Pain management vels

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Shri Isari Velan Mission hospital

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A comfort care center
Provide comprehensive care to serious illness
To live with comfort and dignity to life’s fullest
extent
A charitable Trust that provides patients the
greatest comfort and peace of mind

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“Palliative care is both a philosophy of care and an
organized, highly structured system for delivering
care. Palliative care expands traditional diseasemodel medical treatments to include the goals of
enhancing quality of life for patients and family,
optimizing function, helping with decision-making
and providing opportunities for personal growth.
As such, it can be delivered with life-prolonging
care or as the main focus of care”

~ National Consensus Project for Quality Palliative Care, 2004

Life-prolonging and
restorative treatments
Hospice
Palliative Care
Disease Progression

Diagnosis

Bereavement

Death

Ferris F, Balfour H, Bowen K, Farley J, Hardwick M, Lamontagne C, Lundy M, Syme A, West P. A model to guide
patient and family care. Based on nationally accepted principles and norms of practice. J Pain Symptom Manage.
2002;24(2):106-23.

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“There is nothing more that I can do.”
“I don’t want to be the one to tell him.”
“I can’t stop this treatment now, that would kill her.
I wish we hadn’t started this.”
“Continuing treatment in this case seems futile.”

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Pain
Dyspnea/respiratory
distress
Nausea/vomiting
Anorexia/cachexia

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Pruritis/dermatitis
Intractable seizures
Delirium
Incontinence
Pressure ulcers

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Palliative care is appropriate for all patients with
serious illness



The goal of palliative care is to enhance quality of
life through assiduous symptom management and
attention to psychological, social and spiritual
needs of the patient and family



Palliative care is patient and family centered care



Hospice is both a philosophy of care and a
Medicare benefit available to patients who are
nearing the end of life

The Vedic chant "Sarve Santu Niramaya" meaning
"may all be disease-free" has been the part of Hindu
prayers for ages. Apart from Hinduism, every major
religion has focussed on freedom from disease and
PAIN.

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Define Pain
Review Pain Physiology
Review Evaluation of Pain and its effects
Review Classes of Pain medications
General Approach to Pain Management
Prescriptions

Definition
pain is an, unpleasant sensory and emotional
experience associated with actual or potential tissue
damage (IASP)
Pain is a personal and subjective experience that can
only be felt by the sufferer.
Pain is whatever the experiencing person says it is
and exists whenever they say it does.

Process of pain physiology
nociceptor
TRANSDUCTION
TRANSMISSION
PERCEPTION
MODULATION



Pain stimuli is converted to
electrical energy known as
Transduction. This stimulus
sends an impulse across a
peripheral nerve fiber
(nociceptor).



Biochemical mediators: “Chemical Soup”
Prostaglandins
Bradykinins
Serotonin
Histamines
Cytokines
Leukotrienes
Substance P
Norepinephrine

Transmission:
 A delta fibers (myelinated) send
sharp, localized and distinct
sensations.
 C fibers (unmyelinated) relay
impulses that are poorly localized,
burning and persistent pain.
 Pain stimuli travel- spinothalamic
tracts.



Defined as:
Projection of pain
into the
Central Nervous System



A synapse contains three
elements:
the presynaptic terminal
the synaptic cleft
the receptive membrane

The

presynaptic terminal is the
axon terminal of the presynaptic
neuron
Here that the presynaptic neuron
releases neurotransmitters which
are found in vesicles

Peripheral Excitatory Mediators
(Pain)
Substance

Receptor

Mechanism

Substance P

NK1

↑ neuronal excitability, edema

(SP)
Prostaglandin

?

(PG)
Bradykinin

Sensitize nociceptors,
inflammation, edema

B2 (normal)

Sensitize nociceptors

B1 (inflammation)

↑ PG production

H1

C-fiber activation, edema,

5-HT3

vasodilatation
C-fiber activation, release SP

Histamine
Serotonin

Norepinephrine α1
(NE)

Sensitize nociceptors
Activate nociceptors

Perception:
 Person is aware of pain –somatosensory
cortex identifies the location and
intensity of pain
 Person unfolds a complex reactionphysiological and behavioral responses is
perceived.

Modulation:
 Inhibitory neurotransmitters like
endogenous opioids work to
hinder the pain transmission.
 This inhibition of the pain
impulse is known as modulation

Pain pathway and modulation
Ascending nociceptive pathways
Interpretation in
cerebral cortex:
pain

Stimulation of nociceptors
(Aδ and C fibers) /
Release of
neurotransmitters and
neuromodulators (i.e. PG)

1

Descending inhibitory controls /
Diffuse noxious inhibitory controls
Activation of serotoninergic
and noradrenergic pathways

Release of serotonin,
noradrenalin and enkephalins
at spinal level

Injury
1. Adapted from: Bonica JJ. Postoperative pain. In Bonica JJ, ed. The management of pain. Philadelphia: Lea
and Febiger;1990:461-80.

Do you think that how we conceptualize pain
--PATHWAY vs DYNAMIC DISTRIBUTED SYSTEMS-- influences how we
treat pain and the success of those treatments?
PAIN PATHWAY

Pain Seminar, Lecture #5, PAIN TREATMENTS, p.2

s
ter
n
n e e…
Pai er
h

Let’s see…
PAIN
?

Pain Seminar, Lecture #45, PAIN TREATMENTS, p. 3



The substances released from the traumatized
tissue are:
prostaglandins
bradykinin
serotonin
substance P
histamine





Bradykinin- most potent pain producing
chemical
Prostaglandins- increase sensitivity to
pain experience . Is a potent vasodilator
and increase the production of
bradykinin resulting edema







Substance P- transmits pain
impulses to brain centers and causes
vasodilatation and edema
Serotonin- causes pain by altering
sodium flow—neuron to fire
Histamine,Leukotrienes and nerve
growth factor are released

Endorphins& Dynorphins- morphine
like substances.
 Located in the brain, spinal cord &
GIT
 Produce analgesia when attached
with opiate receptors in the brain



Gate control theory of pain is the
idea that physical pain is not a
direct result of activation of pain
receptor neurons, but rather, its
perception is modulated by
interaction between different
neurons

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Nerve fibers (A delta (fast channels)) and C
fibers (slow channels) transmit pain impulses
from the periphery
Impulses are intercepted in the dorsal horns of
the spinal cord, the substantia gelatinosa
In this region, cells can be inhibited or
facilitated to the T-cells (trigger cells)

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When cells in the substantia
gelatinosa are inhibited, the
‘gate’ to the brain is closed
When facilitated, the ‘gate’ to
the brain is open



Similar gating mechanisms exist in
the nerve fibers descending from the
thalamus and the cortex. These areas
of the brain regulate thoughts and
emotions. Thus, with a pain
stimulus, one’s thoughts and
emotions can actually modify the
pain experience.

