PATHOPHYSIOLOGY AND

MANAGEMEMENT
OF PAIN

DR. SUBODH KUMAR MAHTO,

DEPT. OF MEDICINE
PGIMER,DR.RML HOSPITAL.
NEW Delhi
OBJECTIVES
 INTRODUCTION
 NEUROANATOMY
 PATHOPHYSIOLOGY
 TYPES OF PAIN
 HISTORY
 ASSESSMENT OF PAIN
 MANAGEMENT
 Pain is an unpleasant , sensory and emotional experience
usually associated with noxious stimuli

 Pain is
◦ Subjective
◦ Protective
◦ And it is modified by developmental, behavioral
personality and cultural factors
 The word “pain” is derived from the Latin word “poena”
meaning fine, penalty, or punishment.

 Pain Threshold – level of noxious stimulus required to alert

an individual of a potential threat to tissue

 Pain Tolerance – amount of pain a person is willing or able to

tolerate
 A person experience pain through

◦ Sensory- discriminative system: this processes the

information about the strength, intensity, quality, spatial,
temporal aspects of pain.
◦ Motivational- affective system: It determines the
individuals avoidance- approach behavior.
◦ Cognitive –evaluative system: It overlies the individuals
learned behavior concerning the experience of pain. It
may block, modulate or enhance the perception of pain.
Types of nerve fibers
Large fibre Small fibre

Unmyelinated Myelinated

Slow conducton Fast conduction

Responds to thermal chemical and Responds to mechanical and

mechanical stimuli mechanothermal stimuli

Produces sensation of sharp Produces sensation of dull

pain(epicritic pain) pain(protopathic pain)
Neuroanatomy of pain
 The areas of nervous system responsible for pain
pathways are:

 Afferent pathways
 CNS
 efferent pathways
Pain pathway
 Afferent pathways terminate in the dorsal horn of the spinal

cord(1st order neuron)

 The nerve fibers from the dorsal root ganglia enter the spinal cord

through dorsal root and send branches 1-2 segments up and down

the spinal cord.

 Second order neurons transmit the impulse from the substantia

gelatinosa and lamina through the ventral and lateral horn

crossing the same or adjacent segment to the other side of the

cord.
Pain pathway

The impulse is then carried through the spinothalamic tract

to the somatosensensory cortex, frontal cortex and cingulate
gyrus. There are two divisions of spinothalamic tract which
transmit in different areas of brain.
 Neospinothalamic tract
 Paleospinothalamic tract
Neospinothalamic tract projects to VPL nucleus of thalamus.
Paleospinothalamic tract projects to central nuclei of
Thalamus.
PHYSIOLOGY OF PAIN
Peripheral mechanisms of pain
Mediators
Neurotransmitters
 Pain Initiators  Pain Inhibitors
◦ Glutamate - Central ◦ Serotonin
◦ Substance P - Central ◦ Endorphins
◦ Brandykinin - ◦ Enkephalins
Peripheral ◦ Dynorphin
◦ Prostaglandins -
Peripheral
 Sensitization
 When intense, repeated, or prolonged stimuli are applied to
damaged or inflamed tissues, the threshold for activation is
lowered, and the frequency of firing is intensified.

 mediators - bradykinin, nerve-growth factor, and leukotriene

 Sensitization occurs
◦ At peripheral nerve terminal (peripheral sensitization)
In damaged or inflamed tissues an increase in the production,
transport, and membrane insertion of chemically gated and
voltage-gated ion channels occurs.
◦ At the dorsal horn of the spinal cord (central sensitization).
Pain modulation pathway
Endogenous Opioid Systems
Gate-Control Theory –
Ronald Melzack (1960s)
 Described physiological mechanism by which
psychological factors can affect the experience of pain.
 Neural gate can open and close thereby modulating
pain.
 Gate is located in the spinal cord in SG.
 When the gate is closed signals from small diameter
pain fibres do not excite the dorsal horn transmission
neurons.
 When the gate is open pain signals excite dorsal horn
transmission cells
Gate control theory
Three Factors Involved in Opening and
Closing the Gate
 The amount of activity in the pain fibers.

 The amount of activity in other peripheral fibers.

 Messages that descend from the brain.

