Sedation of Phobic Dental Patients
With an Emphasis on the Use of Oral Triazolam


Fred Quarnstrom, D.D.S. F.A.G.D., F.A.S.D.A., F.I.C.D.
Diplomate, American Dental Society of Anesthesiology

First Published: December 1996


"A USA Today article quoted ADA figures detailing that '12 million Americans are dental phobics. Another estimated 12 to 24 million suffer dental anxiety.' Coping with the difficult-to-manage patient has long plagued the profession. The high cost of malpractice insurance, government regulations that dictate who can and cannot be hospitalized, and the threat of litigation have caused many dentists to avoid under taking dental treatment on all but the most cooperative and easily managed patients and to turn their back on 36 million Americans who want but, for reasons beyond their control, are unable to undertake dental care in a usual manner."

"A major problem that continues to have an impact on the teaching of anesthesia, pain, and anxiety control is the rising costs of liability insurance. In the 'real world,' annual premiums of almost $20,000 are required before the dentist can administer IV sedation." Whether or not we provide various forms of sedation depends on our education, state regulations, costs of insurance, our competency, and equipment. IV sedation is seldom used because of insurance costs, the need for postdoctoral education and, more recently, regulations in various states as to who can perform this technique.

Do you really want to see phobic patients?

When deciding on using sedation in our practice we must ask some important questions. First and foremost, we must honestly evaluate ourselves. Do we have the temperament to handle phobic patients? (At best, these patients are very difficult in many ways.) Can we handle the stress of the potential problems that can occur with sedation? Are we adequately trained to handle potential problems? (At a minimum, we and our staff should all have a CPR course on a yearly basis.) Do we have an emergency response team within a reasonable distance from the office to assist if an emergency should occur?

In this discussion, considerable space will be spent referring to the patient who is unconscious (asleep) and explaining why I am in no way comfortable with such a patient. On the other hand, the patient who is awake will respond to verbal directions and is, therefore, a safe patient. So long as your patient remains conscious, you can relax and enjoy performing dentistry. With proper preoperative evaluation, careful use of the right drug and calculation of its dose, you should never have a patient lose consciousness, that is, go to sleep. Should this occur, however, all else should cease until the patient is again verbally responsive. Some states have regulations that go one step further and require the equipment and training necessary to administer general anesthesia if a patient is rendered unconscious. But it is a little late to start buying equipment and getting training when you find, through misadventure or miscalculation, that a patient is no longer verbally arousable.

Once we discuss Triazolam, it will become obvious that the chance of problems arising with this drug when it is used properly is very slight. But even if complications should occur, with the availability of a selective reversal agent flumazenil - we'll all be able to breathe a sigh of relief. As you'll see later, flumazenil is reported to rapidly reverse the sedation of benzodiazepine drugs much as Naloxone does the opiate drugs.

Since there is a significant cost in lost productive time for training and purchase of equipment, both must be justified if one is going to start sedating patients. Because of the precipitous rise in malpractice insurance, several years ago many dentists who were qualified to administer deep sedation/general anesthesia had stopped offering this service. The phobic patient is left with the option of having teeth extracted at an oral surgery office under IV sedation or having restorative dentistry completed with oral sedation or nitrous oxide inhalation sedation. The purpose of this paper is to show that general dentists can provide these sedation services if they are interested, willing to take extra training and purchase some additional equipment, and will limit the drugs and the quantities of the drugs they use.

Who are the patients?

Adults: Phobic adult dental patients come in all sizes, shapes and colors and are phobic for many different reasons, both psychological and physical. Often these phobias developed when they were young children for all the usual reasons children develop dental phobias, including traumatic dental treatments. In some cases, troubles start much later due to an especially difficult treatment, particularly if pain control was incomplete.

It has also been postulated that a few people lack active pain suppression systems or suffer from depressed pain suppression mechanisms, including descending pain suppression pathways from the higher centers of the brain, and suppressed endorphin production or receptor systems. These patients have a very difficult time with pain control. They are the ones who appear to have a complete anesthetic block but who experience pain once a procedure is started and, in spite of the most diligent efforts of their practitioner, continue to have mild to moderate pain for most dental procedures.

