**2. Conclusions**

This historical review of vivisection reveals that anaesthetics and analgesics have had a major beneficial e ffect on laboratory animal welfare. Scientific concerns that anaesthetic and analgesic drugs may temporarily disperse data and a ffect scientific conclusions continue to be countered by demonstrating the similar, though adverse and oft-prevailing e ffects of pain. In any case, the use of analgesics increases the external validity of animal models used in the study of noxious human conditions: that animal models of painful human conditions should be deprived of the care that the modelled human could expect is fundamentally unjust and scientifically unsound.

Persistent philosophical objections to the use of animals in research are accommodated by the replacement principle, which aims to achieve the eventual exclusion of all animals from all experiments. The funding and promotional activities of Fund for the Replacement of Animals in Medical Experimentation (FRAME) and the NC3Rs attest to the sincerity of this aim. However, public objections—which have historically been based on the argumen<sup>t</sup> that animal research is cruel (and pointless)—are immediately addressed by the refinement a fforded by terminal anaesthetics, or appropriate anaesthetic and analgesic techniques in recovery studies. Repeated Ipsos Mori polls reveal that societies' majority acceptance of animal experimentation—at least in the UK—is based on assurances that it is for medical research purposes, that there is no alternative and that there is no unnecessary su ffering [77]. The latest poll also revealed a public belief that laboratory animal veterinarians continue to be the most trusted source of information on animal research. It follows that the publics' general concerns with the use of animals in research may be further allayed were qualified veterinary specialists, e.g., Diplomates of the European (or American) Colleges of Veterinary Anaesthesia and Analgesia, to become increasingly involved in assisting their colleagues in laboratory animal medicine when noxious animal experiments are planned.

Despite *some* success in replacing and reducing the numbers of animals used in research, the constant introduction of new research methodologies, e.g., gene editing, imaging, et cetera, and the requirement for new diagnostic or therapeutic devices to undergo pre-clinical safety and e fficacy testing in animals, makes continuous demands on those concerned with experimental refinement. Arguably, this may apply less to anaesthesia. The compulsory training of laboratory animal personnel in the safe delivery of modern anaesthetic techniques, combined with the widespread availability of information, has reduced the need for any urgen<sup>t</sup> change—at least in the managemen<sup>t</sup> of non-invasive, non-painful and straightforward procedures. This does not apply to the use of analgesics, particularly when noxious recovery procedures are involved, because considerable gaps persist in the field of laboratory animal pain recognition and treatment. Some have suggested that this justifies the need for prospective pain studies [78]. However, the point has already been made [79] that refinement principles are better served by improved reporting. The original ARRIVE guidelines (2010) requested that articles describing animal experiments provide: (1) precise details of how anaesthetics and analgesics are used; (2) a description of welfare-related assessments and interventions; and (3) that all details of adverse events, e.g., unmitigated pain, be described, and that any modifications made to experimental protocols in order to reduce adverse events are revealed, e.g., the provision of e ffective analgesia. Given that these requirements have not been forthcoming, it has been suggested that amongs<sup>t</sup> ARRIVE-subscribing journals (and others) a more determined editorial enforcement of the guidelines would go a long way to increasing the information available on pain managemen<sup>t</sup> in laboratory animals [79]. Unfortunately, the ARRIVE 2.0 guidelines have relegated, "interventions taken in experimental protocols to reduce pain, su ffering, and distress" and "reports of expected or unexpected adverse events" to the "Recommended Set" rather than the obligatory "Essential 10". It remains to be seen what e ffect this will have on the role of anaesthetics and analgesics in the ongoing refinement of animal experiments.

**Funding:** This research received no external funding.

**Acknowledgments:** The author is grateful to Ron Jones, Alistair McKenzie, Ngaire Dennison, Polly Taylor, David Morton, Judy MacArthur Clark, Yves Moens, Amanda Novak, Stephen Greenhalgh, Ambra Panti and Stefano Guido for providing hitherto unpublished information, and to Gabby Musk for commissioning this work.

**Conflicts of Interest:** The author has no financial nor personal relationship with people or organisations that could inappropriately influence or bias this submission's content.
