Intraoperative Use of Opioids for Anesthesia

Currently, opioids are the cornerstone in anesthesia (Figure III-1), whether it is in classical neuroleptic analgesia, using the butyrophenone droperidol or in a balanced type of anesthesia, where in addition to the analgesic low concentrations of a volatile agent are added for a sufficient depth of unconsciousness. Also, opioids are used in total intravenous anesthesia (TIVA), where no volatile agent is utilized and only an opioid with a short duration of action (e.g. remifentanil) and a hypnotic (preferably propofol) are employed for the maintenance of anesthesia.

The development of intravenous anesthesia with opioids was initially slow, has been erratric with long periods of stagnation, especially when volatile anesthetics, in particular ethrane and chloroform were the agents of choice. Due to their obvious side effects, especially the necessary high concentration needed to induce a sufficient level of analgesia, the slow onset of action, and long overhang of effects, led to the proposal to use an intravenous anesthetic agent for induction and maintenance of anesthesia.

Hexobarbital was the first drug to make intravenous anesthesia popular. It was synthesized by Krop and Taub from Bayer company in Elberfeld/Germany and was first used by Weese and Scharff in 1932. Shortly thereafter thiopental was synthesized and originally employed as the sole anesthetic given in intermittent dosages together with nitrous oxide and oxygen (Figure III-2). Potentiation of anesthesia with unconsciousness and concomitant attenuation of reactions of the autonomic nervous system at that time were considered sufficient to cover all parts in anesthetic practice.

However, similar to high concentrations of gaseous volatile anesthetics, side effects such as a significant cardiovascular depression and a delayed awakening were still

HYPNOTIC

OPIOID

CIRCULATION

VIGILANCE X MUSCLE TONE PAIN SENSATION

VEGETATIVE REACTION

Figure III-1. The three major components in anesthesia where the opioid is the main component resulting in a beneficial stabilization of the cardiovascular system and a preservation of autonomic functions evident. In order to minimize these side effects, another technique was introduced into the field of anesthesia when Gray ands Geddes from Liverpool/England propagated their "Relaxant Anaesthesia" in 1959 [1]. With this technique, high doses of a muscle relaxant were given followed by artificial hyperventilation and a paCO2 between 20 and 25 mmHg with resulting respiratory alkalosis. In retrospect, this type of anesthesia may have worked because hyperventilation induced the concomitant release of endogenous opioids resulting in an alleviation of nociception. As this was followedby an increase in the level of analgesia, all other components of anesthesia (i.e. unconsciousness, analgesia and autonomic stabilization) were of lesser significance

Figure III-2. Classical potentiation of anesthesia with intermittent dosages of a barbiturate, where unconsciousness (sleep) dominates the technique
Figure III-3. Dominance of high dose muscle relaxants with hyperventilation as used in Relaxant Anesthesia

(Figure III-3). Due to the insufficient depth of analgesia and the hypocapnia-related reduction in cerebral perfusion, this was detrimental for the elderly patient population, which in addition to the simultaneous hyperventilation-related reduction in cardiac stroke volume, induced hypotensive episodes. Also, an overhang of muscle relaxant effects made a reversal necessary, which by itself was disadvantageous.

Thereafter, another component of anesthesia, i.e. blockade of the autonomic nervous system, became the target of a new anesthetic technique, called "Neuroplegia". Originally introduced by Laborit and Huegenard from France as a lytic cocktail in 1948, it first contained hyocine with morphine and later chlorpromazine plus hydergine. These agents were given together with the opioid pethidine (meperidine, USP). The cocktail was used in "hibernation artificielle" or artificial sleep for hypothermia in anesthesia, and for sedation in acute psychosis [2]. Following the synthesis of newer and more potent neuroleptic agents derived from the butyrophenones, the advantages of a complete neuroplegia with a stable autonomic nervous system became obvious. First, and most of all, the dose of the narcotic agent pethidine could be reduced. Secondly, any disturbance from a stimulated autonomic nervous system emerging during aggressive surgery, was eliminated. Thirdly, the patient was protected from stressful reaction resulting in a psychological indifference to the environment. This is because neuroleptic agents block subcortical centers such as the thalamus, the reticular activating system (RAS) and the limbic system (Figure III-4). However, since neuroleptic drugs also block the dopaminergic transmitter system, an imbalance in the dopaminergic-cholinergic equilibrium in the striatum and parts

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