PAIN PATHWAY

DR.BHAKTRAJ SINGH

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 Pain
“An unpleasant sensory and emotional sensation associated
with actual or potential tissue damage or described in terms of
such damage”. Pain is always subjective.
NOCICEPTIVE – Chemical or physical stimulation of nerve
endings
•Nociceptive pain is opioid responsive
NEUROPATHIC – Arises from disturbances in neural pathways
and is often resistant to opioids and other analgesics

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 Assessment of pain

• Chronicity
• Severity
• Quality
• Contributing/associated factors
• Location/distribution or etiology of pain, if identifiable
• Mechanism of injury, if applicable
• Barriers to pain assessment

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Pain perception, or nociception (from the Latin word for
"hurt"), is the process by which a painful stimulus is relayed
from the site of stimulation to the central nervous system.
There are several steps in the nociception process:
 Contact with stimulus -- Stimuli can be mechanical
(pressure, punctures and cuts) or chemical (burns).
 Reception -- A nerve ending senses the stimulus.
 Transmission -- A nerve sends the signal to the central
nervous system. The relay of information usually involves
several neurons within the central nervous system.
 Pain center reception -- The brain receives the
information for further processing and action.
Pain Signal Reception
Like normal sensory neurons, nociceptor neurons travel in
peripheral sensory nerves. Their cell bodies lie in the
dorsal root ganglia of peripheral nerves just inside the
spine. Nociceptors sense pain through free nerve endings
rather than specialized endings such as those in neurons
that sense touch or pressure. However, while normal
sensory neurons are myelinated (insulated) and conduct
quickly, nociceptor neurons are lightly or non-myelinated
and slower. We can divide nociceptors into three classes:

• A δ mechanothermal receptors -- lightly myelinated,

faster conducting neurons that respond to mechanical
stimuli (pressure, touch) and to heat

• Polymodal nociceptors (C fibers) -- unmyelinated,

When you cut your hand. Several factors
contribute to the reception of pain: Neuron Reactions

• Mechanical stimulation from the sharp

object
• Potassium released from the insides of
the damaged cells
• Prostaglandins, histamines and
bradykinin from immune cells will
invade the area during inflammation
• Substance P from near by sensory
nerve fibers. These substances cause
action potentials in the nociceptor
neurons.
The signal for this pain is conducted rapidly by the A δ-type nociceptors. The
pain is followed by a slower, prolonged, dull ache, which is conducted by the
slower C-fibers. The three primary neurotransmitters that "ship" pain signals
to the brain are substance P, NMDA (n-methyl-d-aspartate), and glutamate.
Pain Signal
Transmission Pain Signal Transmission

The signals from your cut

hand travel into the spinal
cord through the dorsal
roots. There, they make
synapses on neurons
within the dorsal horn (the
top half of the butterfly-

shaped gray matter).

NEUROMODULATION
Ascending Pain Pathway
The secondary neurons send their signals upward through an
area of the spinal cord's white matter called the spinothalamic
tract. This area is like a superhighway where traffic from all of the
lower segments rides up the spinal cord. The signals of the
spinothalamic tract travel up the spinal cord through the medulla
(brain stem) and synapse on neurons in the thalamus, the brain's
relay center. Some neurons also synapse in the medulla's reticular
formation, which controls physical behaviors.
Nerves from the thalamus then relay the signal to various areas of
the brain's somatosensory cortex -- there is no single pain center
in the brain.
• As the ascending pain pathways travel through the
spinal cord and medulla, they can also be set off by
neuropathic pain -- damage to peripheral nerves,
spinal cord or the brain itself. However, the extent of
the damage may limit the reaction of the brain's
descending pathways. The influences of the
descending pathways might also be responsible for
psychogenic pain (pain perception with no obvious
physical cause).
 Pathway

