Acute versus Chronic Pain

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

Past president-American Academy of Pain Managementwww.MarylandClinicalDiagnostics.com

Lecture 1

Anatomy of a Nerve- I• Everything in the body works due to nerve input• Nerves are the signal system of the body• Think of a nerve as an electrical telephone wire

which transmits information from one place to another, via electrical impulses

• Just like an electrical wire, nerves have insulation, called myelin, which can be very thick, or thin.

• The myelin is made by a special cell called a Schwann cell.

• The myelin wraps around the nerve in layers

Anatomy of a Nerve - II• A nerve has a cell body, which provides the

metabolic energy for the nerve, and receives information from other nerves.

• The fiber extending from the cell body is an axon• The axon ends in a “button termineaux” or

terminal button or swelling, where the chemicals called neurosynaptic transmitters are made

• These neurosynaptic transmitters are what create the specificity of nerve transmission

• Nerve activity can be modified at the cell membrane electrically & the synapse chemically

Anatomy of a Nerve III• The center of a axon is called axoplasm, which

transports nutrients to the entire nerve• The cell wall of the nerve is a lipo-protein

membrane with channels through it, modified by sodium (Na+), potasium (K+) calcium (Ca++), magnesium (Mg++) and other cations

• When a nerve discharges, due to stimulation of the cell body, the channels change, and allow Na+ into the axon, and K+ goes out

• Then a pump in the axon (Na+/K+ ATPase) moves the cations back to original position

Anatomy of a Nerve IV• The transient flow of Na+ into the axon, and K+ out

of the axon creates a electron flow along the axon• This flow moves a signal electrically along the nerve• This electrical signal reach the end of the nerve and

causes the release of the chemicals- the neurosynaptic transmitters

• So a sensory nerve receives stimulation, either mechanical or chemical, and transmits this information electrically, along the axon, until it reaches the end where it then converts it to a chemical message again.

Anatomy-Peripheral Receptors• Meissner's corpuscles are mechanoreceptor, in

the skin, which senses vibration, and light touch • Pacinian corpuscles in the skin sense pressure• Free Nerve endings have no myelin-so sensitive• Afferent Nervous System-carries sensory

messages to the brain- pain is one of these• There are three major types of pain nerves• A beta fibers have a moderate amount of myelin• A delta fibers have some myelin• C fibers – have no myelin or very little myelin

Electrical vs chemical transmission• Once a peripheral pain receptor is stimulated,

this starts a series of events which allow the message of pain to reach the cortex of the brain

• This transmission is electrical along the axon and chemical at the end of the nerve with the neurosynaptic transmitters

• Without pain information reaching the cortex of the brain, there is no perception of pain

• Pain relief is directed to preventing the message of pain from reaching the cortex of the brain

Blocking the Pain Message• Modify the electrical transmission in the axon

using anti-convulsants to stabilize the membrane, by hyper-polarizing the membrane, or put in cations, like lithium (Li+), which interfere with normal cation activity of Na+, K+, Mg++ and Ca++

• Modify the release of neurosynaptic transmitters, by enhancing those which produce pain relief, and blocking those which transmit the message of pain

• Stop cortical reception by electrical stimulation of the sensory cortex or cutting out the cortex

Electrical & Chemical Transmission• Acute pain is a fast transmission process, i.e. the

time from stimulation ‘til the message reaches the brain is short

• Chemical transmission of a message at the synapse is much slower than the electrical transmission along the axon

• Acute pain is a fast pain pathway, with only 2 synapses. You want fast transmission when your hand is In a fire. Pain tells you something is wrong

• Chronic pain is a slow pain pathway with many synapses. It tells you something is still wrong

The Value of Spinal Synapses• Pain information from sensory nerves enters

lamina III and V of the posterior horn of the spinal cord, and synapse there.

• Wide dynamic range neurons modify this information, regulating intensity

• Neuronal plasticity allow pain to continue to exist at a spinal level, even after the source of the original source of the pain is removed

• Crossing pain fibers in the spinal cord help localize the location of the pain

Neurochemical and Anatomical Pathway For Acute Pain-Fast Transmission

(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 synapses lends specificity, and a site to manipulate pain perception

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)-Slow

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

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

Neurochemical and Anatomical Pathway For Chronic Pain

• Palleo-Spino-Thalamic Tract (Chronic Pain)-slow

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, and 95% of biogenic amines exist in the

same area

The Synapse and Neuro-Synaptic Transmitters (NST)

• Pre-synaptic Synapse Post-synaptic• MAO and 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 (as an example, there are 20 subtypes of serotonin receptors)

• Medication can work on the nerve membrane (more non-specific).

