Phenothiazines were the pharmacological agents of choice in the 1960s for the treatment of acute and chronic mental disorders.¹ They have, however, become a subject of controversy over the past decades with regard to their mode of action, effectiveness, and toxicity. Such disputes have arisen from the facts that phenothiazines have a broad spectrum of pharmacological effects and a remarkable collection of side effects. Phenothiazines exert their antipsychotic actions mainly through the blockade of synaptic receptors for dopamine in the brain. Other targets involved in the pharmacological activity of phenothiazines include sodium channels, calcium channels, serotonin receptors, cholinergic receptors, mitochondrial ATP synthase, and calmodulin.^2,3 The promiscuous propensities of phenothiazines also cause them to have a formidable array of side effects. To cite just a few, extrapyramidal dyskinesia, sympatholytic effects, cholestatic jaundice, nausea, agranulocytosis, and purple pigmentation of the face and the lens (skin-eye syndrome) stand out as notables. Their most notorious side effect, however, is their cardiovascular effects which may lead to sudden death.

Phenothiazines were first tested as a local anesthetic in 1971. Sharma et al found that some phenothiazines could produce a similar anesthetic effect as that of procaine on Guinea pig cornea.⁴ In this issue of Acta Anaesthesiologica Taiwanica, Chen et al reports on their study where six different phenothiazines (mesoridazine, promazine, chlorpromazine, fluphenazine, perphenazine and triflupromazine) were tested as local anesthetics in male Sprague- Dawley rats.⁵ Using cutaneous trunci muscle reflex as a test model, they found that phenothiazines couldproduce cutaneous analgesia. They also noted that among the six phenothiazines tested, mesoridazine and promazine were the most potent and were similar to bupivacaine. In addition, the anesthetic duration of mesoridazine was longer than that of bupivacaine. They conducted this experiment based on the premise that phenothiazines are sodium channel blockers. Based on this assumption, we pose two questions. First, do all sodium channel blockers possess local anesthetic activity? Second, has Chen et al’s study directly proven that the tested phenothiazines are authentic local anesthetics?

Let us consider the first question. The authors recently published two papers elsewhere.^6,7 They asked the same questions and used the same model, but with different types of drug. They applied class I antiarrhythmic drugs in their first paper⁶ and dextromethorphan or dextrorphan in their second one,⁷ and came to the similar conclusion that the two drug classes have a local anesthetic effect because they are all sodium channel blockers. There are some classes of drugs that also possess sodium channel blockade activity, for instance, the anticonvulsants lamotrigine or carbamezapine. It is not clear at this moment if lamotrigine or carbamezapine has local anesthetic activity because no studies have tested them.

Now let us consider the second question. The action of local anesthetics does not solely work on sodium channels.⁸ Therefore, it is plausible that agents which have sodium channel blockade activity are not necessarily authentic local anesthetics. In addition, the drug affinity for different receptors (promiscuity), the structure-activity relationships of side chains,⁹ and the pharmacokinetic profile of phenothiazines are important factors that must be considered if the phenothiazines are truly local anesthetics. For instance, the effectiveness of mesoridazine in this study might be attributed to its slower rate of deactivation and to the relatively large proportion of free mesoridazine that is available for penetration to the target area.¹⁰ The results or evidence from Chen et al’s study are not solid enough to conclude that phenothiazines are local anesthetics.

So what is the significance of their study? We believe that the future pharmacology of anesthesia will have three main directions: first, to discover new compounds from nature that possess anesthetic activity; second, to modify the side chain of an anesthetic or the delivery vehicle of an anesthetic; third, to test an “old” pharmacological agent to sort for “new” indications. Many drugs being tested for off-label use in clinical trials indicate the feasibility of the last pathway. Chen et al’s study is an illustra-tion of “an old drug with a new indication”. It is too early to say that phenothiazines might one day be used as local anesthetics. It is also clear that there are many things, both laboratory tests and clinical trials, that need to be done before phenothiazines can be used clinically as local anesthetics.

Michael J. Sheen, MD
Executive Editor,
Acta Anaesthesiologica Taiwanica
Attending Anesthesiologist,
Chang Gung Memorial Hospital, Linkou
Assistant Professor,
National Defense Medical Center

Shung-Tai Ho, MD, MS
Editor-in-Chief,
Acta Anaesthesiologica Taiwanica
Professor and Attending Anesthesiologist,
Tri-Service General Hospital,
National Defense Medical Center