Causes of Pain

13Guide to Pain Management in Low-Resource Settings, edited by Andreas Kopf and Nilesh B. Patel. IASP, Seattle, © 2010. All rights reserved. Th is material may be used for educational and training purposes with proper citation of the source. Not for sale or commercial use. No responsibility is assumed by IASP for any injury and/or damage to persons or property as a matter of product liability, negligence, or from any use of any methods, products, instruction, or ideas contained in the material herein. Because of the rapid advances in the medical sciences, the publisher recommends that there should be independent verifi cation of diagnoses and drug dosages. Th e mention of specifi c pharmaceutical products and any medical procedure does not imply endorsement or recommendation by the editors, authors, or IASP in favor of other medical products or procedures that are not covered in the text.

Guide to Pain Management in Low-Resource Settings

Nilesh B. Patel

Chapter 3

Physiology of Pain

Pain is not only an unpleasant sensation, but a complex

sensory modality essential for survival. Th ere are rare

cases of people with no pain sensation. An often-cited

case is that of F.C., who did not exhibit a normal pain

response to tissue damage. She repeatedly bit the tip of

her tongue, burned herself, did not turn over in bed or

shift her weight while standing, and showed a lack of

autonomic response to painful stimuli. She died at the

age of 29.

Th e nervous system mechanism for detection of

stimuli that have the potential to cause tissue damage is

very important for triggering behavioral processes that

protect against current or further tissue damage. Th is is

done by refl ex reaction and also by preemptive actions

against stimuli that can lead to tissue damage such as

strong mechanical forces, temperature extremes, oxy-

gen deprivation, and exposure to certain chemicals.

Th is chapter will cover the neuronal recep-

tors that respond to various painful stimuli, substances

that stimulate nociceptors, the nerve pathways, and the

modulation of the perception of pain. Th e term nocicep-

tion (Latin nocere, “to hurt”) refers to the sensory pro-

cess that is triggered, and pain refers to the perception

of a feeling or sensation which the person calls pain,

and describes variably as irritating, sore, stinging, ach-

ing, throbbing, or unbearable. Th ese two aspects, noci-

ception and pain, are separate and, as will be described

when discussing the modulation of pain, a person with

tissue damage that should produce painful sensations

may show no behavior indicating pain. Nociception can

lead to pain, which can come and go, and a person can

have pain sensation without obvious nociceptive activi-

ty. Th ese aspects are covered in the IASP defi nition: “An

unpleasant sensory and emotional experience associ-

ated with actual or potential tissue damage, or described

in terms of such damage.”

Physiology of pain

Nociceptors and the transduction of painful stimuli

Th e nervous system for nociception that alerts the

brain to noxious sensory stimuli is separate from the

nervous system that informs the brain of innocuous

sensory stimuli.

Nociceptors are unspecialized, free, unmyelin-

ated nerve endings that convert (transduce) a variety of

stimuli into nerve impulses, which the brain interprets

to produce the sensation of pain. Th e nerve cell bodies

are located in the dorsal root ganglia, or for the trigemi-

nal nerve in the trigeminal ganglia, and they send one

nerve fi ber branch to the periphery and another into the

spinal cord or brainstem.

Th e classifi cation of the nociceptor is based on

the classifi cation of the nerve fi ber of which it is the ter-

minal end. Th ere are two types of nerve fi bers: (1) small-

diameter, unmyelinated nerves that conduct the nerve

impulse slowly (2 m/sec = 7.2 km/h), termed C fi bers,

14 Nilesh B. Patel

and (2) larger diameter, lightly myelinated nerves that

conduct nerve impulses faster (20 m/sec = 72 km/h)

termed Aδ fi bers. Th e C-fi ber nociceptors respond poly-

modally to thermal, mechanical, and chemical stimuli;

and the Aδ-fi ber nociceptors are of two types and re-

spond to mechanical and mechanothermal stimuli. It

is well known that the sensation of pain is made up of

two categories—an initial fast, sharp (“epicritic”) pain

and a later slow, dull, long lasting (“protopathic”) pain.

