Unfortunately, these new drugs are expensive. A few years ago, it took about 10 years for the average drug to be approved in the USA at an average cost of $125 million. By 1992, the cost of a new drug had increased to $231 million, and it took an average of 12 years for FDA approval. Today the average new drug takes 12 to 13 years from discovery to approval and costs $280 million. This is too costly and too long for all but the drugs that will generate billions of dollars of revenue. These facts also suggest that we may begin to see older drugs given by new routes and delivery systems. These approaches should increase the efficiency of drug delivery, decrease the cost of drugs and drug delivery, improve safety, improve convenience and compliance, and optimize the pharmacokinetic characteristics of the older drugs. The traditional routes may be with us for a little while longer, but their limitations, side effects, costs, pain of administration, and inefficiency in terms of bioavailability and patient compliance will be among the reasons they are eliminated.
Anesthetic delivery has not appreciably changed in the past 150 years. We still give drugs using needles. We still ask patients to breathe the vapors of very potent volatile liquids—drugs that could take the paint off a car. We still ask patients to swallow pills and solutions, some of which actually produce the desired effect some of the time. Much of the time there is very little effect, and some of the time there is an overdose, even though the dose administered is that recommended in the package insert.
The new routes and delivery systems promise improved convenience, improved safety, increased effectiveness, increased bioavailability, continuous delivery with fewer peaks and valleys, decreased side effects, decreased dosage and frequency of administration, and decreased cost. The pharmaceutical companies are interested in drug delivery because it provides new uses for old drugs, new patents for old drugs, and decreased FDA approval time for old drugs.
Some of these new drug delivery systems have become clinically available in the past decade. Patient-controlled analgesia (PCA), epidurally as well as intravenously, is available at some institutions. PCA is an example of precision drug delivery. In it patients control the administration of an analgesic until they achieve a plasma concentration resulting in analgesia (pain relief). PCA results in less overdosing, less underdosing, and more optimal drug delivery. It is popular because analgesia is achieved faster, and as a result patients are mobilized and out of the hospital sooner. In some studies, patients go home a day to a day and a half sooner than after standard postoperative analgesic regimens. Oral slow-release drug systems, patches, iontophoretic techniques, and transmucosal delivery are also available. These drug systems are more efficient and safer than intramuscular or intravenous drug delivery.
Intravenous anesthesia is also evolving. The trend is toward a continuous drug infusion rather than an intermittent bolus approach. The obvious advantages of continuous drug infusion are less total drug given, faster recovery, more optimal hemodynamic control, and more appropriate depth of anesthesia. Prevention of less-than-threshold blood concentrations and concentrations over toxic levels is, of course, the objective of continuous drug delivery. Ideally, this keeps the plasma drug levels within the therapeutic window. Care has to be taken, however, not to strive for a constant plasma concentration, because even though a drug may be within the therapeutic window, increases and decreases may be needed as the surgical stimulus changes. Intravenous anesthetic or automated drug infusion machines are being developed and are undergoing early clinical testing. These studies will focus on the use of propofol, opioids, and other drugs that can be given intravenously as slow continuous infusions. The computer is going to have a great impact in future intravenous anesthesia by helping to adjust intravenous infusions according to precalculated dosing schemas.
We need to be able to instantaneously measure the depth of anesthesia and to rapidly and accurately measure plasma concentrations of the agents we use. One technology being pursued is reverse diffusion through the mucosa of the mouth. This technique can allow rapid assessment of plasma concentrations of drugs (anesthetics) in the vessels immediately below the mucosa of the mouth. It is still in early development, but if it is successful it may be a method that enables rapid determination of the plasma concentrations of the agents we infuse intravenously.