Tony Dickenson, Neuroscience, Physiology and Pharmacology

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Tony Dickenson, Neuroscience, Physiology and Pharmacology
Placebo and central pain modulation
ONE PAIN CAN INHIBIT ANOTHER…
Tony Dickenson, Neuroscience, Physiology and Pharmacology
University College London
Jean-Joseph-Xavier Bidaud (1758-1846) Vien: Siege of a City(1795)
Key types of pain
Post-surgical pains
Nociceptive pain
Neuropathic pain
Pain caused by
an inflammatory or
Pain initiated or caused
by a primary lesion or
disease in the
peripheral or central
nervous system
non-inflammatory
response to a
noxious stimulus
Mixed pains
Low back pain
Cancer pains
Tissue damage
Idiopathic
Neuropathic
components
Nerve damage
Nociceptive pain
Chemical activation
Neuropathic
pain
Electrical events
NSAIDs
The Search for the Holy Grail?
Lido
GBP
Cortex - where and how much pain
Limbic areas - unpleasantness
Restore normal modulation
Brain stem descending controls
Peripheral events
Tissue and nerve
damage
Remove the source - surgery…
Spinal events
Risk factors
Failure of descending inhibition
Presence of central sensitisation
UVB - sunburn
40C for 5 minutes x 2
(30hrs)
UVB plus heat rekindling
Neuronal coding and human
quantitative sensory testing
Peripheral
sensitization
Chemical activation
Central sensitization
Wind-up etc..
Spinal mechanisms central hypersensitivity
Altered pain states
Subsequent inputs
Early C-fibre inputs
++++++
Wind-up - temporal summation
Long-term potentiation
Peripheral and descending pathways converge …
Tissue damage
Primary hyperalgesia
Hyperalgesia
Spontaneous
pain
Allodynia
FMS
OIH
PERIPHERAL
ACTIVITY
Nerve damage
CENTRAL
SENSITIZATION
Decreased
threshold to
peripheral
stimuli
Expansion of
receptive
field
Increased
spontaneous
activity
Secondary hyperalgesia - a couple of segments
Spinal wind-up and temporal summation
Central sensitisation
“Pain score” 2
Wind-up takes it to 8
And area of pain increases
Peripheral input is small
Brain message is large
Predicts chronic pain after
surgery
So if there is a spread of
Pain around the site = CS
Petersen KK et al., Presurgical assessment of temporal summation of pain predicts the development of chronic postoperative
pain 12 months after total knee replacement Pain 2015;156(1):55-61
Limbic brain
Affective aspects
of pain
Fear, anxiety,
sleep
Cortex
Location and
intensity
Descending controls
Allow top-down processes
to enhance pain - link mood, sleep and pain
Noradrenaline
5HT
Spinal cord
Integrates, amplifies and modifies
incoming messages
Output to brain
Incoming peripheral nerves
•
Convey touch, temperature
•
Convey painful messages - heat, mechanical, chemical
•
Are altered by tissue and nerve damage
Periphery is sensitised in inflammation
Periphery is abnormal in neuropathy - loss and gain
Disconnect between x-ray or MRI and pain
High pain from minor damage
Central sensitisation will enhance pain - spinal - local
BUT - low pain from major damage with coping
High pain from minor damage and anxiety etc
Mood changes and widespread pains
Descending controls are broad and diffuse
And bidirectional…..
What is the Pharmacology of Descending Controls?
NA and 5-HT are Key Transmitters
PAIN
Limbic System
Amygdala
Hypothalamus
Mood, fear, anxiety, rage
panic, sleep-wake…
Same circuits
imaged in Periaqueductal
humans grey PAG
Neutral Cell
Locus coeruleus
Off-Cell
Rostroventral medial medulla RVM
Noradrenaline
On-Cell
5-HT
Alpha-2 adrenoceptor
Inhibitorycontrols
controls
Inhibitory
Excitatory controls
controls
Excitatory
Adapted from: Bannister K, Bee LA, Dickenson AH, Neurotherapeutics 2009;6(4):703-12
Group activation maps for somatic (first column) and visceral (second column) pain.
Dunckley P et al. J. Neurosci.