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Tissue damage activates free nerve
endings (nociceptors) of peripheral
nerves
Pain signal is transmitted to the spinal
cord, hypothalamus, and cerebral
cortex
Pain is transmitted to spinal cord by
A-delta fibers and C fibers

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

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A-delta fibers transmit fast, sharp,
well-localized pain signals
C fibers conduct the pain signal
slowly and produce poorly localized,
dull, or burning type of pain
Thalamus is the relay station for
incoming stimuli, incl. pain

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A delta fibers found in the skin and
muscle, myelinated, respond to
mechanical stimuli. Produce intermittent
pain.
C fibers distributed in the muscle as well
as the periosteum and the viscera. These
fibers are unmyelinated, conduct thermal,
chemical and strong mechanical stimuli.
Produce persistent pain.

Parasympathetic responses
 Decreased blood pressure
 Decreased pulse
 Nausea & vomiting
 Weakness
 Pallor
 Loss of consciousness

Sympathetic responses
 Pallor
 Increased blood pressure
 Increased pulse
 Increased respiration
 Skeletal muscle tension
 Diaphoresis

Characteristic

Acute Pain

Chronic Pain

Cause

Generally known

Often unknown

Duration of pain

Short,
well-characterized

Persists after
healing, ≥3 mo

Treatment
approach

Underlying disease

Underlying disease
and pain disorder

Physical
Physical

Psychological
Psychological

Total Pain
Total Pain

Spiritual
Spiritual

Social
Social

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Nociceptive pain
 Transient pain in response to noxious stimuli
Inflammatory pain
 Spontaneous pain and hypersensitivity to pain in
response to tissue damage and inflammation
Neuropathic pain
 Spontaneous pain and hypersensitivity to pain in
association with damage to or a lesion of the
nervous system

Functional
Woolf. Ann Intern Med. 2004;140:441-451.

Nociceptive
Pain

Mixed Type
Caused by a
combination of both
primary injury or
secondary effects

Caused by activity in
neural pathways in
response to potentially
tissue-damaging stimuli

Neuropathic
Pain
Initiated or caused by
primary lesion or
dysfunction in the
nervous system

CRPS*
Postoperative
pain

Arthritis

Mechanical
low back pain

Sickle cell
crisis

Sports/exercise
injuries
*Complex regional pain syndrome

Postherpetic
neuralgia
Neuropathic
low back pain

Trigeminal
neuralgia
Central poststroke pain

Distal
polyneuropathy
(eg, diabetic, HIV)

Is responsive to NSAID’s, coxibs,
paracetamol and opiates
Noxious Peripheral Stimuli

Pain-Autonomic Response

Heat

- Withdrawal Reflex

Cold
Intense
Mechanical
Force

Nociceptor Sensory
Neuron

Brain

Chemical
Irritants
Spinal Cord


Somatic Pain
•
•
•
•

Aching, often constant
May be dull or sharp
Often worse with movement
Well localized

Eg/
– Bone & soft tissue
– chest wall

Visceral Pain
•
•
•
•

Constant or crampy
Aching
Poorly localized
Referred

Eg/
– CA pancreas
– Liver capsule distension
– Bowel obstruction

Is responsive to NSAID’s,coxibs,
paracetamol, and opiates Pain
Inflammation
Spontaneous

Macrophage
Mast Cell

Neutrophil
Granulocyte

Pain Hypersensitivity
-Allodynia
-Hyperalgesia

Nociceptor Sensory
Neuron

Brain

Tissue
Damage
Spinal Cord


FEATURES OF NEUROPATHIC PAIN
COMPONENT
Steady,
Dysesthetic

Paroxysmal,
Neuralgic

DESCRIPTORS
•
•
•
•
•

Burning, Tingling
Constant, Aching
Squeezing, Itching
Allodynia
Hypersthesia

EXAMPLES
• Diabetic neuropathy
• Post-herpetic
neuropathy

• Stabbing

• trigeminal neuralgia

• Shock-like, electric

• may be a component
of any neuropathic
pain

• Shooting
• Lancinating

Spontaneous Pain
Pain Hypersensitivity

•May respond to
• local anaesthetic
• anticonvulsants
• antidepressants
Peripheral Nerve
Damage

•Less responsive to opioids Injury
Spinal Cord

Brain
Stroke

•No response to NSAID’s, coxibs, or
.
paracetamol
Woolf. Ann Intern Med. 2004;140:441-451



Functional pain
Fibromyalgia, IBS etc.



Central neuropathic pain
Poststroke ,
Spinal cord injury ,
Trigeminal neuralgia, and
Multiple sclerosis .

Pain is inevitable. Suffering is optional.
Andrew Parchman

Acute Pain
Increased
sympathetic
activity

GI effects

Splinting,
shallow
breathing

Increased
catabolic
demands

Anxiety
and fear

Peripheral/
central
sensitization

Myocardial
O2
consumption↑

GI motility↓

Atelectasis,
hypoxemia,
hypercarbia

Poor wound
healing/muscle
breakdown

Sleeplessness,
helplessness

Available
drugs

Myocardial
ischemia

Delayed
recovery

Pneumonia

Weakness
and impaired
rehabilitation

Psychological
Chronic
pain

Courtesy of Sunil J Panchal, MD

Insomnia

Sexual
dysfunction

Suicide
risk

Anxiety/
frustration/
irritability

Depression

Impaired
relationships

Low
self-esteem

Decreased
productivity

Decreased
driving
ability

UNRESOLVED
PAIN

Reduced
functional
capacity

Increased
healthcare
need/costs

American Pain Foundation. Overview of Pain Surveys:
http://www.painfoundation.org/Voices/VoicessurveyReport.pdf

Loss of
income

Inability to
concentrate

Fatigue

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Sensations









burning
paresthesia
paroxysmal
lancinating
electriclike
raw skin
shooting
deep, dull, bonelike
ache



Cardinal signs/symptoms


Allodynia: pain from a
stimulus that does not
normally evoke pain
 thermal
 mechanical



Hyperalgesia: exaggerated
response to a normally painful
stimulus

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Chemical excitation of non nociceptors
Recruitment of nerves outside of site of injury
Excitotoxicity- Dis inhibition of pain
Sodium channels - abnormal
Ectopic discharge
Deafferentation – phantom pain
Central sensitization
 maintained by peripheral input
Sympathetic involvement
Antidromic neurogenic inflammation

Algesic
sub

Nociceptor

Nociceptor

Innocuous
stimulus

Na+
channels

Pain
sensation

Adapted from Woolf CJ et al. Lancet. 1999;353:1959-1964.