Th is pattern is explained by the diff erence in the speed

of propagation of nerve impulses in the two nerve fi ber

types described above. Th e neuronal impulses in fast-

conducting Aδ-fi ber nociceptors produce the sensation

of the sharp, fast pain, while the slower C-fi ber nocicep-

tors produce the sensation of the delayed, dull pain.

Peripheral activation of the nociceptors (trans-

duction) is modulated by a number of chemical sub-

stances, which are produced or released when there is

cellular damage (Table 1). Th ese mediators infl uence the

degree of nerve activity and, hence, the intensity of the

pain sensation. Repeated stimulation typically causes

sensitization of peripheral nerve fi bers, causing lower-

ing of pain thresholds and spontaneous pain, a mecha-

nism that can be experienced as cutaneous hypersensi-

tivity, e.g., in skin areas with sunburn.

Hypersensitivity may be diagnosed by taking

history and by careful examination. Certain conditions

may be discriminated:

a) Allodynia: Pain due to a stimulus that does not

normally provoke pain, e.g., pain caused by a T-shirt in

patients with postherpetic neuralgia.

b) Dysesthesia: An unpleasant abnormal sensation,

whether spontaneous or evoked. (Note: a dysesthesia

should always be unpleasant, while paresthesia should

not be unpleasant; e.g., in patients with diabetic poly-

neuropathy or vitamin B 1 defi ciency.)

c) Hyperalgesia: An increased response to a stimu-

lus that is normally painful. (Note: hyperalgesia refl ects

increased pain on suprathreshold stimulation; e.g., in

patients with neuropathies as a consequence of pertur-

bation of the nociceptive system with peripheral and/or

central sensitization.)

d) Hyperesthesia: Increased sensitivity to stimula-

tion, excluding the special senses, e.g., increased cuta-

neous sensibility to thermal sensation without pain.

With the knowledge of pain pathways and sen-

sitization mechanisms, therapeutic strategies to inter-

act specifi cally with the pain generation mechanisms

can be developed.

Central pain pathways

Th e spinothalamic pathway and the trigeminal pathway

are the major nerve routes for the transmission of pain

and normal temperature information from the body and

face to the brain. Visceral organs have only C-fi ber noci-

ceptive nerves, and thus there is no refl ex action due to

visceral organ pain.

Th e spinothalamic pathway

The nerve fibers from the dorsal root ganglia en-

ter the spinal cord through the dorsal root and send

branches 1–2 segments up and down the spinal cord

In addition, local release of chemicals such

substance P causes vasodilation and swelling as well

as release of histamine from the mast cells, further in-

creasing vasodilation. Th is complex chemical signaling

protects the injured area by producing behaviors that

keep that area away from mechanical or other stimuli.

Promotion of healing and protection against infection

are aided by the increased blood fl ow and infl ammation

(the “protective function of pain”).

Fig. 1. Some chemicals released by tissue damage that stimulates nociceptors. In addition release of substance-P, along with hista- mine, produce vasodilation and swelling.

Skin

Released by tissue damage: Bradykinin K+ Prostaglandins

Histamine

C fibers

Aδ fibers

To spinal cordInjury

Mast Cell

Table 1

Selected chemical substances released with stimuli

suffi cient to cause tissue damage

Substance Source

Potassium Damaged cells

Serotonin Platelets

Bradykinin Plasma

Histamine Mast cells

Prostaglandins Damaged cells

Leukotrienes Damaged cells

Substance P Primary nerve aff erents

Physiology of Pain 15

(dorsolateral tract of Lissauer) before entering the spi-

nal gray matter, where they make contacts with (inner-

vate) the nerve cells in Rexed lamina I (marginal zone)

and lamina II (substantia gelatinosa). Th e Aδ fi bers in-

nervate the cells in the marginal zone, and the C fi bers

innervate mainly the cells in the substantia gelatinosa

layer of the spinal cord. Th ese nerve cells, in turn, in-

nervate the cells in the nucleus proprius, another area

of the spinal cord gray matter (Rexed layers IV, V, and

VI), which send nerve fi bers across the spinal midline

and ascend (in the anterolateral or ventrolateral part of

the spinal white matter) through the medulla and pons

and innervate nerve cells located in specifi c areas of

the thalamus. Th is makes up the spinothalamic path-

way for the transmission of information on pain and

normal thermal stimuli (<45°C). Dysfunctions in the

thalamic pathways may themselves be a source of pain,

as is observed in patients after stroke with central pain

(“thalamic pain”) in the area of paralysis.