My feeling in the past had been if they would only relax, we would have better pain control. I was blaming their lack of anesthesia on their apprehensions. I now wonder if I should have been blaming their apprehensions on the fact that most procedures they had undergone were done with only partial pain control because of their lack of endogenous pain suppression systems. This brings to mind the age old question of "Which came first, the chicken or the egg?" - a question that can thankfully remain unanswered so long as the practitioner treats the patient's apprehension symptomatically and adequately. Once patients are relaxed, adequate pain control is almost always possible.

Unfortunately, most adults never completely free themselves of their apprehensions - but they will improve over time with careful treatment and good pain control. Many will be able to be treated with less potent forms of sedation, if they are seen regularly and have comfortable treatments. A few may even graduate to no sedation for their dental treatments. Other patients will be refractory to any attempt at treatment without profound sedation. We should accept all three types and be non-judgmental toward those who continue to need sedation to undergo dental treatment.

Children: Many children can be treated if sufficient time and effort is spent to communicate with them and if gentle, empathetic treatment techniques are used. However, the younger the child, the more difficult this task becomes. Below a certain age, most children will need some help if extensive treatment is required. Unfortunately, the younger child also tends to be the smaller child, and the smaller the child, the more careful we must be as their safety margin - the area between sedation and overdose - becomes narrower. These patients are often the ones that go from uncontrollable to unresponsive with minimal changes of sedation, i.e. kicking, scrming, biting, scratching one moment and unconscious and unresponsive the next, with concentration changes of nitrous of only a few percentage points. Our oral medications often come in unit dosages that are not easily divided to provide a more accurate dose for any given weight.

It also is amazing to me how many parents do not know their child's weight. Often when we ask them what it is, we are told "somewhere between 20 and 30 pounds." This is a 50% range; we like to be a little more than 50% accurate with our doses of medication. For this reason, it's a good idea to have a scale in the office to check the child's weight.

Unfortunately, most of the very young, small patients are those who need extensive treatment due to baby bottle caries. These children will tend to continue to need extensive treatment as they get older because of their oral conditions and, in many cases, their treatments will be further complicated by family dynamics. For instance, if a child is left on the bottle, it is sometimes because of a very permissive atmosphere in the family where the child's every qualm is indulged. These are the children that get all the candy they want, receive little discipline, and have overprotective, often first-time parents who themselves do not do well in new surroundings. If there is one patient we want to become a good patient, it's the one we'll be seeing on a regular basis for extensive work. These overprotective parents foster overly dependent, insecure children requiring enormous amounts of extensive dental care at a very early age. It is hard to conceive of a worse combination.

Somewhat older children are easier to treat from a sedation standpoint because their size and physiology offer a wider range of safe dosages. Often these children's fears are a result of peer or sibling descriptions of dental treatment ("The dentist has a needle th-i-i-s-s-s big"), cartoons or other TV programs (who can forget Curley chasing Larry and Mo around a dental chair with a syringe large enough to use on King Kong), and, occasionally, parental phobias or mistreatments. Here's some of a conversation I overheard in a supermarket, "If you do not stop that and behave, I will take you to the dentist and he will give you a shot!" How relieved I was that the family was not one of my patients!

Various forms of oral sedation have been used by dentists to help apprehensive patients. Patient comfort can be achieved by the practitioner who uses anxiolytics, opioids, and nitrous oxide to allay anxiety and apprehension. This also decreases the likelihood of stress induced medical emergencies. The difficulty of using oral agents, however, is the time it takes to get an effect.

How safe is sedation?

Sedation can be performed safely and effectively by dentists with proper training. Most dental therapy can be accomplished on phobic patients using local anesthesia and sedation. Therefore, adequate use of local anesthesia must be considered as the first step of not only pain control but also anxiety control. Many central nervous system (CNS) depressants can alter the level of consciousness. Most of these can produce a hypnotic state if given in high enough doses, but only a select few can actually produce a complete state of general anesthesia. However, the potential for complications is not limited to the general anesthetic state; it may accompany any degree of drug-induced CNS depression. Respiratory and cardiovascular depression are the most feared complications. Respiratory depression represents the principal negative variable introduced with conscious sedation and, left unrecognized and untreated, is the cause of most serious complications.

Further complicating the question, To Sedate or Not To Sedate? is that fact that nearly all dentistry is elective. It is very rare to face the situation where a life will be lost if treatment is not instituted. A nerve may die, a tooth may be lost... all the teeth may be lost ... but the patient will still be alive and reasonably healthy. It is very difficult to accept a dental procedure where there is even a slight risk of death.

