J Oral Maxillofac 50:989-997.

Surg

1992

Oral Benzodiazepines and Conscious Sedation: A Review PAUL M. LOEFFLER,

DDS*

A large number of benzodiazepines have been studied for use as sedatives and for their anxiolytic potential as premedicants for outpatient surgery. Potent, new, orally-administered drugs with short half-lives, rapid onset, and minimal residual effects have been developed. Dose-dependent amnesia is also produced by some of these agents. Advances in understanding receptor physiology have shed light on specific pharmacologic activities and aided the discovery of benzodiazepine antagonists with antidote properties. While these drugs have relatively low toxicity, dose-related oversedation remains a risk in susceptible patients, especially when combined with other sedatives.

dosage incrementally to a clinical end point with reliable and less variable effect than can be obtained by the oral or intramuscular (IM) route.’ However, IV sedation is not always feasible or necessary for preoperative anxiolysis.3

The administration of oral tranquilizing drugs has long been a popular method of obtaining conscious sedation and relief of anxiety before oral surgery. Oral sedatives are commonly used as the sole premeditation for minor outpatient procedures and as an adjunct to intravenous (IV) sedation and general anesthesia. Numerous agents have been used, including barbiturates, chloral hydrate, antihistamines, neuroleptics, and pblockers. Before the introduction of the benzodiazepines, the barbiturates were the principal sedativeanxiolytics. However, the barbiturates often produced unacceptable drowsiness and possessed a narrow therapeutic index. Since their introduction 30 years ago, the benzodiazepines have become the most widely prescribed medications in the world’ and are wellestablished as the drugs of choice for oral sedation and anxiolysis. The purpose of this review is to examine the uses and characteristics of oral administration of this large family of drugs, rather than to debate their use as a substitute for other standard parenteral sedation techniques. The advantages of IV administration of sedative drugs are well known: notably, the ability to titrate

Physiology of Action y-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter of the central nervous system (CNS). It is now known that the benzodiazepines bind to specific receptors on GABA-mediated chloride ion channels, enhancing inhibitory neurotransmission. GABA receptors have been identified on neurons in the brain, spinal cord, and retina of humans; it is estimated that 30% of all mammalian CNS synapses are GABA-ergic. 4,5Activation of the GABA receptor causes membrane chloride channels to open, increasing the influx of negative chloride ions through the cell membrane, thereby preventing depolarization of the neuron (Fig 1).4 The GABA-receptor complex is directly affected by barbiturates, ethanol, and other drugs, and their wide distribution in the CNS accounts in part for the relatively broad sedative effects of these agents. Benzodiazepines appear to potentiate GABA-mediated inhibition in a more selective manner by increasing the affinity of GABA for its receptor, rather than by producing a direct effect, While the GABA system plays a regulatory role in neurotransmission, the benzodiazepines may represent an evolutionary fine-tuning of

* College of Medicine, Michigan State University, East Lansing. Address correspondence and reprint requests to Dr Loeffler: College of Medicine. A-234 Life Sciences Bldg, Michigan State University, East Lansing, MI 48824. 0 1992 American Association of Oral and Maxillofacial Surgeons 0278-2391/92/5009-0012$3.00/O

989

990

ORAL BENZODIAZEPINES

PRESYNAPTIC

l

NEURON

GABA RECEPTOR

/

CHLORIDE CHANNEL

AND CONSCIOUS SEDATION

BENZODIAZEPINE RECEPTOR

BENZODIAZEPINE

NEURONAL MEMBRANE

FIGURE 1. A, GABA increases chloride conductance, reducing the excitability of the target cell. B, This action is further enhanced in the presence of benzodiazepine. (Adapted with permission.‘3)

