Minimising Pain and Distress in Laboratory Animals

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: