Flecknell

Paul Flecknell was influenced by Yoxall's advocacy of analgesic use in animals and in 1984 authored "The Relief of Pain in Laboratory Animals" [60]. This work reviewed the analgesic drugs then available and the experimental evidence for their e fficacy in laboratory animals. The information was then extrapolated to the clinical situation to provide guidance as to methods of achieving e ffective analgesia. The publication was the first to emphasize that anaesthesia did not necessarily ensure freedom from post-operative pain and su ffering and that analgesics, as distinct from, and in addition to anaesthetics were required for the optimal refinement of noxious procedures.

This message was continued in a 1994 publication, "Refinement of animal use—assessment and alleviation of pain and distress" which also focused on pain recognition [61]. Warning against the dangers of uncritical anthropomorphism, Flecknell complained that the methods used for the assessment of pain and distress then available were unsatisfactory and appealed for more objective methods. This appeal led to a measureable increase in laboratory animal pain research, not least from the Comparative Biology Centre at the University of Newcastle, where Flecknell was Director.

In recognition of the increasing vintage of Green's contribution, Flecknell's "Laboratory Animal Anaesthesia: An Introduction for Research Workers and Technicians" was published by the Academic Press in 1987 [62]. As the full title suggests, these "introductions" were intended to be, and have remained, relatively uncomplicated guides for sta ff with limited training in veterinary anaesthesia. However, they provide enough information for laboratory workers to be able to safely anaesthetize commonly encountered laboratory animal species. That subsequent editions have appeared in 1996, 2009 and 2015 attests to the book's appeal.

The advances being made in laboratory animal anaesthesia and analgesia at this time meant that the Animal (Scientific Procedures) Act 1986 (A[SP]A) did not justify *major* changes to the general use of anaesthetics and analgesics in laboratories. Beyond reviewing the licensing system, providing more specific definitions for "regulated procedures" and "protected animals", and introducing named personnel to ensure compliance at establishment level, the Act required additional personal and project license fulfilments for those intending to use neuromuscular blocking agents. Personal licensees were required to provide evidence that they were competent in managing anaesthetics in the species they intend to paralyse and were conversant with Appendix H (Guidance on the use of neuromuscular blocking agents [NMBAs]) [63].

Between 2005 and 2011, Flecknell and colleague conducted four structured reviews of the biomedical literature [64–67] which, in recording the reported use of analgesics in laboratory animals in the biomedical literature, acted as an estimate of experimental refinement—at least in terms of analgesic use (see Table 1 for details of these, and related studies) [68]. All studies intimated that analgesics were not being extensively used in noxious experimental procedures, but aware that discrepancies may have existed between the *reported* and *actual* use of analgesics, Richardson and Flecknell (2005) made retrospective contact with the corresponding authors of papers in which analgesics had not been mentioned [64]. Of these, 71% replied that analgesic use had not been reported because they had not been used, revealing the existence of a widespread problem.


**Table 1.** The Extent of anaesthetic and analgesic administration in animal experimentations as determined by literature analysis. NA: not applicable.

Flecknell's contribution to practical training in laboratory animal anaesthesia continues in the form of e-learning modules which have been reformulated to meet the learning outcomes set out by the EU Expert Working group on Education and Training Framework [69]. The latter was established by the European Commission to develop a common education and training framework for the EU to fulfil the requirements under Articles 23, and 24 of Directive 2010/63/EU on the protection of animals used for scientific purposes.

The burgeoning availability of educational resources and information over the last two decades may be exemplified by the NORECOPA website (https://norecopa.no) which has extensive information on laboratory animal anaesthesia and analgesia as well as a collection of links to international guidelines, information on textbooks, and links to resources for education and training. The website currently runs to some 10,000 pages and cites global resources of relevance to the 3Rs.

### Kilkenny, Parsons, Kadyszewski, Festing, Cuthill, Browne, Emerson, Altman and Smith (2010–2020)

Flecknell's findings [64–67] supported a growing view that biomedical reportage was inadequate, causing the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), a UK Government-sponsored scientific organisation, to commission a survey to review standards of description in the animal research literature. The subsequent report indicated that serious omissions were present in the way research involving animals was reported [70].

After widespread consultation the ARRIVE guidelines were published. These consisted of 20 items describing the minimum information that scientific publications reporting animal research should include. With respect to anaesthetics and analgesics, three explicit and four potential requirements were listed indicating the relative importance attributed to these in reporting animal experiments [71].

However, despite widespread uptake of the ARRIVE guidelines by journals, funding bodies, universities, organisations and learned societies, it soon became clear that their e ffect on reporting animal experiments was limited. For example, an examination of 400 scientific articles describing major survival surgeries in dogs, primates, pigs, mice, rats and other rodents for the completeness of the information they provided on anaesthesia and analgesia concluded that the current scientific literature could not be trusted to present full details on the use of animal anaesthetics and analgesics [72]. Another compared the extent to which all elements of the guidelines had been fulfilled in Journals which supported, or did not support the guidelines at time-points before and after guideline introduction, and found that journal support for the ARRIVE guidelines had not resulted in, "a meaningful improvement in reporting quality, contributing to ongoing waste in animal research" [73]. The reported use of NMBs in laboratory pigs in the literature was examined [74] and, based on (1) the absence of information confirming that animals were adequately anaesthetized, and (2) the a ffirmation by corresponding authors that reported information reflected the actuality, prompted the conclusion that a proportion of laboratory pigs undergoing noxious procedures are likely to be aware under general anaesthesia.

The ARRIVE 2.0 guidelines were introduced in 2020 in an attempt to resolve poor reporting tendencies [75]. However, it had already (2018) been pointed out that the complete description of badly planned and managed experiments would not increase study reproducibility, refine the conditions for, nor reduce the number of animals wasted in such a study [76]. Consequently, the PREPARE (Planning Research and Experimental Procedures on Animals: Recommendations for Excellence) guidelines were developed as one of Norecopa's (https://norecopa.no/PREPARE) contributions to tackling the reproducibility crisis. It is to be seen whether these and, or ARRIVE 2.0 will a ffect the implementation and reporting of refinement in terms of providing and describing the use of anaesthetics and analgesics in future animal experiments.
