triple response of Lewis - South West Peninsula Deanery

Dr Andrea Magides & Dr D I Natusch
South Devon Pain Service

Peripheral small unmyelinated nerve fibres
Picture courtesy of Astellas Pharma

The triple response of Lewis is
a cutaneous response that
occurs from firm stroking of the
skin, which produces an initial
red line, followed by a flare
around that line, and then
finally a wheal the “Lewis
Effect”.
The triple response of Lewis is
due to the release of histamine
and other vasoactive
substances.

picture
A complex inflammatory and humeral cellular “conversation”

Ionotropic Receptor Subtype Ligand
TRP 1,2,A Heat, Capsaicin, H+
(A = noxious cold)
Acid Sensing DRASIC ; ASIC H+
Purine P2X3 ATP
Serotonin 5HT3 SHT
NMDA NR1 glutamate
AMPA iGluRI glutamate
kainate iGluR5 glutamate

Slide courtesy of Astellas Pharma

Receptors) Subtype Ligand
Glutamate mGluR1,2/3,5 glutamate
Prostanoids EPI-4,IP PGE2, PGI2
Histamine HI HA
Serotonin 5HTIA, 5HT4,5HT2A 5HT
Bradykinin B1,B2 BK
Cannabinoid CB1-2 anandamide
Tackykinin NK1 Substance P,
Neurokinin A
Opioid Mu, Delta, Kappa Enkephalins

Congenital Pain Insensitivity seen rarely in
humans and animals.
Channelopathies / receptor defects.
Recent studies have identified some families
with genetic defects causing pain syndromes
all of which affect peripheral nerve systems
only.

Beggs et al. Molecular Pain 2010

Primary afferents contain excitatory amino acids (glutamate)
and neurotransmitters (substance p). These depolarise AMPA
receptors for a short and predictable time.
Repeated C-Fibre input results in progressive membrane
depolarisation and removal of the magnesium block from
NMDA receptors (Windup) mediated by glutamate acting on
NMDA receptors and Substance P on neurokinin receptors.
Fast high density stimulation activates long-term
potentiation. This with windup and secondary hyperalgesia
including the effect of wide dynamic neurones use partially
overlapping systems all contribute to central sensitisation.
Intense ongoing stimuli further excite transmission. And cause
activation of cFOS genes and changes in cellular protein
expression.
Further excitatory processes involving many types of
transmitter and messengers occur in the dorsal root ganglia.

Ketamine

Tyr-gly-gly-phe-met
Tyr-gly-gly-phe-leu
Small penta peptides that are made from precursors-
Proenkephalin
Pro-opiomelanocortin
Prodynorphin
Work on specific receptors – Cause a hyper polarisation
of cells as a result of calcium influx leading to a
decreased release of transmitters and decreased
synaptic activity. Depending on the cell activity this can
have a depressive or an excitatory effect.

Mu (morphine) MOP
Kappa (ketocyclazocine) KOP
Delta (vas deferens) DOP
Nociceptin Orphanin FQ peptide receptor
(NOP)

Classic opioid dose
response curves you
have been taught are
not actually based on
pharmacdynamic data
in patients with pain.
Nimmo and Smith 1994

Naturally occurring
phenanthrene derivative
Low lipid solubility and slow
penetration of the bloodbrain
barrier
Extensively metabolised by
gut wall and liver to
M3G(70%) and M6G(10%)
and sulphate conjugates
M6G 10-20X more potent
than morphine and is
excreted in urine

„partial agonist‟ at mu opioid
receptor, weak agonist at
delta opioid sites and
antagonist kappa opioid
receptor.
Intrinsic anti-tolerance
effects

Buprenorphine has a ceiling effect for analgesia.
*Buprenorphine induces a ceiling in respiratory depression but not analgesia.
Dahan A et al, BJA 2006,96(5):627-32
No evidence of a plateau (0.1-10mg) in humans.
Buprenorphine is a partial agonist and will antagonise the effects of other
opioids
Persistent blockade of Mu receptor does not occur and subsequent use of
other opioids is not affected in the acute or chronic situation.
Lack of Naloxone reversibility of respiratory depression.
Buprenorphine induced respiratory depression can be reversed by naloxone
albeit in higher doses. Budd K. Old dog- new matrix BJA 2003; 90(6) 722-
724

Weak agonist at all opioid
receptors (MOP 20X)
Inhibits neuronal reuptake of
norepinephrine.
Potentiates release of serotonin
and causes descending
inhibition of nociception.
Metabolised by demethylation
Several metabolites –one active
(o-desmethyltramadol)
Mu-opioid receptor agonist
and norepinephrine
reuptake inhibition
Main metabolic pathway for
elimination of tapentadol is
phase II glucuronidation
No active metabolites
Low potential for drug-drug
interaction
TRAMADOL
TAPENTADOL

Watkins Trends Pharcol 2009

Ensure other treatment options have been maximised.
Consider opioid therapy as an adjunct ; sole opioid therapy is rarely
successful.
Use goal directed therapy; set limits and goals and agree to these.
Unless pain is occasional base regime on long acting opioids and avoid
breakthrough medication.
Be prepared to wean and discontinue if treatment goals are not met.
Ballentyne and LaForge K S. Opioid Dependence and addiction during
opioid treatment of chronic pain.
Pain 2007 ; 129 : 235-255
Pain Clinic –negotiating firm limits

“The brain is an organ whose function is
to make meaning”
Dr Dorothy Rowe, Psychologist

Subconscious
„detection system‟
„messaging system‟ to central processing in the spinal cord
and brain
„message modulation‟ system
automatic neural & endocrine changes and responses
The Brain has the ability to processes information and at
some level this becomes part of consciousness and has
to make sense.