Conditions that Open the Gate Conditions That Close the Gate

 Physical conditions  Physical conditions

◦ Extent of injury ◦ Medications
◦ Inappropriate activity level ◦ Counter stimulation (e.g.,
 Emotional conditions heat, massage)
◦ Anxiety  Emotional conditions

◦ Tension ◦ Positive emotions

◦ Depression ◦ Relaxation, Rest
 Mental Conditions  Mental conditions

◦ Focusing on pain ◦ Intense concentration or

distraction
◦ Boredom
◦ Involvement and interest in
life activities
 Types
 Pain can be categorized according to inferred pathology:
Nociceptive pain
Somatic - Skin, tendons, ligaments, bone etc..
Visceral – Organs, cavity linings
Neuropathic pain- stimuli abnormally processed by the
nervous system. Ex- diabetic neuropathy, phantom limb
pain.
Referred pain
 By duration:
 Acute
 Chronic
Somatic pain
 Source: Skin, muscle, and connective tissue
 Examples: Sprains, headaches, arthritis
 Description: Localized, sharp/dull, worse with
movement or touch
 Pain med: Most pain meds will help, if severe, need a
stronger medication
Visceral pain
 Causes
Abnormal distention and contraction of the hollow viscera
muscle walls
Rapid stretching of the capsule
Abrupt anoxemia
Direct action of chemical stimuli (oesophagus)
Traction or compression of ligaments and vessels
Inflammatory processes and Necrosis of some structures
(myocardium)
Visceral pain
 Characteristic features of visceral pain
It is dull aching, deep, not well defined, and differently
described by the patients

Difficult to locate

Induces strong autonomic reflex phenomena

Much more pronounced than in pain of somatic origin

(psychic alarm reaction -"angor animi" - in angina pectoris)
 Referred pain
Skin
(usual stimulus)

Primary sensory
Kidney neurons
(uncommon stimulus)

Secondary Ascending sensory

sensory path to somatosensory
(b) neuron cortex of brain
Figure 10-13b
Acute pain
 It is a protective mechanism that alerts the individual to a
condition that is immediately harmful to the body. Which
leads to the following responses:
◦ Increased HR & RR
◦ Elevated BP
◦ Pallor or flushing, dilated pupils
◦ Psychological and behavioural response to acute pain
 Fear
 General sense of unpleasantness
 Anxiety
Chronic pain
 It is persistent or intermittent usually defined as lasting at least 3-
6 months

 The cause is often unknown, often develops insidiously, very often

is associated with Depression.
 Chronic pain produces significant behavioural and psychological
changes:
depression
an attempt to keep pain - related behaviour to a minimum
sleeping disorders
preoccupation with the pain
tendency to deny pain
Common pain syndrome
 Neuropathic pain  Post stroke pain
1. Peripheral nerve syndrome
pain  Cervicogenic headache
2. Central pain  Low back pain
 CRPS  Migraine
 Pain in association with  Phantom limb pain.
psychiatric disease  Neuralgias
 Chronic pain of
indeterminate cause
 Cancer pain
Neuropathic pain
 Dysesthesia-Any abnormal sensation described as unpleasant
by the patient
 Hyperalgesia- Exaggerated pain response from a normally
painful stimulus
 Hyperesthesia (hypesthesia) - Exaggerated perception of touch
stimulus
 Allodynia - Abnormal perception of pain from a normally
nonpainful mechanical or thermal stimulus
 Analgesia - Reduced perception of pain stimulus

 Paresthesia - Mainly spontaneous abnormal sensation that is

unpleasant; usually described as "pins and needles"
Complex regional pain syndrome
 Old terminology - Casualgia.

 It is a painful condition that includes regional pain, sensory

changes, abnormal sudomotor activity , skin changes, edema
following an inciting event such as trauma.

 Commonly seen in females in 3rd n 4th decade

 Precipitating factors:
-Fracture -Strain/ sprain
-Post surgery -Crush injury
 Types

CRPS I- No definable nerve lesion

CRPS II- Involves nerve lession.

 C LINICAL FEATURES:
 Excruciating pain
 Edema of affected limbs.
 Autonomic dysfunction.
 Motor dysfunction.
Cancer pain
 Mechanism
Direct tumour invasion of local tissues.
Metastatic bone pain.
Osteoporotic bone and degenerative joint pain in older
people.
Visceral obstruction.
Nerve compression and plexus invasion.
Ischaemia.
Inflammatory pain.
Chemotherapy induced neuropathy, paraneoplastic
neuropathy and arthropathy.
 Post-surgical pain and radionecrosis.
Post stroke pain syndrome

