Forum on the use of analgesia in animal research
Date:
Tuesday 27th August 2013, 10h00-12h00
Venue:
Groote Schuur OMB, Venue 12
Speakers: Dr Bert Mohr (FHS Veterinarian; Director, UCT Research Animal Facility)
The potential detrimental effects of pain on research outcomes; and an overview
of available options for analgesia
A/Professor Jo-Ann Passmore (Head of Mucosal Immunology Laboratory,
Division of Medical Virology, IIDMM)
Anti-inflammatories in immunological research
Professor David Benatar (Professor and HOD of Philosophy; Director, UCT
Bioethics Centre)
Can the withholding of analgesia from (animal) research subjects be morally
justified?
Chair: Associate Professor Anne Pope
Aide memoire
Attendees were welcomed and the topic contextualised. As the notice of the event
indicated
It is currently UCT policy that ‘experiments accompanied by pain [are] allowed only if
they are shown to be for the purpose of producing results that could benefit
humans, and where the benefits are clearly commensurate with the amount of pain
caused. In such cases, analgesia must be used to alleviate pain and distress. In
special circumstances, the requirement for analgesics may be relaxed.’ (See C (c) of
the FHS Research Animal Facility Use of Animals in Research and Teaching SOP June
2013)
The SAEC wishes to examine the aspect of the policy that permits relaxation of the
requirement for analgesics more carefully, and seeks to gauge the views of the wider
university community, especially researchers who use animals, on this topic. You
are cordially invited to attend and provide input on this issue.
The objective of the meeting was to gather information and to hear views from three
colleagues in the first instance and then to invite comments and queries from the floor.
Presentations
Dr Mohr gave a presentation on pain in animals that explained that non-human animals are
sentient and do experience pain, albeit that they do not necessarily show it in ways that
humans can easily recognize; that the UCT Policy emphasises that pain, amongst other
aspects, must be avoided if possible or minimised; that controlled laboratory experiments
try to limit confounding factors that may interfere with results; and that it is increasingly
recognized that pain itself can be a significant confounding factor. This point is relevant to
arguments that support withholding analgesia on the basis that some drugs may be
confounding factors. Unalleviated pain can be a potent physiological stressor that can
disturb homeostasis, cause dysregulation of the immune system, lead to the release of
stress hormones, mental depression, neuronal remodeling, weight loss and a catabolic
state. As an uncontrolled study variable, pain itself can decrease the stability of animal
models. If a subset of animals in a study experience more severe pain than others,
conclusions may be flawed.
It became clear that insufficient supporting information is available to make withholding of
analgesia justifiable in general terms. However, it is also clear that the roles of pain and
analgesia seem to be very specific which makes investigation complicated. Evidence-based
science is needed. It was pointed out that different types of analgesic drugs have very
different physiologic effects; that only a subset of analgesics has the mechanism of action
that interrupts inflammatory pathways; and that some types of analgesics seem not to
significantly affect immune responses. Several examples exist of pain-killers, e.g.
buprenorphine, being successfully used in immune and infectious studies.
However, in the absence of good guiding information, policy choices have to be made, and
UCT’s policy choice is an example. Other institutions, e.g. in northern hemisphere, may
choose to make analgesia mandatory. A changing moral view is evident: more people seem
to think that use of animals in research is not acceptable when unalleviated pain is inflicted.
This changing view will affect the ethics policies and the scientific framework. But this
happens fairly slowly. In the interim, responsible informed deliberation is required. This
deliberation should be inclusive so that clinicians with human immunological-suppression
experience and pharmacologists are part of the discussions.