inhibition by acting as a parent regulator of the GABA system. Major advances in benzodiazepine pharmacology have resulted from the elucidation of cell receptorligand interactions. Specific benzodiazepine receptors were first described in 1977 as stereospecific, reversibly binding, and widely distributed in the CNS.6 They are independent from the more numerous GABA receptors, but are closely affiliated, probably on the same protein complex. 6-8The potency of a specific benzodiazepine appears to be dependent on the drug concentration at the receptor site,g as well as its degree of affinity for the corresponding receptor. These receptors may be heterogeneous, with different subtypes responsible in some way for specific clinical effects; certain drugs have been found that selectively block some benzodiazepine activities but not others. “J ’ Unlike opiate receptors, for which endogenous endorphins have been identified as ligands, endogenous benzodiazepine receptor ligands have not been found with certainty. Identification of such an agent is an area of intense investigation and could facilitate further development of benzodiazepine antagonists. Several potent and specific inhibitors of benzodiazepine activity that bind competitively to the receptor complex have been discovered. Among these, flumazenil has been extensively studied since I98 1 for use in reversing sedation. It probably acts by inducing a conformational change in the benzodiazepine receptor, thereby neutralizing the binding site.” Flumazenil appears to have little intrinsic activity aside from its an-

tagonist properties, and has no effect on benzodiazepine pharmacokinetics.‘3 Anatomic Considerations Numerous studies have shown that anxiety is associated with neural activity in specific areas of the brain.14 Benzodiazepines appear to selectively suppress these areas, exerting their greatest inhibitory effects on the subcortical limbic system. This area of anatomically related structures in the medial aspect of the brain lies between the neocortex, major sensory systems, and hypothalamic-pituitary axis, and includes the hippocampus, cingulate gyrus, septum, and amygdala. Benzodiazepine receptors are abundantly distributed in regions of the limbic system thought to be involved in anxiety, occurring in highest density in the hippocampus, l4 a neural substation that receives input from areas of the brain stem. Stimulation of the hippocampus in experimental animals has been shown to produce alarm reactions.’ The amygdala assigns emotional weight to sensory input before sending the information to the cortex for evaluation. Surgical disruption of connections between the frontal lobes and limbic system has been shown to relieve anxiety syndromes.15 The frontal cortex monitors input from the limbic system, overriding excessive emotional responses such as panic, anxiety, or crying, when such behavior is inappropriate. The hippocampus and amygdala appear to play an important role in memory function. Disruption or

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damage to these structures prevents conversion of information into long-term memory, although memory of prior events is not affected. Inhibition of these areas by benzodiazepines may be responsible for the anterograde amnesia characteristically produced by these drugs. Pharmacology The action of the benzodiazepines is essentially limited to the CNS, although slight cardiovascular effects may be observed. While all produce some degree of sedation and drowsiness, and share other clinical effects, the relative strengths of these activities vary between compounds because of important differences in absorption, distribution, and elimination (Table 1). These pharmacokinetic differences must be considered when choosing a drug, as they are responsible for substantial variation in clinical effects and greatly affect therapeutic utility.16 Benzodiazepines are well absorbed by the gastrointestinal tract (Table 2), with the rate of absorption determining the onset of action. Drugs with high lipid solubility reach receptor sites more rapidly, but are also quickly redistributed to peripheral fat.16 Some long half-life agents with active metabolites may not reach peak therapeutic effect for several days when administered in repetitive doses. The mechanisms of action of individual benzodiazepines may be distinct, with some showing selectivity for receptors in anxiety-producing areas of the brain, while others have greater affinity for spinal motor nerve

Table 1. Pharmacokinetics of Commonly Used Benzodiazepines

Compounds with active metabolites Chlordiazepoxide Chlorazepate Diazepam Nitrazepam Flurazepam Halazepam Prazepam Compounds with inactive or shortlived metabolites Midazolam Triazolam Temazepam Oxazepam Lorazepam Alprazolam Quazepam

Half-life (hl

Maximum Plasma Concentration After Oral Intake (h)