 Patients complaints of spontaneous severe paroxysmal and

burning type pain sensation.
 It has been postulated that damaged sensory pathways or
damage to the central inhibitory may be responsible for
pain.
 Following stroke about 40- 60 % patients develop shoulder
pain. It usually improves following physiotherapy.
 Phantom limb pain
 Phantom = ghost. Phantom limb feels real. Sometimes
amputees try to walk on their phantom limb.
 Several studies have shown that 75% of patients with
PLP develop pain within the first few days after
amputation.
 Usually intermittent; only few patient’s are in constant
pain. Located in distal parts of the missing limb.
 Mechanism- stump neuroma, spinal plasticity , cerebral
reorganization.
 Treatment – multi disciplinary approach. TCAs, TENS,
Mirror box therapy etc..
Cerebral reorganization.
Mirror box therapy
 Persons with amputated limb use either a mirror or
mirror box to reflect an image of the intact limb. It is
hypothesized that this works by preventing cortical
restructuring
 History
 Site of pain
Primary location
Radiation
 Circumstances associated with pain onset including details of
trauma or surgical procedures
 Character of pain - Sensory descriptions eg sharp, throbbing,
aching
 Intensity of pain

 At rest
 Movement
 Temporal factors
 Duration
 Current pain, during last week
 Aggravating or Relieving factors
 Associated symptoms (eg nausea)
 Effect of pain on activities and sleep
 Treatment history

 Current and previous medications

 Other treatment eg. transcutaneous
electrical nerve stimulation
 Assesment of pain
 McGill pain questionnaire
◦ Part I - To localize the pain
◦ Part II- Incorporates the visual analogue scale.
◦ Part III- The pain rating index. It includes 20
categories and 76 descriptions.
VISUAL ANALOG SCALE
Neuropathic pain
questionnaire
Treatment
Classes of medication
 Non narcotic  Complementary
analgesics and alternate
 Narcotics medicine:
analgesics  Hyperbaric
 Anti depressants oxygen.
 Anti convulsants  Acupuncture.
 Anti arrythmics  Electrical
 Muscle relaxants stimulation
devices.
 Trigger point
injections.
Pain ladder approach
 Adjuvant therapy ‐

 Tricyclic anti‐depressants
 Anticonvulsant medications – Gabapentin, Pregabalin, and
Carbamazepine
NSAIDs (non‐steroidal anti‐inflammatories) ‐ can be used
as co‐analgesics and are useful in reducing inflammation
NSAIDS
Drugs dosages Adverse effects Uses
Acetylsalicylic 650 mg PO Reye’s syndrome in children Headache, muscle
acid Avoid in women in late ache, backache, fever,
pregnancy, kidney or liver and arthritis menstrual
disease, asthma, high blood cramps .
pressure, or bleeding disorders.
Peptic ulcer.

Acetaminophen 650 mg PO May be harmful for people with Headache, muscle

kidney or liver disease or those ache, backache, fever,
who drink alcohol heavily and arthritis.

Ibuprofen 400 mg PO May be harmful for people with Headache, muscle

kidney or liver disease, asthma, ache, fever, sprains,
bleeding disorders, or those who menstrual cramps,
drink alcohol heavily. backache, and arthritis
pain.

Naproxen 250-500 mg Not recommended for children Headache, muscle

PO without a health care ache, fever, menstrual
professional’s supervision Cardio cramps, backache,
vascular risks and G.I toxicity arthritis pain and
inflammation.
Drugs Dosages Adverse effects uses

Celecoxib 100-200 mg PO Generally well- Muscle aches, joint

tolerated pain, arthritis, pain
and inflammation

Ketorolac 15-60 IM/IV May be harmful for Headache, muscle

people with kidney ache, fever,
or liver disease or menstrual cramps,
those who drink cold or flu aches
alcohol heavily.
Not recommended
for children
 OPIOIDS
 Most potent analgesics
 It produces analgesia by activating pain-inhibitory neurons
and directly inhibit pain-transmission neurons.
 Modes of delivery:
 Oral
 IV and IM
 Nasal spray
 Transdermal & transmucosal patch
 Sublingual route
 Suppository
 Epidural & Intrathecal route
Short acting opiods
Peak effect - 1–2 hrs
Duration – 4 hrs
Uses
 Acute pain - in moderate to severe chronic pain.
 Rescue medication for break through pain.
Eg –
 Codeine( 30- 60 mg PO QID)
 Tramadol (50- 100 mg PO QID)
 Morphine( 30 mg PO QID , 5 mg 4 hourly IV)
Long acting opiods

Steady pain relief for 12 hours.

