79#7 neuro pharmacology and chronic pain

Neuro-Pharmacology of Chronic Pain
Chapter 7
Nelson Hendler, MD, MS,
Former Assistant Professor of Neurosurgery
Johns Hopkins University School of Medicine
Past president-American Academy of Pain Management
www.DiagnoseMyPain.com
Based on information from
Hendler, N.: Pharmacotherapy of Chronic Pain
Neurosurgical Management of Pain.
Chap. 9: pp.117-129, ed. North, R., Levy, R.,
Springer-Verlag, New York, 1997
Hendler, N.: Pharmacological Management of Pain,
Chapter 12 in Practical Management of Pain,pp. 145-155,
Third edition, P. Prithvi Raj Editor,
Mosby, St Louis, 2000.

Types of Medication Used for Pain
• Narcotics
• Anti-Convulsants
• Anti-depressants
• Muscle Relaxers
• Anti-Psychotics
• Local Anesthetics and Neurotoxins
• Anti-Anxiety Medication
• Vaso-Active Medication
• Epidural Medication

How A Nerve Works to Stop the
Message of Pain
• A message must be received by the brain to
feel pain.
• Nerves work by converting mechanical,
chemical or electrical energy into an
electrical nerve impulse.
• This electrical nerve impulse travels until it
reaches the end of the nerve at a synapse.
• The synapse transfers information from
electrical to chemical form to jump to the
next nerve. The type of chemical lends
specificity.

Neurochemical and Anatomical
Pathway For Acute Pain
(2 synapses)
• Neo-Spino-Thalamic Tract (Acute Pain)
BRAIN
Spinal Cord sends message to the brain
Peripheral Sensory
Nerve (A beta, A delta, C
fibers) carries the
message to the spinal
cord
Mechano or
pressure receptor
(Meisner or
Pachinian
corpusule) or
chemoreceptor
(C fiber) in a
finger
Synapses (Chemically mediated)
Thalamus
Somato-
Sensory
Cortex
(Pain)
Chemical mediation lends specificity, and a site to manipulate

Neurochemical and Anatomical Pathway For Chronic Pain
(Many areas of the brain are involved and multiple synapses-
so this is slower transmission)
• Palleo-Spino-Thalamic Tract (Chronic Pain)
BRAIN
Spinal Cord sends message to the brain
Peripheral Sensory
fibers) carries the
message to the spinal
cord
Mechano or
pressure receptor
(Meisner or
Pachinian
corpusule) or
chemoreceptor
(C fiber)
Synapses (Chemically mediated)
Reticular
Activating
System
Thalamus
Hypothalamus
Limbic
System
Somato-
Sensory
Cortex (Pain)
Chemical transmission is slower than electrical transmission

Significance of Pathways of Pain
• Pain patients have trouble sleeping due to
pain, they get depressed, anxious, and
they have pain.
• Natural sleep (REM, stage 3 and stage 4)
is caused by build-up of serotonin at the
dorsal median raphe nucleus of the
reticular activating system in the brain
stem.

Other Neurosynaptic transmitters in
the Brain
• Biogenic Amines: dopa, dopamine, nor-
epinephrine, epinephrine, serotonin.
• 35% of neurosynaptic transmitters-GABA
• 10% of neurosynaptic transmitters-Ach
• 2%-5% of all neurosynaptic transmitters in
the brain use biogenic amines
• 95% of biogenic amines transmitters are
in the hypothalamus and limbic system.
• 90% of encephalins are in limbic system

Neurosynaptic Transmitters
• Neurosynaptic transmitters can be inhibitory or
excitatory, working by different mechanism of
action
• Neurosynaptic transmitters are made in the
pre-synaptic area of the nerve
• Various enzymes control the production or
degradation of the neurosynaptic transmitters
• MAO (monoamine oxidase) exists pre-
synaptically, and makes transmitters
• COMT (Catechol-0-methy-transferase)exists in
the synapse and breaks down transmitters

Neurochemical and Anatomical
Pathway For Chronic Pain
• Palleo-Spino-Thalamic Tract (Chronic Pain)
BRAIN
Spinal Cord
Peripheral Sensory
fibers)
Mechano or
pressure receptor
(Meisner or
Pachinian
corpusule) or
chemoreceptor
(C fiber)
Sleep caused by serotonin
Reticular
Activating
System
Thalamus
Hypothalamus
Limbic
System
Somato-
Sensory
Cortex (Pain)
Encephalin, 95% of biogenic amines

The Synapse and Neuro-Synaptic
Transmitters (NST)
• Pre-synaptic Synapse Post-synaptic
• MAO makes NST COMT break down NST
• 1)Transmitters are released from nerve A, 2) bind to the receptors, on nerve B,
causing nerve B to fire, and 3) then reuptake occurs to stop the action of the NST.
Post-Synaptic
Receptor Sites
Nerve transmission
of information
Nerve transmission
of information
Neuro-synaptic
transmitter
(NST)
1
2
3
1
COMT
MAO
BA

How medications works on the synapse
• Increase activity by
1)Cause Release 2) Stop Reuptake 3)Mimic NST
Post-Synaptic
Receptor Sites
Nerve transmission
of information
Nerve transmission
of information
Neuro-synaptic
transmitter
2
3
1
I

How medications works on the synapse
• Decrease activity by
1) Stop Release 2) Increase Breakdown 3)Block NST
Post-Synaptic
Receptor Sites
Nerve transmission
of information
Nerve transmission
of information
Neuro-synaptic
transmitter
3
1
COMT
2
2

The Axon and Cell Body
• Transmission along a nerve, causing Na+
influx
K+
Na+
Axoplasm
Extracellular fluid
Na+/K+ channelK+ comes out,
Na+ goes in
Pumps Na+ out,
and K+ back in
This entire process generates a current (90uV) across cell membrane

Mechanism of Action of Various Drugs
• Medication can work at the synapse,
which is very specific (there are 20
subtypes of serotonin receptors)
• Medication can work on the nerve
membrane (more non-specific).
• Medication can inhibit natural transmitters
by blocks release or receptor sites,
• Medication can release transmitters, or
block reuptake pre-synaptically.

