ANALGESICS

Agenda
What is pain
Classification of analgesics
Description
Conclusion

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

Pain is whatever the experiencing

person says it is and exists whenever
he says it does.

Analgesics
(Drugs to Treat Pain)
What is pain?
Sensory stimuli comes from
release of prostaglandins, ,
bradykinins, histamine from
Thalamus
damaged tissue
Substance P released from
sensory nerves, causes spread
of pain
Stimuli carried by sensory fibres
to Thalamus & Cerebrum

Sensory Cortex

Spinothalamic
Nerve
Tract

Goals of pain management

To relieve suffering
Increase functional capacity
Improve quality of life

Analgesics are drugs which relieve pain

without loss of consciousness

Routes of analgesic administration

Oral
Preferred route
Goal for discharge and outpatient managment

Disadvantages:
Delayed absorption & action
No implications for acute pain management

Intramuscular Injection
Used occasionally for short periods
More potent than oral route
Patient may be NPO
Disadvantages:
Absorption delay
Painful
Site rotation necessary

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Intravenous Injection
Uses:
Widely used for acute pain
Effective for exacerbations of chronic pain
Terminal comfort

Methods of administration:
Direct IV push
Patient controlled analgesia (PCA)
Drip

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PCA: patient controlled analgesia

Self-administration of IV analgesic
Very effective
Prevents delays
Reduces patient anxiety

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Other routes
Transdermal
Fentanyl patch
Prolonged duration
Sublingual

Morphine
Fast acting

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Epidural Administration
Catheter inserted in epidural space
Continuous or intermittent infusion
Very effective
Side effects: itching, urinary retention,
hypotension

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Epidural analgesia

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Classification of analgesics
Opioid

Non-Opioid

Agonist
Antagonist
Mixed
AND / OR
Natural alkoloids
Semi synthetic
Synthetic
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Terminology

Pure Agonist: has affinity for binding plus efficacy

Pure Antagonist: has affinity for binding but no efficacy;
blocks action of endogenous and exogenous ligands
Mixed Agonist-Antagonist: produces an agonist effect at
one receptor and an antagonist effect at another
Partial Agonist: has affinity for binding but low efficacy

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History of Opioids
Opium is extracted from poppy seeds
(Paper somniforum)
Used for thousands of years to produce:
Euphoria
Analgesia
Sedation
Relief from diarrhea
Cough suppression

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History contd
Used medicinally and recreationally from
early Greek and Roman times
Opium and laudanum (opium combined
with alcohol) were used to treat almost all
known diseases
Morphine was isolated from opium in the
early 1800s and since then has been the
most effective treatment for severe pain

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History and Background

Invention of the hypodermic needle in
1856 produced drug abusers who self
administered opioids by injection
Controlling the widespread use of opioids
has been unsuccessful because of the
euphoria, tolerance and physiological
dependence that opioids produce

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Terminology
opium is a Greek word meaning juice,
or the exudate from the poppy
opiate is a drug extracted from the
exudate of the poppy
opioid is a natural or synthetic drug that
binds to opioid receptors producing
agonist effects

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Natural opioids occur in 2 places:

1) In the juice of the opium poppy (morphine
and codeine)
2) As endogenous endorphins
All other opioids are prepared from either
morphine (semisynthetic opioids such as
heroin) or they are synthesized from
precursor compounds (synthetic opioids
such as fentanyl)

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Endogenous opioids
Peptides having morphine like actions
isolated in brain,pitutary,spinal cord and
g.I.t
Three distinct families
ENDORPHINS [Pro opiomelanocortin]
ENKEPHALINS [Pro enkephalin]
DYNORPHINS

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Mechanism of action
Activation of peripheral nociceptive fibers
causes release of substance P and other painsignaling neurotransmitters from nerve terminals
in the dorsal horn of the spinal cord
Release of pain-signaling neurotransmitters is
regulated by endogenous endorphins or by
exogenous opioid agonists by acting
presynaptically to inhibit substance P release,
causing analgesia

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Primary Effect of Opioid Receptor Activation

Reduction or inhibition of neurotransmission, due largely

to opioid-induced presynaptic inhibition of
neurotransmitter release
Involves changes in transmembrane ion conductance
Increase potassium conductance (hyperpolarization)
Inactivation of calcium channels

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Three Opioid Receptors

Mu [1 and 2]
Kappa
Delta

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Mu and Kappa Receptor Activation

Response

Mu-1

Mu-2

Kappa

Analgesia
Respiratory
Depression
Euphoria
Dysphoria
Decrease GI
motility
Physical
Dependence