This is not to say that there is not a very slight risk to even the simplest procedures. Even administration of local anesthesia has resulted in death. For this reason, the safety of a sedative system is of the utmost importance.

Sedation, deep sedation/general anesthesia, has a remarkable safety record; however, there have been studies showing that the deeper the sedation, particularly when administered to medically compromised patients, the very young and the elderly, the greater the risk over other procedures. Dione reported that overall mortality in the U.S. associated with general anesthesia, based on self-report of oral surgeons, has ranged from 1:860,000 to 1:349,000; however, self-reportings are usually given little credence due to a strong negative biases. A more credible study came out of records from the United Kingdom where the overall mortality risk was 1:248,000 for general anesthesia and 1:1,000,000 for conscious sedation (one patient died in a motorcycle accident later in the day of sedation). Only very low risk could be determined for local anesthesia. The risk of sedation and anesthesia can be dramatically decreased with modern monitoring devices and the use of persons trained in monitoring and administration of anesthesia. It has been shown that the risk of anesthesia is dramatically reduced when a separate practitioner trained in general anesthesia administers and controls the sedation/anesthesia. In the case of two-operator administered anesthesia, the risk went from 1:248,000 to 1:598,000 This is particularly true when treating patients with underlying medical problems.

Patient ambulation

A problem that was unique to dentistry but is now affecting our medical colleagues who use day surgery is the need for rapid ambulation. We need to get our patients back to a state that allows them to leave the office in a timely manner. Their reflexes need to be such that they can walk unassisted, although I insist that another adult take their arm for additional support. They should not drive, undertake any task that might be hazardous, be placed in a position of responsibility (i.e. taking care of children) or make important decisions; even climbing stairs should be avoided. They need to be accompanied and supervised by a responsible adult for the rest of the day, during which time their activities should be limited to watching TV, and operating the remote control is about as complex a cognitive activity as they should attempt. It should be stressed to the patient that although they may feel normal, their reflexes may sill be dessed. They need to take the rest of the day off.

It should be mentioned that some of the benzodiazepine drugs are initially bound to plasma proteins. This binding tends to reverse about 6 hours after administration. This phenomenon is known as a "second peak effect". When using most benzodiazepines, it is necessary to inform our patients that they will experience an increase in sedation about 5-8 hours after leaving the office. Interestingly, even after this time, blood concentrations of active drug have been reported to be close to 50% of what they were during sedation. For this reason, it is imperative that they not undertake any activity requiring cognitive or coordination skills the rest of the day. Because of the long half-life of diazepam, some practitioners felt there was reason for some concern even the next day.

Drug selection

Our choice of drugs is guided by consideration of elimination, half-lifes and side effects: When we examine sedative systems we find a continuum of effects from slightly noticeable changes through more profound sedation to general anesthesia - eventually leading to death, if enough drug is administered. "General anesthesia is less safe than conscious sedation, which is less safe than local anesthesia."

It is our goal to chose a sedation system with a very wide difference between desired effect and death in a very broad range of patients. It is ideal if the effects of the drugs can be reversed at will if our system seems to be getting out of control.

It is also our goal to create a state of tranquility that will allow the patient to comfortably undergo the needed procedure. A pain-free state can always be achieved by rendering the patient unconscious, but with a much greater risk of serious complications. I try to keep the patient conscious and treat their apprehension as opposed to rendering them unaware. If I can alleviate apprehension without changing any other of the patient's parameters, I have achieved success. In fact, we always cause some change in our patients' physiology; however, with modern drugs these changes are much less hazardous than was accepted a few years ago.

Routes of drug administration

In attempting to create a state of tranquility, we must get a certain concentration of agent to the appropriate location in the central nervous system (CNS). The effect can be altered by varying the agent. Some agents are more therapeutic than others. In gaining access to the appropriate areas of the CNS, a variety of routes of administration can be used. Ultimately, this access depends on getting the drug into the circulation of arterial blood going to the brain. Since we are treating apprehensive patients, it is important to gain this access with as little pain as possible. Through inhalation, gaseous agents gain access via the lungs; liquid agents may be injected into the venous circulation, sprayed on nasal mucosa, absorbed sublingually, and injected under the skin into underlying muscle or swallowed and absorbed from the stomach and small intestine. Some agents have been administered rectally. When considering routes, we should consider patient comfort, time to achieve effect, control of the effect, ease of administration, the skill needed for administration of the drug, necessary equipment for administration and monitoring of the patient. Unfortunately, we must also consider medical-legal questions of insurance and regulation by governmental organizations.