Normal sensory
function

Aβ fiber
mechanoreceptor

Innocuous
Na+
stimulus channel

Na+
channel

Weak
synapse

Nonpainful
sensation

Increased nociceptor drive leads to central sensitization of dorsal horn
neurons

Innocuous
Na+
stimulus channel

Na+
channel

Increased
synapsis
strength

Painful
sensation

Adapted from Woolf CJ et al. Lancet. 1999;353:1959-1964.

Visual Analog Scale

Verbal Pain Intensity Scale
No
pain

Mild Moderate Severe Very
Worst
pain
pain
pain severe possible
pain
pain

Worst
possible
pain

No
pain

0–10 Numeric Pain Intensity Scale

0 1
No
pain

2

3

4 5 6
Moderate
pain

7

8

10
Worst
possible pain

Faces Scale

9

0

1

2

3

4

5

Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice. FA Davis; 1996:8-10.
Wong DL. Waley and Wong’s Essentials of Pediatric Nursing.
5th ed. Mosby, Inc.; 1997:1215-1216.
21
McCaffery M, Pasero C. Pain: Clinical Manual. Mosby, Inc. 1999:16.

The “Four A’s of Pain”



Activities of daily living



Adverse effects


20

Analgesia

Aberrant drug-taking behaviors

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Pharmacotherapy and other
medical/surgical care with
appropriate medicine reorganization
Restorative care including active
physical and occupational therapy
Psychological counseling utilizing
cognitive-behavioral pain
management strategies

Continual follow-up and monitoring are
essential to good opioid analgesic therapy.
 Reassess the “Four A’s of Pain”
 analgesia
 activities of daily living
 adverse effects
 aberrant drug-taking behaviors
 Review treatment options
33

Titrate only one drug at a time

Modes of action of analgesics

1,2,3,4

Paracetamol

↓
Inhibition of central Cox-3 (?)
(Inhibition of PG synthesis)

Opioids

↓
Activation of
opioid receptors

Paracetamol

↓
Interaction with
serotoninergic descending
inhibitory pathway

NSAIDs / Coxibs

1. D’Amours RH et al. JOSPT 1996;24(4):227-36.
2. Piguet V et al. Eur J Clin Pharmacol 1998;53:321-4.
3. Pini LA et al. JPET 1997;280(2):934-40.
4. Chandrasekharan NV et al. PNAS 2002;99(21):13926-31.

↓
Inhibition of peripheral and
central Cox-1 / Cox-2
(Inhibition of PG synthesis)

1.

Medication must result in:
 Significant pain relief
 Tolerable side effects
function

2.

Both physician & patient must
realize significant individual
variability

3.

Slow titration until either:
a) Significant pain relief
b) Intolerable side effects
c) “Toxic serum level”

Satisfactory Symptom Management
Opioid for moderate to severe pain
+ Non-opioid + Adjuvant

Pain persisting or increasing
Opioid for mild to moderate pain
+ Non-opioid + Adjuvant

Pain persisting or increasing
Mild Pain
Non-opioid- NSAID + Adjuvant

Pain

Factors that lower pain
threshold

Factors that raise pain
threshold

Discomfort
Insomnia
Fatigue
Anxiety
Fear
Sadness
Depression
Boredom
Introversion
Mental isolation
Social abandonment

Relief of symptoms
Sleep
Rest
Empathy
Companionship
Diversional activity
Reduction in anxiety
Elevation of mood
Analgesics
Anxiolytics
Antidepressants

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NSAIDs/Cox-2
Paracetamol
Steroidal Anti-inflammatory Drugs
Antidepressants
Anticonvulsants
Oral local anesthetics
Alpha adrenergic agents
Neuroleptics
NMDA receptor antagonists
Muscle relaxants
Topical analgesics
Emerging Agents

NA

Cortico-Spinal

Receptors

Peripheral Nerve

Copyright Dr Andrew
Dean

5HT

Spino-thalamic

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Nonsteroidal Anti-inflammatory
Drugs (NSAIDs)
Steroidal Anti-inflammatory Drugs
Miscellaneous Drugs

Pharmacological control of inflammation:
Preventing the release of inflammatory
mediators
 Inhibiting their actions
 Treating pathophysiologic responses to them


General characteristics
 Drugs that inhibit one or more
steps in the metabolism of
arachidonic acid (AA)
 Aspirin-like

drugs or COX inhibitors

Major action:
 inhibit Cyclooxygenase (COX)
Pharmacological effects
 Suppress inflammation
 Relieve pain
 Reduce fever

Tissue Trauma
Cell Membrane Phospholipids

Phospholipase

Arachidonic Acid
C
O
X

Cyclo-oxygenase

Endoperoxides
Toxic Oxygen Radicals

Thromboxane
Prostaglandins

Prostacyclin

(phospholipids)

Cell Membrane
phospholipase A2
Lipoxygenase (LOX)

Arachidonic acidLeukotrienes

cyclooxygenase

indomethacin

aspirin,

(COX1 & COX2)

PGH2)
prostacyclin
thromboxane
synthetase
synthetase
prostacyclin
Thromboxane A2

Cyclic endoperoxides (PGG2,
prostaglandin
synthetase
PGE2

PGF2α



Salicylic acid
derivatives













Ibuprofen
Naproxen
Ketoprofen

Flunixin meglumine

Hydroxamic acid
derivatives




Piroxicam
Meloxicam

Nicotinic acid
derivatives




Phenylbutazone
Dipyrone

Oxicams



Etodolac
Ketorolac

Propionic acids






Meclofenamic acid
Tolfenamic acid

Pyrazolones or
enolic acids



Indomethacin

Pyranocarboxylic
acids





Acetaminophen

Indole and indene
acetic acids

Fenamates



Aspirin

Para-aminophenol
derivatives




Tepoxalin

Coxib-class NSAIDs



Cyclooxygenase has 2 forms:
 COX-1

(good COX) : found in all
tissues
 Mediates “housekeeping chores”
 Protect gastric mucosa
 Support renal function
 Promote platelet aggregation

