minimising pain and distress in laboratory animals
TRANSCRIPT
Paul Flecknell
Minimising Pain and
Distress in Laboratory
Animals
๏ “Reducing to a minimum
the pain and distress
experienced by those
animals used in research”
๏ When could they occur?
๏ How can we detect or
assess them?
๏ What can we do about it?
Refinement
๏ Unless evidence to the contrary, assume that procedures
that would cause pain or distress in an animal will also
cause pain or distress in a human
๏ The same amount of pain or distress?
๏ For the same time?
๏ In the same way in all species?
Refinement and the
precautionary principle
Moving forward with refinement?
๏ The precautionary principle is a good starting point, but a dead end for animal welfare
๏ It gives us an easy answer for IACUCs
๏ It never challenges our assumptions
๏ It encourages anthropomorphic attitudes
๏ It hampers efforts to assess the degree of pain and distress in animals
๏ To minimise pain and distress, we need to refine our
research procedures
๏ But to recognise the value of refinements, we need to
assess the presence and intensity of pain and distress
๏ This must include assessment of emotional states, so that
we can assess animal welfare more fully
Moving forward with
Refinement
๏ "Contingent inhumanity" -
inevitable consequences of
laboratory housing
(General causes)
๏ "Direct inhumanity" arising
as a direct consequence of
experiments (Specific
causes)
Refinement
When could pain and
distress occur?
Fight wounds
received after
changing
social groups
Ageing -
arthritis
Spontaneous
(natural)
disease(Pneum
onia)
Ulcerated feet
as a result of
poor housing
Environmental
problems
Behavioural
abnormalities
due to poor
housing
๏ Caging systems, Environment, Intercurrent disease, Injury
(eg fighting), Ageing (arthritis, neoplasia)
When could pain and distress
occur? - General causes
QuickTime™ and aSorenson Video 3 decompressorare needed to see this picture.
QuickTime™ and aSorenson Video 3 decompressorare needed to see this picture.
Caging systems - standardised
but barren
๏ Laboratory rodents retain behavioural adaptations to their ‘natural’ habitatsThey are highly motivated to perform behaviours no longer essential for survival (in a lab environment)If they are prevented from carrying out these behaviours welfare will be compromised
๏ Alteration to the
animal’s environment
which enhances the
welfare and improves
the biological
functioning of the
animal
‘Environmental enrichment’
What is it?
๏ Increase the frequency and diversity of positive natural
behaviourDecrease frequency of abnormal
behaviourMaximise utilisation of the
environmentIncrease animal’s ability to cope with the
challenges of captivity
In order to be classed as an
‘enrichment’ it must:
๏ An enriched environment may produce more “normal”
animalsIt may enhance their welfareIt may change their
biological characteristicsIt may increase variability
Environmental enrichment -
the controversy
๏ Discuss enrichment
strategies with animal
users
๏ Do not allow “ad-hoc”
enrichments
๏ Once introduced, maintain
a constant policy
๏ But….some species need
novelty
Environmental enrichment -
the controversy
Genetic
modifications
Postoperative
Pain Disease
models
๏ Post-surgical pain, procedural pain, specific disease
models, genetic modifications....
When could pain and distress
occur? - Specific causes
Developing humane end-
points
๏ Which clinical signs?Can they be graded? (0-3, 1-10, + or -)How reproducible (between studies, between observers)Parallels with attempts to develop pain scoring
Direct prob examples
1
2
3
๏ Species VariationSex variationStrain VariationIndividual
variation (sensitivity to analgesic)Individual variation
(emotional state) e.g. stress induced analgesia
Variation in response to
analgesics
๏ Analgesic regimen
should be determined
by assessing the
nature, intensity and
duration of pain
๏ But pain assessment in
animals is difficult, time
consuming, and at
present simply not
reliable in most
circumstances
Selecting an analgesic and
a dosing regimen
Improving pain scoring
๏ Quantify behavioural changes - and identify key pain-related behavioursEstablish variation between different procedures and types of pain
๏ Develop reliable, reproducible, practically-applicable scoring systems
๏ For all species....
QuickTime™ and aSorenson Video 3 decompressorare needed to see this picture.
Rats placed in an observation cage for 10 min - Normal
lighting (previous study used red-light)
• Back-arch
• Writhe
• Belly press
• Stagger/Fall
• Twitch
Pain scoring in rats
Beh
avio
ur
Fre
qu
ency
+1
SD
Rats post-laparotomy
Roughan and Flecknell, 2004
QuickTime™ and aSorenson Video 3 decompressorare needed to see this picture.
What about other laboratory species?