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Delta Receptor
It is unclear what deltas responsible for.
Delta agonists show poor analgesia and
little addictive potential
May regulate mu receptor activity

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Opium Alkoloids
Chemically divided into 2 groups
Phenanthrene
Morphine
Codeine
Thebaine

Benzyl iso quinoline

Papaverine
Noscapine

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Morphine Pharmacological actions

CNS
Analgesia
Euphoria, sedation, hypnosis
Respiration
Pupils
Nausea and emesis
Cough separation
Vagus stimulation
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Morphine Pharmacological actions

GIT
Spasm
Anal

Other

smooth muscles

CVS

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Morphine absorption, fate,

excretion
Highly water soluble
Not suitable as oral prep
Metabolized in liver
Excreted in urine

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Morphine preparation & dosage

Preparation and dosage:
'
(i) Tincture opium: is a hydro alcoholic solution containing
10 per cent opium and I per cent morphine WN. Dose: 0.3 to
2.0 m!. by mouth.
(ii) ChIorodyne: This is a chloroform and morphine tincture
containing 0.229 per cent' of morphine hydrochloride. Dose :
0.3 to 0.6 m!
.
(iii) Morphine solutions (2-20 mg/ml) .are available for oral
use. Oral dose in adults is 1030 mg. Much larger doses (up to
200 mg) may be needed in patients with terminal cancer:
Oral administration is only about one sixth as effective as
parenteral administration.
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Morphine preparation & dosage

(iv) Morphine hydrochloride or sulfate injection.
Each ampoule contains 10 mg of the salt. Dose:
10-20 mg s.c. or i.m.; 2.5-5 mg i.v. slowly over 5
minutes. It has also been used by a continuous,
low dose, intravenous infusion and by epidural
and intrathecal administration. If given by LV.
infusion, 10 mg are infused over the first I hour
and another 10 mg over the next 4 hours.

Morphine
Preparation & doses : adult tab 1050mg every 4hrs; child 5-10mg every 4hrs
Adult 10mg SC/IM every 4hrs ; children
less than 1month 0.15mg/kg ; 2yrs 2.55mg ; 12yrs 5-10mg

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Adverse reactions
Tolerance
Respiratory depression
Constipation
Hypotension
Urinary retention
Drug dependance
Acute morphine poisoning.
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Withdrawl Reactions
Acute Action

Analgesia
Respiratory Depression
Euphoria
Relaxation and sleep
Tranquilization
Decreased blood pressure
Constipation
Pupillary constriction
Hypothermia
Drying of secretions
Reduced sex drive
Flushed and warm skin

Withdrawl Sign

Pain and irritability

Hyperventilation
Dysphoria and depression
Restlessness and insomnia
Fearfulness and hostility
Increased blood pressure
Diarrhea
Pupillary dilation
Hyperthermia
Lacrimation, runny nose
Spontaneous ejaculation
Chilliness and gooseflesh
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Therapeutic uses of morphine

Relief of pain
Sedation and sleep
Pre anesthetic medication
Acute LVF
To produce constipation, relief of severe
diarrhoea

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Precautions with Morphine Therapy

Diminished respiratory reserves
Low BMR in myx oedema
Hypovolumic shock
Old people and infants
Head injuries
Acute abdomen

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Other Phenanthrene Alkoloids of

Opium
Codiene
Avialable for oral and IM use
Dosage : 30 60 mg orally 3-4 times a day

Papaverine
Noscapine

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Semi synthetic derivatives of natural

opium alkoloids
Heroin (di-acetyl morphine, dia-morphine,
brown sugar)
Dosage : 1.5mg every 4hrs (for analgesic
effect)
Addiction

Apomorphine
stimulant of CTZ

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Synthetic morphine substitutes

Pethidine and its congeners
Methadone and its congeners
Morphinan compounds
Benzomorphan derivatives
Misc nalbuphine, buprenorpnine

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PETHIDINE
Action same as morphine
No miosis seen
No anti-tussive activity
Preparation : 25-100mg by SC or IM or
25-50mg by IV every 4 hourly; child IM
0.5-2mg per kg every 3-4hrs

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Methadone (Physeptone)
Same as morphine
Preparation & dosage : 5mg tab 2 times a
day ; same as above for sc

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Buprenorpnine
Same as morphine
Action cannot be readily reversed by
nalaxone
Doses : IM/ IV 0.3mg in 1ml by deep IM or
slow IV over 2mins, repeat after 6hrs ;
children 2-12yrs 2-6mcg/kg 6 hourly

