Pain is one of the most commonly occurring of perception in human being. Steps and mechanism involved in pain are discussed here.

1. Submitted to,
Dr. Sreeja P A
Dept. of Pharmacy Practice
Submitted By,
Ameena Kadar K A
Second Sem M Pharm
Dept. of pharmacy practice
Sanjo College Of Pharmaceutical Studies
PAIN
PATHWAYS
ASSIGNMENT

2. PAIN
 Pain is a subjective, unpleasant, sensory, and emotional experience associated with actual
or potential tissue damage or described in terms of such damage.
 It serves biological functions, warning of external danger, e.g. excessive heat or physical
trauma, and internal pathology, e.g. inflammation or blockage of a ureter by a kidney stone,
enabling avoidance or treatment.
 It is inherently self-limiting when the provoking source is removed or cured.
 This indicates that pain is not simply a physical sensation.
 Pain perception also depends on the patient’s emotional reaction to the stimulus.
 TYPES OF PAIN

3.  Acute pain lasts 30 days longer than the usual healing process for that type of injury, and
occurs after muscle strains and tissue injury, such as trauma or surgery. The pain is usually
self-limiting, decreasing with time as the injury heals. It is described as a linear process, with
a beginning and an end. Increased autonomic nervous system activity oft en accompanies
acute pain, causing tachycardia, tachypnea, hypertension, diaphoresis, and mydriasis.
Increased anxiety also may occur.
 Chronic pain is persistent or episodic pain of a duration or intensity that adversely affects
the function or well-being of the patient and can persist after the resolution of an injury.
Some define it as lasting more than 6 months.
a. Chronic nonmalignant pain may be a complication of acute injury in which the
healing process does not occur as expected or may be caused by a disease such as a
rheumatologic disorder (e.g., osteoarthritis, rheumatoid arthritis, fibromyalgia).
 The elderly are more likely to experience chronic pain because of the increased
prevalence of degenerative disorders in this age group.
 The pain is constant, does not improve with time, and is described as a cyclic process
(vicious circle).
 Compared to acute pain, there is no longer autonomic nervous system stimulation, so
the patient may not appear to be in pain. Instead, the patient may be depressed; suffer
insomnia, weight loss, and sexual dysfunction; and may not be able to cope with the
normal activities of daily living, including family and job-related activities.
 Chronic cancer pain occurs in 60% to 90% of patients with cancer. Its characteristics are
similar to those of chronic nonmalignant pain. In addition to depression, prominent
characteristics are fear, anger, and agony. The cause of chronic cancer pain can be related to
the tumor or cancer therapy or can be idiosyncratic. Tumor causes of pain include bone
metastasis, compression of nerve structures, occlusion of blood vessels, obstruction of bowel,
or infiltration of soft tissue.
 Pain threshold and assessment
The patient’s mood, morale and the meaning of the pain for that patient affect their pain
perception. Thus if a patient has chest pain and a relative or close friend has recently had an MI,
the patient may interpret his or her pain as a life-threatening event. This results in the pain

4. threshold being lowered, i.e. anxiety is algesic, resulting in less tolerance of the pain or greater
awareness of it. Conversely, if another friend with a similar pain interprets it as indigestion, or it
is diagnosed as such, this would not be very stressful, the pain threshold would not be lowered,
and the pain may be tolerated. However, this may not be a rational response. Although it is
possible to measure an individual’s pain threshold, e.g. by applying a defined stimulus, usually a
constant heat source at a defined distance and recording the time from application to withdrawal,
this is purely a research tool, e.g. when assessing the effectiveness of a new analgesic or for
comparing analgesics. However, this does not help when assessing a patient’s pain. Further,
attention must always be paid to factors that modulate the pain threshold.
 Factors affecting the pain threshold
 Assessment of pain