Pain Pathway
Once the pain information is in
the brain, signals go to the motor
cortex, then down through the
spinal cord and to the motor
nerves. These impulses would
cause muscle contractions to
move your hand out of the way
of whatever is causing the pain.
• These descending pathways originate in the somatosensory
cortex (which relays to the thalamus) and the hypothalamus.
Thalamic neurons descend to the midbrain. There, they
synapse on ascending pathways in the medulla and spinal
cord and inhibit ascending nerve signals.
• This produces pain relief (analgesia). Some of this relief
comes from the stimulation of natural pain-relieving opiate
neurotransmitters called endorphins, dynorphins and
enkephalins.
• Pain signals can set off autonomic nervous system pathways
as they pass through the medulla, causing increased heart
rate and blood pressure, rapid breathing and sweating. The
extent of these reactions depends upon the intensity of pain,
and they can be depressed by brain centers in the cortex
through various descending pathways.
Thoughts, emotions and "circuitry" can affect both ascending and descending
pain pathways. So, several factors, physiological and psychological, can
influence pain perception:

Age -- Brain circuitry generally degenerates with age, so older people have
lower pain thresholds and have more problems dealing with pain.

Gender -- Research shows that women have a higher sensitivity to pain than
men do. This could be because of sex-linked genetic traits and hormonal
changes that might alter the pain perception system. Psychosocial factors
could be at work, too -- men are expected not to show or report their pain.

Fatigue -- We often experience more pain when our body is stressed from lack
of sleep.

Memory -- How we have experienced pain in the past can influence neural
 Gate Control Theory

Gate Control Theory of Pain

To explain why thoughts and

emotions influence pain
perception, Ronald Melzack and
Patrick Wall proposed that a
gating mechanism exists within
the dorsal horn of the spinal
cord. Small nerve fibers (pain
receptors) and large nerve
fibers ("normal" receptors)
synapse on projection cells
(P), which go up the
spinothalamic tract to the brain,
and inhibitory interneurons (I)
within the dorsal horn.
The interplay among these connections determines when
painful stimuli go to the brain:

• When no input comes in, the inhibitory neuron prevents the

projection neuron from sending signals to the brain (gate is
closed).

• Normal somatosensory input happens when there is more

large-fiber stimulation (or only large-fiber stimulation). Both
the inhibitory neuron and the projection neuron are
stimulated, but the inhibitory neuron prevents the projection
neuron from sending signals to the brain (gate is closed).
• Nociception (pain reception) happens when there is more
small-fiber stimulation or only small-fiber stimulation. This
inactivates the inhibitory neuron, and the projection neuron
sends signals to the brain informing it of pain (gate is open).
• Descending pathways from the brain close the gate by
inhibiting the projector neurons and diminishing pain
perception.
Types of Pain
• Physicians and neuroscientists generally classify pain in the
following ways:
• Acute pain is caused by an injury to the body. It warns of
potential damage that requires action by the brain, and it can
develop slowly or quickly. It can last for a few minutes to six
months and goes away when the injury heals.
• Chronic pain persists long after the trauma has healed (and
in some cases, it occurs in the absence of any trauma).
Chronic pain does not warn the body to respond, and it
usually lasts longer than six months.
• Cancer (or malignant) pain is associated with malignant
tumors. Tumors invade healthy tissues and exert pressure
on nerves or blood vessels, producing pain. Cancer pain can
also be associated with invasive procedures or treatments.
Some physicians classify cancer pain with chronic pain.
• Pain Information from the Face
• Your face has its own mini spinal-cord system called the
trigeminal nerve.
• Somatosensory neurons (and pain receptors all over the face
and head) travel into the central nervous system through the
trigeminal nerve.
• They synapse in the trigeminal nucleus (group of neurons) in
the mid-medulla and also on neurons in the lower medulla. Then
these neurons send signals through the tregeminal-thalamic
tract within the midbrain to the thalamus. Neurons in the
thalamus relay signals to the somatosensory cortex and limbic
system.
• Congenital Analgesia: Congenital analgesia is a rare genetic
disorder where the individual is unable to feel pain. You might think
this sounds like a good thing, but it's actually a life-threatening
condition. Pain serves as a warning against injury, so people
who don't feel it can be severly injured hurt by things that most of
us would react quickly to. For example, Ronald Melzack and
Patrick Wall describe a girl who got third-degree burns on her
knees by climbing on a hot radiator. There was no signal for her to
stop. Researchers are trying to reproduce this condition by
genetically altering mice so that they can study the genetic
contributions to pain perception.
• Pain Management
• Physicians treat pain in numerous ways. Pain
management can include medications, surgery,
alternative procedures (like hypnosis, acupuncture,
massage therapy and biofeedback) or combinations of
these approaches.
• Different types of pain medications act at different places in
the pain pathways. The type of medication depends upon
the source of the pain, the level of discomfort and possible
side effects.
• Non-opioid analgesics, like aspirin, acetaminophen
(Tylenol), ibuprofen (Advil), and naproxen (Aleve), act at the
site of pain. The damaged tissue releases enzymes that
stimulate local pain receptors. Non-opioid analgesics
interfere with the enzymes and reduce inflammation and
pain. They can have some adverse effects in the liver and
kidneys and can cause gastrointestinal discomfort and
bleeding with prolonged use.
• Opioid analgesics act on synaptic transmission in various