 COX-2

(bad COX) : found at sites of
tissue injury
 Mediates inflammation and sensitize

receptors to painful stimuli
 Also present in brain- mediates fever and

 COX-1

inhibition

 Results largely in harmful effects

 Gastric erosion and ulceration
 Bleeding tendencies
 Acute renal failure
 Results in some beneficial effects
 Protection against myocardial
infarction
 COX-2

inhibition

 Results in beneficial effects

 Suppression of inflammation
 Alleviation of pain



Drugs with anti-inflammatory
properties
NSAIDs—Nonsteroidal anti-inflammatory
drugs: 2 types
 First generation (inhibit both COX1 and
COX2)
Non-selective COX inhibitors
- aspirin

 Second generation (inhibit COX2 only)

Preferential COX2 inhibitors (partial specificity

for COX2)

- celecoxib (human drug)
Selective COX2 inhibitors (full specificity for

COX2)

- rofecoxib (human drug)



NSAIDs
act

to block the first step of
prostaglandin synthesis
by binding to and inhibiting
cyclooxygenase



Dose and drug dependent
The major therapeutic, toxic,
and potency of NSAIDs



Ratio of COX1 to COX2 (COX1:COX2

ratio)
 describes the amount of drug necessary
to inhibit the respective isoform of the
cyclooxygenase enzyme (IC50)
 Calculation: COX1:COX2 ratio = IC50COX1 /

IC50COX2





COX1 to COX2 ratio > 1 is desirable,
or
COX2 to COX1 ratio < 1

Examples












Aspirin
0.343
Carprofen (racemix mixture)
129
Carprofen (S isoform)
181
Carprofen (R isoform)
4.19
Etodolac
0.517
Flunixin meglumine
0.635
Ketoprofen








As weak acids, well absorbed after PO
Small volume of distribution (10%)
Highly protein binding (90%)
Clearance:
hepatic metabolism both phase I and
II
Conjugated metabolites -> urine





Analgesia, antipyresis, and
control of inflammation
Relative potency in lab animals
and human
Meclofenamic

acid >
indomethacin > naproxen >
aspirin



Relative potency in horses
Flunixin

meglumine >



Gastrointestinal system




GI ulceration

Hematopoietic system
Bleeding dyscrasias
 All NSAIDs are able to impair platelet
activity
 Platelet aggregation defects caused by
aspirin can last up to 1 week




Renal system
Analgesic nephropathy
 In kidney, vasodilatory and tubuloactive
prostaglandins are protective










GI damage is the most common
and serious side effect of NSAIDs
Dogs – very sensitive
Inhibition of COX1-stimulated
PGE2-mediated bicarbonate and
mucous secretion,
epithelialization, and increased
blood flow
Direct irritation of acidic drugs
Salicylates cause backdiffusion of

Non-Selective COX
inhibitors











Acetaminophen
Aspirin
Etodolac
Flunixin
Meglumine
Ketorolac
Naproxen
Phenylbutazone
Piroxicam
Tolfenamic acid
Vedaprofen

Preferential COX-2
inhibitors
(Partial specificity for COX-2)



Carprofen
Meloxicam

Selective COX-2
inhibitors
(no significant effect on COX1)





Deracoxib
Firocoxib
Robenacoxib
Mavacoxib

Dual COX and LOX
inhibitors


Tepoxalin





Most frequently used and misused
drugs in medicine
Needs an understanding of their
actions on all body systems

Corticotropinreleasing factor (CRF)

Adrenocorticotropic hormone (AC



Glucocorticoid receptors
 Intracellular,



3 subtypes at least

activated receptor-glucocorticoid
complex
 ->

binds to glucocorticoid responsive
element
 -> modulate gene transcription


Target proteins could be induced or
inhibited
 result

in pharmacologic effects of
glucocorticoids



Differential gene regulation by

Induced







Inhibited

Lipocortin-1
Cytokines
Beta2-adrenoreceptor
Natural killer
receptor
Angiotensin-converting enzyme Inducible
nitric oxide synthase
Neutral endopeptidase
Cyclooxygenase
Endotheslin
Phospholipase
Collagenase





Protect glucose-dependent tissues
(brain, heart)
Hyperglycemic effect
 Increase

gluconeogenesis, insulin
antagonism



Increased breakdown of proteins
 Skeletal

muscles and collagen
 Provides gluconeogenic precursors
 Result in muscle wasting, delayed wound
healing, and thinning of the skin


Promote lipolysis



Increase the RBC content of the
blood
 Retarding






Lymphopenia
Eosinopenia
Monocytopenia
Neutrophilia
 Increased

marrow



erythrophagocytosis

release from bone

This blood cell profile: Stress











Inhibit early and late phases of the
inflammation
Inhibit edema formation, fibrin
deposition, leukocyte migration,
phagocytic activity, collagen
deposition, and capillary and
fibroblast proliferation
Inhibit enzyme phospholipase A2 and
COX-2
Inhibit release of TNF-α, IL-2, and
platelet activating factor
Inhibit inducible nitric oxide synthase



Absorption
 Several

products are well absorbed

orally
 Topical use -> well absorbed
 Long-term use - > systemic effect


Metabolism
 Eliminated

by oxidation or
reduction, and followed by
conjugation



Duration of action
AntiInflam potency
Short acting
(< 12 hr)
 Hydrocortisone

1
 Topical use


(identical to cortisol)

Intermediate acting
 Prednisolone

(12 – 36 hr)

and Prednisone

4
 Methylprednisolone (has lipid
antioxidant activity)
5
 Triamcinolone
5
 Alternate day administration













Iatrogenic adrenocortical
insufficiency
Iatrogenic hyperadrenocorticism
Susceptibility to infection
Glucocorticoid-induced polyphagia
Muscle weakness and muscle
atrophy
Reversible hepatopathy
Polyuria and polydipsia
Pulmonary thromboembolism
Hypertension













