Chapter 18 PHARMACOLOGY FOR ENDODONTICS

Paul D. Eleazer

Infections concur with many endodontic conditions. Accordingly, it behooves the practitioner to be well prepared to use drugs that help ght infection. Unfortunately, pain has also become associated with endodontics, at least in the publics mind. Fortunately, for both pre- and postoperative pain, relief through drugs is readily available. In addition to pain, anxiety about endodontic treatment is also rampant. Again, modern antianxiety drugs have been developed, displacing the sedatives, hypnotics, and soporics often misused to control anxiety in the past. In the present-day pharmacy, drugs are available that work directly against anxiety without many of the side effects, making dental treatment easier for the patient and the practitioner alike, enabling more patients to receive optimal dental care. The up-to-date dentist, and the endodontist in particular, must be prepared to handle any pharmacologic exigency. One must know not only actions and reactions to drugs but also indications and contraindications, as well as side effects, toxicity, half-life, and any interaction the newly prescribed drug may have with other drugs the patient may be taking. This chapter is meant to be a specic overview of drugs vital to endodontics. For in-depth details about any of these drugs, the reader is referred to a pharmacology text, the Physicians Desk Reference (PDR), or the U.S. Pharmacopeia (USP). INFECTION CONTROL The overwhelming importance of microorganisms to endodontics was highlighted in 1965 by the classic experiment of Kakehashi et al.1 They found that exposing the pulps of germ-free rats to the oral environment caused no pulpal destruction beyond the operative wound. In control animals, however, with normal oral ora, the same pulpal exposure resulted in pulpal necrosis and periradicular abscess, just as it does in the endodontic patient.

In the usual scenario, pulpal invasion begins with a mixed infection of aerobes and anaerobes. As the infection continues, oxygen is depleted, and obligate anaerobic bacteria and facultative bacteria predominate.2 For many years, endodontists suspected bacteria as the pathogens in necrotic pulps but were not able to prove the point because of inadequate culture methods. After the development of anaerobic culture techniques, however, investigators were able to show nearly 100% infection of necrotic pulps (Table 18-1).3 One of the primary goals of endodontic treatment is to eliminate a hospitable place for microorganisms to grow. Dbridement of the canal soft tissues and debris should be as thorough as possible. The space should be totally obturated to isolate any remaining tissue from the body and to close off that path for oral bacteria to reach beyond the apex. Sterile technique should be used throughout the procedures to avoid introducing any new microbes into the patient. Attention to proper technique also protects the entire staff from receiving pathogens from the patient. Periapically, bacteria do not usually hold the advantage, and infection is less likely. Without a doubt, situations occur where chronic infections persist in the periapex following root canal therapy. Tronstad believes that most periapical granulomas are infected.4 Gatti et al. showed bacterial presence in chronic asymptomatic, enlarging, periapical radiolucent lesions discovered at postendodontic recall.5

Table 18-1

Bacterial Pathways to the Pulp

Caries Periodontal disease Fractures Dentinal tubules not covered by cementum Anachoresis

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Endodontics Table 18-3 Common Examples of Oral Penicillins and Cephalosporins

Penicillins Penicillin V 500 mg qid Ampicillin 500 mg qid Amoxicillin 500 mg tid/qid Augmentin 500 mg tid/qid Cephalosporins First generation Cephalexin (Keex) 500 mg qid Cefadroxil (Duricef) 500 mg qid Second generation Cefuroxime (Ceftin) 250 or 500 mg bid Cefaclor (Ceclor) 500 mg tid Third generation Cexime (Suprax) 400 mg daily
Dosages may vary with the specic situation.

They used the highly accurate deoxyribonucleic acid (DNA) probe technique. Ratner et al. have shown anaerobes within bone lesions from old extraction sites to be related to trigeminal neuralgia.6 Others discovered similar-appearing lesions around failing root canals at surgery.7 ANTIBIOTICS Antibacterial agents, commonly called antibiotics, are very useful because they kill bacteria without damage to the host. These drugs attack cell structure and metabolic paths unique to bacteria and not shared with human cells. Systemic antibiotics are used frequently in the practice of medicine and dentistry. Some say they are overused. Although this is probably true, it is also difficult to tell when an infection might spread to cause life-threatening problems, such as cavernous sinus thrombosis, Ludwigs angina, danger-space swelling reaching into the mediastinum, brain abscess, or endocarditis, all of which have developed as sequelae of root canal therapy. It is probably wise to use systemic antibiotics when there is a reasonable possibility of microorganisms beyond the root canal. The immunologically compromised patient should also be considered an indication for antibiotic therapy, regardless of the condition of the canal. This discussion of antibiotics will not include parenteral-use drugs or drugs used rarely in dental patients, which need monitoring by a physician because of potential side effects. The dental practitioner should be acutely aware of signs of infection not responding to oral antibiotic therapy and be speedy in referring such patients to an infection specialist. CLASSIFICATION Antibiotics may be classied into two main categories: those that kill bacteria rapidly and those that kill more slowly by retarding bacterial protein synthesis (Table 18-2 and 18-3). Generally speaking, the faster-killing antibacterial agents are more desirable.