Causes of Pain
• Pain is produced when there is tissue
damage
• If there is sufficient heat, or pressure or cold,
or stretching, or chemical damage to disrupt a
cell, this causes the release of inflammatory
chemical which irritate the pain fibers
• Specific types of tissue have specific pains
• Blood vessel compression causes a throbbing
pounding pain, while muscle damage may
cause spasm, or cramping pain, while nerve
irritation may cause sharp, shooting pain

Narcotics and How They Work
• Mimic action of u1 and u2 morphine receptors to
give pain relief.
• Side effects: work on K1 and K2, S1 and S2 and
enkephlin receptors in brain, gut, spinal cord, heart,
etc., give respiratory depression, psychosis, low
testosterone
• Tachyphylaxis: excite their own break-down, so
need more to keep working.
• Receptor site upregulation so need more over time.
• Used to control most acute pain –less useful in
neuropathic (nerve) pain, and chronic pain

Anti-Convulsants and How They Work
• Cell membrane stabilization, Na+
channels.
• Neurosynaptic transmitters- most GABA
• Prevent cascade of protein synthesis to
prevent “kindling.” (Uni. of Wisconsin).
• Used to control nerve pain, neuropathic
pain, peripheral neuropathy, trigeminal
neuralgia, post-herpetic pain.

Anti-Depressants and How They Work
• Prevent reuptake of neurosynaptic
transmitters.
• This leaves more neurosynaptic transmitter
at the post-synaptic receptor site.
• Primarily block the reuptake of serotonin,
and nor-epinephrine, and one works on
dopamine (also stops smoking).
• Used to helps sleep, depression, pain by
working blocking encephalin hydrolyzing
enzyme, leading to increased encephalins

Muscle Relaxants and How They Work
• Works centrally on glycine receptor,
• Works peripherally on GABA receptor, at a
spinal cord level.
• Some like Zanaflex work by inhibiting the
release of nor-epinephrine pre-synaptically
• Used: to treat secondary muscle spasm,
post-op spasm, acute injuries.

Anti-Psychotics and How They Work
• Post-Synaptic blockade of dopamine
• Also inhibits the encephalin hydrolyzing
agent, allowing accumulation of leucine
and methionine encephalin, naturally
occurring pentapeptide neurosynaptic
transmitters with morphine like properties.
• Used: for neuropathic pain, post-herpetic
neuralgia, anti-anxiety

Local Anesthetics and Neurotoxins
and How They Work
• Lidoderm Patch stabilized Na+ channels
• Zostrix – may work on substance P.
• Capsaisin – actually kills the small C fibers
• Used: Local application for small C fiber
mediated pain, which is most susceptible
to local analgesic effect, mostly in the skin

Anti-Anxiety Medications and How They Work
• May work on GABA receptor in the brain,
glycine receptor, and the benzodiazepine
receptor.
• Calms the patient
• May cause intellectual impairment in 70%
of patients (Hendler, Cimini, Ma, Long, Am. J. Psych, 1982).
• Used: Pre-op relaxation, post-op
relaxation.

Vasco-Active Medications and How They Work
• Inderal - beta blocking agent
• Clonidine – partial alpha 2 agonist
• Phenoxybenzamine –postsynaptic alpha 1
blocking agent
• Phentolamine – post-synaptic alpha 1 blocking
agent
• Mexiletine – cell membrane inhibitor
• Nifedipine – Calcium channel blocking agent
• Used: headaches, CRPS II, Raynauds

Epidural Medication
• Morphine –a u1 and u2 synaptic agent
• Clonidine – a partial alpha 2 agonist
• SNX-111 – a conotoxin - a calcium
channel blocking agent that is orally
degraded. From sea snail venom.
• Dextromethorphan- work on NMDA
receptors
• Kappa 2 agonist – for neuropathic pain
• Used: in an implantable pump, for spinally
mediated pain

Issues With Chronic Narcotics
• Psychological Addiction
• Physiological Habituation
• Intellectual Impairment (Hendler, Am J.
Psych)
• Diversion (Rudy Giulliani- Rx Action
Alliance)
• Loss of Sexual Activity (Hendler
testosterone studies)
• Physician Concerns (DEA directives)

Narcotics Problems
• Constipation
• Not particularly effective in neuropathic
pain, i.e. nerve entrapments, CRPS I,
radiculopathies, trigeminal neuralgia,
peripheral neuropathies.
• Dosage escalation.
• Patient compliance.
• Need for a contract.

Narcotics Problems
Routes of administration-oral, nasal,rectal, IM,TC.
Transcutaneous- skin thickness, hair, temperature,
adhesives, variable absorbsion rates, sweating,
compliance, (One colleague told me he told a
patient to apply a patch q 2 days, and gave him
a 90 day supply. The patient returned
complaining he is running out of room to put
patches. Yes- indeed- he had 45 patches on his
body. Now instructions include remove the old
patch before applying the new one).

79#7 neuro pharmacology and chronic pain

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