NSAIDs/Cox-2
Acetaminophen
Antidepressants
Anticonvulsants
Oral local anesthetics
Alpha adrenergic agents
Neuroleptics
NMDA receptor antagonists
Muscle relaxants
Topical analgesics
Emerging Agents










Effective in treating a variety of pain states
Block the reuptake of norepinephrine (and
5HT), which modulates pain
Analgesia at lower doses than antidepressant effect
Use limited by side effects (anti-cholinergic)
Amitriptyline vs desipramine
Caution: coronary disease

Tricyclic

SSRI

Other

Amitriptyline (Elavil®)

Fluoxetine (Prozac®)

Nefazodone (Serzone®)

Desipramine
(Norpramin®)

Paroxetine (Paxil®)

Venlafaxine (Effexor®)

Doxepin (Sinequan®)

Sertraline (Zoloft®)

Trazodone (Desyrel®)

Imipramine (Tofranil®) Fluvoxamine (Luvox®)
Nortriptyline
(Pamelor®)

Citalopram
(Celexa)

*Partial list
SSRI = selective serotonin reuptake inhibitor

Bupropion
(Wellbutrin®)

Meta-analysis by Onghena (1992)
Diagnosis

Synthesis by Magni (1991)

No. of Studies

Effect Size

Diabetic neuropathy

1

1.71

Responsive

Postherpetic neuralgia

2

1.44

Responsive

Tension headache

6

1.11

Responsive

Migraine

4

0.82

Responsive

Atypical facial pain

3

0.81

Responsive

Chronic back pain

5

0.64

Minimal clinical benefit

Rheumatological pain

10

0.37

Fibrositis responsive;
Osteo- and rheumatoid
arthritis probably
responsive

Not specified or mixed

7

0.23

Probable effect









Carbamazepine*
Divalproex
sodium*
Gabapentin
Pre Gabalin
Clonazepam
Phenytoin








Lamotrigine
Topiramate
Zonisamide
Oxcarbazepine
Levatriacetam
Tiagabine










Demonstrated effectiveness in variety of
neuropathic pain states
Reduce firing of sensory neurons
Agents: Carbamazepine, phenytoin,
gabapentin, lamotrigine
No ceiling dose: Start low and titrate
upward until adverse effects appear
Adverse effects vary
 Most

common are sedation, mental clouding,
dizziness, nausea, unsteadiness



Postherpetic neuralgia



gabapentin
 pregabalin




Diabetic neuropathy
carbamazepine
 phenytoin
 Gabapentin
 pregabalin
 lamotrigine




lamotrigine

Trigeminal neuralgia
carbamazepine
 lamotrigine
 Oxcarbazepine
 Pregabalin



*Not approved by FDA for this use.
43

HIV-associated
neuropathy





Central poststroke pain


lamotrigine










Chemically related to gabapentin
used for treating pain caused by neurologic
diseases such as postherpetic neuralgiaas well as
seizures and treating fibromyalgia.
The mechanism of action of pregabalin is
unknown.
Pregabalin binds to calcium channels on nerves
and may modify the release of
neurotransmitters.
Reducing communication between nerves may
contribute to pregabalin's effect on pain and
seizures.

Oral or transdermal Clonidine:
 Enhance the effect of narcotics
 Decreases the daily narcotic
requirement
 Excellent Adjuvant therapy for
narcotic dependent patients
 Effective for neuropathic pain










Trigeminal neuralgia (Fromm 1993)
Chronic low back pain(Berry 1988)
Cluster headache (D’alessandro 1996)
Chronic tension-type headache
(Nakashima 1994)
Spasmodic torticollis (Houten 1984)
Neuropathic pain
Chronic headache(2002)

Mu-Opioid-R
Activation

Nerve Injury
NMDA-R
Inhibitors

PKC

↑ Excitability

Neurotoxicity

Hyperalgesia

↓ Mu-Efficacy
Mu-Opioid
Tolerance








Dextromethorphan
Ketamine
d-Methadone
Amantadine
Memantine
Amitriptyline







Cyclobenzaprine
Carisoprodol
Methocarbamol
Metaxalone
Orphenadrine citrate






Structurally similar to tricyclics
Centrally acting
Nocturnal muscle spasm effects
Side effects:
 Drowsiness - Cardiac dysrhythmias
 Anticholinergic
 Dry mouth
 Blurred vision
 Urine retention
 Constipation
 Increased intraocular pressure






Precursor of meprobamate
Centrally active
Reduction of muscle spasm
Side effects:
 Sedation, drowsiness, dependence
 Withdrawal symptoms
 Agitation
 Anorexia
 N/V
 Hallucination
 Seizures








Investigative usage: MS
Daily dosage: 1000 mg qid
Side effect: drowsiness
Mechanism of action:
 Centrally active
 Inhibits polysynaptic reflexes
Clinical effects:
 Reduction of muscle spasms






Daily dosage: 400-800 mg tid
Clinical effects:
 Reduction in muscle spasm
Side effects:
 Nausea
 Drowsiness
 Dizziness







Investigative usage: SCI
Daily dosage: 100 mg bid
Analog of diphenhydramine
Given IV for antispasticity trials
Side effects:
 Anticholinergic
 Rare aplastic anemia



Topical agents are active within the skin, soft
tissues and peripheral nerves.



In contrast to transdermal, oral or parenteral
medications, use of a topical agent does not
result in clinically significant serum drug levels.



Other benefits include lack of systemic side
effects and drug-drug interactions.



The mechanism of action of a topical analgesic is
unique to the specific agent considered.










Aspirin preparations
 eg, aspirin in chloroform or ethyl ether
Capsaicin
Local anesthetics
- lidocaine patch 5%/eutectic mixture of
local anesthetics
Tricyclic antidepressants
Opiates ( Buvalor, Fentenyl )
Investigational agents





Salicylic acid derivative (a.k.a. wintergreen oil,
sweet birch oil)
Lipid solubility increases toxicity
More toxic than aspirin
 1 teaspoon (5ml) wintergreen oil contains 4,000 mg
salicylate
 30ml wintergreen oil is a fatal dose in adults




Risk of toxicity reduced with use for acute pain,
limited to a small area of dermal application
Chyka, P.A., et al., 2007







Neuropathic pain states
studied include:
diabetic neuropathy,
PHN, post-mastectomy pain,
HIV neuropathy.
Non-neuropathic pain states such as
osteoarthritis have been studied as well.
Efficacy demonstrated in some of these
studies but limited by adverse effects and
compliance issues..