8-24 5-15 20-50 18-36 47-100 14-100 50-100

0.5-4.0 NA 1.0-1.5 2.0 0.5-2.0 1.o-3.0 6.0

1.5-2.5 1.5-5.0 3-6 5-15 8-25 1l-19 39

0.5-1.0 1.3 0.5-1.0 I .o-4.0 1.0-2.0 1.o-2.0 2.0

Data from the American Medical Association.74

Tabb 2. Benzodiazepine Absorption Rates After Oral Administration Fast

Intermediate

Slow

Diazepam Clorazepate Flurazepam Midazolam

Clonazepam Chlordiazepoxide Alprazolam Triazolam Lorazepam

Oxazepam Temazepam* Prazepam

Rates shown are during a fasting state. * Variable, depending on formulation. Data from the American Medical Association.‘6

pathways, providing clinical efficacy as muscle relaxants. The selective anticonvulsant and seizure-inhibiting activity of some benzodiazepines is caused by their ability to reduce nerve cell excitability, thereby blocking the epileptic focus and further spread of the impulse.4 Ethanol-withdrawal seizures are also suppressed. However, tolerance develops to these effects, limiting their usefulness for long-term treatment. Benzodiazepines exert a depressant action on spinal reflexes mediated by the brain stem reticular formation, with ataxia resulting from the same GABA-ergic effect on supraspinal and cerebellar pathways. Drugs with selective anticonvulsant and muscle relaxant activity include diazepam and clonazepam, although only clonazepam has been effective in nonsedative doses.” Anxiolysis appears to result from the effect of the benzodiazepines on GABA-mediated modulators of anxiety in the limbic system. This effect may be doserelated, as anxiolysis is observed at doses that do not produce overt sedation or significant interference in cognitive function.2 Sedative-hypnotic effects may result from inhibition of normal stimulatory (anxietycausing) pathways, rather than from direct inhibition of centers of alertness. The amnesic effect of the benzodiazepines, primarily anterograde reduction of episodic memory, is not well understood, although it is apparently mediated by central benzodiazepine receptors. The mechanism appears to be selective and dose-related, acting on long-term memory and impairing the acquisition of new information.” Other drugs with similar action include scopolamine, alcohol, and marijuana. Additionally, scopolamine impairs information retrieval, while the benzodiazepines do not. I9 It is uncertain whether the sedative action of these drugs plays a role in producing amnesia. The benzodiazepines stimulate the production of hepatic microsomal enzymes and undergo extensive hepatic metabolism. Some metabolites are pharmacologically more active than the parent drug and are responsible for a prolonged duration of action, an effect that is most pronounced in the elderly, young children,

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and individuals with impaired hepatic function. An elderly patient may require less than half of the dose necessary to produce a similar clinical effect in a young adult.20 Therapeutic Applications The benzodiazepine family comprises an increasing number of drugs, with a variety of therapeutic uses as muscle relaxants, anticonvulsants, and hypnotics, and uses related to their antipanic effects, such as presurgical sedation and anxiolysis. However, unlike many barbiturates, most benzodiazepines will not by themselves induce general anesthesia. Several are available for IV administration, providing peak plasma levels almost immediately, although the onset of therapeutic effect may be delayed if activity is additionally conferred by a metabolite as well as the parent drug. When considering the use of premeditation, the clinician must often determine the need for anxiolytic drugs based on only a brief evaluation of the patient. Anxiety may be intensified by the intimidating effect of the surgical operatory and personnel, a lack of time spent with the patient before the procedure, and in the young, first-time patient. The decision to manage anxiety pharmacologically also requires additional behavioral techniques.2 The objectives of premeditation are the relief of anxiety and pretreatment stress to provide a calm, cooperative patient; amnesia of the surgical procedure may also be desirable. Sedation is observable by the clinician as a decreased level of activity and excitability, while hypnosis is analogous to drowsiness or a stage of sleep from which the patient can be easily aroused. Anxiolysis is a more subjective effect, desired by the patient, but not always observable by the clinician. The ideal premeditation for conscious sedation provides anxiolysis and some sedation, and should have the following attributes: (1) rapid absorption and onset of action, (2) a high therapeutic index of safety, and (3) rapid recovery without prolonged psychomotor impairment. In selecting a suitable drug for preoperative medication, consideration must be given to the additive effect of preoperative and p&operative sedatives and anticipated recovery time, with dosages adjusted accordingly. A premedicant can be used to provide a baseline of sedation, decreasing the intraoperative sedation requirement. For anxiolysis, the administration of fractionated doses of oral sedatives may be more effective than a single dose, with intake of the drug the evening before the procedure and repeated the following morning or just before the operation.21 The result is to blunt the onset and buildup of anxiety experienced by some patients before surgery, as well as to alleviate sleep disturbances.

