Neuro-Pharmacology of Chronic PainChapter 7

Nelson Hendler, MD, MS, Former Assistant Professor of NeurosurgeryJohns Hopkins University School of Medicine

Past president-American Academy of Pain Management

www.DiagnoseMyPain.com

Based on information fromHendler, 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)

BRAINSpinal 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)

BRAINSpinal 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)

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)

BRAINSpinal Cord

Peripheral Sensory Nerve (A beta, A delta, C 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

1COMT

MAO

BA

How medications works on the synapse

• Pre-synaptic Synapse Post-synaptic

• 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

1I

How medications works on the synapse

• Pre-synaptic Synapse Post-synaptic

• 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

31

COMT

22

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

• It is important to ask the type of pain

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

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

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

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.

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

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

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

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.

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

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

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

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

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

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.

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

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

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

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).