Fast-killing antibacterial agents are often called bactericidal, meaning that they are observed to kill quickly in the laboratory. Penicillins, cephalosporins, and metronidazole are the bactericidal antibiotics commonly used against endodontic pathogens. The rst two kill by integrating into and weakening a newly made cell wall, whereas the latter impedes DNA manufacture. Both require actively growing organisms to be effective, so antibiotics that ght bacteria by slowing their protein synthesis (bacteriostatic antibiotics) are generally not given along with these bactericidal drugs. Allergies Serious anaphylactic allergic reactions are rare with oral penicillins and cephalosporins, although they are possible. If allergic to one penicillin, the patient should be considered allergic to all penicillins and possibly to cephalosporins as well. Because of a close molecular structure, there is about a 10% cross-reactivity between these groups, that is, 1 in 10 who are allergic to penicillins will be allergic to cephalosporins and vice versa. Resistance The main biochemical structural similarity of penicillins and cephalosporins is the -lactam ring. Some bacteria can produce an enzyme, called -lactamase or penicillinase, which cleaves this ring, thus disabling the antibiotic. Microbiologists have identied about 30 different types of this enzyme. Some penicillins and cephalosporins have been altered to defeat this bacterial trick with altering a slightly different three-dimensional structure. Potassium clavulanate has been added to amoxicillin, for example, to

Table 18-2

Types of Antibiotics

Rapid-killing antibiotics Penicillins and cephalosporins Metronidazole (Flagyl) Fluoroquinolones Antibiotics that slow protein synthesis Erythromycins (macrolides) Clindamycin (Cleocin) Tetracyclines

Pharmacology for Endodontics make it stable in the presence of -lactamase. The combination is called Augmentin. Bacterial resistance may also be developed by mutation of the DNA molecule or can be acquired from other bacteria by DNA transfer, even from one species of bacteria to another. In addition to enzymatic destruction of antibiotic molecules, as with -lactamase, bacteria sometimes become resistant by not allowing an antibiotic to pass through the cell wall or cell membrane. Another resistance situation occurs when the bacteria can pump the antibiotic molecule overboard faster than it can enter. Bacteria generally pass on their resistance genes to their offspring. Fortunately, if not used, this DNA will sometimes not be passed on to future generations. Although recent laboratory research is developing new antibiotics awaiting approval, these new drugs will probably fall prey to new forms of bacterial resistance. It behooves the professions to limit antibiotic therapy to those situations in which the patient will likely benet from treatment and not expose the wonder drugs to bacterias resistance-making mechanisms. Replantation of avulsed teeth, on the other hand, calls for systemic antibiotic therapy in conjunction with endodontic treatment for best results. Success, as measured by the degree of inammatory root resorption, was judged to be superior by Hammarstrom and coworkers when permanent incisors of monkeys were replanted under controlled conditions.8 Penicillins Penicillins have a short half-life, limited to about 1 hour. It is important to tell patients the need to be prompt in taking their pills. Because they are excreted unchanged by the kidneys, they are very useful in treating urinary tract infections, where they accumulate in powerful killing levels. In patients with compromised kidney function, reducing the dosage is appropriate. The dentist should discuss with the patients physician, if the individual patient is undergoing kidney dialysis, and tailor the penicillin or cephalosporin dosage according to the dialysis schedule. Penicillins are unique in their lack of toxicity. That is, if the patient is not allergic, there is no maximum dose of penicillin and no side effects from overdosage. Amoxicillin is generally considered the penicillin of rst choice because of its somewhat better absorption from the gut. Cephalosporins Cephalosporins have been developed over the last three decades. Because of the -lactam ring, many consider

