chapter 7 Oral Sedation
The oral route is the oldest route of drug administration and still the most commonly used. It is also the most convenient, and most economic method of drug administration. The oral route may be used quite effectively in dentistry for the reduction of stress before or during dental treatment and as a means of managing preoperative and postoperative pain. Although other routes of drug administration may be more reliable and more effective in producing a desired clinical effect, the oral route still maintains a valued place in dentistry’s armamentarium against pain and anxiety.
Most adults do not object to taking drugs by mouth. For better or worse, we have become a “pill-popping” society, a fact that makes the prescription of an anxiety-reducing drug before dental treatment all the more palatable to the patient. Many dentists in North America have been trained to provide anxiolysis (minimal sedation) or moderate sedation to their adult patients using oral central nervous system (CNS) depressants. An important exception to the acceptability of orally administered drugs is the young, immature child, who frequently proves unwilling to take any drugs by mouth.
Oral drugs are exceptionally easy for the dentist to administer. In some cases, the drug prescribed for sedation will be taken by the patient at home. In an increasing number of situations, however, it is more prudent for the dentist to administer an oral CNS-depressant drug to the patient personally on arrival in the dental office to better ensure proper dosage and time of administration. In either case, the administration of drugs via the oral route requires only that the dentist have knowledge of the pharmacologic action of the drug administered, its side effects, potential drug-drug interactions, and any contraindications to its administration. No special equipment or personnel is required for the safe use of the oral route (in the adult patient).
The cost of most oral drugs is usually quite low, especially for the small number of doses employed in dentistry. Although there is significant variation in the cost of drugs, the oral form of a drug is usually less expensive than its parenteral counterpart.
Complications are possible whenever drugs are administered, regardless of the route of administration. Drug idiosyncrasy, allergy, and overdose in addition to other adverse actions can and do occur. Drug-related side effects are less likely to develop after enteral drug administration (i.e., oral, rectal) than after parenteral drug administration. In addition, adverse reactions following oral administration are often much less intense than those noted following parenteral administration of the same drug. This is not to imply that serious complications do not occur following oral drug administration. Berger, Green, and Melnick1 reported cardiac arrest following oral diazepam intoxication, and Gill and Michaelides2 described an anaphylactic response to oral penicillin. Other serious adverse reactions to orally prescribed drugs, including suicide, have been reported.3–5
The convenience of the oral route is a primary reason for its popularity. This technique can be employed with minimal risk if the dentist prescribing the drug(s) is knowledgeable of (1) the pharmacologic actions of the drug; (2) its indications, contraindications, precautions, side effects, and dosage; and (3) the medical history of the patient, especially as it relates to prior drug use, specific contraindications to the use of particular drugs, and prior reactions to the drug to be administered. No special equipment (e.g., needles, syringes) and no additional personnel are required when oral drugs are administered to adult patients.
The aforementioned advantages make the use of orally administered drugs quite compelling. However, there are, as with all routes of drug administration, some distinct disadvantages that effectively limit the clinical use of this route of drug administration.
When prescribing drugs for oral administration before coming to the dental office, the dentist must rely on the patient to take the drug as prescribed (the proper dose at the proper time). Although most patients will medicate themselves properly, some do not. This potential problem, termed noncompliance, is significant in medicine, especially in relation to long-term drug administration (e.g., antihypertensive drugs). The Council on Patient Information and Education estimates that 35% to 50% of all prescriptions dispensed by physicians are taken incorrectly by patients and that one in five patients never even bother to have the prescription filled. One in seven stops taking the drug too soon. Noncompliance rates among patients older than 65 years are more than 55%.6 Although noncompliance is not as critical a problem in the dental situation, the administration of too small or too large a dose, too soon or too late, may significantly alter the drug’s effectiveness during the treatment period. A common form of noncompliance is the taking of a dose larger than that prescribed; the patient’s rationale is “if one (tablet or capsule) is good, then two or more will be better.” This type of thinking leads to oversedation, overdose, and other unwanted and unpleasant complications. Fortunately (in this situation, at least) the erratic and incomplete absorption of orally administered drugs minimizes the development of serious problems from drug overadministration.