BENZODIAZEPINES

AND CONSCIOUS

SEDATION

The discovery in 1957 of chlordiazepoxide (Librium, Roche, Nutley, NJ), the parent compound of the benzodiazepine family, and its unique pattern of actions, represents a milestone in the development of the psychoactive drugs. 22Chlordiazepoxide is a prodrug, producing active sedative metabolites and giving it a delayed period of onset. It is also available compounded with the antidepressant amitriptyline (Limbitrol, Roche) and with the antispasmodic clinidium (Librax, Roche). Modification of this three-ring compound has led to the synthesis of a large number of therapeutically useful drugs. More than 3,000 related compounds have been synthesized, with about 35 of these in clinical use throughout the world. While most of these agents have been developed for their anxiolytic potential, all possess sedative-hypnotic, muscle-relaxant, and anticonvulsant properties to varying degrees, with remarkably low capacity to produce fatal CNS depression, respiratory depression, or cardiovascular collapse.” Diazepam First introduced in 1963, oral diazepam (Valium, Roche) remains the most widely used anxiolytic for outpatient procedures. It is rapidly absorbed from the gastrointestinal (GI) tract, and because of its high lipid solubility, rapidly crosses the blood-brain barrier, resulting in a fast onset of action. However, it is also rapidly redistributed to peripheral fat, resulting in a fairly short duration of action after a single dose, despite a prolonged elimination half-life of up to 50 hours and active metabolites with even longer duration.‘6,23 Receptor tolerance to diazepam occurs as well, contributing to the disappearance of clinical effects within 2 to 3 hours, although prolonged psychomotor impairment may persist.24 Diazepam has been studied extensively as an orally administered premeditation. One double-blind study comparing 10 mg of diazepam with the short-acting oral agents midazolam, 15 mg, and triazolam, 0.25 mg, found diazepam to differ little from placebo.25 Another compared diazepam, 0.25 mg/kg, with placebo as an anxiolytic premeditation, finding no significant differences.26 When the preoperative waiting time is as long as 6 hours, benzodiazepines with long half-lives have been shown to be useful for premeditation without loss of sedative effect.26s27 Temazepam Temazepam (Restoril, Wyeth-Ayers& Philadelphia, PA), a derivative of diazepam, is a short-acting hypnotic agent with several properties making it suitable for use as an oral premeditation. The rate of absorption varies with formulation; it is rapidly absorbed when administered in soft gelatin capsules, with peak plasma con-

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centration reached in 20 to 40 minutes.28 Its elimination half-life of 3 to 7 hours is one of the shortest of the benzodiazepines available in oral form, and it is metabolized to inactive products and a small amount of oxazepam. 29-3’Several clinical studies have shown doses of 20 to 30 mg to be superior to diazepam, oxazepam, and placebo, producing sedation and anxiolysis within 60 minutes and without prolonged recovery time.32”4 In a study by Hargreaves comparing temazepam, 20 mg, with oral midazolam, 15 mg, midazolam produced superior anxiolysis, sedation, and amnesia, but with a slower recovery rate. 3o Patients receiving temazepam recovered to preoperative status as rapidly as those receiving placebo. Nightingale et al found temazepam, 20 mg, to be comparable to midazolam, 20 mg, in anxiolytic effect, with less drowsiness.29 Obey et al found temazepam, 10 to 20 mg, to be an effective anxiolytic and amnestic agent, with rapid recovery and discharge, suggesting that it is the premedicant of choice for outpatient surgery.35 Although most studies have used 20- to 30-mg doses, several have evaluated 40-mg doses, with one finding them to be an effective alternative to IV diazepam, 10 mg, in surgery to remove third molars. The age of these patients ranged from 18 to 32 years, with full recovery from sedation reported 120 minutes after initial dosing. 36Ratcliff et al found the maximum effect of temazepam, 40 mg, on memory, sedation, and anxiety occurred 1 hour after administration when most patients were asleep but easily awakened.37 These patients, with a mean age of 42 years, were still drowsy 4 hours after the initial dose. Midazolam