• Medication can inhibit natural transmitters by blocking release of transmitters or blocking receptor sites,

• Medication can release transmitters, or block reuptake pre-synaptically, so the transmitter remains on a receptor longer

Psychological FactorsAcute Pain- impacted by psychological statesAcute Pain –is reduced by enkephlins, ACTH, and

endorphins released at time of stress. Chronic Pain- less influenced by psychological

states, but causes depression and anxietyChronic Pain goes through 4 stagesNo psychological change-expecting to get wellSomatic concern and anxiety when not getting wellDepression when realizing that pain is chronicAdjustment to the deficit

Other Factors Influencing Acute Pain• Pain tells a person “something is wrong with your

body”• If the cause of pain is obvious, like your finger in a

fire, you know to withdraw your finger from a fire• But when a blister forms, this can not only

produce pain, but also fear of the unknown• Will the skin fall off? How long will the pain last? • Will the pain spread to my hand? Will this get

infected? Will I lose sensation in the finger? • Fear of the unknown produces anxiety

Psychological Issues of Acute Pain• The “psychological state” of anxiety worsens the

perception of pain • When someone is in an accident, with a serious

injury, the anxiety over the loss of the use of an arm or leg is overwhelming.

• Education about the body, and reducing the “anxiety about the unknown” can be reduced by education of the injured person

• Convert “anxiety” into a realistic “fear” by education about the body,

• Tell the truth. Avoid phony reassurances

Modification of Acute Pain• Assess the type of pain which is present• See the next slide for an overview method• The next slide has only suggestions. It is not a

substitute for clinical judgment on the scene• Tell the patient what you are finding, and what

you think the source of the pain might be• Educate the patient, with drawings of the body• Give the patient odds about outcome—”The

medical literature says about 90% of patients have no residual problems” etc.

Mechanism of Pain• Pain occurs when tissue damage occurs, due to

excessive heat, cold, stretching, pressure, cell disruption from a cut, or chemical irritation

• Different types of pain are caused by damage to the bone, blood vessels, skin, muscle or nerve

• Cellular damage causes the release of a series of inflammatory chemicals

• The chemical irritation creates an electrical discharge from the sensory nerves which then leads to a series of neuronal transmissions to the brain

Damage to Different Tissue Feels Differently• NOTE: Damage to different tissue feels differently• Pain can be constant or intermittent• Damage to nerves feels like a burning pain, or

pins and needles• Damage to bone feels like a deep achy pain• Damage to muscles feels like a cramp or spasm• Damage to blood vessels feels like a throbbing,

pounding pain• Damage to skin feels like a burning, sharp pain• Each type of pain responds to best a different

type of medication

Methods to Assess PainBurning Throbbing Sharp Dull Aching Spasm

Constant This suggest nerve irritation – chemical, metabolic, or viral

This suggest vascular compression-look for the source of the compression

This suggests entrap-ment of sensory nerves in skin

Suggest a compres-sion, tumor, deep bruise, or infection-get bone scan

Deep achy pain suggests bone bruise or fracture get bone scan

This suggest nerve entrapment, or compression look for the source of compression

Intermittent This would be associated with spasm of muscle or blood vessel-treat those sources

This suggest vascular spasm- use medications which reduce spasm like Imitrex

Seen in visceral spasm, such as Crohn’s disease- use anti-spasmotic

Pain only with use- sprain or strain due to damage to tendon or ligament

This suggests inflama-tory process-use non-steroidal anti-inflama-tory drugs

This suggests muscle spasm-use muscle relaxants

Overview of the Nervous SystemOrganization

Efferent -motor autonomicAfferent –sensory

Brain

Spinal Cord

Sympathetic Parasympathetic

Alpha Beta Muscaric Nicotinic

Alpha 1 Alpha 2 Beta 1 Beta 2

MusclesSkin

Systems Associated with Pain• Motor Nerves leave the brain to the spinal cord• They emerge from the spinal cord as nerve roots• The nerve roots then mix in either the brachial or

lumbar plexus, and emerge as mixed motor sensory nerve, with specific names such as the ulnar nerve or sciatic nerve

• As an example, the sciatic nerve has contributions from the L1-L2, L2-L3, L3-L4,L4-L5, and L5-S1 nerve roots, which mix in the lumbar plexus, and create the sciatic nerve, a mixed motor-sensory nerve

• These mixed nerves have motor and sensory fibers

Mixed Motor-Sensory Nerve in Cross-section

The motor fibers come from the brain to the muscle. The sensory nerves come from the skin, muscle and bone, and go to the brain. The sensory fibers are the A beta, A delta and C fibers. The mixed motor-sensory nerve arises after the lumbar or brachial plexus, and is a named nerve, like the ulnar nerve, sciatic nerve or tibial nerve. The sensory nerve fibers carry messages to the brain, and the motor nerve carries message from the brain to the muscle.