2005;25:7333-7341
©2005 by Society for Neuroscience
Descending controls under
hormonal control in females
The strength of the spinal-PAG coupling predicted
individual pain ratings….acute pain conversations
Spinal cord-midbrain functional connectivity is related to perceived pain intensity: a combined spino-cortical FMRI study.
Sprenger C, Finsterbusch J, B¸chel C.J Neurosci. 2015 Mar 11;35(10):4248-57.
CHANGED IN PERSISTENT PAINS
Descending inhibitions
Noradrenaline
Protects
QuickTime™ and a
decompressor
are needed to see this picture.
Alpha2 AR
NA
Descending excitations
5-HT
Promotes
QuickTime™ and a
decompressor
are needed to see this picture.
5HT2/3R
DESCENDING INHIBITIONS IN HUMANS
Pain rating
OPIOID INFUSION
“Off”
nocebo
“On”
placebo
16% Placebo baseline
22%
Placebo plus
37%
Drug alone
52%
Drug plus
placebo
Altered fMRI resting-state connectivity in
periaqueductal gray networks in migraine
Used by placebo (inhibitions) yet facilitations seen in OA
Mainero C et al. Ann Neurol 2011;70:838-45
Pain changes our brain functions
Difficulty sleeping
60
55
Lack of energy
39
Drowsiness
Concentration difficulties
36
Depression
33
27
Anxiety
18
Poor appetite
0
10
20
30
40
50
60
70
% patients with moderate to very severe
discomfort due to symptoms (n=126)
Meyer-Rosberg K et al. Eur J Pain 2001;5:379–89
Loss of Descending Inhibition - Gain of Facilitation
Reduced NA function
- osteoarthritis up
and neuropathy
Excitations
– Inhibitions
Increased 5HT function - osteoarthritis,
cancer pain and neuropathy
Maintains evoked and ongoing pains
Loss of protection
Spinal cord mechanisms
NA
Central sensitisation and opioid modulation
down
Translation to patients…..
PAG activation
Patients > Controls
High PainDETECT > Low PainDETECT
% change of BOLD signal
(vmax) within PAG mask
Psychophysical and Functional
Imaging Evidence Supporting
Presence of Central
Sensitisation in a Cohort of
Osteoarthritis Patients
2.0
1.5
1.0
0.5
0.0
0
5
10 15 20 25
Pain DETECT score
Gwilym SE et al. Arthritis Rheum 2009; 61(9):1226-34
Punctate mechanical hypersensitivity
Response Frequency (%)
100
vF 8g
Maintained hypersensitivity
after peripheral neuropathy
and abnormal cold…
75
50
Ablation of RVM descending
facilitations
25
Control values
0
0
5
10
Post-operative Day
15
Could there be time-related events in neuropathic pain?
Bee LA, Dickenson AH. Pain 2008;140:209-23
Descending inhibition:
Activated by placebo analgesia
Reduced in OA and neuropathy
Descending facilitation relates
to pain scores in OA
5HT
promotes
pain
NA
protects
Noradrenaline
- no CPM
- good CPM
Low 5HT transporter
Enhanced synaptic 5HT
Reduced CPM - 5HT3?
So 5HT may prevent
CPM - descending
facilitations - bad cop….
Cortex
Pain sensitivity
Limbic brainin fibromyalgia is associated Location and
intensity
with catechol-O-methyltransferase (COMT) gene.
Affective
aspects of pain
Fear, anxiety, sleep,
hunger
Serotonin transporter
temperature… gene (SLC6A4) polymorphism
in patients with irritable bowel syndrome and healthy controls.
Descending controls
Allow top-down processes to alter
pain - link mood, sleep and pain
Spinal cord
Integrates, amplifies and modifies
incoming messages
Output to brain
Incoming peripheral nerves
• Convey touch, temperature
• Convey painful messages - heat, mechanical, chemical
• Are altered by tissue and nerve damage
Sleep, mood, fatigue, smells
+ ++
+
Fibromyalgia
2-4% of the population
Descending controls are diffuse
and widespread….