Midazolam (Versed, Roche) is a potent imidazobenzodiazepine with amnestic and anxiolytic properties typical of the benzodiazepines.38 First synthesized in 1975, it has become widely used for brief diagnostic procedures, conscious sedation, and for inducing general anesthesia. The basicity of the imidazole ring distinguishes midazolam from the parent group, allowing the preparation of water-soluble salts that make it welltolerated in injectable form.22 It is also acts directly on receptors and is rapidly metabolized. Both oral and parenteral forms are effective, although the tablet form is not yet available in the United States. When given orally, midazolam is rapidly absorbed, reaching peak effect in 30 minutes, with an elimination half-life of about 1.75 hours and a systemic availability of 41%.39@ The respiratory depressant potential of midazolam has been compared to that of thiopental when used in IV anesthetic induction doses of 10 to 20 mg.4’ Amnesia is a consistent and probably dose-related finding with oral midazolam, as with the IV form. Klopfenstein et al observed amnesia in 14 of 20 patients

premeditated with oral midazolam, 14 to 22.5 mg.42 Hargreaves found oral midazolam, 15 mg, produced significant anterograde amnesia, but also caused a greater delay in recovery. 3oA number of studies comparing oral midazolam, 7.5 to 15 mg, with temazepam, 20 mg, found both to be effective and comparable anxiolytic and sedative agents with similar recovery times, although midazolam produced greater amnesia.43,44 Typically, an effective oral dose is 7.5 to 15 mg. Raybould et al found 7.5 mg of midazolam ineffective for producing significant anxiolysis and sedationm whereas others have found the sedation from a 15-mg dose to be excessive in both intensity and duration, noting altered psychomotor function up to 2 hours following recovery.44,45 Triazolam

Triazolam (Halcion, Upjohn, Kalamazoo, MI) is approved for use as a hypnotic agent, but with the trend toward using shorter-acting agents, it has become popular as a premeditation for surgery. It reaches peak plasma concentration in 1 hour, ” and is rapidly broken down to active metabolites, which may potentiate the parent compound, but are themselves rapidly eliminated. In a study by Forrest et al, oral triazolam, 0.25 mg, administered as an outpatient anxiolytic produced less sedation and amnesia than oral midazolam, 15 mg, but required longer recovery time.45 Others have found this dose provided effective sedation, amnesia, and impaired psychomotor performance, but is unsatisfactory for anxiolysis.46 Abrupt cessation of potent, short-acting benzodiazepines used to treat sleep disorders for extended periods results in rebound insomnia and withdrawal symptoms. A number of other side effects have been reported with the use of triazolam, including memory impairment, mental confusion, hallucination, nightmares, and serious behavioral disorders. While these effects may represent a disinhibitory-type response, they also may be the result of a unique reaction to the chemical structure of this particular drug.47 Although these effects have been reported after extended use of the drug, it is unclear whether one-time dosing predisposes a patient to these reactions. Flurazepam

Flurazepam (Dalmane, Roche) is a hypnotic agent used in the short-term treatment of insomnia. It is a prodrug, becoming active in metabolized form, with a fast onset of 0.5 to 1 hour causing rapid induction of sleep, and having a long elimination half-life of 47 to 100 hours4’ Effectiveness increases after 2 to 3 days of use because of accumulation and slow elimination of active metabolites. Flurazepam has been used as a nighttime sedative presurgically. Luyk et al found that

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ffurazepam given the evening before oral surgery did not significantly decrease preoperative anxiety, and its use had no effect on the amount of IV diazepam required to reach clinical sedation the following morning, although it was effective in inducing sleep.49

AND CONSCIOUS SEDATION

Several other drugs with similar clinical profiles are currently used for anxiolysis and sedation, including prazepam, halazepam, and chlorazepate. These drugs have intermediate half-lives and delayed onset, limiting their uses as premedicants, and appear to offer no additional advantages over those previously described.