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them a subgroup of the penicillin family. Their improvement has seen three major improvements in their ability to kill stubborn infections, so the drugs are classed as rst, second, and third generation. First-generation cephalosporins have the most value in dentistry since they kill most oral pathogens and should be considered for use in most infections. Second- and thirdgeneration cephalosporins are used for refractory infections, probably after laboratory results of a culture. Oral cephalosporins lag behind parenteral ones in the development process. One must give consideration to hospitalization and intravenous antibiotic therapy if the seriously ill patient does not respond to oral drug therapy. Metronidazole Metronidazole (Flagyl) is also considered a bactericidal drug because of its fast killing time. It attacks the bacterias DNA and works against obligate anaerobes but not against facultative bacteria or aerobes. Metronidazole is often used in combination with another antibiotic, usually amoxicillin, to combat the stomach ulcercausing Helicobacter pylori. This combination of two fast-killing drugs also helps in severe dental infections. Periodontists nd metronidazole helpful in destroying deep-pocket anaerobes, bacteria that obviously infect the root canal in many instances. Metronidazole shares properties with disulram (Antabuse), a drug used to help alcoholics avoid alcohol by inducing violent vomiting. So patients taking metronidazole should be cautioned about not using alcohol for the time they are taking the drug plus 1 day following to allow the drug to be eliminated from their system. The half-life of metronidazole is in the 8- to 10-hour range. Side effects include an unpleasant, metallic taste and brown discoloration of the urine, effects that are dose related. Fluoroquinolones Fluoroquinolones interfere with DNA replication, classifying them as bactericidal. However, they are not effective against microbes commonly seen in endodontic infections. Their use in dentistry should probably be limited to cases in which culture and sensitivity results prove their indication. Macrolides Erythromycins kill bacteria by slowing the manufacture of bacterial protein but do not alter the rate of human protein synthesis. Because of their large molecule, erythromycins are also called macrolides (Table 18-4). These drugs kill about the same bacteria as penicillins, albeit by different means, so they are the drug of

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Endodontics ifestations such as cardiac arrhythmias. It should be noted that clarithromycin (Biaxin) is metabolized by both the liver and the kidney, perhaps causing less bottleneck in the liver. Caution is warranted, however, in patients with either kidney or liver compromise because the half-life of the drug is prolonged. The half-life of most erythromycins is in the range of 1 to 2 hours, whereas the newer ones remain active longer. Clarithromycins half-life is 6 hours, and azithromycin has a remarkable 40-hour half-life. There are a few case reports of severe muscle weakness in patients taking lovastatin (Mevacor) for cholesterol reduction who have been given a macrolide. Although this relationship is not clearly dened, it would be wise to select another antibiotic when the patient is taking this type of cholesterol-lowering drug (Table 18-5).9 Clindamycin Clindamycin (Cleocin) is often indicated in endodontic infections. It is rapidly and completely absorbed and has a good spectrum of killing oral pathogens, including many anaerobes. It was, however, the rst antibiotic to be associated with causing pseudomembranous colitis, a life-threatening condition in which large patches of gut slough epithelium because of toxins from overgrowth of the nonsusceptible organism Clostridium difficile. This serious condition requires hospital management with intravenous uids and antibiotics specic for the causative Clostridium. Patients being treated with clindamycin who experience diarrhea or another gut problem should immediately be referred to their physician for evaluation. Other broad-spectrum antibiotics have been associated with this phenomenon as well. The average half-life of clindamycin is about 3 hours. Although clindamycin does not cross the bloodbrain barrier, it does penetrate into abscesses and other areas of poor circulation rather well. Tetracyclines There is one standout among the tetracycline family of antibiotics: doxycycline (Vibramycin). It has a long

choice for patients allergic to penicillins. They are notorious for causing stomach cramps because they increase gut motility, and many patients who are susceptible to this phenomenon report that they are allergic. True allergy exists, so the doctor must use judgment based on a thorough history before deciding to use this type of drug. The macrolides kill many grampositive bacteria but have a limited spectrum for gramnegative bacteria. At one time, dentists were particularly fond of using erythromycins because of the lack of risk of life-threatening anaphylactic allergic reaction, but recently discovered serious interactions with other drugs have lessened their popularity. The wider-spectrum new macrolides, azithromycin and clarithromycin, are more useful for dental infections if the practitioner is cautious of potential drug interactions. The newer macrolides also develop higher tissue concentrations. These recently discovered problems with other drugs are because they share the same metabolic pathway. The rst discovered problem drugs were the largemolecule antihistamines terfenadine (Seldane) and astemizole (Hismanal). Seldane is no longer available in the United States because of fatal reactions with other drugs metabolized similarly. Mid-size molecule antihistamines, fexofenadine (Allegra), loratidine (Claritin), and cetirizine (Zyrtec), do not seem to be a problem. Cisapride (Propulsid), given to increase gut motility and treat esophageal reux, has been associated with fatal heart arrhythmias when these patients have concurrently taken macrolide antibiotics. The elimination half-life of cisapride is 8 to 10 hours. This serious contraindication should encourage all practitioners to update the patients medical history frequently. Another serious potential problem lies with the bronchodilator theophylline, used for asthmatic patients, often at doses near the toxic level, in whom there is real potential for severe complications with the macrolides. Both of these drugs share the same metabolic pathway. Too many molecules of the drug overwhelm the pathway and high systemic levels result, giving rise to toxic man-