On many occasions, I have observed this phenomenon in pediatric dental patients: A parent or guardian administers a tablespoon of drug instead of a teaspoon, or a larger dose than desired, because the child did not take all of the first dose. Significant overdose, with attendant respiratory depression, can develop in this manner if the administered drug is a CNS depressant. The consequences of these actions are formidable, with potential morbidity or mortality as the result. This has led to the enactment of legislation in a number of states restricting the use of oral sedation in patients younger than 13 years of age to dentists who have received appropriate education and training in this patient population.7 Oral sedation regulations vary considerably.
Oral Sedation in Children. As of April 2008, the American Dental Association (ADA) was aware of three states having enteral sedation permits specific to administration to minors (e.g., Louisiana has a permit entitled “restricted” that allows the dentist to administer to adults only). Three other states mention within their enteral sedation permit language stating, “additional training requirements to administer to children.” Three other states have language within their enteral sedation laws that require the dentist to have a parenteral “conscious” sedation permit to administer enteral to children.7
Oral Sedation in Adults. The ADA is aware of two states having oral sedation permits specific to adults. This does not take into account those other states that require the dentist to obtain a parenteral sedation permit to administer to children. For example, Idaho has a limited permit and comprehensive permit. The comprehensive (IV sedation) permit is required to administer to children; therefore one could argue that the limited is an adult-only permit.7
Oral Sedation, in General to Any Patient. Absent occasional references to PALS (pediatric advanced life support) for dentists treating pediatric patients, the ADA is aware of 14 states that have fairly straightforward options for enteral permits that do not mention additional training for administration to pediatric or minor patients.7
The dentist prescribing oral drugs for the management of anxiety must never forget that these drugs are CNS depressants and that excessive CNS depression (e.g., oversedation or general anesthesia) is always possible. To minimize concern over patient noncompliance, the dentist should (1) tell the patient, or the parent or guardian, exactly how much of the drug to take and at what time to take it; (2) write these instructions down and give them to the patient; (3) make sure that the prescription is clearly marked with these same instructions; (4) prescribe only the dose the patient is to take (this is warranted even though prescriptions for larger numbers of tablets or capsules are less expensive per item than are single doses); and (5) record the instructions given to the patient and the drug and its dose in the patient’s chart.
When the patient or parent (guardian) of a child is believed to be unreliable, the patient should be requested to appear in the dental office 1 hour before the scheduled treatment, where the drug may be administered to the patient by the dentist in a controlled manner.
A significant disadvantage of the oral route is its relatively long latent period (the period following administration before a clinical effect is observed). Most orally administered drugs have a latent period of approximately 30 minutes. At this time (30 minutes), the blood (plasma) level of the drug is at the minimum (therapeutic) level required for clinical activity to be observed. Absorption of oral drugs occurs primarily from the small intestine with some absorption from the stomach (alcohol and aspirin are exceptions where significant absorption occurs from the stomach). Drug absorption into the cardiovascular system continues, and the blood level of the drug increases until a maximum level is reached. With most oral drugs, peak blood levels occur approximately 60 minutes following ingestion or 30 minutes following the onset of clinical activity. Peak blood level is equated clinically with maximal drug action (i.e., most intense analgesia or sedation).
In addition to a long latent period, most oral drugs are absorbed erratically and incompletely from the GI tract, which makes consistent clinical results difficult to achieve. A number of factors act to influence absorption of drugs from the GI tract as follows:
Both the lipid solubility of the drug and the pH of the gastric tissues affect drug absorption from the GI tract. Lipid-soluble drugs are absorbed more rapidly than non–lipid-soluble drugs. Gastric fluid has a pH of approximately 1.4. Drugs that are organic acids, such as aspirin, freely diffuse across the gastric mucosa into the circulatory system. Drugs that are bases (e.g., codeine) are poorly absorbed from the highly acid environment of the stomach. As gastric fluid leaves the stomach to enter the small intestine, its pH changes dramatically as a result of the addition of biliary, intestinal, and pancreatic secretions. In the intestinal environment, with its pH of approximately 4.0 to 6.0, the absorption of aspirin is slowed, whereas absorption of the more basic codeine is accelerated.