Associate Professor Passmore spoke about her expertise in human genital tract
inflammation and HIV susceptibility, pointing out that inflammation is necessary for the
susceptibility to HIV to exist. In this context, she emphasised that the translation of this
research focus was the use of anti-inflammatories or analgesics in women to reduce their
inflammation and hence susceptibility to HIV infection. Regarding analgesic use in animal
experimentation that involve infectious diseases, she suggested that there is unlikely to be
single solution – at a scientific technical level, as many of the classes of analgesics target
core pathways in the immune inflammatory pathway, the mechanisms of analgesics to
control inflammation and pain may fundamentally affect the primary endpoint of the study,
i.e. inflammation is an integral part of the immune response to infectious diseases (including
TB, malaria, HIV, listeria, and others) and to minimize this discomfort and pain necessarily
diminishes the inflammation. There are many studies and meta-analyses that look at the
mechanisms by which analgesics dampen immune responses and inflammation although
there are no clear trends in terms of impact on immune responses. Some have shown no
impact on antibody responses, while others have shown broad impact on NK cells and
macrophages and multiple arms of the immune response. Because of the (1) complexity
and redundencies intrinsic to the host immune response to different infectious diseases, (2)
the fact that different classes of analgescis act on different pathways within this complex
network differentially, (3) that not all infectious diseases rely on the same immune
response, and (4) different animals have slightly different responses to infectious diseases;
makes a one-size-fits-all recommendation to use of analgesics in infectious disease models
in animals. All of this makes it very difficult to extrapolate general principles. There are very
few systematic reviews of studies. These might be useful for purposes of better
understanding the issues.
Professor Benatar posed the question whether withholding of analgesia in (animal) research
can be justified morally. His discussion focussed on trying to answer the question. Two
assumptions informed the discussion: that the pain under consideration is non-negligible;
and that inflicting that pain would not be permissible if the research participant were a
human.
He said that if one thinks that the answer to the question depends on the species of the
research subject, one needs to show that the species difference is relevant (in the way in
which race, sex, religion, ethnicity, etc is not). Otherwise one would be guilty of specieism,
an analogue of racism and sexism in which one treats one being worse than another merely
on the grounds of its species.
He then considered and rejected various arguments for why the species difference is
relevant:
First, he considered the suggestion that humans’ higher cognitive capacity might make them
suffer more. Two problems confront this view: (a) not all humans have greater cognitive
capacity than animals – and it would surely not be acceptable to withhold analgesia from
such humans; and (b) reduced cognitive capacity can sometimes make suffering worse
because the being does not understand what is happening.
Second, he considered the suggestion that humans with lower cognitive capacities should
enjoy greater protection than animals because they (the humans) belong to a species with
greater cognitive capacity. The problem with this argument is that our treatment of beings
should be based on their individual attributes rather than on the attributes of the group to
which they belong.
Third, he considered the argument that we should treat cognitive impaired humans better
than animals because they are our fellow humans. However, this argument merely begs the
question by assuming that conspecificity is relevant. (The racist, for example, assumes that
he should treat fellow members of his own race better.)
He then considered whether withholding analgesia could be justified on the grounds of
“necessity” – that is, the research could not be done if analgesia were provided because of
the confounding effect of analgesia (assuming that this claim is accurate). He considered a
number of responses to this, but the most basic one is that if the necessity argument
worked it would also justify doing the painful research on humans. Indeed, it would more
readily justify such research because humans would be a much better model of human
disease than would animals. This ‘thought experiment’ is a useful tool for seeing the issues
more clearly.
Discussion
A question was asked about whether animals might be able to suppress pain rather than
just not show it in a recognizable way. Dr Mohr responded that in clinical veterinary
practice, if no pain is confirmed but after a dose of analgesia a positive
behavioural/physiologic change is seen, then this is regarded as indicative that pain was
indeed present.
A point was made about animals not being able to consent to research participation and
how this is unacceptable; that blue sky research should not be permitted with animals if
research is being done just to further career development. It was pointed out that career
development is a legitimate human goal; and that not all humans who are research
participants are able to consent. Consequently, the tensions must be acknowledged in
principled manner to guide deliberations about these matters.
Someone commented that, since the translatability rate of blue sky research into products
that benefit humans is less than 0.1%, the argument favouring use of analgesia is strong. It is
difficult to understand a justification to cause pain to animals in basic research.
Furthermore, since the deliberative process for Animal Ethics Committees (AECs)
purportedly relies on utilitarian principles in respect of cost/benefit analysis, it seems
reasonable that the experience of pain by humans and other animals should be treated
similarly.
If all harm was impermissible, then certain types of research would not be possible. At
present, society is not expressing this view through the prevailing policies. Dr Mohr pointed
out that the AEC performs a harms/benefit analysis in terms of which the potential life-time
harm as well as the degree of such potential harm to the animals is weighed against the
potential benefit (to humans/animals/the environment) anticipated from the research.