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Fentanyl
Pharmacokinetics
Routes of Administration
* Oral, and transdermal (possibly
intravenous)
*Highly lipophilic
*latency to onset (7-15 minutes oral; 12-17
hours transdermal
*duration of action ( 1-2 hours oral; 72hours
transdermal)
*80 85% plasma protein bound
*90 % metabolized in the liver to inactive
metabolites
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Fentanyl cont.
Other properties
* 80 times the analgesic potency of
morphine and 10 times the analgesic
potency of hydromorphone.
*high efficacy for mu 1 receptors.
*most effective opiate analgesic

Opioid Antagonists
Noloxone
Nolorphine
Naltrezone (50mg/day)

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Opioid Antagonist:
Naloxone (Narcan)
Used to reverse opioid
overdose
displaces receptor-bound
opioids
Good for overcoming
respiratory/CV
depression
Dosage : 0.4mg/ml, IV
bolus in the dose of 0.82mg every 2-3mins;
children 10mcg/kg IV

Just beat it!

Naloxone
Morphine

Opioid Receptor
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Nalorphine
N allylnormorphin
To a morphine addict

Preparation & dosage : 10mg SC/IV every

6hourly

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NSAID

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History/Actions
Bark of willow tree: Pain relief from chemical in bark,
salicin (chemically related to aspirin)
NSAID prototype:
Acetylsalicylic acid (ASA) = aspirin
Action of NSAIDs:
through either selective or non-selective blocking of
enzymes involved in the synthesis of prostaglandins

NSAID= non-steroidal anti-inflammatory drug

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Classification of NSAID
I. The salicylates and their congeners -aspirin
II. The para-aminophenol derivatives e.g.
phenacetin, paracetamol.
III. The pyrazolon derivatives e.g.
phenylbutazone and related compounds.
IV. Indoles and related drugs: indomethacin.
sulindac, tolmetin and ketorolac,
V. Phenylacetic acid derivatives: diclofenac.
VI. Propionic acid derivatives: ibuprofen,
fenoprofen, naproxen, ketoprofen and pirofen.
VII. Fenamates e.g. flufenamic acid and
mefenamic acid.
VIII. Oxicams e.g. piroxicam.

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TISSUE DAMAGE
release
PHOSPHOLIPIDS

Phospholipase A
ARACHIDONIC ACID

PLATELET-ACTIVATING
FACTOR

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ARACHIDONIC ACID
LOX

COX
PGG2, PGH2

5-HPETE

PROSTACYCLIN
PGI2
LEUKOTRIENES
and
HETE

THROMBOXANE

PROSTAGLANDINS
TXA2
PGD2, PGE2, PGF2
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LEUKOTRIENES
and
HETEs

Chemotactic
Polymorphs attracted to area
lower the firing threshold of
pain fibers
Stimulate nociceptors directly

PGI2
PGD2, PGE2, PGF2

Sensitize nociceptors to
noxious and non noxious
stimuli

TXA2
** PGE2
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HEPTEs
HYDROPEROXYEICOSATETRAENOIC ACIDS

HETEs
HYDROXYEICOSATETRAENOIC ACIDS

57

Where do NSAIDs Work?

Cell Membrane

Phospholipase A2

NSAIDs

Arachidonic Acid
Lipoxygenase

Leukotrienes

Cyclooxygenase

Prostaglandins
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Adverse effects of prostaglandins

Vasodilation
Enhance actions of other mediators
Amplify pain
Amplify transmission of
pain

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COX-1 = PGH synthase-1

Normal constitutive enzyme
Present under normal situations

COX-2 = PGH synthase-2

Inducible enzyme
Present under abnormal situations
May increase up to 20-fold

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COX Enzyme:Prostaglandin Effects

COX-1: beneficial COX-2: harmful
Peripheral injury
site

Inflammation

Brain

Modulate pain
perception
Promote fever
(hypothalamus)

Stomach

protect mucosa

Platelets

aggregation

Kidney

vasodilation
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Effects of COX Inhibition

by Most NSAIDS
COX-1
Gastric ulcers

COX-2
Reduce inflammation

Bleeding

Reduce pain

Acute renal failure

Reduce fever

NSAIDs : anti-plateletdecreases ability of blood to clot

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Salicylates [asprin,colsprin, ecosprin]

Esters or salts of salicylic acid
e.g. methyl salicylate,
sodium salicylate
or acetyl salicylic acid

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Pharmacological actions of
Salicylates
CNS (Analgesia, Antipyretic, Respiration)
Acid base balance and electrolytes
GIT (dyspepsia, nausea, vomiting, peptic
ulceration)
Anti inflammatory effect
Uricosuric effect
Metabolic effects