Low back pain
Osteoarthritis
Chronic myofascial pain
Acute soft tissue injury pain
Post-operative pain



1. Galeotti N, DeCesare Mannelli L,
Mazzanti G, et al. Menthol: a natural
analgesic compound. Neurosci Lett
2002 Apr 12;322(3):145-148. This article
is particularly interesting as the authors
review evidence which suggests that
one of the mechanisms of analgesia for
menthol, a common ingredient in over
the counter preparations may actually
be the activation of kappa opiate
receptors.

Menthol generates
analgesic
activity through:
 Ca2+ channel blocking
activity
 Binding to kappa
opioid receptors

Stanos, S.P., 2007



Effect of topical morphine for mucositisassociated pain following concomitant
chemoradiotherapy for head and neck
carcinoma. (Cerchietti LC, Navigante AH,
Bonomi MR, et al., Cancer 2002 Nov
15;95(10): 2230-6.)
Patients (n=26) with cancer-related mucositis
treated with topical morphine or topical
lidocaine/ diphenhydramine/ magnesium
topical solution.






Botulinum Toxin (Type A, Type B)
New intraspinal agents
Thalidomide
Topical antidepressants




Special issues
Evidence for efficacy

Altered behavioral response to pain and
diminished ability to perceive pain impulses without
loss of consciousness.
Opioid Analgesic Actions:
Analgesia
Decreased G.I. Motility
Respiratory Depression
Euphoria
Classes of Analgesics:

NCH 3
H
OH
O
OH

Morpheus - son of Hypnos

Non-narcotic – e.g. aspirin, ibuprophen, etc. Act mainly in the
periphery as anti-inflammatories with some CNS activity as well.
Narcotic/Opioids – Analgesic action is in the CNS. Morphine is the
prototype (From “Morpheus” Greek god of dreams).
Opium is the juice from the poppy and has been used for thousands of
years to relieve pain.

"Among

the remedies which it has
pleased Almighty Godto give to
man to relieve his sufferings, none
isso universal and so efficacious as
opium."Thomas Sydenham(1624 1689)

17th century engraving
of man in Eastern dress
collecting juice from the
buds of poppy plants

He was among the first to describe scarlet
fever, differentiating it from measles and
naming it, and to explain the nature of hysteria
and St. Vitus' dance (Sydenham's chorea).
Sydenham introduced laudanum (alcohol
tincture of opium) into medical practice, was
one of the first to use iron in treating irondeficiency anemia, and helped popularize
quinine in treating malaria.
Derided by his colleagues, Sydenham
benefited immensely from a consequent

Early victims of the War On Drugs. A battle-scene
from the First Chinese Opium War (1839-42)



Central Mu
 respiratory

depression
 analgesia
 euphoria
 miosis


Peripheral Mu
 cough

suppression
 constipation

Small peptides. β-endorphin is a 31 amino acid peptide.
Examples:
Tyr – Gly –Gly – Phe – Met

( Met Enkephalin)

Tyr – Gly –Gly – Phe – Leu

( Leu Enkephalin)

•Similar activity to the opioids (analgesia)
•Similar addiction and withdrawal effects
•Enkephalins are antagonized by opioid antagonists (same receptor)
•Enkephalins are rapidly inactivated by specific peptidases in the brain.
Details of Enkephalin Mechanism
•Enkephalinergic system exists to modulate pain.
•Enkephalin release inhibits adenylate cyclase, decreasing cAMP levels and
causing a K+ efflux that hyperpolarizes the “pain neuron”, which inhibits
nerve cell activity. Opioids also bind the enkephalin post-synaptic receptors.
•Enkephalinergic neurons have an “auto-receptor” that can bind enkephalin
or exogenous opioids.
•Opioid binding to the “auto-receptor decreases enkephalin release, this
results in tolerance,

Second Messenger Effects
Opioids and Enkephalins inhibit cAMP synthesis by inhibiting adenylate cyclase. The
physiological response is to make more enzyme to compensate.
Tolerance develops. When opioids are removed, an excess of AC is available and
now active, overstimulation produces withdrawal.
Opioid antagonists don’t cause withdrawal symptoms in naive subjects.
Enkephalin SAR
L-tyrosine is required along with a terminal NH2.
D-tyrosine is inactive
Phe is very important, partial or full loss of activity occurs upon substitution
D-amino acids at other positions, particularly the Gly’s decrease hydrolysis and
therefore increase potency.
D-amino acids and bulky amino acids affect activity and may increase receptor
selectivity
Rigid analogs are useful for assessing preferred conformations and may be more
selective for different receptors.

All bind morphine and endogenous enkephalins, all are antagonized by
naloxone
µ is the analgesic receptor. µ2 subtype is associated with respiratory
depression and with GI receptors.
δ may be the antitussive receptor for codeine and related compounds.
The antitussive actions of µ and δ specific agonists are antagonized by
naloxone. However dextromethorphan sites don’t bind codeine, and
binding at these sites (likely σ sites) are not antagonized by naloxone.
Therefore, there are at least two antitussive receptors.
J. Pharm. And Exp. Therapeutics (2000) 292, 803-809
κ is also analgesic. Binding site of several mixed agonist/antagonist
compounds.
Pentazocine – agonist at κ, antagonist at µ
Buprenorphine – partial agonist at µ (slowly dissociates), antagonist
at κ
Butorphanol – agonist at κ, antagonist at µ

κ agonists produce psychotomimetic/dysphoric side effects
similar to those seen with the σ receptor agonist PCP. High
doses of pentazocine have this effect.
σ and κ receptors are not analgesic on their own, but specific
κ agonists do cause analgesia.
Nature (1996) 383, p.759; pp.819-823.
µ knockout does not produce analgesia with morphine,
Perhaps µ/δ, µ/κ receptors interact. κ binding could induce
activity in µ receptors.
Other points:
µ (MOR) knockouts are fully functional, no adverse side
effects.
Conclusion: opioid system is not active under normal resting
conditions. That’s why you don’t get addicted to your own
enkephalins.