Used for chronic pain.
Eg-
 Hydromorphone(2-4 mg PO QID)
 Methadone(5-20 mg PO/IV TDS)
 Buprenorphine
 Fentanyl( 25-100 µg/hour transdermal patch for 72
hour)
 Oxy codone(5-10 mg POQID)
What Dose to Give an Opioid Naïve
Patient?
 For opioid naïve start at a morphine equivalent of 2 to 5
mg IV or 10 mg PO
 Dose escalation should be more than 30 to 50% of base
dose to observe a meaningful change.
 Frequency of parenteral dosing can be as often as every
15 to 30 minutes until adequate analgesia is achieved
Opiod Analgesic Usual Starting
Dose
Drug Equianalgesic Starting iv iv:po ratio Starting dose Duration of
parenteral dose po Action
dose /transdermal
Morphine 10 mg Bolus 1:3 0.15-0.3 3-4 hours
dose=0.05-0.1 mg/kg/dose q
mg /kg q 2-4 4 hours
hours
Continuous
infusion=0.01-
0.04 mg/kg/hr
Hydromorphone 1.5 mg 0.015-0.02 1:5 0.06 mg/kg q 3 2-4 hours
mg/kg q 4 to 4 hours

Oxycodone 5-10 mg N/A 0.1-0.2 mg/kg 3-4 hours

q 3 to 4

Fentanyl 100mcg 1 to 2 25 mcg 72 hours

mcg/kg/hr as patch/hour
continuous
infusion
Methadone 10 mg 0.1 mg/kg q 4 1:2 0.2 mg/kgq 4 12 to 150
to 8 hours to 8 hours hours
 Opioid-responsiveness – It is the ability to achieve pain relief
with evidence of improved function without the
development of unmanageable or intolerable side effects.
 Addiction-
1. Compulsive use and preoccupation with the drug and
its supply.
2. Inability to consistently Control the quantity used.
3. Craving the psychological effects of the drug.
4. Continued use despite adverse effects from the drug.
 Physical dependence - manifested by a withdrawal syndrome
which includes
 Sleeplessness -
 Anxiety and agitation – Anxiolytics
 Stomach cramps - Dicyclomine
 Body aches (flu-like symptoms) - Anti-inflammatory pain relievers
 Muscle cramps - Muscle relaxants
 Nausea, vomiting, diarrhea, sweating and skin crawling

 Alternative opioids - during detoxification.

 Methadone
 Buprenorphine decrease by 10-20 % per week.
 Tramadol
Therapeutic monitoring
Four A’s:
 Analgesia (pain relief – often measured by a
10-point rating scale).
 Activities of daily living (physical, psychological,
and social functioning).
 Adverse effects.
 Aberrant or abnormal drug-related behaviors.
  Is the person’s day centered around taking medication?
 Does the person take pain medication only on
occasion, perhaps three or four times per week?
 Have there been any other chemical (alcohol or drug)
abuse problems in the person’s life?
 Does the person in pain spend most of the day
resting, avoiding activity, or feeling depressed?
 Is the person in pain able to function (work, household
chores, and play) with pain medication in a way that is clearly
better than without?
Three Complications of Chronic High Dose
Opioid Therapy
1. Neurotoxicity
2. Tolerance
3. Opioid Induced Hyperalgesia

 Tolerance
Due to prolonged use of opiates
It occurs when there is a progressive lack of response
to a drug requiring increased dosing
Higher doses of opiates are required to elicit same
amount of analgesia
Opioid-induced Neurotoxicity
 Mediated through non-opioidergic mechanisms
 Due to neuro-excitatory metabolites of opioids
(morphine-6-glucuronide, oxymorphone-3-glucuronide)
 Causes spectrum of symptoms ranging from mild
confusion or drowsiness to hallucinations, delirium and
seizures
 Typically develops on initiation to a week of initiating an
opioid or reaching a dose that causes metabolite buildup.
Opioid Induced Hyperalgesia
 Clinical features- Hyperalgesia, allodynia,Myoclonus,
Confusion etc..
 Related to but different from tolerance
 Different from opioid neurotoxicity
 Has been observed and documented in literature since
19th century (Observed by Albutt in 1870)
 Treatment – dose reduction, Utilize NMDA antagonists,
Interventional pain techniques or neurosurgical
procedures
Anti Depressants
 Tricyclic anti depressants:
 Amitriptyline (25- 300 mg PO)
 Imipramine (75-400 mg PO)
 Desipramine (50- 300 mg PO)
 Nortriptyline (40- 150 mg PO)

 Adverse effects- Dry mouth, Blurred vision, Constipation,

Difficulty urinating , Worsening of glaucoma, Palpitations, Wt
gain and hypotension.
SSRIs(Selective Serotonin reuptake Inhibitors