Oxazepam Oxazepam (Serax, Wyeth-Ayerst), like temazepam, is a short-acting, rapidly metabolized derivative of diazepam that has been used as a hypnotic and anxiolytic agent. Peak serum concentration of oxazepam occurs 2 hours following oral administration because of slow GI absorption,” several times longer than that for temazepam. Greenwood et al compared oxazepam, 30 mg, with temazepam, 20 mg, and placebo, finding that it produced minimal sedation and anxiolysis 1 hour after oral administration.32 Alprazolam Alprazolam (Xanax, Upjohn) is one of the few benzodiazepines used specifically to treat panic disorders, for which it is effective and well established. In this regard, it displays actions similar to the monoamine oxidase inhibitors and antidepressant drugs, but acts more rapidly and is better tolerated.‘*5’ Studies have linked panic behavior with increased blood flow to the hippocampal gyrus, an area with direct connections to the limbic system. 52Although alprazolam is not a drug of choice for premeditation, it illustrates the discrete action of some benzodiazepines on the CNS and the therapeutic application for this specificity. Lorazepam Lorazepam (Ativan, Wyeth-Ayerst), a derivative of the main metabolite of diazepam, has been used for short-term insomnia, panic disorders, and as a premedicant. As with alprazolam, it is a potent, shortacting agent with no active metabolites.53 In comparing lorazepam, 2.5 to 5.0 mg, with diazepam, 10 to 20 mg, flunitrazepam, 1 to 2 mg, and placebo before outpatient surgery, Male et al concluded that lorazepam was superior to placebo, but was not as effective as flunitrazepam.54 Others have found lorazepam, 2.5 to 5 mg, to be effective for sedation, but not anxiolysis; prolonged drowsiness has been a significant side effect.55x56 The longer-acting drug clonazepam, marketed for its specific anticonvulsant properties, also has antipanic activity. It is among the most potent agents available, behind only midazolam and triazolam in its affinity for benzodiazepine receptors.’ Benzodiazepines with longer half-lives have smoother treatment courses and less severe withdrawal symptoms than short half-life agents when used in an extended course of treatment.

Discussion The benzodiazepines produce a triad of actions (anxiolysis, sedation/hypnosis, and amnesia), making them useful premedicants for outpatient surgery. The various agents produce these effects to different degrees; altering the parent molecule can produce a compound with enhanced effect in a particular aspect of activity.57 The distinct and selective actions of the various benzodiazepines also seem to be proportional to their relative potencies.45 There is no generally accepted criteria for defining what constitutes adequate premeditation. Direct comparison of anxiolytic, sedative, and amnestic effects is complicated by the use of different scales by various investigators, the subjective nature of these studies, and individual differences in drug response. It is difficult to experimentally discriminate the sedative from anxiolytic effects of a drug. To assess and quantify such subjective phenomena as anxiety, most studies have used a linear analog scale similar to that proposed by Maxwell.58 Although the evaluation of anxiety necessitates psychological measurements and self-reporting by the patient, sedation is assessed by the clinician. The effects of a drug as experienced by the patient and as seen by the observer must be differentiated; a drug providing good anxiolysis, but without evidence of CNS depression, might be rated efficacious by the patient, but not by the clinician. Conversely, a drug rendering a calm, sedated patient might not be considered by the patient to have been beneficial in relieving anxiety. Although amnesia of the surgical event is a beneficial side effect, prolonged amnesia is undesirable. Initial reports of amnesia following use of benzodiazepines occurred with IV diazepam, with the degree of amnesia increasing linearly with increasing dosage.59 Subsequent studies have shown that related drugs and oral administration also produce amnesic effects.60@ Whether amnesia can occur in nonsedative doses is uncertain, as is the effect of anxiety on memory. For patients who may require additional surgical treatment, amnesia produced by a sedative agent can be a valuable clinical feature, as patients equate it with unconsciousness.62 Sedation and postoperative drowsiness were variable findings in the studies reviewed. While anxiolytic effects are produced by some agents without causing sedation, it is uncertain whether sedation is simply a dose-related continuum of response or an independent feature. Al-