parts of the central nervous system by binding to natural

opioid receptors. They inhibit ascending pathways of pain

perception and activate descending pathways. Opioid

analgesics are used for higher levels of pain relief -- they

include morphine, meripidine (Demerol), propoxyphene

(Darvon), fentanyl, oxycodone (OxyContin) and codeine.

They can be easily overdosed and become addictive.

• Adjuvant analgesics (co-analgesics) are primarily used for
treating some other condition, but they also relieve pain.
These compounds are useful in treating neuropathic pain
(chronic pain that comes from injury to the central nervous
system). They include the following:
• Anti-epileptic drugs reduce membrane excitability and
action potential conduction in neurons of the central
nervous system.
• Tricyclic antidepressants affect synaptic transmission of
serotonin and norepinephrine neurons in the central
nervous system, thereby affecting pain-modulating
pathways.
• Anesthetics block action potential transmission by
interfering with sodium and potassium channels in nerve
cell membranes. Examples include lidocaine, novocaine
and benzocaine.
• Surgery
In extreme cases, surgeons may have to sever pain pathways
by altering areas of the brain associated with pain perception --
or performing a rhizotomy (which destroys portions of
peripheral nerves) or a chordotomy (destroys ascending tracts
in the spinal cord). These surgeries are usually a last resort.
• Surgical interventions can be aimed at eradicating the source
of the pain. For example, many people suffer back pain from
herniated disks between the vertebrae. An inflamed disc can
compress a nerve and cause neuropathic pain. If the patient
does not respond to medication, a surgeon might try to remove
at least part of the disc and relieve pressure on the nerve.
AlternativeTherapy
These approaches do not involve drugs or surgery.
• Chiropracty manipulates joints to relieve
compression of nerves.
• Massage stimulates blood flow, relieves muscle
spasms and increases somatosensory
information, which can relieve pain through the
gate control theory
• Hot applications increase blood flow, and cold
applications reduce inflammation, which
contributes to pain.
• Stimulation of the skin with small electrodes can
close the gate to pain.
• Acupuncture may stimulate nerve cells and release
endorphins. The increased stimulation might also
close the gate to pain.
• Mental control techniques rely on the ability of the
mind and emotions to control and alleviate pain
through descending neural pathways. They include
relaxation techniques, hypnosis, biofeedback and
distraction techniques.
• Pain-management plans involve the participation of
doctors, patients, family members and other
caregivers. As with any medical treatment, the source
ofpain, pain tolerance, and the potential benefits and
risks of treatmen must be considered.
 TREATMENT
NONPHARMACOLOGIC THERAPY
Stimulation Therapy:
1.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).
2.Massage stimulates blood flow, relieves muscle spasms and
increases somatosensory information, which can relieve pain
through the gate control theory.
3.Hot applications increase blood flow, and cold applications
reduce inflammation, which contributes to pain.
Visual analogue scale

Describe your pain on a scale of 0 to 10

NO PAIN MILD MODERATE SEVERE WORST POSSIBLE

0 1 2 3 4 5 6 7 8 9 10
Depending on the severity of the pain, start management at the
corresponding step.