Primary absorption of most drugs occurs from the small intestine rather than the stomach. This is true even for drugs such as aspirin because although the lower gastric pH favors its absorption, more than 90% of the absorption of aspirin occurs in the small intestine. The architecture of the small intestine is the primary reason for this. The process of absorption is facilitated by the small intestine’s considerable surface area, consisting of microvilli, villi, and the folds of Kerckring. The stomach, by contrast, is a relatively smooth organ, poorly adapted for absorption.
Because the small intestine is the primary site for drug absorption, it is important to get the drug through the mouth, esophagus, and stomach and into the small intestine as rapidly as possible. The removal of foods and other substances from the stomach occurs by contraction of the antrum of the stomach. The time required for a substance to be expelled from the stomach is the gastric emptying time. Liquids, when taken alone, require approximately 90 minutes to be removed, and a mixed meal of food and liquid requires about 4 hours to reach the duodenum. Liquids are discharged from the stomach into the duodenum at a rate of 10 ml/min. The presence of fat in the stomach significantly increases gastric emptying time. It is therefore recommended, as a general rule, that oral drugs be taken with a glass of water (approximately 8 oz) in the absence of food. In this manner, the drug’s delivery to the duodenum is maximized, permitting more reliable absorption. Anxiety is another factor that delays gastric emptying. It is estimated that gastric emptying time can be delayed by as much as two times in the fearful patient,8 thereby delaying the onset of action of antianxiety drugs. Thus a negative cycle is established. Oral antianxiety drugs are administered 1 hour before treatment to lessen the patient’s fear of impending dental or surgical care, yet the very fear that we are seeking to manage inhibits the absorption of the drug into the cardiovascular system. This helps explain why, in the presence of extreme fear, orally administered drugs may prove ineffective despite having been administered as directed by the dentist.
Drugs administered in aqueous solution are more rapidly absorbed than those given as an oily solution or in tablet or capsule form. The tablet or capsule must first dissolve in the gastric fluid before absorption can occur. Once it has dissolved, the size of the resulting particles of drug is important. The smaller the particle is, the greater the rate of drug absorption.9 There is significant variation in the clinical effectiveness of different forms (i.e., liquid, capsule, tablet) of the same drug (see Bioavailability).
Some drugs, such as morphine, cannot be administered orally because a significant level of drug inactivation occurs before they reach the cardiovascular system. Although the acidity of the stomach is the major cause of this, intestinal contents can also affect the actions of oral drugs. The hepatic first-pass effect is also involved. Drugs absorbed from the GI tract (stomach, intestine, colon) are first delivered to the liver via the hepatic portal system before entering into the systemic circulation. The liver is rich in enzymes that biotransform certain drugs into pharmacologically inactive byproducts. A prime example of this is the antidysrhythmic drug lidocaine. Lidocaine is so completely transformed via the hepatic first-pass effect that the drug is essentially useless when administered orally.10 However, modifying the chemical structure of lidocaine produced the chemical analog tocainide, which is clinically effective as an oral antidysrhythmic.11 In the area of drugs used for anxiety reduction, there is a subtle (but not clinically significant) hepatic first-pass effect noted with the opioid analgesics.
The presence of food in the stomach decreases absorption of drugs into the cardiovascular system by increasing gastric emptying time, and if the drug is bound to food, it will not be available for absorption.12 As mentioned previously, it is recommended that oral drugs be ingested with a full glass of water without food (unless a drug specifically requires that it be administered along with food as a means of minimizing gastric upset).
Two tablets of the same dosage of the same drug from different manufacturers are said to be chemically equivalent. If the ensuing blood levels of the drugs are equivalent, they are said to be biologically equivalent. They are therapeutically equivalent if they are equally effective therapeutically. Drugs that are chemically equivalent are not necessarily biologically or therapeutically equivalent. These differences are termed bioavailability. Differences in bioavailability of drugs are most often seen with oral preparations. The difference in absorption of chemically equivalent drugs is related to differences in the size of particles or shape of crystals and to the rates of disintegration and dissolution of the drugs.