In general, the faster the drug reaches the CNS and has an effect the better control we have of the sedation. By titrating for effect, we can give just that amount of drug that is necessary to control apprehension. Both intravenous and inhalation agents can be readily controlled in this manner. Other routes of administration require administering an appropriate dose and waiting up to an hour to see the desired effect. It is obvious that it is impractical to titrate when we must wait for an hour to see the effect. These routes require very specific dosages usually associated with body size. They require conservative dosages as hypersensitivity to a medication will not be obvious until it is much too late to adjust the dosage. It is imperative that a drug with a very wide range of safety be used when these slower routes of uptake are utilized. Ideally, we will have reversal agents that can deactivate the drug in the case of overdose when using these routes.

We in dentistry have used and continue to use a variety of agents and combinations of agents. Multiple agents often complicate the treatment as each has side effects which may be addictive. They all are CNS depressants and some have unwanted depressing effects on respiratory and the cardiovascular systems. The combination of all these effects can lead to problems that are hard to predict and even more difficult to control. However, if only one agent is used, the side effects are often more predictable.

In general terms, it is easier (safer) to use a single agent as we then only have one set of side effects to contend with. This, of course, assumes a single agent will provide the needed effect at a concentration where few side effects are present. When Dione looked at combinations used by 264 dentists he found 82 distinct combinations. "The scientific basis for the use of such a diverse group of agents and combinations is unclear."

Inhalation sedation

The inhalation route of administration offers a major advantage when we consider an overdose. By removing the source of the drug (having the patient breathe room air or 100% oxygen), they will excrete most inhalation agents via the lungs, thus reversing the overdose. A practitioner must assure that the patient's respiratory system is functioning normally and that their tidal volume is adequate to provide the oxygen they need and remove their carbon dioxide both for their safety and to remove the inhalation agent. It should be remembered that all agents depress the respiratory system to some extent and it is important to have monitors that assure that an adequate exchange is taking place. It is necessary that the practitioner be skilled in assisting respiration should significant depression take place.

Intravenous sedation

With the regulations that are now in place in many states, it is nearly impossible to use intravenous sedation. Many states require a 60 hour course in addition to any training that was received in dental school. These courses have not been taught for a number of years and do not seem to be coming back. The cost of malpractice insurance to do intravenous sedation is another problem. If the added cost of malpractice insurance is passed on to the patient, it can increase the cost of each appointment $100 to $200. Intravenous sedation has several advantages to the oral route of administering medication. When giving a drug IV, one slowly titrates the concentration of a drug to the level of sedation desired. For most drugs, these effects began to diminish in a short period of time - first, due to redistribution to other tissues (primarily fat stores) and then more slowly as the drug is metabolized into inactive forms (in some cases less active forms) or eliminated in the urine or feces.

Oral Sedation

Several factors come to light when we consider oral sedatives. The time from ingestion to sedation becomes very important. For any effect to take place, the drug must be absorbed into the blood stream and delivered to the site of action, usually thought to be in the central nervous system, in sufficient quantities to be effective. Some drugs can be absorbed sublingually, others must be swallowed and absorbed from either the stomach or small intestine. Depending on the time necessary for absorption, it may be necessary to have the patient take the drug at home before coming to the office. However, I prefer to administer the drug in the office because then I know how much was taken, when it was taken, and by whom it was taken. Also, I don't have to worry about the patient trying to drive to the appointment as the drug starts to take effect. Last but not least, should there be a reaction to the drug, the patient is in the office where aid can be administered.

We need a predictable means of determining dosage. Because it will take 45 minutes to one (1) hour to get the desired sedation, we can not easily titrate or alter the dose if a patient is not adequately sedated. Because of the length of time necessary to get sedation, we can not depend on redistribution of the drug to counter its effect. With some intravenous drugs you can give a dose necessary for sedation and within a few minutes have the patient nearly back to normal because the drug concentration in the blood stream has been reduced as the drug is redistributed to other tissues of the body.