Table 18-4 Macrolide Antibiotics

Erythromycin base 250500 mg qid Erythromycin stearate 250500 mg qid Erythromycin estolate (Ilosone) 250500 mg qid Clarithromycin (Biaxin) 250500 mg bid Azithromycin (Zithromax) 500 mg bid 1 d, then one daily

Table 18-5 Other Oral Antibiotics Commonly Used in Dentistry

Metronidazole (Flagyl) 250500 mg qid Clindamycin (Cleocin) 150300 mg qid Doxycycline (Vibramycin) 100 mg bid

Pharmacology for Endodontics half-life and is least affected by heavy metal ions such as calcium, so the patient does not have to avoid dairy products and antacids. Tetracyclines kill the broadest spectrum of microbes of all antibiotics. They have recently found a place in periodontal infection ghting and should be included in the endodontists armamentarium since periodontal pathogens frequently invade the root canal and periapical tissues. Recall that all tetracyclines cause staining of developing teeth as they bind to calcium during formation of teeth and bones. This means that their use should be avoided in children and pregnant women if at all possible. A rare side effect is phototoxicity, where exposure to the sun causes severe sunburn or rash. Patients should be cautioned to avoid sun exposure while taking tetracyclines unless they are sure that they are not susceptible to this side effect. Half-lives of most tetracyclines are about 10 hours, whereas doxycyclines half-life is 16 hours, allowing twice-daily dosing. Sulfa Drugs Sulfa drugs, often combined with trimethoprim to reduce resistance problems, are frequently used for urinary tract infections. Sulfa drugs predate penicillin by a decade but were quickly replaced by the more dramatic bacteria killer. Sulfa drugs cannot kill rapidly because they merely compete with a precursor in the bioformation of folic acid, which many bacteria cannot obtain from other sources and must manufacture for themselves. Their kill speed is dependent on the amount of natural precursors in the environment. In other words, sulfa drugs are the slowest of the slow, the poorest of bacteriostatic antibiotics. Their main plus is that they accumulate in the bladder. They are not generally useful in dentistry. Caveats In prescribing antibiotics, it seems warranted to continue therapy for 2 or 3 days after symptoms have resolved. In theory, if viable bacteria are present when antibiotic levels drop below the killing threshold, mutations can occur more readily. Patients are often not conscientious about continuing medications once their symptoms resolve. A reminder telephone call to check on their condition and reinforce the need to nish their prescription is well advised. Females of childbearing age should be told that perhaps antibiotics will interfere with the effectiveness of oral contraceptives. If they need antibiotics, other means of birth control should be used through the next cycle. Some researchers believe that antibiotic-induced reduction in the gut ora causes malabsorption of the

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hormones in birth control pills. This side effect remains unproved. Change in gut ora is denitely associated with increased levels of digitalis preparations, commonly used in heart conditions. Dangerously high levels can occur, and such patients need a consultation with their physician. Diminution of gut bacteria by antibiotics also changes output of vitamin K, needed in blood clotting, so patients on anticoagulant therapy should also be cautioned to consult with their physician. Endodontists are in a unique position among dentists because of the preponderance of anaerobes in the conditions treated. A good specimen for culturing can often be obtained by needle aspiration from an abscess that has not yet drained. The specimen should be placed in an oxygen-free container available from a local hospital laboratory. A culture can be a big advantage when a patient does not respond to the rst antibiotic. The practitioner can telephone the laboratory and quickly learn which drug to use next. Hospitalization for administration of antibiotics intravenously should be considered when the patient is not responding to oral antibiotics. Many new-generation antibiotics are available only parenterally, and the continuous dosage of intravenous administration gives higher blood levels without the complication of oraldosing variables such as half-life and patient compliance. The results of culture and sensitivity tests can greatly aid in selection of the appropriate drug when hospitalization is warranted. Use of corticosteroids to reduce inammation remains popular among some practitioners. Reducing inammation relieves symptoms but also reduces the efficiency of white blood cells, which are crucial to infection ghting. Sometimes prophylactic antibiotics are prescribed as a precaution when corticosteroids are used. Antibiotic Prophylaxis Dentists should all be aware of the need, before dental treatment, to premedicate with antibiotics patients who have certain heart ailments. Systemic diseases compromising the immune system also call for consideration of prophylactic antibiotics in situations for which they might not otherwise be indicated. The goal of antibiotic prophylaxis is to prevent clinical infection by helping destroy small numbers of bacteria present before or introduced during treatment. Oral bacteria released during dental treatment clearly can cause heart and articial joint infections. Oral streptococci, in particular, have been indicted as causative organisms for seeding heart and implanted joints, causing morbidity or even death.