The slow onset of clinical activity of oral drugs prevents their titration. Ability to titrate a drug permits individualization of drug dosages for all patients. Undersedation or oversedation should not occur where titration is possible. The ability to titrate a drug to clinical effect is one of the greatest safety factors in drug administration. Unfortunately, the 30-minute latent period and 60-minute delay for the drug to reach peak blood level (for most oral drugs) preclude titration. Care must be exacted to prevent underadministration or overadministration of orally administered CNS-depressant drugs.
Another disadvantage of orally administered drugs is the inability to either lighten or deepen the level of sedation rapidly. Should the effect of the drug prove inadequate, a second dose may be given; however, the same time factors (30 and 60 minutes) will be required to achieve full benefit of the drug, making this option unattractive in the clinical setting. If, on the other hand, the effect of the initial dose proves too intense, there is no effective means of reversing it. This lack of control over the actions of the drug seriously impairs the usefulness of orally administered drugs in a typical outpatient dental environment.
The duration of clinical action of most oral drugs is approximately 3 to 4 hours. For the typical 1-hour dental appointment, this duration of action is entirely too long. Unfortunately, however, there is no means of reversing the clinical action of the orally administered drug. The patient will remain under the influence of the drug well into the postoperative period and be unable to leave the dental office unescorted. Patients receiving oral CNS depressants for stress reduction must always be cautioned against driving or operating potentially hazardous machinery. If patients receive oral sedative drugs at home before their dental appointment, they must be similarly cautioned.
When the advantages and disadvantages of the oral route are compared, it becomes obvious that a number of significant disadvantages are associated with the use of this technique. These combine to produce a route of drug administration in which the administrator has little control over the ultimate clinical action of the drug.
This lack of control over drug action is a potential problem every time a drug is administered orally. This is particularly so when the drug is a CNS depressant, as are those used in stress reduction. The potential for oversedation, respiratory depression, and loss of consciousness must always be considered when administration of an oral drug for anxiety relief is contemplated.
Despite the negative factors associated with oral sedation, there is considerable need in dentistry for orally administered drugs for stress reduction. The primary use of the oral route is in the management of anxiety before the dental procedure. However, because of the lack of control over the ultimate drug action, it is strongly suggested that only minimal to moderate sedation be sought via the oral route. Minimal sedation may prove adequate to reduce anxieties that develop before the dental appointment, but may prove inadequate in diminishing the fears occurring once the patient enters the dental office and commences treatment. It is possible to produce moderate to deep sedation with the oral route. However, the clinician must always keep in mind the lack of control over drug action and the wide range of individual responses to a given drug dose. The possibility of overdose, respiratory depression, impaired consciousness, or unconsciousness is increased as the degree of CNS depression increases. Persons untrained in the management of the unconscious airway ought not attempt to achieve deep sedation by the oral route. In addition, the dentist prescribing or administering oral drugs must possess a thorough knowledge of the drug’s actions, contraindications, side effects, and precautions. The dentist must also be capable of prompt recognition and management of any adverse reaction that might develop (e.g., unconsciousness). This is the concept of “rescue” from a level of sedation beyond what is intended. If deep sedation is required, a more controllable technique of sedation (i.e., inhalation or IV) should be considered.
What then represents the rational use of the oral route in a typical dental practice? From the standpoint of safety, it is important that the clinician never seek to achieve a level of sedation beyond which he or she is comfortable (has been trained to use) and is capable of recognizing and managing any undesirable side effects that might develop. For these reasons, the rational use of oral sedation includes only minimal sedation or, in selected situations, moderate sedation. Deep sedation should be restricted to more controllable techniques.
The most common use of oral sedation is for the relief of anxiety in the hours immediately preceding a dental appointment. An antianxiety or sedative-hypnotic drug is used to reduce anxiety so that the patient will appear in the dental office for the scheduled appointment. More controllable techniques may be used at this time for intraoperative sedation. When using oral drugs for this purpose, the clinician must remember to remind the patient of the absolute prohibition against driving a motor vehicle or operating hazardous machinery. If the patient has taken the drug at home, he or she should be advised against driving a car and should be accompanied to the office by (driven by) a responsible adult. For medicolegal purposes, this should also be noted in the patient’s chart.