PAUL M. LOEFFLER

though a calm, quiescent patient is preferred by the surgeon, drowsiness should not be equated with anxiolysis.53 The use of an oral sedative the night before surgery has not been shown to reduce anxiety at the time of the operation4’ Short half-life drugs such as triazolam have been used for their sleep-inducing effects, but longer acting agents with active metabolites, including flurazepam and quazepam, are more effective hypnotics because accumulation, especially with multiple doses, produces a “carryover” effect. 16,49 This extended action, although beneficial in promoting deep sleep, is undesirable for a short outpatient procedure. Complications of prolonged benzodiazepine use, such as rebound anxiety, rebound insomnia, and the development of tolerance, occur more rapidly with the short half-life agents, but are not significant in single-episode administration. The benzodiazepines as a group are remarkable for their relatively low toxicity and mild side effects. which are often extensions of their pharmacologic actions. While overdosage may result in mental confusion, ataxia, and hypnosis progressing to stupor, relatively few deaths have been reported from benzodiazepines alone, even with dosages in excess of 700 mg of diazepam or chlordiazepoxide. 4~17 Psychomotor impairment may persist at levels greater than that estimated by the patient, affecting the ability to operate a motor vehicle. Hypersensitivity and anaphylactic reactions are extremely rare. 63Paradoxical or dose-related disinhibitory reactions, though rare, result from overriding of the normal restraining influence of the cortex, causing agitation, talkativeness, or hostility similar to that seen in some cases of alcohol intoxication. Recognition of these reactions, which may occur more commonly with short-acting agents, is imperative to avoid misinterpreting them as an indication for greater sedation.64 Respiratory depression from benzodiazepines is minimal, having been observed somewhat more often with midazolam and diazepam, especially after rapid IV administration. 65Nevertheless, as with any sedative drug, a patient with respiratory compromise must be considered at increased risk. In numerous cases of benzodiazepine overdose, where respiratory assistance was required, another CNS depressant was usually involved, as interaction with other sedatives greatly exacerbates the hypnotic effect, with potentially devastating results.” Cardiovascular effects are minor, with a slight decrease in systolic blood pressure and an increased heart rate. A number of cases of serious and occasionally fatal cardiopulmonary depression occurring with IV administration of midazolam, sometimes during conscious sedation, have been reported.66 Midazolam has been shown to decrease cerebral blood flow when administered at higher dosages.67 Most patients experiencing complications were over 60 years of age, and