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Endodontics ond category. These act at the site of injury to reduce pain-invoking prostaglandins that are made within the damaged cell. Although not classed as a pain reliever, corticosteroids relieve pain by this mechanism as well but have many side effects. Finally, acetaminophen (Tylenol) is the third type. Acetaminophen acts primarily on the brain to relieve pain. Modern endodontic therapy does not elicit much pain. However, many patients associate it with pain, partly because pain was a hallmark of early endodontic treatment and partly because the media often portray endodontics in this light. Just as a placebo will alleviate symptoms if the brain is convinced it will work, the patient who anticipates pain usually needs higher doses or stronger types of drug for relief. For patients anticipating pain, a prescription drug is often the only thing that will be effective (Table 18-7). Surgical pain, postoperative pain, and where the patient has signicant preoperative pain usually warrant narcotics. Narcotics can cause addiction, with characteristics unique from other types of addiction. Both physical and psychological addiction occur. Patients may present a story of drug allergies, leaving the practitioner no choice but to prescribe narcotics. Be aware of this type of patient and make certain that there is a real medical need for narcotics; otherwise, you may be feeding someones addiction or helping a drug pusher obtain his stock. Narcotics are central nervous system (CNS) depressants and work synergistically with all other CNS depressants. The most commonly available CNS depressant, alcohol, is contraindicated with narcotics. Narcotics reduce reaction times, and narcotized patients must not drive or operate machinery. Usually, narcotics are combined with acetaminophen or aspirin or an NSAID to make them more effective without excessive narcotic side effects. Propoxyphene was originally introduced as a nonnarcotic; however, it is now known as a rather weak narcotic. It works for many patients, perhaps in part because its characteristic, dizziness, makes the patient feel that it must be helping with the pain. Darvon is available plain or with aspirin; with acetaminophen, it is called Darvocet-N. Codeine has been a standard drug in dentistry for many years because it is usually powerful enough to control dental pain. It is irritating to the stomach in high doses, however, so addicts are seldom appeased. Unfortunately, many patients with legitimate pain are troubled with this gastrointestinal upset. Hydrocodone (Vicodin), a development of the 1980s, is less irritating to the gut and has become very

Oral streptococci are weak pathogens known as viridans strep. They are -hemolytic, meaning that they cannot totally metabolize blood on a culture plate. They can, however, store energy molecules intra- and extracellularly. These external stores are long-chain polysaccharides, also known as the sticky substance of dental plaque. These long chains become seriously pathogenic when viridans colonies form on heart valves, trapping blood cells and brin and thereby reducing heart efficiency by hindering closure of the valves. Furthermore, portions of the sticky vegetations, as they are called, break off and lodge in small vessels at distant sites, causing ischemia with possibly disastrous consequences. For many years, the American Heart Association has made recommendations for antibiotic therapy to kill bacteria released into the bloodstream when certain dental procedures are performed. These recommendations have been updated as new knowledge became available. The most recent was in 1997.10 Following these suggestions, the American Academy of Orthopaedic Surgeons and the American Dental Association collaborated to make further recommendations for patients with articial joints.11 There was an addendum to these recommendations in late 1997 about patients taking the diet pills commonly known as fen-phen because of a propensity of these drugs to cause heart valve defects.12 The drugs fenuramine (Pondamin) or dexfenuramine (Redux), with or without phentermine (Adipex or Fastin), have been associated with an alarming development of permanent, serious heart valve defects, primarily in women. Patients who have taken these diet pills, even for a short time, should be premedicated unless an echocardiogram has proven that their heart is properly functioning. Over-the-counter diet pills have not been associated with any heart problem. It is important to note that all of these recommendations are guidelines, not mandates, and that modications may be needed for some situations. Consultation with the patients physician is always in order if any doubt exists. Bender et al. pointed out the value of destroying intraoral bacteria with an antiseptic prior to invasive procedures.13 Heimdahl and coworkers also demonstrated bacteremia from endodontic procedures conned to the canal (Table 18-6).14 PAIN CONTROL There are three categories of pain control medications. Narcotics are the most powerful. They have three types of receptors in the brain. Aspirin and the nonsteroidal anti-inammatory drugs (NSAIDS) make up the sec-

Pharmacology for Endodontics Table 18-6 Summary of Guidelines for Antibiotic Prophylaxis for Heart and Articial Joint Patients
Medical History Prophylaxis Needed Prophylaxis Not Needed