A second use for oral sedation is one that is often overlooked by a busy clinician. As noted earlier (see Chapter 4), not only do patients with fears of dentistry or surgery become apprehensive immediately before their appointment, often their anxieties start to build the day before the scheduled appointment. These persons might be unable to sleep the night before the appointment as they anticipate their upcoming “ordeal” and will be fatigued when they appear in the dental office the next day, a factor leading to a lowering of the pain reaction threshold. An antianxiety or hypnotic drug taken 1 hour before sleep (1 hr hs) the night before the appointment can help ensure a restful night’s sleep and a more stress-tolerant patient during treatment.
A large number of drugs may be administered orally in the management of anxiety. The overwhelming majority of these are classified as either antianxiety or sedative-hypnotic drugs. Other drug groups that may be used for this purpose are histamine blockers and opioids.
Before we discuss these drugs, a word is in order regarding the appropriate dosages to be used. The clinician must use as much information as is available to make an informed decision regarding the appropriate dose to administer, particularly when using the oral route. Information available to the clinician includes the patient’s medical history, age, weight, and previous drug reactions. In addition, the clinician must determine the degree of anxiety present and the level of sedation sought. After consideration of these factors, a drug dose is determined.
A source of information regarding recommended dosages of drugs is the drug package insert or publications such as Facts and Comparisons,13 Physicians’ Desk Reference,14 or Mosby’s Dental Drug Reference, eighth edition.15 Online sources of drug information, such as ePocrates.com16 or Mosby’s MD Consult17 are readily available for downloading onto a desktop computer or hand-held device. An advantage of online drug data resources is that they are updated on a regular basis.
A common problem associated with the use of recommended doses is that they often lead to inadequate anxiety reduction in the dental or surgical setting. There is a reasonable explanation for this: The package insert recommends a certain dose of a drug to induce sedation or sleep in a nonstress situation, such as the home environment. The dose of a drug that would effectively relax an apprehensive individual at home will probably prove ineffective when the stresses of the dental office environment are added. For this reason, the doses recommended for oral sedation in this chapter and in many textbooks of pediatric dentistry may be somewhat higher than those in the package inserts.18,19
Many antianxiety and sedative-hypnotic drugs for oral administration are produced in three dosage forms. When a dosage is chosen for stress reduction in dental practice, these three dosage forms correlate with the normal distribution (“bell-shaped”) curve (Figure 7-1). The middle dosage form represents the “average” dose, producing clinically effective results (in nonstress situations) in approximately 70% of persons receiving it. The larger dosage form is for persons in whom the average dose proves to be ineffective or who have a greater degree of anxiety. The smaller dosage form is for persons in whom the average dose provides too intense a clinical effect, for persons with a lesser degree of anxiety, for elderly patients, or for debilitated patients. It must be remembered that the added stresses associated with dental or surgical treatment will increase the percentage of patients requiring larger than “usual” doses for management of their treatment-related fears.
Figure 7-1 Normal distribution curve (“bell-shaped” curve). Persons will respond to drug dosages in dissimilar ways. Approximately 2.5% of persons will be extremely resistant to a “usual dose,” and 2.5% will be quite sensitive to the same dose.
(Data from Bennett CR: Jorgensen Memorial Lecture: Drug interactions, Anesth Prog 30(4):106-112, 1983.)
Although titration (individualization of drug dosages) is not possible with orally administered drugs—a significant impediment to their safe use—it is possible in situations in which oral drugs are to be used over multiple appointments to titrate by appointment. This concept was introduced to me by Dr. Ronald Johnson, then chairman of the Department of Pediatric Dentistry at the University of Southern California.20 Quite simply, titration by appointment means that the dentist will assess the efficacy of sedation achieved at the first appointment with a given drug dosage and, if necessary, increase or decrease the dosage of drug(s) administered at subsequent appointments. Therefore over a period of two to three visits, the appropriate dosage for that patient can be achieved (titrated). Titration by appointment is discussed more fully in the chapter on pediatric sedation (see Chapter 35).
Antianxiety drugs are used to manage mild to moderate daytime anxiety and tension. Drugs in this group share a similar CNS-depressant action: At therapeutic dosages they produce the level defined as minimal sedation usually without impairing the patient’s mental alertness or psychomotor performance. Groups of drugs that are commonly categorized as antianxiety drugs are as follows:
For the management of mild to moderate levels of anxiety, the benzodiazepine antianxiety drugs are preferred. Benzodiazepine antianxiety drugs have a wide therapeutic dosage range and thus are less likely to produce undesirable side effects.