Drug options

Historically, many drugs and routes of administration have been used to control apprehension in the dental offices of general practitioners. As stated earlier, insurance companies, state regulatory bodies and other factors have all but eliminated intravenous sedation from the armamatarium of general dentists.

If we trace the history of the other methods of sedation, however, we will see that all is not lost for the phobic patient.

Nitrous Oxide

Nitrous oxide has an interesting history. Originally it was used as an attraction at public science shows. It was at such a program that a dentist, Horris Wells, saw a participant in a nitrous frolic bark a shin, causing a dramatic wound ... with no pain. He took this knowledge to his office and began offering painless dentistry using nitrous oxide as a general anesthetic. This was a major breakthrough when you consider that any dentistry or surgery up until that time was accomplished with no pain control and depended to a great extent on the speed of the surgeon if the patient was to survive the shock of the procedure. Thus, surgeons became known for their speed. But in the quest for speed, accuracy sometimes suffered and more than one assistant lost a digit or two to the surgeon's knife when holding a limb for amputation. Not surprisingly, the fastest surgeons sometimes had a difficult time finding willing assistants. Ever since Wells' first use of Nitrous oxide in a medical environment, it has been used as a general anesthetic and, more recently, as a sedative on the conscious patient. Its history as a general anesthetic has brought dentistry some criticism. Nitrous oxide is such a weak anesthetic agent, at one atmosphere of pressure, that 80% nitrous oxide is usually considered to be the minimum concentration that will achieve unconsciousness. Even at this concentration, however, it is not possible to render some patients unconscious and if we go to a higher concentration, we begin to encroach on the 21% O2 found in the atmosphere and expose our patients to hypoxia.

The standard of years gone by was to watch the patient's color. When they began to show a blue tinge of cyanosis, the procedure was started. I like to state, tongue in cheek, that dentists hoped the pain of the extraction would restart the heart. Actually, many general anesthetics were done by this technique with an amazing safety record, which may be more testimony to a patient's desire to live than to the the safety of the procedure. Today, hypoxic anesthesia would be severely criticized, and rightly so. Because it is absorbed and removed from the blood stream via the lungs essentially unchanged, nitrous oxide is a very safe sedative. But its major disadvantage - its relative weakness - is also its major advantage. In other words, although sedation with nitrous oxide is not adequate for our most phobic patients, because it is such a weak anesthetic agent there is little risk of sedation rendering the patient unconscious, that is, in a state of general anesthesia with its depressed reflexes and other hazards.

Our primary concern in anesthesia is the loss of swallowing and laryngeal reflexes that can lead to regurgitation of stomach contents and aspiration of the low pH matter into the lungs. So long as a 50% concentration of nitrous oxide is not exceeded, there is little chance of general anesthesia or other more minor complications occurring.

The complications that may be arise are not serious ones. Occasional vomiting may be seen. But since our patients are always conscious, this is not serious as protective laryngeal reflexes are present; however, the patient is definitely uncomfortable and vomiting certainly can be messy. The euphoria of nitrous may remind some patients of periods when they were sedated for other reasons, which may be traumatic if the occasion was due to a personal tragedy. Patients will occasionally hallucinate; this again can be uncomfortable for them.

Treatment consists of removing the source of nitrous oxide, and reassuring the patient, typically by telling them they are all right and will return to normal in a few minutes. I find it helpful to continually assure the patient until the hallucination is over. Use their first name, and remind them they are in the dental office, that they should relax and will be back to normal in a few minutes.

Another potential problem deserves mention - that of sexual aberrations. A certain number of female patients will experience sexual feelings while on nitrous oxide. This can happen at relatively low concentrations. Some patients describe the sensation of sexual orgasm. It is not all that easy to identify when this is taking place and what is happening. However, if it looks like a duck, walks like a duck and quacks like a duck, the chances are we are observing a duck. This may, in fact, be the ultimate distraction to dental treatment. Fortunately, it is very rare. For this reason it is important that a male dentist always be accompanied by a female dental assistant when treating female patients with nitrous oxide. This phenomenon has never been documented in male patients.