5. PATHOPHYSIOLOGY OF PAIN
Gate Theory:
 Various theories have tried to integrate the anatomical pain pathways and the psychological
and neurological components that contribute to the perception of pain.
 The generally accepted model is the ‘gate control theory’.
 This was first proposed by Melzack and Wall in 1965, and has since been modified as
knowledge has increased.
 The theory proposes that neuronal impulses generated by noxious stimuli are modified in the
dorsal horn of the spinal cord by a specialized mechanism (‘gate’), which can tend to either
inhibit or facilitate transmission of the pain impulse from peripheral organs to the brain.
 The gate is not an ‘all-or-none’ mechanism, and a balance between opposing factors
determines how much of the initial nerve impulse is transmitted through it.
 It has been shown recently that the SNC9A gene determines the structure of the
voltage gated sodium channels that are responsible for the transmission of signals along
afferent pain fibers.
 Mutations in the gene may result in an inability to sense pain or excessive pain sensitivity
(hyperalgesia).
 This discovery points the way to a new type of analgesic.
 Pain receptors and fibers
 Two main groups of skin receptors have been identified:
• High-threshold mechanoreceptors (HTMs), which detect local deformation, e.g. touch.
• Polymodal nociceptors, which detect a variety of types of injury (e.g. heat) and noxious
(harmful) stimulation. These do not have a specialized structure and are simply bare
nerve endings in the periphery.
o Stretch receptors also occur in muscles, the wall of the gut and the capsules of internal
organs.
o Three types of nerve fibers are involved in pain transmission.
1. The A-beta fibers are large, myelinated and fast-conducting (30–100 m/s).

6. o They have a low stimulation threshold and respond to light touch.
2. The A-delta fibres are small, lightly myelinated and slower-conducting (5–15 m/s).
o They respond to pressure, heat, chemicals and cooling, and give rise to the sensation of
sharp pain, producing reflex withdrawal and other prompt action.
3. The C fibres are small and unmyelinated and therefore slow-conducting (0.5–2 m/s); they
respond to all types of noxious stimuli and transmit more prolonged, dull pain signals.
o The last two of these types of fibres usually require high-intensity stimuli to trigger a
response.
o According to the gate control theory, A-delta and C fibres transmit pain signals to the
dorsal horns of the spinal cord.
o Impulses in these fibres can be modulated by A-beta activity that can selectively block
impulses from being transmitted to the transmission cells in the substantia gelatinosa of the
spinal cord.
o Such blockage prevents upward transmission to the CNS, and no pain sensation is
perceived.
o This explains why rubbing an injured area, or applying a ‘counter-irritant’ such as
capsaicin, which stimulates the A-beta fibres, can relieve the pain caused by an injury to
that area, which stimulates the smaller C-fibres.
o The gate control mechanism is believed to operate continuously, even in absence of an
apparent trigger, because there is a continuous barrage of impulses from, principally, the
C fibres, whose receptors are continually active and react only slowly to stimuli.
o The effect is to set a threshold below which there is no effector response.
o Action subsequent to stimulation depends on the numbers of fibres involved, their firing
rate, the proportion of large and small fibres, and the effect of central control mechanisms.

7. Gate control theory of the transmission of pain impulses. +, excitation; -, inhibition
MECHANISMS OF PAIN
 Pain sensation involves a series of complex interactions between peripheral nerves and the
central nervous system (CNS). This process is modulated by excitatory and inhibitory
neurotransmitters released in response to stimuli. Such stimuli can be physical,
psychological, or both.
 An example of a physical stimulus is a burn or cut to the skin. In a short time, local reactions
occur in the damaged area that initiate the release of chemical mediators involved in
inflammation. This is followed by sensitization of the nerve endings, which ultimately send
signals to the sensory cortex of the brain.
 Nociception, or the sensation of pain, is composed of four basic processes:
1. Transduction
2. Transmission
3. Modulation
4. Perception.
1. Transduction is the process by which noxious stimuli are translated into electrical signals at
peripheral receptor sites. This begins when nociceptors (free nerve endings located
throughout the skin, muscle, and viscera) are exposed to a sufficient quantity of mechanical,
chemical, or thermal noxious stimuli. In addition, a variety of chemical compounds (e.g.,
histamine, bradykinin, serotonin, prostaglandins and, substance P) are released serially from

