PAIN

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue
damage or described in terms of such damage.

MECHANISM OF PAIN (University question)

The mechanism of nociception involves following five steps:

1. Pain stimulation
2. Transmission
3. Perception
4. Modulation
5. Adaptive inflammation
1. Stimulation
The first step leading to the sensation of pain is stimulation of free nerve endings known as nociceptors.
These receptors are found in both somatic and visceral structures. They distinguish between noxious
and innocuous stimuli.

They are activated and sensitized by mechanical, thermal, and chemical impulses.

The underlying mechanism of these noxious stimuli (which may sensitize/stimulate the receptor) may be
the release of bradykinins, potassium ion (K+), prostaglandins, histamine, leukotrienes, serotonin, and
substance P (among others) that sensitize and/or activate the nociceptors.

Receptor activation leads to action potentials that are transmitted along afferent nerve fibers to the
spinal cord.

2. Transmission
Nociceptive transmission takes place in Aδ and C-afferent nerve fibers. Stimulation of large-diameter,
sparsely myelinated Aδ fibers evokes sharp, well-localized pain, whereas stimulation of unmyelinated,
small-diameter C fibers produces dull, aching, poorly localized pain.

These afferent, nociceptive pain fibers synapse in various layers (laminae) of the spinal cord’s dorsal
horn, releasing a variety of neurotransmitters, including glutamate, substance P, and calcitonin gene–
related peptide.

The complex array of events that influence pain can be explained in part by the interactions between
neuroreceptors and neurotransmitters that take place in this synapse.

These pain-initiated processes reach the brain through a complex array of at least five ascending spinal
cord pathways, which include the spinothalamic tract.

The thalamus acts as a relay station, as these pathways ascend and pass the impulses to central
structures where pain can be processed further.

3. Pain Perception
At this point in transmission, pain is thought to become a conscious experience that takes place when
signals reach higher cortical structures.

The brain may accommodate only a limited number of pain signals, and cognitive and behavioral
functions can modify pain.

Relaxation, distraction, meditation, and guided mental imagery may decrease pain by limiting the
number of processed pain signals.

In contrast, a change in our neurobiochemical makeup that results in states such as depression or
anxiety may worsen pain.

4. Modulation
The body modulates pain through a number of complex processes. One, known as the endogenous
opiate system, consists of neurotransmitters (e.g., enkephalins, dynorphins, and β-endorphins) and
receptors (e.g., μ, δ, and κ) that are found throughout the central nervous system (CNS).

Endogenous opioids bind to opioid receptor sites and modulate the transmission of pain impulses.

Other receptor types also can influence this system. Activation of N-methyl- D-aspartate (NMDA)
receptors, found in the dorsal horn, can decrease the μ-receptors’ responsiveness to opiates.

The CNS also contains a highly organized descending system for control of pain transmission. This
system can inhibit synaptic pain transmission at the dorsal horn and originates in the brain.

Important neurotransmitters here include endogenous opioids, serotonin, norepinephrine, γ-

aminobutyric acid (GABA), and neurotensin.

5. Adaptive Inflammation
Inflammatory pain can be thought of as the body’s shifting from preventing tissue damage to the
promotion of healing (e.g., surgical wounds, traumatic injury).

As a result of the inflammatory process, the pain threshold is reduced and the injured area becomes
more sensitive to pain.

This process decreases our contact with and movement of the injured area, thus promoting the
progression of healing.

When this course of action outlives its functionality or when it is caused by diseases such as arthritis, it
can move from an acute to a chronic problem (maladaptive inflammation). In response to tissue damage
and inflammation, a significant alteration occurs in the chemical composition and properties of the
neurons that innervate the inflamed tissues. These alterations reflect the nature and levels of the
different proteins expressed by the sensory neurons. Altered production of these proteins may modify
the phenotypes of the neurons, changing their transduction and transmission properties.

Inflammatory pain is also associated with an increase in the excitability or responsiveness of neurons
within the CNS, referred to as central sensitization. This phenomenon is a major cause of
hypersensitivity to pain after injury.
PAIN PATHWAYS (University Question)
Ascending pathways of pain
The Primary Afferent Nociceptor
The pain pathway begins with the primary afferent nociceptor. A peripheral nerve is the primary
afferent nociceptor and consists of the axons of three different types of neurons:

1. primary sensory afferent

2. motor neurons
3. sympathetic postganglionic neurons

The primary afferent axon bifurcates to send one process into the spinal cord and the other to
innervate tissues.
The axons of primary afferent nociceptors enter the spinal cord via the dorsal root.
They terminate in the dorsal horn of the spinal gray matter.