Motor nerves have thick myelin, and sensory nerve have less myelin. Both types of nerves are wrapped together in a bundle, which is a mixed motor-sensory nerve. .

Types of Sensory Nerve Fibers • The sensory fibers are sparsely myelinated, or

unmyelinated • The sensory fibers are the A beta, A delta and

C fibers• C fibers are unmyelinated unlike most

other fibers in the nervous system.[1] This lack of myelination is the cause of their slow conduction velocity, which is on the order of no more than 2 m/s.[1] C fibers are on average 0.2-1.5 μm in diameter.[1]

Purves, Dale; et.al (2004). Neuroscience. Massachusetts: Sinauer Associates, Inc

C Fiber Activity• C fibers are considered polymodal because

they can react to various stimuli. They react to stimuli that are thermal, or mechanical, or chemical in nature. C fibers respond to all kinds of physiological changes in the body. For example, they can respond to hypoxia, hypoglycemia, hypo-osmolarity, the presence of muscle metabolic products, and even light or sensitive touch. C fiber receptors include the following functions

Purves, Dale; et.al (2004). Neuroscience. Massachusetts: Sinauer Associates, Inc

Functions of C-Fibers

• C fiber nociceptors– responsible for the second, burning pain

• C fiber warming specific receptors– responsible for warmth

• ultra-slow histamine-selective C fibers– responsible for itch

• tactile C fibers– sensual touch

• C mechano- and metabo- receptors in muscles or joints– responsible for muscle exercise, burn and cramps

A -delta Fiber Activity

• Because of their higher conduction velocity, Aδ fibers are responsible for the sensation of a quick shallow pain that is specific on one area, termed as first pain. They respond to a weaker intensity of stimulus. C fibers respond to stimuli which have stronger intensities and are the ones to account for the slow, but deeper pain, and spread out over an unspecific area

Purves, Dale; et.al (2004). Neuroscience. Massachusetts: Sinauer Associates, Inc

Spinal Connections• C fibers synapse to “second-order

projection neurons” in the spinal cord at the upper laminae of the dorsal horn in the substantia gelatinosa. The second-order projection neurons are of the wide dynamic range (WDR) type, which receive input from both nociceptive terminals as well as myelinated A-type fibers.

• Baron, Ralph (2006). "Mechanisms of Disease: neuropathic pain—a clinical perspective". Nature Clinical Practice Neurology 2.

Spinal Synapses• After repeated stimulation, WDR (wide

dynamic range) neurons, in the substania gelatenosa, experience a general increase in excitability

• C fibers cause central sensitization of the dorsal horn in the spinal cord in response to their hyperactivity.

• Sensitized C fibers release glutamate• Glutamate interacts with the

postsynaptic NMDA receptors, which creates the sensitization of the dorsal horn.

Various lamina of the dorsal hornI-V are sensory laminae. Synapses occur here.

Various nuclei, which are a collection of cell bodies, which give rise to axons

Pain Connections After the Spine• The second-order neurons ascend to

the brain stem and thalamus in the ventrolateral, or anterolateral, quadrant of the contralateral half of the spinal cord, forming the spinothalamic tract. The spinothalamic tract is the main pathway associated with pain and temperature perception, which immediately crosses the spinal cord laterally. This crossover feature is clinically important because it allows for identification of the location of injury.

• Purves, Dale; et.al (2004). Neuroscience. Massachusetts: Sinauer Associates, Inc

Pathway of chronic pain-Spine to Brain • Central sensitization of the dorsal horn neurons that is

evoked from C fiber activity is responsible for temporal summation of “second pain” (TSSP). This event is called ‘windup.’ Windup is associated with chronic pain and central sensitization. Functional MRIs show common areas activated by the TSSP responses which include contralateral thalamus, anterior and posterior insula, mid-anterior cingulate cortex, and supplemental motor areas. TSSP events are also associated with other regions of the brain that process functions such as somatosensory processing, pain perception and modulation, cognition, and pre-motor activity in the cortex.

(1) Staud, Roland; et. al (2007). "Brain activity related to temporal summation of C-fiber evoked pain". Pain (1-2

ed.) 129 (1–2): 130–142.

Activity in the Brain• Pain transmission reaches a variety of cells of

the lamina 1 of the cortex of the brain • There are different cell types in this layer• These varying neurons are responsible for the

different feelings we perceive in our body• They can be classified by their responses to

ranges of stimuli • The brain uses the integration of these signals

to maintain regulation of the body, by positive or negative feedback, like a thermostat