Th e trigeminal pathway

Noxious stimuli from the face area are transmitted in

the nerve fi bers originating from the nerve cells in the

trigeminal ganglion as well as cranial nuclei VII, IX, and

X. Th e nerve fi bers enter the brainstem and descend to

the medulla, where they innervate a subdivision of the

trigeminal nuclear complex. From here the nerve fi bers

from these cells cross the neural midline and ascend to

innervate the thalamic nerve cells on the contralateral

side. Spontaneous fi ring of the trigeminal nerve gan-

glion may be the etiology of “trigeminal neuralgia” (al-

though most of the time, local trigeminal nerve dam-

age by mechanical lesion through a cerebellar artery is

found to be the cause, as seen by the positive results of

Janetta’s trigeminal decompression surgery).

Th e area of the thalamus that receives the pain

information from the spinal cord and trigeminal nuclei

is also the area that receives information about nor-

mal sensory stimuli such as touch and pressure. From

this area, nerve fi bers are sent to the surface layer of the

brain (cortical areas that deal with sensory informa-

tion). Th us, by having both the nociceptive and the nor-

mal somatic sensory information converge on the same

cortical area, information on the location and the in-

tensity of the pain can be processed to become a “local-

ized painful feeling.” Th is cortical representation of the

body—as described in Penfi eld’s homunculus—may also

be a source of pain. In certain situations, e.g., after limb

amputations, cortical representation may change, caus-

ing painful sensations (“phantom pain”) and nonpainful

sensations (e.g., “telescoping phenomena”).

Appreciating the complexity of the pain path-

way can contribute to understanding the diffi culty in as-

sessing the origin of pain in a patient and in providing

pain relief, especially in chronic pain.

Pathophysiology of pain

Pain sensations could arise due to:

1) Infl ammation of the nerves, e.g., temporal neuritis.

2) Injury to the nerves and nerve endings with scar

formation, e.g., surgical damage or disk prolapse.

3) Nerve invasion by cancer, e.g., brachial plexopathy.

4) Injury to the structures in the spinal cord, thala-

mus, or cortical areas that process pain information,

which can lead to intractable pain; deaff erentation, e.g.,

spinal trauma.

5) Abnormal activity in the nerve circuits that is

perceived as pain, e.g., phantom pain with cortical re-

organization.

Modulation of the perception of pain

It is well known that there is a diff erence between the

objective reality of a painful stimulus and the subjec-

tive response to it. During World War II, Beecher, an

anesthesiologist, and his colleagues carried out the

fi rst systematic study of this eff ect. Th ey found that

soldiers suff ering from severe battle wounds often ex-

perienced little or no pain. Th is dissociation between

injury and pain has also been noted in other circum-

stances such as sporting events and is attributed to the

eff ect of the context within which the injury occurs.

Th e existence of dissociation implies that there is a

mechanism in the body that modulates pain percep-

tion. Th is endogenous mechanism of pain modulation

is thought to provide the advantage of increased sur-

vival in all species (Überlebensvorteil).

Th ree important mechanisms have been de-

scribed: segmental inhibition, the endogenous opioid

system, and the descending inhibitory nerve system.

Moreover, cognitive and other coping strategies may

also play a major role in pain perception, as described in

other chapters in this guide.

Segmental inhibition

In 1965, Melzack and Wall proposed the “gate theory

of pain control,” which has been modifi ed subsequently

16 Nilesh B. Patel

but which in essence remains valid. Th e theory propos-

es that the transmission of information across the point

of contact (synapse) between the Aδ and C nerve fi bers

(which bring noxious information from the periphery)

and the cells in the dorsal horn of the spinal cord can

be diminished or blocked. Hence, the perception of the

painfulness of the stimulus either is diminished or is not

felt at all. Th e development of transcutaneous electrical

nerve stimulation (TENS) was the clinical consequence

of this phenomenon.