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Heart patients Any articial valve Previous endocarditis Pulmonary shunt Most congenital defects Rheumatic heart disease Hypertrophic cardiomegaly MVP with regurgitation Fen-phen diet pill history Articial joint patients Immunocompromised/immunosuppressed Inammatory arthropathies Rheumatoid arthritis Systemic lupus erythematosus Disease, drug, or radiation immunosuppression Other patients Insulin-dependent diabetes mellitus Articial joint within past 2 y History of failed articial joint Malnutrition Hemophilia
Dental Treatment Prophylaxis Needed

Isolated atrial-septal defect Coronary artery bypass graft Surgical repair of septal defect Functional murmur Rheumatic fever without valve damage Pacemaker MVP without regurgitation Fen-phen with a normal echocardiogram

Prophylaxis Not Needed

Extraction Periodontal procedures, even probing Subgingival antibiotic ber placement Prophylaxis Implants Instrumentation beyond apex Intraligamentary (PDL) injection Ortho band placement

Restorative treatment even with retraction cord Radiographs Local anesthesia, except PDL Impressions and partial dentures Fluoride treatments Endoscope within canal Rubber dam Suture removal Shedding of primary teeth

Prophylactic Antibiotic Regimen Amoxicillin 2000 mg Cephalexin (Keex) 2000 mg Clindamycin (Cleocin) 600 mg Azithromycin (Zithromax) or clarithromycin (Biaxin) 500 mg
All dosages are given 1 hour preoperatively, with no following doses, unless otherwise indicated. Macrolides are NOT recommended for prophylaxis of articial joints MVP = mitral valve prolapse; fen-phen = fenuramine-phentermine.

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Endodontics Pain Control Medications Taken Orally receptor, decreases respiration, and increases intracranial pressure. It also causes dizziness, nausea, and constipation and potentiates other CNS depressants. Unlike other opiates, tramadol is not fully reversed by naloxone (Narcan). Further, it inhibits reuptake of serotonin and norepinephrine, a monoamine; hence, concomitant administration with monoamine oxidase inhibitor drugs is not recommended. Tramadol is well absorbed orally, and the usual adult dose is 50 to 100 mg four times a day. Aspirin has been a standard drug for dental pain for many years and is still useful. It, however, prolongs bleeding, and for this reason is a poor presurgical drug. The anticoagulant effect comes from interference with platelet formation. Aspirin irreversibly binds the enzyme cyclooxygenase, key to the pathway from injuryinduced arachidonic acid, that is released from the membranes of all cells, leading to production of inammation and pain-causing prostaglandins. Platelets in circulation do not have enough protein synthesis reserves to replace the bound cyclooxygenase and are thus unable to participate in clotting for the remainder of their cell lifearound 11 days. Many patients are on routine, lowdosage aspirin therapy for prophylaxis against stroke or heart attack. Prior to endodontic surgery, consultation with their physician may be in order. For patients with stomach problems, consider the use of coated aspirin, such as Ecotrin. The coating will not dissolve until reaching the alkaline conditions of the small intestine. This means that drug action will be delayed for the usual 2-hour stomach transit time. Alternatively, aspirin buffered with chemicals such as magnesium, calcium, or aluminum compounds to decrease stomach complaints (Bufferin, Ascripton) can be considered for sensitive patients. Nonsteroidal anti-inammatory drugs (Motrin/ Advil) do not cause interruption of platelet synthesis for nearly as long because their binding to cyclooxygenase is reversible. Bleeding proles return to normal shortly after NSAIDS are metabolized. Nonsteroidal anti-inammatory drugs were found to be superior to 60 mg of codeine for pain relief in many pain studies. They have also been injected locally into the jaws, with good result in diminishing postoperative pain associated with pulpectomy. 15 Both NSAIDS and aspirin cause stomach upset and can be ulcerogenic. The deleterious stomach (and kidney) effects of aspirin and NSAIDS are caused by action on one of the cyclooxygenase enzymes, cyclooxygenase 1 (COX-1), which seems to predominate in the stomach and kidney. Arachidonic acid is released by damaged cell membranes. Two forms of the

Table 18-7

Narcotics Propoxyphene: Darvon (plain or with aspirin), Darvocet-N (with acetaminophen) Codeine: Phenaphen, Empirin (with aspirin), Tylenol with Codeine Hydrocodone: Vicodin, Lorcet, Lortab, Vicoprofen (with ibuprofen) Oxycodone: Percodan (with aspirin), Percocet, or Tylox (with acetaminophen) Meperidine: Demerol Morphine: Oramorph, others Aspirin and nonsteroidal anti-inammatory drugs (NSAIDS) Aspirin Ibuprofen: Motrin, Advil, Nuprin Etodolac: Lodine Fenoprofen: Nalfon Naproxen: Aleve, Naprosyn, Anaprox Cyclooxygenase 2 inhibitor NSAIDS Celecoxib: Celebrex Rofecoxib: Vioxx Acetaminophen Tylenol