The terminals of primary afferent axons contact spinal neurons that transmit the pain signal to
brain sites involved in pain perception.
The axon of each primary afferent contacts many spinal neurons, and each spinal neuron
receives convergent inputs from many primary afferents.
The convergence of sensory inputs to a single spinal pain-transmission neuron is of great
importance because it underlies the phenomenon of referred pain.
A majority of spinal neurons contacted by primary afferent nociceptors send their axons to the
contralateral thalamus.
These axons form the contralateral spinothalamic tract, which lies in the anterolateral white
matter of the spinal cord, the lateral edge of the medulla, and the lateral pons and midbrain.
The spinothalamic pathway is crucial for pain sensation in humans.
Interruption of this pathway produces permanent deficits in pain and temperature
discrimination.

Spinothalamic tract axons ascend to several regions of the thalamus.

There is tremendous divergence of the pain signal from these thalamic sites to broad areas of
the cerebral cortex that subserve different aspects of the pain experience.
One of the thalamic projections is to the somatosensory cortex (SS).
This projection mediates the purely sensory aspects of pain, i.e., its location, intensity, and
quality.
Other thalamic neurons project to cortical regions that are linked to emotional responses, such
as the cingulate (C) gyrus and other areas of the frontal lobes.
These pathways to the frontal cortex subserve the affective or unpleasant emotional dimension
of pain.
This affective dimension of pain produces suffering and exerts potent control of behavior.
Because of this dimension, fear is a constant companion of pain.

Descending pathways of pain

Descending pain modulatory system starts from the brainstem (where the PAG and RVM
reside) to a number of higher level brain areas including; cingulofrontal regions, the
amygdalae and the hypothalamus. This explains the role that emotions and cognition have
in processing nociceptive information.

Underpinning the descending pain modulatory system is theendogenous opioid system and
this system may be activated by a variety of reflex and cognitively trigged states.
At the spinal cord (dorsal horn) level, the opiod system causes inhibition of sub stance P
from peripheral noxious mechanical stimulation via release of noradrenaline from the
dorsalateral PAG (dPAG) and thermal nociceptive stimuli via the release of serotonin from
the ventrolateral PAG (vPAG).
TYPES OF PAIN (University Question)
 1. Acute pain

Acute pain is short-term pain that comes on suddenly and has a specific cause, usually tissue
injury. Generally, it lasts for fewer than six months and goes away once the underlying cause is
treated.

Acute pain tends to start out sharp or intense before gradually improving.

Acute pain can be a useful physiologic process warning individuals of disease states and
potentially harmful situations.
Severe, unremitting, undertreated, acute pain, when it outlives its biologic usefulness, can
produce many deleterious effects (e.g., psychological problems).

Acute pain usually is nociceptive, although it can be neuropathic in nature, with a relatively
strong relationship to levels of pathology.
Common causes of acute pain include surgery, acute illness, trauma, labor, and medical
procedures.

2. Chronic pain

Pain that lasts for more than six months, even after the original injury has healed, is considered
chronic.

Chronic pain can last for years and range from mild to severe on any given day.

This type of pain can be nociceptive, neuropathic/ functional, or both.

Some common examples of chronic pain include:

1. frequent headaches

2. nerve damage pain

3. low back pain

4. arthritis pain

5. fibromyalgia pain
A.Nociceptive pain

Nociceptive pain is the most common type of pain. It’s caused by stimulation of nociceptors,
which are pain receptors for tissue injury.

Nociceptors are present throughout the body, especially in the skin and internal organs. When
they’re stimulated by potential harm, such as a cut or other injury, they send electrical signals
to the brain, causing the perception of pain.

This type of pain is perceived when there is any type of injury or inflammation.

Nociceptive pain can be either acute or chronic.

It can also be further classified as being either visceral or somatic.

Visceral pain

Visceral pain results from injuries or damage to the internal organs. It can be felt it in the trunk
area of the body, which includes the chest, abdomen, and pelvis. It is often hard to pinpoint the
exact location of visceral pain.

Visceral pain is often described as:

• pressure

• aching

• squeezing

• cramping

You may also notice other symptoms such as nausea or vomiting, as well as changes in body
temperature, heart rate, or blood pressure.

Examples of things that cause visceral pain include:

 • gallstones

• appendicitis

• irritable bowel syndrome

Somatic pain

Somatic pain results from stimulation of the pain receptors in the tissues, rather than the
internal organs.

This includes skin, muscles, joints, connective tissues, and bones.

It is often easier to pinpoint the location of somatic pain rather than visceral pain.

Somatic pain usually feels like a constant aching or gnawing sensation.

It can be further classified as either deep or superficial:

For example, a tear in a tendon will cause deep somatic pain, while a canker sore on the inner
check causes superficial somatic pain.

