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 numbers, the safer the drug. 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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