popular in dentistry. It is less powerful than its cousin oxycodone, which is notoriously famous among drug addicts for its euphoria. Percodan is oxycodone with aspirin, whereas Percocet and Tylox are oxycodone with acetaminophen. Occasionally, patients will experience sufficient pain from endodontic procedures to require high-level narcotics, such as oxycodone or meperidine (Demerol). A stronger drug effect carries more frequent side effects, including constipation, euphoria, sedation, impaired coordination, and pupillary constriction. Morphine is available orally as Oramorph and by other trade names. Like most other drugs given orally, because of rapid liver metabolism following oral dosing, a larger dose is required than is typical of the parenteral dose. Morphine pills are available in 10, 15, 30, 60, and 100 mg amounts. The higher levels are reserved for terminal cancer patients. For severe dental pain, such as when the bony cortical plates conne infection pressure, necessitating very strong drug therapy, morphine remains a viable choice for the astute practitioner. Tramadol (Ultram) is a new, potent, synthetic pain reliever that has similarities and differences with the classic opiates. Similarly, it binds with the mu opioid

Pharmacology for Endodontics enzyme cyclooxygenase transform the arachidonic acid into prostaglandins, which have diverse actions. The action we are interested in moderating is the one that produces inammation and pain, which is catalyzed by the cyclooxygenase 2 (COX-2) pathway. Celecoxib (Celebrex) and rofecoxib (Vioxx) have the unique capability of limiting prostaglandin synthesis from the pathways controlled by COX 2. This spares the side effects of prostaglandin inhibition of the COX1 pathway that can harm the gut and/or kidneys.16 The other NSAIDS have action on both pathways. These new COX-2 inhibitor NSAIDS were introduced with great promise of exclusive targeting of the paininducing prostaglandin production. Unfortunately, clinical use has shown them to have serious gut and kidney side effects in some patients. The incidence of these side effects is lower than with classic NSAIDS. As with all new drugs, the practitioner should carefully weigh the potential benets with the higher costs always related to development of new drugs, as well as the potential for yet undiscovered side effects. Acetaminophen (Tylenol) gives patients relief via its action directly on an unknown site in the brain. It was discovered many years ago, and its cousin phenacetin was popularized in the now unavailable APC formulation of aspirin, phenacetin, and caffeine. Although it is effective against pain and fever, inammation remains unchanged by acetaminophen. Some practitioners alternate acetaminophen and aspirin every 2 hours to enhance pain relief. Excedrin, Goodys Headache Powder, and other preparations contain aspirin and acetaminophen. Acetaminophen is metabolized by the liver and should be used cautiously in patients with liver disease or chronic alcohol use. Considerable controversy exists about use of acetaminophen in alcohol abusers with compromised liver function. Most recent evidence suggests that a metabolite is the problem and that abrupt cessation of alcohol intake can lead to higher levels of the toxic metabolite than if some alcohol intake was continued.17 Obviously, it is best to avoid acetaminophen when liver capability is in question. On the positive side, acetaminophen does not cause stomach irritation. Also interesting is the fact that research data show that acetaminophen is better for elevation of the threshold for sharp pain, such as with dental treatment, than other types of pain relievers.18 ANXIETY REDUCTION As mentioned earlier, many patients view endodontic therapy as a painful process and avoid treatment, to the detriment of their dental and general health. In a

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recent study, nearly 30% of laypersons surveyed said that they were nervous about going to the dentist. Over half of this group said that they would go to the dentist more often if given a sedative drug.19 It is a common observation in practice that patients arrive fearful. To worsen matters, epinephrine, commonly administered to retain local anesthetic in the area of injection, increases anxiety. Caffeine can also release endogenous catecholamines and aggravate the fear reaction. Perhaps it would be wise to recommend avoiding caffeine and to reduce epinephrine if feasible for anxious patients. Smoking also prolongs caffeines half-life of 5 to 7 hours. For many years, anxious patients were treated by verbally belittling their fear or by inappropriate drug therapy. Narcotics and/or barbiturates and other sedatives were used without much success. They were not working on the fear itself. Benzodiazepines are now available that act directly on the brain centers that control fear. This class of drug not only relieves anxiety but is also an anticonvulsant, an amnestic, a sedative, and a muscle relaxant. The rst of the benzodiazepines discovered was diazepam (Valium). Its usefulness is limited by its long half-life, approaching 60 hours. One reason for the long life span of the drug is that two of its metabolites are pharmacologically active. By administering one of these metabolites or a similar drug with a shorter half-life, the duration of drug effect is lessened. Lorazepam (Ativan) is an example of using a diazepam metabolite as the administered drug, with its half-life in the 14-hour range. Triazolam (Halcion), a slightly different molecule, has a half-life of approximately 3 hours and is popular for dental procedures. Any drug administered orally has considerable variation because of the rst-pass effect, as drug-laden blood from the stomach and small intestine goes rst to the liver, where signicant metabolism immediately reduces the drug level before it reaches its target. Berthold and coworkers showed that slowly dissolving a 0.25 mg tablet of triazolam intraorally gives higher blood plasma levels than swallowing the same amount of drug, probably by allowing absorption through the oral mucosa that does not progress directly to the liver.20 Ehrich et al. also found oral 0.25 mg triazolam superior to 5.0 mg diazepam for decreasing anxiety, superior amnesia, and better patient perception of drug effectiveness. 21 Oral drug administration should occur in the office to allow monitoring and should occur about 1 hour prior to treatment. As with all CNS depressants, one must consider lowering the dose when the patient is