Examples of somatic pain include:

– bone fractures

– strained muscles

– connective tissue diseases, such as osteoporosis

– cancer that affects the skin or bones

– skin cuts, scrapes, and burns

– joint pain, including arthritis pain

B.Neuropathic pain/ Functional pain

Neuropathic pain is a result of nerve damage, whereas functional pain can be thought of as
abnormal operation of the nervous system.

The mechanism responsible for neuropathic and functional pain may be the nervous system’s
endogenous dynamic nature. Nerve damage or certain disease states may evoke changes seen
in inflammatory pain, ectopic excitability, enhanced sensory transmission, nerve structure
reorganization, and loss of modulatory pain inhibition. Pain circuits rewire themselves both
anatomically and biochemically. This produces spontaneous nerve stimulation, autonomic
neuronal pain stimulation, and a progressive increase in the discharge of dorsal horn neurons.
You may also feel pain in response to things that aren’t usually painful, such as cold air or
clothing against your skin.

Examples of neuropathic pain syndromes (e.g., postherpetic neuralgia, diabetic neuropathy)

and functional pain syndromes (e.g., fibromyalgia, irritable bowel syndrome, sympathetic
induced pain, tension-type headaches, and some noncardiac chest pain)

Neuropathic pain is described as:

• burning

• freezing

• numbness

• tingling

• shooting

• stabbing

• electric shocks

Clinically, patients present with spontaneous pain transmission, exaggerated painful response
to normally noxious stimuli (hyperalgesia), and/or painful response to normally nonnoxious
stimuli (allodynia).
 3. Cancer pain

Pain associated with potentially life-threatening conditions is often called malignant pain or
simply cancer pain.

This type of pain includes both chronic and acute components and often has multiple
etiologies.

It is pain caused by the disease itself (e.g., tumor invasion, organ obstruction), treatment (e.g.,
chemotherapy, radiation, surgical incisions), or diagnostic procedures (e.g., biopsy).

MANAGEMENT OF PAIN

Goals of Treatment

Acute pain: pain relief that allows for attainment of defined functional goals

Chronic pain: Improve level of functioning, decrease pain, reduce medication use if possible,
improve quality of life

Cancer pain: pain relief that enables patients to tolerate diagnostic and therapeutic
manipulations, preserves function as much as possible while minimizing adverse effects.

Nonpharmacological therapy

Stimulation Therapy

Transcutaneous electrical nerve stimulation (TENS) has been used in managing both acute and
chronic pain (e.g., surgical, traumatic, low back, arthritis, neuropathy, fibromyalgia, and oral-
facial pain).

Psychological Intervention

Simple interventions (e.g., introductory information about sensations to expect after certain
procedures) reduce patient distress and greatly reduce postprocedure suffering. Other
successful psychological techniques, including relaxation training, imagery, and hypnosis, have
proven effective in the management of postprocedure pain and in cancer-related pain.
Cognitive behavioral therapy and biofeedback also may be useful nonpharmacologic tools in
managing chronic pain.

Acupuncture

Acupuncture involves the insertion of very thin needles through the skin at strategic points on
the body to relieve pain.

Massage therapy

In this therapy, a trained massage therapist manipulates the soft tissues of the body- muscle,
connective tissue, tendons, ligaments and skin using varying degrees of pressure and
movement to relieve pain.

Invasive procedures

This involves procedures such as neurosurgery or neurolytic nerve blocks.

Pharmacologic therapy

This involves the use of analgesic agents to relieve pain

Analgesic ladder

The World Health Organization (WHO) analgesic ladder forms the basis of many approaches to
the use of analgesic drugs. There are essentially three steps: non-opioid analgesics, weak
opioids and strong opioids.
Analgesic drugs

Refer Pharmacotherapy Handbook (Pg no 570) for the following topics:

1. Nonopioid agents
2. Opioid agents: Weak opioids, Strong opioids (Refer miss’ ppt)
3. Coanalgesics

Regional analgesia

Regional analgesia with local anesthetics is useful for both acute and chronic pain.

Anesthetics can be positioned by injection (ie, in the joints, epidural or intrathecal space, nerve
plexus, or along nerve roots) or applied topically.

High plasma concentrations of local anesthetics can cause dizziness, tinnitus, drowsiness,
disorientation, muscle twitching, seizures, and respiratory arrest. Cardiovascular effects include
myocardial depression, heart block, and hypotension.

Skillful technical application, frequent administration, and specialized follow-up are required.

Examples: Procaine, Chloroprocaine, Tetracaine, Lidocaine

 ALGORITHM FOR THE TREATMENT OF ACUTE PAIN

Note: You may refer Pg no 571 in Pharmacotherapy Handbook for the algorithm given below.