995 may have been sedated with other drugs as well, illustrating the great variability in dose-response to the benzodiazepines and the need to adjust dosage in older patients, especially when a potent, rapidly acting agent is used. Although there have been no reports of similar complications following oral administration of midazolam, equal concern is warranted. Premeditation in children is controversial. Significant variation in individual response is typical, and assessment of sedation can be difficult. In addition, the younger age group often rejects oral medications. Although some studies have shown that benzodiazepines provide good results, with greater consistency and safety than other drugs, others differ. Van der Walt et al found diazepam 0.25 mg/kg premeditation to be less satisfactory for sedation than droperidol and trimeprazine, while producing the greatest incidence of postoperative vomiting.68 In a study involving 248 children averaging about 5 years of age, Saarnivaara et al concluded that oral midazolam 0.5 mg/kg was preferable to chloral hydrate 75 mg as a premedicant because of palatability; no complications were reported.69 Several drugs have been used as benzodiazepine antidotes. Physostigmine, an anticholinesterase inhibitor, has been effective in treating benzodiazepine-induced respiratory depression and sedation, possibly because of its direct effect on CNS cholinergic receptors.” However, this drug has a narrow range of safety and can precipitate serious complications. Theophylline, an adenosine antagonist, has also been used in a few situations. Flumazenil has been effective in reversing benzodiazepine and alcohol intoxication, with antagonist potential about equivalent to the agonist effect of diazepam on corresponding receptors. However, because its half-life of about 1 hour is less than that of even the shortest-acting benzodiazepines, resedation may occur.13 Although oral flumazenil is effective and wellabsorbed, with nausea and vomiting being the only significant adverse effects,” its value in a heavily sedated patient is doubtful. When dosage is matched appropriately with the benzodiazepine it is used to counteract, it may prove valuable in reducing postoperative complications of oversedation. Summary The goal of premeditation is the relief of fear and anxiety, ensuring a calm, cooperative patient able to tolerate a procedure comfortably. As cardiovascular and respiratory complications of anesthesia have been reduced, greater importance is placed on the psychological preparation of the patient. Other benefits are also conferred by anxiety relief: Decreased catecholamine release lessens circulatory response and antag-

996 onism of the anesthetic agent and lowers the minimum dose required.72 Despite the large number of benzodiazepines available, it is difficult to justify the routine use of more than one or two of them for combined oral premedication and IV sedation. The choice of premeditation for outpatient surgery should be based on the experience of the clinician and an understanding of the different pharmacokinetic properties and selectivity of these drugs, which result in significant differences in clinical action. A well-documented agent with a wide range of therapeutic safety and rapid elimination, and without prolonged activity, is desirable. The benzodiazepines come closest to meeting these criteria, and must be favored over barbiturates and opiates for this purpose. The newer, short-acting agents temazepam and midazolam most consistently meet the ideal criteria for premeditation in the studies reviewed. Other commonly used agents were disappointing in their observed anxiolytic or sedative potential for outpatient procedures. Midazolam, a promising premedicant, is not yet available in an oral form in the United States. Because of a tendency to produce hypoxia in IV use, especially when combined with an opiate, further study of this potent drug is needed to establish its efficacy when administered orally. Close attention must be paid when a technique combining oral agents and IV administration is used, as absorption and onset of effect is more variable. With the use of rapid-acting, short-duration benzodiazepines as preoperative anxiolytics, it should be possible to titrate a decreased dosage of the IV agent to the desired endpoint, with the premedicant providing a baseline level of sedation. Although the benzodiazepines have established an impressive safety record, the discovery of the antagonist flumazenil may provide the clinician with an additional safeguard. With the development of a new generation of potent orally administered benzodiazepines, there is a compelling need for further evaluation of clinical techniques and applications for these drugs in outpatient procedures. References 1. Mindus P: Anxiety, pain and sedation: Some psychiatric aspects. Acta Anaesthesiol Stand 32:7, 1987 (suppl 88) 2. Moore PA, Ramsay DS, Finder RL, et al: Pharmacologic modalities in the management and treatment of dental anxiety. Dent Clin North Am 32:803, 1988 3. Jastak JT: Issues of pain and anxiety control training and continuina education. J Dent Educ 53:293, 1989 4. Oreland L: The Benzodiazepines: A pharmacological overview. Acta Anaesthesiol Stand 32: 13, 1987 (SUDD~88) 5. Enna SJ, Defiance JF: Glycine, GABA and Bdnzodiazepine Receptors, in Enna SJ, Yamamura HI (eds): Neurotransmitter Receptors, part 1. New York, NY, Chapman & Hall, 1980, pp 41-70 6. Mohler H, Okada T: Benzodiazepine receptor: Demonstration in the central nervous system. Science 198:849, 1977

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Oral benzodiazepines and conscious sedation: a review.

A large number of benzodiazepines have been studied for use as sedatives and for their anxiolytic potential as premedicants for outpatient surgery. Po...
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