Opioids have excitatory effects in multiple regions of the nervous
system. Excitation by opioids is generally attributed to inhibition of
inhibitory pathways (disinhibition). However, recent studies indicate
that opioids can directly excite individual cells. These effects may
occur when opioid receptors interact with other G protein coupled
receptors, when different subtypes of opioid receptors interact, or
when opioids transactivate other receptors such as receptor tyrosine
kinases. Changes in the relative level of expression of different
receptors in an individual cell may therefore determine its functional
response to a given ligand. This phenomenon could represent an
adaptive mechanism involved in tolerance, dependence and
subsequent withdrawal.
From inhibition to excitation: Functional effects of interaction between opioid receptors
Life Sciences Volume 76,, (2004), Pages 479-485

“Discouraging data on the
antidepressant.”

 Mechanism—variations on opioid

receptor agonists, mixed agonist
 Route—PO, PR, IV, IV-PCA, IM,
transdermal, transmucosal, epidural/
intrathecal
 Side effects—sedation, respiratory
depression, n/v, constipation, itching

 Contraindications

 Relative—COPD,
hypotension,
impaired renal function,
impaired liver function,
elderly patients
 Absolute—Hypersensitivity,
paralytic ileus,
respiratory depression






6

Era of “Balance”
Growing recognition that opioids are
essential for chronic pain
Potential risks are serious but can be
managed
The goal: maximize symptom relief and
functional improvement while minimizing
addiction, diversion, and side effects









Titrate gradually
Determine cause of symptoms
Change dosing route or regimen
Switch to another opioid
Add an adjuvant and reduce dosage
Eliminate other nonessential agents
Assume that constipation will occur and provide
preemptive treatment

•

Categories
– acute pain
– cancer pain
– chronic (persistent) noncancer pain

•

Temporal pattern
– episodic/continuous

•

Mechanisms
– nociceptive (somatic or visceral)

9

– neuropathic (peripheral or central)



16

Short-acting opioids
 morphine sulfate (eg, Morcontin Morcon )
 Codeine
 Tramadol ( Eg Dolmundin )
 fentanyl
 Buprenorphine

* May contain additional active ingredient.





Gold Standard
Used for severe pain
Hepatic metabolism
45% to 55% to morphine-3-glucuronide, which
produces hyperalgesia, allodynia, hyperactivity
 10% to 15% to morphine-6-glucuronide, which has
greater analgesic properties, fewer adverse effects


(NR) H3CN
14

Modifications of both 3 and 6 positions (hydroxyls).
R=

O

O CCH 3

R=

6

3,6-O-diacetylmorphine, 2 x
morphine. (Heroin)

OH (R1)

O

2

O CCH 3

7

H
1

O

8

3

OH (R)

Greater euphoria, higher addiction liability. Probably metabolized to 6-Oacetate then morphine in CNS.
HEROIN

A powerful remedy for coughs
NCH 3

NCH 3

H

H
O

O

CH3

O

O

O
OH

O

CH3
O

We need analgesics with less respiratory depression that are also less addictive.

Morphinans.

NCH 3

NCH 3

H
H

OH

OH

H

OH

H

OCH 3

levorphanol (Levo-Dromoran)
(-) isomer is an active analgesic,
5 x morphine
(+) isomer is an active
antitussive (dextrorphanol) and
a poor analgesic
N

H

(+) or (d) dextromethorphan
Antitussive activity similar to
codeine, no analgesic activity, no
addiction liability.

butorphanol (Stadol)
4 x morphine as agonist
1 x morphine as antagonist
-low(er) addiction liability
“better for acute pain”

Benzomorphans.
Pentazocine (Talwin)
N

Mixed agonist/antagonist. Used as
an agonist for pain. 1/3 x morphine.
Low addiction.

H3C
CH 3
OH

4-phenyl piperidines. Completely synthetic

CH3
O

OCH 2 CH3

NCH 3

N

H
NCH 3

OH

OCH2 CH 3

O

O
OH

Meperidine

Meperidine

Morphine

4-phenyl piperidine SAR.
•Phenyl and piperidine rings are required.
•3° Nitrogen is optimal. Nitrogen substituent containing a phenyl group increases
potency (fentanyl).
•You can’t make an antagonist by substituting the nitrogen.
•Addition of a meta hydroxyl to the aromatic ring increases potency and addiction
(analogous to morphine)
•C-4 is usually quaternary. Alkyl esters are common for this class. Placing a
nitrogen between the rings increases potency (fentanyl again)
Properties of Phenylpiperidines.
Bemidone – 3 x Meperidine
α-Prodine (Nisentil) – 2 x Meperidine. Not used anymore
Fentanyl (Sublimaze) – ~50-100 x Morphine. Fast onset, short duration.
Used as an analgesic and also as an anesthetic either with or without
droperidol. (About 500 x Meperidine analgesic potency).
Diphenoxylate – Antidiarrheal – Not analgesic at therapeutic doses and can
be dispensed with Atropine
Loperamide (Imodium) – Polar groups decrease intestinal absorption and
eliminate CNS activity. Inhibits GI muscle contraction by interaction with
opioid receptor.

OCH2 CH3

O

NCH3

O

OCH2 CH3

HO

N

Bemidone

CN

OCH 2 CH 3

O

Diphenoxylate

NCH 3
H3 C

α-prodine

O

HO

O

Cl

N

CH 2 CH 3
N
N

Loperamide

Fentanyl
F
N
O

N
O
N

Droperiodol (a butyrophenone, not a phenylpiperidine)

N(CH3 )2

3,3- Diphenylpropyl amines.
Methadone
1x morphine
less sedative
longer acting. 1, 1.5 day half-life. 1 dose every 72 hours will prevent
heroin withdrawal
Propoxyphene
d isomer (Darvon) – analgesic with 1/2 the potency of codeine
l isomer (Novrad) – antitussive action only.