Examples
 Fluoxetine
 Sertraline
 Citalopram
 Escitalopram
 Fewer side effects and are less sedating than TCAs.
 Effective for prevention of migraine but less effective for
other types of pain.
 SNRIs
 Selective Serotonin and Nor-adrenaline Reptake
Inhibitors
Duloxetine (30- 60 mgPO)
Venlafaxine (75-400 mg PO)
Milnacipran(25-100 mg PO)

Serotonin syndrome.
 Antidepressant medications included in this warning are
fluoxetine, sertraline, paroxetine, escitalopram ,
duloxetine, milnacipran, and venlafaxine.
 Migraine drugs include Triptans.
 ANTI CONVULSANT DRUGS
Gabapentin ( 600-1200 mg PO) Neuralgia

Pregabalin (150- 600 mg PO) Postherpetic neuralgia, diabetic

neuropathy, and fibromyalgia
Carbamazepine (200- 300 mg PO QID) Trigeminal neuralgia

Valproic acid (400- 600 mg PO OD) Prophylaxis of migraine

Lacosamide (100 mg PO BD) Diabetic neuropathic pain

Topiramate (25- 200 mg PO OD) Prophylaxis of migraine

SODIUM CHANNEL BLOCKING & ORAL ANTI-
ARRHYTHMIC AGENTS
 Drugs commonly used are
1. Lidocaine
2. Flecainide
3. Mexilitine
 Lidocaine has anti-arrhythmics with local anesthetic
properties and it is occasionally used in refractory pain.

 These drugs interrupt premature firing of damaged nerves

hence less capability of the nerve to trigger pain.
 TOPICAL PAIN RELIEVERS
 Topical agents work locally and must be applied directly
over the painful area
 Transdermal drugs have effects throughout the body and
work when applied away from the area of pain
 Transdermal medication in a patch is absorbed through
the skin by the bloodstream over a period of time.
 Eg –
 EMLA(Eutectic Mixture of Local Anesthetic; contains lidocaine and
prilocaine)

 L.M.X.4 (contains lidocaine 4%),

 Used primarily prior to painful procedures such as while
lumbar puncture (spinal tap), and wart removal.
DRUGS USED AS MUSCLE RELAXANTS IN
CHRONIC PAIN
 Carisoprodol (200 mg PO BD)
 Metaxalone (800 mg PO TDS)
 Chlorzoxazone (250 – 750 mg PO TDS)
 Baclofen ( 5 mg PO TDS)
 Tizanidine (4 mg PO TDS)
Botulinum toxins
 Botulinum toxins have been found to be effective in
decreasing tone in overactive (hypertonic) muscles
 It is used for the treatment of the postural
abnormalities and pain associated with dystonias . Ex-
torticollis .
 Onabotulinumtoxin A is additionally approved by FDA to
prevent headaches in adults with chronic migraine
 Interventional therapy

1. Intra articular steroid injections

2. Viscosupplementation
3. Spinal cord stimulation
4. Implanted targeted intra thecal drug delivery
5. Epidural analgesia
6. Nerve plexus block
 Spinal cord stimulation:
Chronic radicular pain
 CRPS type I and II
 Painful peripheral neuropathies
 Peripheral vascular disease not amenable to
Surgical by pass or conventional therapy.
 Central pain
 Phantomb limb pain.
Patient control analgesia:

Indications:
 Post operative pain
management.
 Trauma
 Burns
 Sickle Cell Crisis
 Epidural analgesia:

 Indication:
 Disk herniation, degeneration, and spondylosis
 Radiculopathy - cervical thoracic, lumbosacral
 Spinal stenosis and facet arthropathy
 Pelvic pain - Aid with pelvic floor physical therapy
 Labor epidural analgesia
TENS
 TENS is a method of treating pain that is non-invasive
and does not use pharmaceuticals.
 The TENS device sends impulses through the skin that
stimulate the nerve

 Indications:
Chronic post operative pain
Chronic post traumatic pain
Herbal Medications
Rules of thumb
 Use the lowest effective dose by the simplest route.
 Start with the simplest single agent and maximize it’s
potential before adding other drugs.
 Use scheduled, long-acting pain medications for
constant or frequent pain.
 Treat breakthrough pain with with parentral, short-
acting medication
Source of information
 Harrison 18th edition
 Bradley neurology
 ACPA guidelines for pain management
 WHO guidelines for pain management
“Pain is a more terrible lord of mankind than
death itself.”
Albert Schweitzer

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