- mice
๏ Twitch – rapid contraction of back musclesBelly Press – pressing of abdomen to cage floor, may include extension of hind limbsWrithe – slow contortion of abdominal musclesStagger/Fall when moving
Vasectomy Laparotomy
Mice post-vasectomy M
ea
n B
eh
avio
ur
Sco
re +
SE
M
Treatment Group
0.0
0.5
1.0
1.5
2.0
2.5
3.0
No VSa VM5 VM10 VM20
Mean Composite Behaviour
Frequency (Belly
Press/Writhe/Flinch/Rear Leg Lift)
Wright-Williams et al, (2007) Pain, 130, 108-118
๏ Very few procedures
assessed
๏ In a small number of
species
๏ Establishing which
behaviours are useful
indicators of pain is VERY
time consuming
๏ Applying scoring can also
be time consuming
๏ ? Automated behaviour
monitors
Behaviour-based scoring -
problems
๏ Is this a problem?
Don’t scientists just
assume surgery
causes pain and give
an analgesic?
๏ How widespread is
analgesic use?
๏ Literature survey of
papers published in
bioscience journals (100
papers each from 1990-
92 and 2000-2002)
๏ Papers involved surgery
in rodents
๏ Followed up with email
enquiry - under-reporting
or under-use?
Analgesic Use
2000-02
No analgesia
Analgesia Anaesthetic
analgesic
๏ Concern over interactions
of analgesics and
experimental protocols
๏ Concern over potential
drug side-effects
๏ No perceived need to
give analgesics - failure
to recognise
pain/differences in
attitudes to animal pain
Why such a low level of
reported use?
Side-effects of analgesics
๏ Clinically significant effects - G-I tract ulceration
(NSAID use), Pica (Opioids), Inappetance, weight
loss (Opioid over-use)
๏ Other effects - Cardiovascular, Respiratory, CNS,
Gastrointestinal, Immune system etc
๏ Effects dependent on analgesic used, dose,
duration and strain, age and sex of animal
Impairs
respiratory
function
Significant
negative
impact on
welfare
Central
sensitisation -
chronic pain
Inhibits GI and
urinary tract
smooth
muscle
Increases
catabolic
response to
surgery
Reduces
“maintenance
behaviours”
Side effects of pain
Anaesthetic/Analgesic side-effects -
consider all interactions
Anaesthetic drug
effects Non-specific
Anaesthetic effects
Surgical stress
response
Hypotension,
Receptor effects
Hypoxia,
Hypercapnia
Hypothermia
Catabolism,
Endocrine effects
Analgesic drug
effects
Resp. depression,
Receptor effects Anorexia,
Increased stress
response
Effects of Pain
Anaesthetic/Analgesic side-effects -
consider all interactions
Anaesthetic drug
effects
Hypotension,
Receptor effects
Analgesic drug
effects
Resp. depression,
Receptor effects
Non-specific
Anaesthetic effects
Surgical stress
response
Hypoxia,
Hypercapnia
Hypothermia
Catabolism,
Endocrine effects
Anorexia,
Increased stress
response
Effects of Pain
Analgesic side-effects -
solutions
๏ Consider research protocol and aims and
objectivesConsider potential interactions with
anaesthesia, analgesia, and effects of surgery (and
pain)Select analgesic regimen to minimise potential
interactions
๏ What analgesic? What dose? What treatment regimen?
๏ A wide range of analgesic agents is available
๏ This allows the agent most appropriate for a particular
procedure to be selectedDevelopments in pain
assessment should enable us to select the appropriate
dosing regimen - BUT…
Pain management - Looking
ahead
Pain management - Looking
ahead
๏ Practical constraints will limit the development and application of pain scoring systems
๏ The best we may hope for is “broad-band” assessments that will fail in some settings
๏ And we won’t detect when they fail…
๏ We need to be prepared to change our analgesic protocols and also our preconceptions about pain and pain behaviour
Pain management - Ethics
Committees ๏ As Ethics Committees - don’t
demand “standard” analgesic protocols
๏ Set guidelines, and demand a good justification if a research protocol claims that analgesics cannot be used
๏ Ask if all the options have been considered: NSAIDs, opioids, local anaesthetic, etc
๏ Be especially critical if the anaesthetic drug effects have been ignored
๏ A final thought.....
Thanks to: ๏ AMGEN, BBSRC, Charles
River, National Centre for the
3Rs, Pfizer, Proctor and
Gambol, UFAW and Wellcome
Trust, (funding current studies)
๏ CAAT, ECLAM/ESLAV, MRC,
(previous work)
๏ The Swiss 3Rs Foundation,
Prince Laurent Foundation,
Solvay Pharmaceuticals, Astra-
Zeneca, Novartis, Pfizer, Merial,
LAVA and IAT for supporting our
educational activities
(www.digires.co.uk,
www.ahwla.org.uk)
๏ Ms Amy Dickenson
๏ Dr. Johnny Roughan
๏ Ms Sian Wright-Williams
๏ Dr. Nilofer Sabrine
๏ Dr. Huw Gollege
๏ Ms Shelley Rhodes
๏ Mr Jon Gledhill
๏ Ms Claire Richardson
๏ Dr Matt Leach
Thanks to: