et al 1999). Combined treatment with 2 gparacetamol and 75mg diclofenac provided clinically onlya minor advantage over monotherapy with paracetamol ordiclofenac with respect to postoperative analgesia or theincidence of side effects in adult tonsillectomy patients(Hiller et al 2004). This would suggest that a minimum of100mg diclofenac is necessary when combined withparacetamol.

Analgesic activity of paracetamol and NSAIDs wasassessed in mice, using the writhing test (abdominal

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constriction after acetic acid intraperitoneal injection). Theisobolographic analysis of the various combinations ofNSAIDs and paracetamol resulted in synergistic interac-tions (Miranda et al 2006). However, further studies todetermine the clinical utility and safety of paracetamol/NSAID combinations as analgesic therapy for commonconditions associated with mild to moderate pain arewarranted (Altman 2004).

10. Strategy of Pharmacotherapyof Acute Orofacial Pain

As stated at the beginning of this chapter, the aim of drugtherapy of acute orofacial pain is to relieve pain at maxi-mum efficacy with minimum side effects. The medical his-tory of the patient is the foremost consideration whenchoosing an analgesic. These aspects have been extensivelydiscussed above. When efficacy, side effects and cost arebalanced, the evidence supports an oral analgesic treat-ment schedule that begins with paracetamol 500mg formild to moderate orofacial pain. Naproxen 500mg or ibu-profen 400mg are efficient alternatives for short-termtherapy; the safest conventional NSAID in terms of GIside effects is ibuprofen in doses of 400mg. Higher dosesmay offer somewhat greater analgesia but with moreadverse effects. Other NSAIDs have failed to demonstrateconsistently greater efficacy or safety than ibuprofen(Sachs 2005). Although naproxen has been associatedwith some increase in CV effects it has consistentlyemerged as the safest NSAID in most studies when CVrisks are considered (Juni et al 2005; Kearney et al 2006;McGettigan and Henry 2006; Antman et al 2007) andmay be combined with a proton pump inhibitor asneeded (Lai et al 2005; Morgner et al 2007), providingexcellent analgesia and GI safety. It is important to appre-ciate that data are constantly accumulating and the evi-dence for risk–benefit ratios in individual drugs must beregularly reviewed by clinicians.

For moderate to severe pain not responding to paracet-amol, and when ibuprofen or naproxen are contraindi-cated, the use of narcotics combined with paracetamol isindicated. The combination of paracetamol 500mg plusoxycodone 5mg gives good analgesia with minimal sideeffects. COX-2 inhibitors provide analgesia equal to tradi-tional NSAIDs for many painful conditions, but lack abetter safety profile in acute pain treatment and are sig-nificantly more expensive (Sachs 2005).

The possibility of preemptive analgesia, i.e. when theanalgesics are administered before surgery, has beenadvocated (Savage and Henry 2004), but the evidence isunclear, and the efficacy of analgesics provided after sur-gery is probably the same. On the whole in the dentalfield this is a somewhat academic debate, taking intoconsideration that the patient is usually anaesthetizedwith a local anaesthetic that outlasts the surgery.

Sometimes a patient prefers a certain analgesic because‘it works better for him/her’, and unless the drugrequested is contraindicated we tend not to argue withpatients’ preferences. One should consider that malesand females may differ in their response to NSAIDs andindeed females enjoy less analgesia with ibuprofen thando males (Walker and Carmody 1998). Also, given thefact that patients may differ genetically in their responseto analgesics the patient may actually be right (Lotschand Geisslinger 2006). On the whole the strategydescribed above is a good starting point when pain sever-ity is our main lead. However, the patient’s age, medicalbackground and habits, such as smoking or alcohol con-sumption, and adverse drug interactions are foremostconsiderations in order to minimize side effects (Haas1999). Table 15.1 summarizes the initial and maintenancedoses and common medical contraindications for thecommon single formulation of non-opioid analgesics.Table 15.2 provides assistance for the management ofacute orofacial pain that takes into consideration bothpain severity and patient’s medical background.

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