FMS, IBS, Opioid hyperalgesia
One pain can inhibit another……but not in neuropathy
Diffuse noxious inhibitory controls (DNIC)
Conditioned pain modulation (CPM)
Descending inhibitions - via brain
90% of normal people have CPM - 30% - and normal rats
Loss relates to chronic post-operative pain
Reduced in peripheral neuropathic pain, headache, facial pains,
arthritis, fibromyalgia……
Reduced in opioid hyperalgesia - no peripheral change
QuickTime™ and a
decompressor
are needed to see this picture.
So - peripheral and central pain states have a common loss of inhibition compounded by depression and sleep issues
One pain inhibits another
Diffuse Noxious Inhibitory Controls
Conditioned pain modulation
Through descending inhibitions
A marker for intrinsic pain modulation
Normal CPM - 94% of the healthy population
Reduced CPM - predicts chronic post-surgical pain
Yarnitsky D et al. PAIN 2008; 138: 22-28
Reduced CPM in many pain conditions
Peripheral neuropathy
Fibromyalgia, Irritable Bowel Syndrome,
Migraine, Tension-type headache,
Temporomandibular joint (TMJ) disorders,
Osteoarthritis and muscle pain,
Interstitial cystitis,
Patients at risk of developing chronic post-surgical pain
Cancer pain patients with
greater opioid-induced hyperalgesia.
Yarnitsky D, Curr Opin Anaesth 2010; 23:611–615
Probing the pharmacology of DNIC
100%
DNIC
normal
DNIC
With
NA α2R
block
DNIC
nerve
injury
DNIC
normal
DNIC
nerve
injury
+
tapentadol
0
DNIC uses descending NA systems - lost after nerve injury
LOSS OF CPM IN PATIENTS - RELATES TO ACTIONS OF DULOXETINE (SNRI)
AND TAPENTADOL (MOR-NRI)- both have NA actions……
Pain. 2012 Jun;153(6):1193-8.
Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy.
Yarnitsky D1, Granot M, Nahman-Averbuch H, Khamaisi M, Granovsky Y.
Br J Anaesth. 2014 Jul;113(1):148-56. doi: 10.1093/bja/aeu056.
Tapentadol potentiates descending pain inhibition in chronic pain patients with diabetic polyneuropathy.
Niesters M1, Proto PL2, Aarts L2, Sarton EY2, Drewes AM3, Dahan A
Restoration of CPM by tapentadol
And weak effect of placebo - that can use descending inhibitions…
DNIC is partly opioid and involves NA via the alpha-2 AR
MOR-NRI
Niesters M et al. Br J Anaesth 2014; 113(1):148-56
MOR - NRI
Severe pain
MOR
Tapentadol
NRI
MOR
} reduces central
sensitisation
NA
5HT
TCA and SNRI
block the
re-uptake transporters
NA - 5HT
Synaptic levels rise
NA….5HT
Transporter
clonidine
dexmedetomidine
Spinal alpha-2 adrenoceptors inhibitory
Triptans 5HT1 agonist
Ondansetron 5HT3
antagonist
Spinal 5HT receptors - 1, 7 = inhibitory
2, 3 = excitatory
When we can’t fixed the source - we can modulate the pain
Cortex - where and how much pain
Limbic areas - unpleasantness
Brain stem descending controls
Restore normal modulation
Peripheral events
Tissue and nerve
damage
Spinal events
Risk factors
Failure of descending inhibition
Presence of central sensitisation
An ongoing struggle between
the outer and inner worlds
Escape
Avoid
Survive
Chronic pain
Culture
Metaphor
Meaning
Pain intensity
Cognition
Memory
Reward
Context
Amplification and filtering
Attention
Anxiety
Depression
Sleep
Sensory inputs
Pain
EMLA is analgesic vs placebo
Nocebo is hyperalgesic
Nocebo - brain - blocks
EMLA - periphery
PLACEBO - CNS - REDUCES
PERIPHERAL PAIN
NOCEBO - CNS - PREVENTS
TOPICAL ANALGESIA OF EMLA
Upstream of TRPV1 and NaV….
Pain. 2015 Jan;156(1):39-46. doi: 10.1016/
Opposite effects of the same drug: reversal of topical analgesia by nocebo information.
Aslaksen PM, Zwarg ML, Eilertsen HI, Gorecka MM, Bj¯rkedal E.
Thank you!

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