8. damaged tissues and can activate or sensitize nociceptors. Serotonin has the additional action
of modulating the peripheral release of primary afferent neuropeptides that are responsible
for neurogenic inflammation. These neuropeptides include substance P, calcitonin gene-
related peptide, and neurokinin A.
2. Transmission involves the propagation of an electrical signal along neural membranes.
Stimuli, such as prostaglandins and inflammatory mediators, change the permeability of the
membrane, producing an influx of sodium and an efflux of potassium, thereby depolarizing
neuronal membranes.
Electrical impulses are transmitted to the spinal cord via two primary afferent nerve
types: myelinated A-fibers and unmyelinated C fibers. The A-delta fiber is responsible for
rapidly conducting electrical impulses associated with thermal and mechanical stimuli to the
dorsal horn of the spinal cord. A-delta fibers release excitatory amino acids, such as
glutamate, which activate α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)
receptors located on dorsal horn neurons. Transmission of signals along these fibers results in
sharp or stabbing sensations that alert the subject to an injury or insult to tissue. CNS input
rapidly produces reflex signals, such as musculoskeletal withdrawal, to prevent further
injury.
The smaller, unmyelinated C-fibers respond to mechanical, thermal, and chemical stimuli
and conduct electrical impulses to the spinal cord at a much slower rate compared with
myelinated A-delta fibers. C-fibers, which also terminate in the dorsal horn, release the
excitatory amino acids, glutamate and aspartate. Unlike A-fibers, C-fibers also release
peptides, such as substance P, neurokinin A, somatostatin, galanin, and calcitonin gene-
related peptide (CGRP). The role of these peptides is not completely understood. Substance P
is known to activate neurokinin-1 receptors, which may play a role in increasing excitability
of spinal cord neurons. Transmission of electrical impulses via C-fibers results in pain that is
dull, aching, burning, and poorly localized or diffuse. This type of pain is known as second
pain because it is perceived after the first pain sensation.
Once dorsal horn receptors are activated, electrical signals are further propagated to the
thalamus, primarily via the spinothalamic tract. From the thalamus, signals are sent to the
cortex and other regions of the brain for processing and interpretation.

9. 3. Modulation of nociceptive information occurs quickly between descending inhibitory
pathways from the thalamus and brainstem and interneurons in the dorsal horn. Neurons from
the thalamus and brainstem release inhibitory neurotransmitters, such as norepinephrine,
serotonin, γ -aminobutyric acid (GABA), glycine, endorphins, and enkephalins, which block
substance P and other excitatory neurotransmitter activity on primary afferent fibers.
4. The conscious awareness, or perception, of pain is the end result of this complex cascade of
actions. The perception of pain involves not only nociceptive processes, but also physiologic
and emotional responses, which contribute significantly to the sensation that is ultimately
experienced by the person. The perception of pain may be influenced by abnormal generation
or processing of electrical pain signals and by the psychological framework created by the
patient’s temporal affective state or from previous painful experiences. Therefore, treatment
that includes drug therapy to alter the nociceptive and physiologic responses, in addition to
cognitive-behavioral strategies (e.g., distraction, relaxation, and imagery) to alter the
psychological response, may be more effective together than if either intervention is used
alone.

10. REFERENCES
1. Pathology and Therapeutics for Pharmacists, A basis for clinical pharmacy practice Third
Edition Russell J Greene, Norman D Harris. Page No: 456-461.
2. Applied Therapeutics: The Clinical Use Of Drugs Ninth Edition, Mary Anne Koda-Kimble,
et.al., Page No: 8.1 – 8.4.