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Absorption, Fate and Excretion

Lipid soluble
Protein bound
LIVER
Excreted in urine

65

Adverse reaction
GIT
Haemopoietic system
Reyes syndrome
Pregnancy and infants
Salicylism
Acute salicylate intoxication
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Preparation & dosage

Cannot be used in children below 12yrs
Adult dose 300 mg to 900mg /4 hourly
In juvenile rheumatoid arthritis 80 100
mg/kg/day

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Theraupetic uses of salicylates

Local application
Analgesic
Antipyretic
Antiinflammatory
Antirheumatic
Antiplatelet

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Para-aminophenol derivatives
Paracetamol [crocin, calpol]
Adverse reaction (neutropenia,
thrombocytopenia, heamolysis, skin reaction,
damage to liver)
Preparation and dosage 500mg tablets, total
daily dose should not exceed 2.5g in adults
Child under 3months 10mg/kg; 3m-1y 60120mg; 1-5y 120-250mg; 6-12y 250-500mg all 34 times/ day
Adult IM 150mg/ml 2ml IM as required

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Pyrazolone derivatives
These are aminopyrine and antipyrine
Phenylbutazone and oxyphenbutazone [phenacid ]
Theraupetic uses
Gout
Ankylosing spondilitis
Arthritis

Preparation & dosage tab 100mg enteric coated

dose 200-400mg daily in divided doses
Adverse reactions GIT, heamotologic, liver and
kidneys
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Indoles and related drugs

Indomethacin [ indocap,inocin]
Preparation & dosage 25mg capsules
total daily dose 50-150mg in divided
doses after food
Theraupetic use not a treatment of
choice for arthritis, acute gout and
ankylosing spondilitis

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Heterocyclic arylacetic derivatives

Diclofenac sodium (voveran)
Not recommended in children, pregnant
women and nursing mothers
Recommended in arthritis and ankylosing
spondilitis
Most extensively used NSATD
Dose 50mg TDS, 75mg deep IM
injection, 0.1% eye drops
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Ketorolac
Frequently used in postoperative and
acute musculoskeletal pain
Dosage oral 10-20mg 4-6hrs not more
than 7days
15-30mg IV or IM 4-6hrs

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Propionic acid derivatives

Ibuprofen
Naproxen
Flurbiprofen
Fenoprofen
Ketoprofen

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Ibuprofen (brufen, ibigesic)

Dosage children 20-30mg/kg in
divided doses

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Analgin (Novalgin, Baralgan)

Adult dose 500mg 4 times/day;
500mg/ml, 1-2ml 2-3times/day IV
Child 12-14y 0.8ml IV 4times/day
Infants 0.1ml IM QID

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sulfonanilides
Nimusilide( preferential COX-2 inhibitors)
Affinity for cox2 than cox1 and stomach
friendly
Dosage 100mg BD.
ADR-G.I.T disturbances
dermatological
fulminant hepatic failure?
Usefulness to asthmatics.
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Fenamates (anthranilic acid

derivative)
Mefanamic acid (dysmen,musculoskeletal
pain)
250- 500mg tab 6hourly;
T.N. MEFTAL,MEDOL.

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Oxicam
Long acting potent NSAID with
antiinflammatory and good analgesicantipyretic action.
Inhibit inflammation in diverse ways
Piroxicam (Pirox) dose 10-20mg once a
day

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Selective Cox-2 Inhibitors

Greater affinity for cyclooxygenase-2
Decreased incidence of negative effects
associated with non-selective COX-inhibitors

Celecoxib-100-200mg BD
Rofecoxib (coxtwo), rofeb-12.525mgOD ,max 50mg
Valdecoxib(vorth,valus)-10mg BD
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Pharmacotherapy of pain

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83

ELEMENTS OF EFFECTIVE 3D PAIN CONTROL

Flexible analgesics strategy

SELECTED OPOID COMBINATION AND ANALGESIC DRUGS

REFERENCES
Essentials of Medical Pharmacology, Analgesics
pg389-409, K. D. Tripathi, 3rd edition
Clinical Pharmacology for Dental Professionals,
Analgesics ch5, Sebastian Ciancio, 3rd edition
Pharmocology and Pharmacotherapeutics, opioid
and analgesics, Satoskar, Bhandarkar, 16th edition
CIMS, apr2004
Indian Journal of Pharmacology, 2003, Thawani et al
The Pharmacological basis of Therapeutics,
Goodman & Gilmans, 8th edition, Vol I

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THANK YOU

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