A potentially more serious problem can arise if we treat chronic obstructive pulmonary disease (COPD) patients with nitrous oxide. These patients do not exchange gasses well in their lungs. Rather than having many small alveoli with the resulting large surface area to exchange gasses with the blood stream, they have fewer large alveoli, often with scarring which thickens the alveolar wall. Carbon dioxide does not diffuse out of the blood stream nor does oxygen enter the blood stream as quickly as is seen in the normal patient. Carbon dioxide levels increase in the blood stream, causing a decrease in pH because of the increased concentration of hydrogen ions. An increase in concentration of bicarbonate ions tends to buffer the effect of this lowered pH, rendering this stimulate, low pH, less effective. These patients depend on low oxygen levels as a primary stimulant to respiration. If we give such a patient nitrous oxide, it tends to depress this secondary system. The relatively high concentrations of oxygen associated with nitrous mixtures, usually greater than 50% oxygen, render this secondary system ineffective and respiration may cease. A further complicating factor has to do with nitrous oxide's tendency to diffuse into closed spaces. The lungs of COPD patients often have large, gas-filled sacks or blebs. If nitrous oxide diffuses into these spaces, it can cause them to enlarge, possibly to the point of rupture.

Should a person be overdosed with nitrous oxide, it is a simple matter of removing the source of the gas and, provided the patient is breathing, they will eliminate the excessive concentration of nitrous oxide.

Probably the greatest chance of complications when using nitrous oxide can be traced to the gasses being switched. I know of 25 to 30 cases where this has occurred. It can happen in several ways: Plumbers may install nitrous oxide and oxygen lines reversed; machines have been reversed by manufacturers; small tanks depend on a safety pin index system. This system has been compromised by having pins displaced from the tank yolk and by practitioners allowing more than one washer to be placed between the tank and the yolk, rendering the pins ineffective.

It has been the standard to oxygenate the patient for 5 minutes after each nitrous oxide administration to avoid diffusion hypoxia. If oxygenation is continued when gasses are reversed, the patient would be receiving no oxygen and the lack of oxygen will eventually lead to death. In a study we did of over 100 patients, we saw no evidence of diffusion hypoxia. For the healthy patient who uses only nitrous oxide for sedation, there is no reason to oxygenate patients after nitrous oxide. It should be stressed that nitrous oxide is a very safe sedative for almost all patients.


Alcohol has been used by some patients for years to help with their dental treatments. It is not unusual for a patient to self medicate themselves with a bit of liquid reinforcement before coming to an appointment. It is important when considering the use of other drugs for apprehension control that patients be warned against using any other substance that is a central nervous system depressant. The combination of benzodiazepines and alcohol has lead to very serious respiratory depression.

Chloral hydrate

This drug has been a favorite, particularly for children. In my experience, however, it was very unpredictable. Evidence is now emerging that indicates it may not be as safe as we all believed. Chloral hydrate is a halogenated derivative of acetaldehyde. Its sedative action comes from its metabolite, trichloroethanol. The peak activity occurs in the plasma within 20 to 60 minutes after oral administration. Its half life is 4 - 12 hours. It acts primarily on the CNS and has little effect on the respiratory and cardiovascular systems of healthy patients. However, a pulse oximeter is advised to monitor as you can get respiratory depression and still have a conscious patient.

Laryngospasm has been reported with 250 mg. Life threatening hypotension and respiratory arrest have been reported in doses exceeding 85 mg/kg. Below 50 mg/kg. there have been few reports of problems. Higher doses tend to induce vomiting, however, thereby lowering the amount absorbed. In one case, although the patient vomited repeatedly starting 5 minutes after an overdose had been administered, they eventually became semi-conscious and suffered cardiac arrest.

In higher doses, chloral hydrate tends to become a cardiac irritant. There have been several reported cases of overdose leading to hypotension. When the hypotension was treated with chatecholamines or agents that released chatecholamines, both patients experienced cardiac arrest; one survived, the other did not. Any other CNS depressant will enhance the sedation-depression of chloral hydrate, including nitrous oxide and narcotics.


Barbiturates were the standard anti-anxiety agent for both medical and dental patients for many years. This was true even though pharmacologists never claimed that barbiturates dealt specifically with the brain mechanisms responsible for anxiety; they simply make a patient drowsy, and sleepy patients tend to be less apprehensive. In larger doses, barbiturates have the potential to render patients asleep. It is in this way that the short and ultrashort acting barbiturates were used as induction agents for general anesthesia and for very brief general anesthetics.

The ratio of the dose necessary for sleep and the dose that will end in death - the therapeutic index - is usually stated to be a factor of 2 as compared to diazepam with a ratio of 20. Unfortunately, these drugs in higher doses tend to be potent cardiac and respiratory depressants. Because of their addictive nature, they were not administered for long-term anxiety control.


