**1. Introduction**

The progression of animal experimentation from classical times to the present has been directed by the rarely compatible views of "scientists", philosophers and legislating authorities and, more recently, vested interest and the public have become influential. Arguably, the greatest hostility between those

for and against animal vivisection—based largely on the questions of animal sentience and the scientific value of noxious animal experiments—was seen in the years between the late 18th and early 19th centuries, when, co-incidentally, the first influential observations on the anaesthetic properties of gases were reported. The introduction of general anaesthetics into medical practice in the mid-19th century greatly facilitated surgery by alleviating the (human) patient's agonies. At the same time, and for the same reason, many felt that anaesthetics increased the ethical defensibility of animal experiments. The similarly opining would also claim that in eliminating the widespread and profound physiological effects of pain and suffering—an effect which had been recognized for some 2300 years—anaesthetics improved data value and increased the validity of animal experiments. Some scientists countered this (and continue to do so) by emphasising that anaesthetics and analgesics can produce similar if not greater degrees of physiological perturbation than the pain itself, and so should be excluded from experimental protocols. Fortunately (for animals) Russell and Burch's "The Principles of Humane Experimental Technique" (1959) [1] established anaesthesia and analgesia as indisputable refinements in animal experimentation and which, along with reduction and replacement, pervades all stages of contemporary animal experimentation in the UK, i.e., from funding application and ethical approval through to the publication of results. A focused historical examination of the contribution of anaesthesia and analgesia to the refinement of animal experiments has not previously been attempted. This article reports an Anglocentric view of the role of anaesthetics, analgesics and anaesthetists in reshaping the attitudes of scientists, philosophers, the authorities and the public to animal experimentation.

### Galen, Vesalius and Paracelsus (330BC-1541)

Beginning with a description of surgical procedures conducted on animals *without* the use of anaesthetics, i.e., vivisection, reveals an early concern with its morality and an ongoing conviction that pain has a disruptive effect on experimental results. Thus, scholars of the Empiric School of Medicine (330 BCE–ca 400 AD) dismissed the study of physiology by vivisection on the grounds of its cruelty and clinical irrelevance [2]. Early descriptions also reveal an ambivalence by vivisectors towards animal suffering and a need to justify its practice. Galen preferred using pigs and goats over apes because, during brain dissections, the unpleasant expression of the ape discomfited him [3]. Vesalius recognized the cruelty of vivisection but justified it for what it revealed: his thesis *"De humani corporis fabrica libri septem"* ("On the Fabric of the Human Body in Seven Books") (1543) features a small capital letter "Q" historiating the dissection of a pregnan<sup>t</sup> bitch. (An historiated initial is an enlarged letter at the beginning of a paragraph that contains a picture.) Whilst conceding that the animal "is cruciata", i.e., is crucified or tortured, "it allowed the demonstration of the unborn puppies struggle to breathe once the placental blood flow was ended" [4]. In the same publication, an historiated capital "Q" shows a conscious pig—immobilized with chains—undergoing tracheal surgery for the placement of a tube allowing periodic lung inflation, the first convincing account of artificial ventilation [5]. That restraining chains were required to immobilize the animal suggests that Vesalius was unaware that, at this time, Paraclesus was using ether (known as sweet oil of vitriol) to produce analgesia in chickens (although the first edition of *Opera Medico-chemica sive paradoxa* ("On the Field of Medicinal Chemistry or Paradoxes") which contains an account of this was not published until 1605). In this thesis, Paracelsus proposed that the sweet oil of vitriol:

### *"...quiets all su*ff*ering without any harm and relieves all pain, and quenches all fevers, and prevents complications in all disease."* [6]

It is unfortunate for both humans and animals that 300 years were to elapse before both innovations, i.e., positive pressure lung ventilation and inhalant anaesthetics, were re-introduced into clinical anaesthetic practice.

### Harvey, Descartes and the Oxford Group (1578–1665)

Had they been contemporaries, Paracelsus' interest in pain relief might have benefitted William Harvey's early studies of "the heart's motion" in conscious animals whose chest walls had been surgically removed. Harvey complained that the heart's action was too fast, a complication which *later* prompted him to use "colder animals, such as toads, frogs and serpents ... " or "dying dogs and hogs" [7]. That the excessive heart rate was the inescapable result of undergoing thoracic surgery whilst conscious was not overlooked: O'Meara (1665) argued that, " ... the miserable torture of vivisection places the body in an unnatural state and that amid the terrible pains of vivisection all the juices are brought to flow together, thus denying the validity of animal experimentation" [3]. Such concerns may have puzzled French philosopher and vivisector Renee Descartes who believed that animals, "When burnt with a hot iron or cut with a knife their writhing and screaming are like the creaking of a hinge, no more" [8]. This belief emboldened some scientists "with less responsible and reflective minds" [3] to conduct even more gruesome experiments [1] whilst elsewhere, it had the opposite effect and promoted consternation—even amongs<sup>t</sup> established vivisectionists. Johann Brunner, Professor of Medicine at Heidelburg, described the animals he dissected as "the martyrs of the anatomists" [3], whilst members of the Oxford Group, specifically Christopher Wren, Robert Boyle and Robert Hooke, not only recognized the cruelty of vivisection and its adverse effects on scientific data, but began preliminary experiments with intravenous anaesthesia. They also considered the use of opium to alleviate the suffering of experimental dogs [9]. Writing to Boyle on the 10th November 1664, Hooke, having that year completed a thoracic dissection and lung inflation study in a dog, complained:

*"I shall hardly be induc'd to make any further trials of this kind because of the torture of the creature but certainly the inquiry would be very noble if we could any way find a way soe to stupify the creature as that it might not be sensible which I fear there is hardly any opiate will performe".*

The reference to opiate use is important because both Wren and Boyle had been conducting observational studies on the use of alcoholic opiate concoctions in dogs for the previous 8 years [9]. In *The Usefulness of Experimental Philosophy* (1663), published one year before Hooke's regretted thoracotomy study, Boyle described an experiment performed by Wren, who injected a warm solution of opium in sack (a sweet white dessert-type wine) into the vein of a dog's hind leg:

*"We had scarce untied the dog..., before the opium began to disclose its narcotick quality; and almost as soon as he was upon his feet, he began to nod with his head, and faulter and reel in his pace, and presently after appeared so stupified, that there were wagers o*ff*ered his life could not be saved"*. (The dog survived).

Perhaps aware that "some narckotic" may have alleviated his animal's suffering, in 1665 a remorseful Hooke wrote:

*"The microscope enables one to look at nature 'acting according to her usual course and way, undisturbed, whereas when we endeavour to pry into her secrets by breaking open the doors upon her, and dissecting and mangling creatures whilst there is life yet within them, we find her indeed at work, but put into such disorder by the violence o*ff*ered that we cannot tell if the results are of any significance",*

He thus revealed his prescient belief that the extreme physiological responses to painful vivisection were not representative of the normal state. That, he asserted, was only discernible by non-invasive means, e.g., microscopy [10].