For mild pain (1–3/10 on a numerical analogue scale), start at step 1

.
For moderate pain (4–6/10), start at step 2.

For severe pain (7–10/10), start at step 3.

Non-opioid Agents
Acetaminophen, acetylsalicylic acid(aspirin), and NSAIDs often
are preferred over opiates in the treatment of mild-to-moderate
pain.

These drugs (with the exception of acetaminophen) prevent

formation of prostaglandins produced in response to noxious
stimuli, thereby decreasing the number of pain impulses received
by the CNS.

NSAIDs may be particularly useful in the management of cancer-

related bone pain.

Switch to another NSAID because of large interpatient variability

with these drugs.
• Non-narcotic analgesics are drugs that have
principally analgesic, antipyretic and anti
inflammatory action.
• Acetaminophen NSAID’s provide effective relief of
many types of acute and persistent pain.
• These agents can relieve many types of mild,
moderate pain.
• Alternatively, for moderate to severe pain they can be
used in combination with opioid drugs to enhance
pain relief.
COX-2 SPECIFIC DRUGS:

Cyclooxygenase exists in two forms COX-1 and COX-2

COX-1 is a constitutive enzyme that exist in normal conditions in a variety of

tissues where it catalyses the formation of essential prostaglandins.

It does not have a role in nociceptior inflammation.

COX-2 Is an inducible enzyme that appears in damaged tissues shortly after

injury & leads to the formation of inflammatory prostaglandins with in these
tissues

COX-2 specific NSAIDS should inhibit the formation of inflammatory

prostaglandins with out affecting the activity of COX-1.

The use of COX-2 specific drugs is associated with reduced risk of gastro
intestinal side effects when compared with non selective drugs.

How ever their use has also linked with adverse effects such as cardio
toxicity and this is now limiting their use.
Class and Generic Usual Dosage Range (mg) Side effects
Name
Salicylates GI irritation and bleeding
Acetylsalicylic 325–1,000 every 4–6 h
acid—aspirin
para- Decreases platelet
Aminophenol aggregation
Acetaminophen 325–1,000 every 4–6 h

Fenamates Na Retention

Meclofenamate 50–100 every 4–6 h

Mefenamic acid Initial 500

250 every 6 h (maximum 7 days)

Pyranocarboxylic Renal insufficiency

acid
Etodolac 200–400 every 6–8 h
 Class and Generic Name Usual Dosage Range (mg Side effects
Acetic acid In some patients, initial 100, hepatotoxicoty
50 three times per day
Diclofenac potassium
Propionic acids asthma
Ibuprofen 200–400 every 4–6 h
Fenoprofen 200 every 4–6 h
Ketoprofen 25–50 every 6–8 h
Naproxen 500 initial
500 every 12 h or
250 every 6–8 h
Naproxen sodium In some patients, 440 initial
220 every 8–12 h
Pyrrolizine carboxylic acid 30–60 hyperuricamia
Ketorolac—parenteral (single IM dose only)
15–30
(single IV dose only
Ketorolac—oral, indicated for 10 every 4–6 h (maximum of Reye’s syndrome
continuation with parenteral 5 days, which includes
only (various) parenteral doses)
In some patients, initial oral
dose of 20
Opioids
• Opioid consisting of three receptors (α,δ,κ).
• All the three type of opioid receptors are G protein coupled
receptors.
• Opioid receptor activation reduces intracellular cAMP
formation ,opens K+ channel, and suppresses voltage gated
ca2+ channels.
• These action results in neuronal hyperpolarisation and reduced
availability of intracellular calcium this result in decreased
neurotransmitter release.
 Opioid receptor actions