The gate control theory explains how counter stimulation
helps pain but it was not sophisticated enough to fully
explain central sensitisation but did recognise the key role
of modulation by the brain and higher centres.

Mantyh and Tracey 2007
Insular Cortex : ?? “ouch it hurts
but is it an important bit and
what is the magnitude?”
Anterior Cingulate Cortex
?? “Alert : Something going on
here!”
Somatosensory Cortex
?? “Its this bit”
Thalamic Nuclei : ?? Information
processing.
Pre frontal cortex
?? “How does this relate to me in
the outside world??”

DIRECTION TO PAIN OR PLEASURE
DEFINED BY Emotional STATE (Valence
-German) as in „AMBIVALENCE „ i.e.
emotions in 2 directions – C.Jung)
Think about “tickling” to see how
context and attentional focus can
alter skin sensitivity and define
pleasure or pain in response to non
harmful stimulus.

Social pain activates the same
Neuromatrix pattern as
nociceptive input…
Eisenberger, Science 302(5643): 290-2

Petrovic et al Science 2002

Moulin et al Lancet 1996

Before and After : Torbay Pain Management Program

Hurt = harm (fear avoidance behaviours)
Movement & re-injury (kinesiophobia).
Worry - Catastrophisation
Can interfere with movement and activity

Cognitive Behavioural Therapy in depression – Aaron Beck noticed
depressed patients have depressive thinking and selectively access
depressive memories. Uses Socratic Questioning techniques as a way
of challenging automatic negative thinking alongside behavioural
experiments. As effective as medication in mild / moderate
depression. CBT has been adapted for Pain and may contain elements
of relaxation / self hypnosis.
Acceptance and Commitment Therapy : learning techniques for
distress tolerance and acceptance of symptoms. Developing
techniques of cognitive diffusion – „notice thoughts but don‟t act on
them‟ and mindfulness meditation- developed from Zen Buddhism by
Cabbot-Zin.
Compassion Focused Therapy – aims to teach compassion skills and
self soothing techniques to people who are not kind to themselves
and have a poor self esteem leading to behavioural problems.
Most Clinical Psychologists use elements of different therapies in
individual therapy or groups (Pain Management Programmes)

CONGNITIVE - BEHAVIOURAL Bio-psycho-social MODEL Model OF PAIN
Pain management unit

Stratified Care in Chronic Pain
Pain, disability
And high distress
Pain, disability
and low Distress
Chronic Pain, low disability low distress

How your brain works!

Receptor Specificity
Noradrenaline
Serotonin
NA+5HT
"NARIS"
Reboxetine
"SSRI"
Fluoxetine
"SNRI"
Venlafaxine
"NASSA"
Mirtirzapine
"RIMA"
Moclobemide
"MAOI"
"TRICYCLICS"
Amitriptyline
Nortriptyline
Lofepramine

Tricyclic Antidepressant
Its metabolite Nortriptyline is equipotent but has
fewer cholinergic and sedative side effects.
TCA seem to be equipotent but differ in terms of
muscarinic side effects and safety in overdosage
(Lofepramine safer and fewer side effects than
most TCA‟s).
TCA‟s in dosing studies have maximal effect for
pain around 70mg.

Duloxetine
Serotonin Noradrenaline Reuptake Inhibitor.
It is effective for depression and generalised anxiety
disorder.
NICE Guidelines for Neuropathic Pain – first line
treatment for neuropathic pain in diabetes.

ANTICONVULSANTS
Enhance inhibition of
GABA
VALPROATE
CLONAZEPAM
Stabalise cell
membranes
PHENYTOIN
CARBAMAZEPINE
Bind to calcium or
sodium channels
GABAPENTIN
PREGABALIN

Gabapentin and Pregabalin do not act on GABA receptor but
A2 Delta receptor ( Calcium Channels).
Effective in Neuropathic Pain and Pregabalin is a first line drug for
neuropathic pain according to NICE Guidelines.
Perioperative gabapentinoids (gabapentin/ pregabalin) reduce
postoperative pain and opioid requirements (U) and reduce the
incidence of vomiting, pruritus and urinary retention, but increase the
risk of sedation (N) (Level I).
Perioperative use of gabapentin after mastectomy reduced the incidence of
neuropathic pain at 6 months postoperatively, from 25% in the placebo to
5% (Fassoulaki et al, 2002 Level II).

Pictures from a variety of sources including Dr Howard Fields with
thanks, South Devon Pain Archive and Wikipedia unless referenced and
information for Acute Pain, The Scientific Evidence,
Faculty of Pain Medicine ANZACA 3 rd Edition