The antianxiety drugs have, in the past, been known by other names, such as minor tranquilizers, anxiolytics, ataractics, anxiolytic sedatives, and psychosedatives. The general category “antianxiety drugs” has become accepted for this group of drugs.
The benzodiazepines are the most effective drugs currently available for the management of anxiety. They also possess skeletal muscle–relaxant properties and are anticonvulsants. More than 2000 benzodiazepines have been synthesized since 1933. Chlordiazepoxide was the first benzodiazepine introduced (1960). In 2008 (May) 31 benzodiazepines (Table 7-1) were available worldwide. Fourteen of the commonly used benzodiazepines are categorized as sedative-hypnotics, 15 as anxiolytics, 7 indicated for use as antiepileptic drugs, and 1 as a skeletal muscle relaxant. (Some drugs are indicated for more than one group.)
The benzodiazepines represent the most popular class of drugs available today for the management of dental fear and anxiety via the oral route of drug administration. Diazepam has remained a frequently prescribed drug in the United States since its introduction in 1977. Orally administered midazolam has become a very popular dental sedative, primarily in pediatrics, whereas in North America, triazolam has undergone a period of enthusiastic acceptance by many general dentists treating phobic adult patients.
The benzodiazepines have depressant effects on subcortical levels of the CNS. The specific anxiolytic effect of benzodiazepines is a result of their actions on the limbic system and the thalamus, those areas of the brain involved with emotions and behavior. Benzodiazepines have been called limbic system sedatives because they impair neuronal discharge in the amygdala and amygdala-hippocampus nerve transmission. Benzodiazepines depress the limbic system at doses smaller than those depressing the reticular activating system (RAS) and the cerebral cortex. Barbiturates and other sedative-hypnotics, on the other hand, do not exhibit this selective depression, producing instead a more generalized CNS depression.
Specific receptors for benzodiazepines have been isolated within the spinal cord and the brain. The location of these receptors parallels that of γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain, and of glycine, the major inhibitory neurotransmitter in the spinal cord.22 Benzodiazepines act by intensifying the physiologic inhibitory effects of GABA by interfering with GABA reuptake.23–25
One of the most significant features of the benzodiazepines as a group is the very wide margin of safety between therapeutic and toxic doses. Ataxia and sedation develop only at doses beyond those required for antianxiety effects.
It is interesting that when aggression and hostility are held in check by fear and anxiety, the ingestion of a benzodiazepine or other anxiolytic drug may produce a “paradoxic” increase in aggression. Other CNS depressants, such as the barbiturates, produce these same effects, but only at doses that produce drowsiness and motor incoordination. The benzodiazepines commonly achieve this action without these side effects.26
Other CNS actions of the benzodiazepines include skeletal muscle–relaxant properties and anticonvulsant effects.27,28 The site of action of the muscle-relaxant properties of benzodiazepines is as yet undetermined; however, it is thought that the effect is central rather than peripheral. Skeletal muscle relaxation appears to be caused by a combination of central depression of the brainstem reticular formation and depression of polysynaptic spinal reflexes.27,29 Anticonvulsant actions of benzodiazepines are produced by a depression of epileptiform discharge in the cerebral cortex and an enhancement of electrical activity of Purkinje cells. For effective anticonvulsant activity, the benzodiazepines must be administered intravenously (although intramuscularly and intranasally administered midazolam has terminated seizures).30 Diazepam and clonazepam are currently approved for anticonvulsant therapy.