CH 3
C

CH 3
CH 3

CH 2 CH N

CH 2

CH 2 CH 3

Methadone

CH

CH 2

N

O

CH 3
O

C

CH 3

O

CH 2 CH 3

Propoxyphene (d or l isomer)

CH 3

O

O
O

N

O

O

O

N

N

N

O

N

N

N N
N N

O
O

O

O

Remifentanil

Alfentanil

Fentanyl

O

N

O

O

N
N

N
S

Sufentanil

Carfentanil

Fentanyl - Actiq (fentanyl on a stick), Duragesic transdermal patches (12, 25, 50, 100 µg/h) Therapeutic
index=400, morphine = 70
Alfentanil - Ultra-short acting, 5-10 minutes analgesic duration
Remifentanil - Shortest acting opioid - 1/2 time is 4-6 minutes. Used in MAC anesthesia. TI=30,000
Sufentanil - 5-10x Fentanyl, used for heart surgery.
Carfentanil - (100x Fentanyl) Thought that it was used in the 2002 Moscow theater crisis to subdue Chechen
hostage takers. Didn’t turn out so well. 42 terrorists and 130 hostages died. Works well on bears.










Greater risk of inducing seizures than other
opioids
No proof of greater effectiveness
May be associated with cardiac conduction
abnormalities (not reversible by naloxone)
Should not be used in the elderly
No longer used in United Kingdom
1/30/09: FDA Advisors voted to recommend
banning propoxyphene.





MOA: exerts its analgesic effect via high
affinity binding to μ opiate receptors in the
CNS; displays both agonist and antagonist
activity
Possible advantages:
It has a lower abuse potential
 is less dangerous in an overdose
 causes fewer withdrawal symptoms when it's
stopped.




Analgesic activity




0.3 mg of parenteral buprenorphine =10 mg of
parenteral morphine

Prescribing restrictions
MDs with special training to use for opioid addiction
outside of a clinic: DEA # starts with “X”.
 MDs using for pain do not need “X” in DEA.


 Encourage them to write “for pain” on rx.



A weak opioid agonist effective in moderate to
moderately severe pain






Also inhibits reuptake of 5HT and NE

Reduced risk of respiratory depression,
physical dependence, and abuse
Most common adverse events are dizziness,
nausea, constipation, somnolence



17

Long-acting opioids
 methadone
 sustained-release morphine
 transdermal Buprenorphine / fentanyl



18

Efficacy of opioids in chronic noncancer pain
established in a number of randomized,
controlled trials, including placebo-controlled
trials of:
 codeine
 tramadol
 morphine
 fentanyl
 Buprinorphone







How does tramadol work?
Which patients might it benefit?
Is it better tolerated than other analgesics?
Does it have abuse potential?
Where does it fit in the analgesic continuum?



Weak µ-opioid receptor effects


Structurally related to morphine and codeine
 ~10-fold less affinity for µ receptor than codeine and

up to 6000-fold less than morphine
 Metabolized to highly active M1→ 300-fold greater affinity

than parent compound



Analgesia only partially blocked by naloxone (~33%)

Serotonin and norepinephrine reuptake inhibition
Effect reduced by > ½ by adrenergic receptor antagonist
 Less than that with imipramine


Grond S, et al. Clin Pharmacokin 2004;43:879-923.
Raffa RB. J Clin Pharm Therap 2008;33:101-8.




Acute Pain
Chronic Pain
Osteoarthritis
 Neuropathic Pain
 Low back pain








Nausea and vomiting
 switch opioids; anti-emetics
Sedation
 lower dose if possible; add co-analgesics; add
stimulants
Constipation
 treat prophylactically with stool softeners,
bowel stimulants, and nonpharmacologic
measures; switch opioids

34







35

Itching
 switch opioids; antihistamines
Endocrine dysfunction/decrease in libido
 switch opioids; endocrine monitoring;
testosterone replacement; endocrine
consultation
Addiction
 refer for comprehensive assessment



Physical dependence: a withdrawal
syndrome would arise if a drug is
discontinued, dose is substantially reduced,
or antagonist is administered



Tolerance: a greater amount of drug is
needed to maintain therapeutic effect, or
loss of effect over time



Pseudoaddiction: behavior suggestive of
addiction caused by undertreatment of
pain



Addiction (psychological dependence):
a psychiatric disorder characterized by
continued compulsive use of a substance
despite harm

What is the difference
between physical
dependence,
tolerance, and
addiction?



Tolerance
No “high” (opioids are metabolized differently as they
address the pain)
 Usually some physical tolerance and dependency to
pain medications develop




Addiction
Psychological

“high”
Intention to harm the body
Negative personal, legal or medical
consequences



Addiction:
Usage is out of control
 Obsession with obtaining a supply
 Quality of life does not improve




Pseudo-Addiction
From under-treatment of pain
Drug-seeking/Crisis of mistrust
Behavior and function improve when
pain is relieved







Numerous pharmacotherapeutic options
are available for the management of
chronic pain.
Proper evaluation including pain
assessment is key to providing the best
analgesic approach.
Optimizing analgesia in the long term
requires achieving a proper balance among
efficacy, adverse effects, cost and other
factors.

1)

2)

3)

Inhibit sustained high-frequency neuronal firing
by blocking Na+ channels after an action potential,
reducing excitability in sensitized C-nociceptors.
Blockade of Na+ channels and increase in
synthesis and activity of GABA, in inhibitory
neurotransmitter, in the brain.
Modulates Ca+ channel current and increases
synthesis of GABA.
Deglin, J.H. & Vallerand, A.H., 2001










Effective in treating a variety of pain states
Block the reuptake of norepinephrine (and
5HT), which modulates pain
Analgesia at lower doses than anti-depressant
effect
Use limited by side effects (anti-cholinergic)
Amitriptyline vs desipramine
Caution: coronary disease

Beydoun A, Backonja. J Pain Symp Management 2003.

Transmission via
spinothalamic tract
to brain

Dorsal
horn

Ion fluxes Tissue injury
(H+/ K+)

Dorsal root
ganglion

Bradykinin
Prostaglandins
Leukotrienes

Spinal cord
Substance P

To brain
Histamine
Substance P, aspartate,
neurotensin, glutamate

Sensitized
nociceptor








Increase peripheral input: increase DH firing
Increase firing: increased NMDA, Ca, PKC,
Nitric Oxide
Increase PKC, Ca: genetic changes
Increase NO: decreased GABA neurons
Increase Neurotrophins: sprouting

Cousins, MJ, 2009 AAPM

Injury
Acute Pain

Normal Healing
Pain Relief

Healing With Plasticity
Allodynia

Hyperalgesia

Chronic
Pain

Adapted from Marcus DM. Am Fam Physician. 2000;61:1331-1338.

Pain management vels

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