However, he conceded that this exercise is inherently difficult because e.g. the potential
benefit cannot really be known. If it were, the research would be unnecessary. Furthermore,
weighing harms against benefits is very inexact – they are not identical or directly
comparable.
Discussed revealed that, if a radical approach were to be taken, questions to ask include
whether painful blue sky research should be permitted; whether potential for translatability
should be a guiding factor in approving studies without analgesia; and whether animal
models are actually useful and predictive for use in humans.
A/Prof Passmore commented that although the number of lead ideas that go to clinical trial
stage is small, it is important to focus on successful processes and to appreciate the
importance of the animal studies that were part of that process. She pointed out that the
view that all research should be done with human participants does not take account of the
fact that data from human studies is largely confounded by the fact that the environment in
which humans function and their genetic makeup (which impacts heavily on immunity and
inflammation) is difficult to control, as is the confounding substances that humans consume.
This leads to the practice of going to reductionist models in animals where potential
confounders can be better managed. As a result, addition of analgesics without a solid
scientific knowledge of their impact on all the different parts of the immune response would
complicate and possibly confound the model. Dr Mohr conceded that the complexity is
great and that confusion is unpleasant but pointed out that simplification is possible. A good
understanding of pain itself is required because it also causes ‘noise’ in research results.
Some experiences of pain will be significant and others perhaps not so. The degree of
interference is thus important. Similarly, the degree of interference of a given analgesic
could vary from minimal to major. The animal ethics committee spends considerable time
weighing things as best possible. However, it is critical that researchers provide sufficient
information in order for these deliberations to be optimal. Recommendations that a study
should begin slowly i.e. in a pilot format are not always well received. This is because the
view is that pilot studies are not funded or do not introduce new approaches. Consequently,
costs become an issue to negotiate. A researcher pointed out that the post-intervention
analgesic administration of animals by researchers used to be three days but is now five
days for some models, which has cost implications for the study.
It is evident that many of these logistical issues require discussion and planning. Dr Mohr
noted that refinement (one of the three Rs of animal ethics policies) is a tool for improving
design of studies. However, this too has cost implications e.g. increased
monitoring/analgesia requriements. A/Prof Passmore recommended that the study of the
impact of analgesics on immune responses in infectious disease models is a field in its own
right. Rather than recommend that each animal research include extra controls in their
studies to addresss the impact of the drug class on their models, it would be more
scientifically sound to take this on within the animal unit or set up a national forum of
animal ethics committees to address this. Much of the published literature cited by A/Prof
Passmore drew from research in anaesthetics and linkage or recommendations with such
research groups would be important to consider. Dr Mohr advised that obtaining funding for
such studies would be important; in some countries there are national centres that fund
such research.
Professor Benatar, in response to a comment, distinguished between different senses of
the word ‘ethical’. It might mean “morally right” or it might mean “compliant with current
research codes”. He noted that research might be ethical in the second sense without being
ethical in the first sense.
In response to another comment he reminded all that weighing up harms and benefits in
animal experimentation is not as hard as people think. The process is assisted by asking how
the calculation would be made if humans were the prospective research subjects. This
provides a frame of reference that reveals the issues clearly. The resort to reductionism is
understandable. It provides methodological strength but also has inherent weakness
because of the low incidence of translatability to humans. It is very clear that it is very
complex to do research with animals. Pragmatism is also part of the mix: the obligation to
do research is clear; the guidelines expect particular standards to be maintained, while
honouring the ethical boundaries of the current paradigm. However, equal interests ought
to be treated equally, which means that the utilitarian model used to work through practical
problems must be applied honestly.
Someone asked whether research with animals to benefit animals is done in South Africa. Dr
Mohr responded that a great deal of work is being done e.g. in the veterinary field, to find
better vaccines and treatments and to address common health problems experienced by
animals.
Conclusion
Overall, it appears that the moral justification for withholding analgesia in situations of nonnegligible pain is without merit. Nevertheless, working within the current paradigm of UCT’s
policy, researchers and AECs can make progress by thinking carefully, deliberately; by using
the suggested thought experiments in the deliberation process; and by requiring evidencebased justification for allowing more than negligible pain in a particular study.
Compiled by Anne Pope; edited by David Benatar, Jo-Ann Passmore and Bert Mohr
17 September 2013