All sedative-hypnotics and antianxiety drugs (including benzodiazepines) are potential respiratory depressants. At usual therapeutic oral dosages in healthy normal-responding patients (middle of the bell-shaped curve), the benzodiazepines, administered alone, do not produce clinically significant respiratory depression and do not potentiate the depressant effects of opiates. Cases of significant respiratory depression and respiratory arrest following oral benzodiazepine ingestion have been reported.31,32
Following oral administration to a healthy patient (American Society of Anesthesiologists [ASA] 1), benzodiazepines produce virtually no changes in cardiovascular function. Indeed, the benzodiazepines are frequently used in the management of anxiety and depression associated with cardiac disease. They are preferred to the barbiturates and other sedative-hypnotics in this situation primarily because they do not produce unwanted degrees of CNS depression or restlessness and because they do not produce cardiovascular depression at therapeutic levels.33
The benzodiazepines undergo biotransformation in the liver (see following section); however, they do not stimulate the induction of hepatic microsomal enzymes. Potentially hazardous drug interactions, such as those observed between the barbiturates and coumarin anticoagulants, are not observed with benzodiazepines. In addition, patients with hepatic dysfunction may receive the benzodiazepines without increased risk of side effects, regardless of the cause of the hepatic dysfunction.
Following oral administration, all benzodiazepines are absorbed relatively rapidly and reliably from the GI tract. The rate at which maximum plasma levels develop exhibits significant variation among the different benzodiazepines and among individuals. Approximate time for peak plasma levels following oral administration of several benzodiazepines is shown in Table 7-2.
|Drug||Peak Plasma Level (hr)|
Benzodiazepines undergo biotransformation in the liver. There is considerable variation in the half-lives of these drugs: Diazepam’s elimination half-life is 20 to 70 hours, whereas triazolam’s is 1.5 to 5.5 hours. In addition, many of the benzodiazepines have biotransformation products that are pharmacologically as active as the parent drug (Table 7-3).
Chlordiazepoxide has a plasma half-life of between 24 and 48 hours and has as intermediate metabolites two pharmacologically active chemicals, desmethylchlordiazepoxide and demoxepam. The half-life of diazepam ranges between 20 and 70 hours (frequently quoted as “1 hour per year of age”). Pharmacologically active metabolites of diazepam include desmethyldiazepam (half-life of 96 hours), temazepam, and oxazepam. Flurazepam, with a plasma half-life of 2.3 hours, has an active metabolite with a half-life of 47 to 100 hours. Medazepam has three active metabolites: diazepam, desmethyldiazepam, and desmethylmedazepam; prazepam (half-life 63 to 70 hours) has among its metabolites desmethyldiazepam and oxazepam. Desmethyldiazepam is a metabolite of clorazepate.
Nitrazepam, oxazepam, lorazepam, midazolam, triazolam, temazepam, and alprazolam are biotransformed into pharmacologically inactive metabolites. The combination of rapid absorption from the GI tract (1 to 4 hours), short elimination half-life (5.7 to 9 hours), and inactive metabolites makes oxazepam an attractive drug for the management of anxiety within the dental or surgical environment. Lorazepam, on the other hand, with a slow rate of absorption (2 hours) and a half-life of 12 hours (range 9 to 24 hours), is less appealing. Triazolam, with a rapid onset of action and short half-life (1.5 to 5.5 hours), is ideally suited as a hypnotic in dentistry.34–36
Psychological and physiologic dependence may develop to benzodiazepines.37 The incidence of physiologic dependence is considerably less than that of psychological dependence. Physiologic dependence is unlikely to develop unless the patient takes doses much greater than therapeutically necessary over long periods of time. Within the dental setting, there is little likelihood of this occurring.
The benzodiazepines represent the most nearly ideal drugs for the management of anxiety. In the dental and surgical setting, the benzodiazepines remain the drugs of choice via the oral route for the management of mild to moderate pretreatment anxiety and apprehension in the adult patient. These drugs provide a level of minimal to moderate sedation in most patients. Many benzodiazepines are currently available, and many more will surely become available in the future. Because there are significant differences in the onset of action and the duration of action among these drugs, the choice of a specific drug should be made only after consideration of the needs of both the patient and the dentist.
Although there are indications for the use of other drugs in specific instances, the drugs most ideally suited for pretreatment anxiolysis via oral administration in the dental and surgical setting are oxazepam and diazepam. For patients requiring sedation (hypnosis) to sleep restfully the evening before their treatment, flurazepam and triazolam are preferred. In the past decade, oral triazolam has become a very popular drug for the provision of minimal to moderate sedation in dentistry in North America.38–40 Triazolam will be reviewed in depth in the section of sedative-hypnotic benzodiazepines.