α δ κ

Action Analgesia Analgesia Analgesia

Endogenous Endomorphins1&2 Leu/Met Dynorphin A&B

agonists B-endorphin enkephalins

Exogenous morphine morphine Ketocyclazocine

agonists

Selective antagonists for α: FUNALTREXAMINE,

nalaxanazone
For δ Naltrindole
For κ Norbinaltorphimine
Opioid Agents Doses indication
Morphine PO 5–30 mg q 3-4h Drug of choice in severe pain
IM 5–10 mg q 3–4 h Use immediate-release
IV 1–2.5 mg q 5 min prn product with SR product to
SR 15–30 mg q 12 h (may control “breakthrough” pain
need to be q 8 h in some in cancer patients Every-24-
patients hour product available
Rectal 10–20 mg q 4 h

Hydromorphone PO 2–4 mg q 3–6 h Use in severe pain More

IM 1–4 mg q 3–6 h potent than morphine;
IV 0.1–0.5 mg q 5 min otherwise, no advantages
Rectal 3 mg q 6–8 h

Oxymorphone IM 1–1.5 mg q 4–6 h Use in severe pain No

IV 0.5 mg initially advantages over morphine
PO immediate release 5–10 Use immediate-release
mg q 4–6 h product with controlled-
PO extended release 10–20 release product to controles
mg q 12 h breakthrough” pain in cancer
Rectal 5 mg q 4–6 h a or chronic pain patients
Levorphanol PO 2–3 mg q 6–8 h Use in severe pain
PO 2–3 mg q 3–6 h Extended half-life useful In
IM 1–2 mg q 6–8 h chronic pain, wait 3 days
IV 1 mg q 3–6 h a between dosage
adjustments in cancer
patients

Codeine PO 15–60 mg q 4–6 h Use in moderate pain

IM 15–60 mg q 4–6 h Weak analgesic; use with
NSAIDs, aspirin, or
acetaminophen
Hydrocodone PO 5–10 mg q 4–6 h Use in moderate/severe
pain
Most effective when used
with NSAIDs, aspirin, or
acetaminophen
Only available as
combination product with
other ingredients for pain
and/or cough

Oxycodone PO 5–10 mg q 4–6 h Use in moderate/severe

Controlled release 10–20 pain
mg q 12 h Most effective when used
Fentanyl IV 25–50 mcg/h Used in severe pain
IM 50–100 mcg q 1–2 Do not use
h transdermal in acute
Transdermal 25 pain
mcg/h q 72 h

Methadone PO 2.5–10 mg q 3–4 h Severe pain, chronic

IM 2.5–10 mg q 8–12 pain,pain does not
h respond to others
PO 5–20 mg q 6–8 h drugs, opioid
addiction

Meperidine IM 50–150 mg q 3–4 Use in severe pain

h Oral not
IV 5–10 mg q 5 min recommended
Propoxyphene PO 65 mg q 4 h Use in moderate
pain Weak analgesic;
most effective when
used with NSAIDs,
aspirin, or
acetaminophen
This drug is not
recommended in the
elderly

Pentazocine PO 50–100 mg q 3–4 h Third-line agent for

moderate-to-severe pain

Butorphanol IM 1–4 mg q 3–4 h b Third-line agent for

moderate-to-severe pain
•Morphine is metabolized to two important metabolites,
morphine- 3-glucuronide (M3G) and morphine-6-glucuronide
(M6G).

•One metabolite, M6G, contributes to analgesia, whereas the

other, M3G, may contribute to side effects if allowed to
accumulate.

•The metabolites are renally cleared and can accumulate in

patients with renal impairment, contributing to greater side
effects.

•Hydromorphone is more potent, has better oral absorption

characteristics, and is more soluble than morphine, but its
overall pharmacologic profile parallels that of morphine. Some
clinicians believe hydromorphone is associated with fewer
side effects, especially pruritus, compared to other opioids.