The first step toward developing drugs that act selectively on anxiety mechanisms came about somewhat by chance. In the 1940's a Czechoslovakian pharmacologist, Frank Berger, was attempting to develop synthetic antibacterial agents that would kill microorganisms resistant to penicillin. One group of chemicals, when injected into mice, caused them to become temporarily paralyzed because of a massive relaxation of the muscles in their limbs although they were were fully conscious. In his first publication on the effects, Berger referred to this effect as "tranquilization." He sought derivatives of this original drug, mephenesin, that might be better at controlling anxiety. He found a derivative, Meprobamate, did just that. Meprobamate was introduced to the public in 1955. Although less effective than hoped, it served to introduce the concept of a drug agent capable of dealing selectively with anxiety. The race was on to find such a drug. It is interesting that in later analysis it was shown that Meprobamate was only a sedative; it did not selectively alleviate apprehension. It had, however, stimulated a search for such specific anti-anxiety drugs. As no one knew the mechanism involved, many drugs were tried on an almost random basis to see if any had the desired effect.

Twenty years earlier, in the 1930's, Leo Sternbach had begun a research career in pure chemistry at the University of Kracow, Poland. On the basis of his early research he began a search of a group of chemicals he referred to as quinazolines, but after two years he had failed to show any of the desired effects in this group of chemicals.

A year and half later, while cleaning up his lab, Sternbach found one of the last quinazoline series he had not tested. He gave it to Lowell Randall, Roache's head of pharmacology. This drug turned out to be the most active agent of the group and became known as Librium. Sternbach discovered it was not a quinazoline class, but in the final stages of synthesis had been transformed into a completely different chemical, a new class known as benzodiazepines. From this early success came a number of librium derivatives, the most effective of these, diazepam.

Librium and diazepam do relieve anxiety. They produce some drowsiness and, unfortunately, are somewhat addicting. Tolerance develops with continued use and withdrawal occurs when the drug is stopped. However, the extent of tolerance and withdrawal are less than what is seen with barbiturates. The most clear-cut advantage of the single agent, benzodiazepine sedation is the fact that overdoses are rarely lethal. In the case of barbiturates, on the other hand, the lethal dose is only a few times greater than the dose necessary to cause sleep. It is not uncommon when testing benzodiazepine drugs on mice to give doses a thousand times greater than is necessary to cause muscle relaxation and behavioral effects and still have the mice, cats, rats, and monkeys all refuse to die. One should not become overconfident, however, as when added to alcohol or barbiturates, death can result.

To deactivate most oral sedatives we generally must wait for the drug to be excreted or metabolized. In the case of diazepam it is metabolized in liver to another sedative, oxipam, that is available as a long term sedative on its own. Triazolam, along with midazolam, has the shortest half-life of the the benzodiazepine drugs; both are in the 1 to 2 hour range. Midazolam is normally considered to be an intravenous drug although it is beginning to be used orally (mixed in cola drinks) and as a nasal spray. Unfortunately, it has been shown to have a noticeable respiratory depressant effect in higher doses. Triazolam has rapid uptake (about 1 hour to maximum effect), and may be given sublingually for an even faster effect, although it is felt that much of the effect still comes from the drug that is swallowed. It has a half life that is about 1 - 2 hours and very little, if any, cardiac or respiratory depressant effect. It is this very short half life that makes Triazolam a favorite of mine. The high incidence of retrograde amnesia on conscious patients further endears it to the dental practitioner. Patients do not have to be asleep for their dental treatments if they can be relaxed enough for us to do the required procedures and not have any memory of the procedure. Triazolam's relative lack of respiratory and cardiovascular sedation is important for safety. Safety is dependant on the ratio of the L/D 50 dose (that dose usually fatal to rats) and the concentration that provides sedation (to rats). It is our hope that this ratio is constant for humans. Evidence from self-inflicted overdose emergencies tends to indicate a similar ratio. The self-inflicted overdose patient may sleep for several days but they usually survive if they have not mixed the benzodiazepines with other drugs such as alcohol or barbiturates. The higher the difference between these numhe safer th For healthy patients it has been estimated that a lethal oral dose - in absence of any other CNS depressant - must be very large and could be impossible to administer orally.


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