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8. Hammarstrom L, Blomlof L, Anderson L, Lindskog S. Replantation of teeth and antibiotic treatment. Endod Dent Traumatol 1996;2:51. 9. Corpier CL, et al. Rhabdomyolysis and renal injury with lovastatin use. JAMA 1988;260:239. 10. Dajani AS, et al. Prevention of bacterial endocarditis. JAMA 1997;277:1794. 11. Advisory statement: antibiotic prophylaxis for dental patients with total joint replacements. J Am Dent Assoc 1997;129:1004. 12. US Department of Health and Human Services Interim Public Health Recommendation. MMWR Morb Mortal Wkly Rep 1997;46:10616. 13. Bender IB, Naidorf IJ, Garvey GJ. Bacterial endocarditis: a consideration for the physician and dentist. J Am Dent Assoc 1984;109:415. 14. Heimdahl A, Hall G, Hedberg M, et al. Detection and quantitation by lysis-ltration of bacteremia after different oral surgical procedures. J Clin Microbiol 1990;28:2205. 15. Penniston SG, Hargreaves KM. Evaluation of periapical injection of ketorolac for management of endodontic pain. J Endod 1996;22:55. 16. Pennisi E. Building a better aspirin. Science 1998;280:1191. 17. Slattery JT, Nelson SD, Thummel KE. The complex interaction between ethanol and acetaminophen. Clin Pharmacol Ther 1996;60:241. 18. Carnes PL, Cook B, Eleazer PD, Scheetz JP. Change in pain threshold to sharp pain by meperidine, naproxen, and acetaminophen as determined by electric pulp testing. Anesth Prog 1998;45:139. 19. Dionne RA, et al. Assessing the need for anesthesia and sedation in the general population. J Am Dent Assoc 1998;129:167. 20. Berthold CE, Corey SE, Dionne RA. Triazolam drug levels following sublingually and orally administered premedication [abstract]. J Dent Res 1997;76:114. 21. Ehrich DG, Lundgren JP, Dionne RA, et al. Comparison of triazolam, diazepam, and placebo as outpatient oral premedication for endodontic patients. J Endod 1997;23:181.

concurrently taking another CNS depressant. Patients must not be allowed to drive or operate machinery. Anxious patients will gladly make arrangements for a driver to escort them home. An additional positive effect of the benzodiazepine drugs is their amnesia. Patients frequently think that the treatment took signicantly less time than it actually did and also have gaps in their recall of events during the procedure, probably from a direct drug effect on their brain. Obviously, it is necessary to have a second person in the treatment room at all times. Although there are wide safety margins with dose, safety is further enhanced by the recent development of a specic drug antagonist, umazenil (Romazicon), which is injected parenterally to offset adverse effects. REFERENCES
1. Kakehashi G, Stanley HR, Fitzgerald R. The effects of surgical exposures of dental pulps in germ-free and conventional laboratory rats. Oral Surg 1965;20:340. 2. Nair PNR. Apical periodontitis: a dynamic encounter between root canal infection and host response. Periodontology 1997;13:121. 3. Kantz WE, Henry CA. Isolation and classication of anaerobic bacteria from intact pulp chambers of non-vital teeth in man. Arch Oral Biol 1974;19:91. 4. Tronstad L.Extraradicular endodontic infections. Endodont Dent Traumatol 1987;3:86. 5. Gatti J, Skobe Z, Dubeck JM, et al. Bacterial DNA in periapical lesions using two surgical techniques [abstract]. J Dent Res 1997;76:58. 6. Ratner EJ, et al. Jawbone cavities and trigeminal and atypical facial neuralgias. Oral Surg 1979;48:3. 7. McMahon RE, Adams W, Spolnick KJ. Diagnostic anesthesia for referred trigeminal pain: part 1. Compend Contin Educ Dent 1992;13:980.