Th e transmission of the nerve impulse across

the synapse can be described as follows: Th e activation

of the large myelinated nerve fi bers (Aβ fi bers) is associ-

ated with the low-threshold mechanoreceptors such as

touch, which stimulate an inhibitory nerve in the spinal

cord that inhibits the synaptic transmission. Th is is a

possible explanation of why rubbing an injured area re-

duces the pain sensation (Fig. 2).

system of internal pain modulation and the subjective

variability of pain.

Descending inhibitory nerve system

Nerve activity in descending nerves from certain brain-

stem areas (periaqueductal gray matter, rostral me-

dulla) can control the ascent of nociceptive informa-

tion to the brain. Serotonin and norepinephrine are the

main transmitters of this pathway, which can therefore

be modulated pharmacologically. Selective serotonin

reuptake inhibitors (SSRIs) and tricyclic antidepressants

(e.g., amitriptyline) may therefore have analgesic prop-

erties (Fig. 3).

Endogenous opioid system

Besides the gating of transmission of noxious stimuli,

another system modulates pain perception. Since 4000

BCE, it has been known that opium and its derivatives

such as morphine, codeine, and heroin are powerful

analgesics, and they remain the mainstay of pain relief

therapy today. In the 1960s and 1970s, receptors for the

opium derivatives were found, especially in the nerve

cells of the periaqueductal gray matter and the ventral

medulla, as well as in the spinal cord. Th is fi nding im-

plied that chemicals must be produced by the nervous

system that are the natural ligands of these receptors.

Th ree groups of endogenous compounds (enkephalins,

endorphins, and dynorphin) have been discovered that

bind to the opioid receptors and are referred to as the

endogenous opioid system. Th e presence of this system

and the descending pain modulation system (adrener-

gic and serotoninergic) provides an explanation for the

Referred pain

Visceral organs do not have any Aδ nerve innervation,

but the C fi bers carrying the pain information from the

visceral organs converge on the same area of the spinal

cord (substantia gelatinosa) where somatic nerve fi bers

from the periphery converge, and the brain localizes the

pain sensation as if it were originating from that somatic

peripheral area instead of the visceral organ. Th us, pain

from internal organs is perceived at a location that is

not the source of the pain; such pain is referred pain.

Spinal autonomic refl ex

Often the pain information from the visceral organs

activates nerves that cause contraction of the skeletal

muscles and vasodilation of cutaneous blood vessels,

producing reddening of that area of the body surface.

C fiber (nociceptive signals)

Projection neuron (nociceptive signal)

Spinothalamic tract Inhibitory interneuron

Aα and Aβ (mechanoceptors)

SPINAL CORD

+

+ −

Fig. 2. Th e gate control theory of Pain (Melzack and Wall). + excitatory synapse; – inhibitory synapse

Cerebral Cortex

Thalamus

Midbrain Brain Stem

PAG

Raphe nucleus Locus ceruleusSpinal Cord

Aδ & C nociceptive fibers

Fig. 3. Ascending (solid lines) and descending pain pathways. Th e raphe nucleus and locus ceruleus provide serotoninergic (5-HT) and adrenergic modulation. PAG = periaqueductal gray matter, part of the endogenous opioid system.

Physiology of Pain 17

Conclusion

Chemical or mechanical stimuli that activate the noci-

ceptors result in nerve signals that are perceived as pain

by the brain. Research and understanding of the basic

mechanism of nociception and pain perceptions pro-

vides a rationale for therapeutic interventions and po-

tential new targets for drug development.

References

[1] Westmoreland BE, Benarroch EE, Daude JR, Reagan TJ, Sandok BA. Medical neuroscience: an approach to anatomy, pathology, and physiol- ogy by systems and levels. 3rd ed. Boston: Little, Brown and Co.; 1994. p. 146–54.

[2] Bear MF, Connors BW, Paradiso. Neuroscience: exploring the brain. 2nd ed. Lippincott Williams & Wilkins; 2001. p. 422–32.

[3] Melzack R, Wall P. Th e challenge of pain. New York: Basic Books; 1983.