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ANALGESICS

Pain Management
What is pain?
A protective mechanism to warn of damage or
the presence of disease
Part of the normal healing process
ANALGESICS
I. Opioid (narcotic) analgesics
1. Agonists of opioid receptors morphine hydrochloride, promedol,
omnopon, fentanyl, codeine;
2. Agonists antagonists and partial agonists of opioid receptors
pentazocin, buprenorphine.
II. Non-opioid analgesics and non steroidal anti-
inflammatory drugs - NSAIDs
acetylsalicylic acid, paracetamol, analgin, indometacin, butadion,
ibuprofen, pyroxicam, diclofenac-sodium, ketorolac, ketoprofen.
III. Substances with mixed mechanism of action
(opioid and non-oioid components)
tramadole
The structures that take part in perception of pain:
thalamus, hypothalamus, reticular formation,
limbic system, occipital and frontal areas of
cortex
System which conducts and perceives pain -
nociceptive
Nociceptors - An Introduction to Pain.mp4
System which protects organism
from pain antinociceptive
Classification of Pain
By Onset and Duration
Acute pain
Sudden in onset
Usually subsides once treated

Chronic pain
Persistent or recurring
Often difficult to treat
Major Sources of Pain
Source Area Involved Characteristics Treatment

Somatic body throbbing, narcotics,


framework stabbing NSAIDS

Visceral kidneys, aching, narcotics,


intestines, throbbing, NSAIDS
liver sharp, crampy

Neuropathic Nerves burning, narcotics,


numbing, NSAIDS,
tingling antidepressants,
anticonvulsants
OPIOID
ANALGESICS
History of Opioids
Opium is extracted from poppy seeds
(Papaver somniforum)
Used for thousands of years to produce:
Euphoria
Analgesia
Sedation
Relief from diarrhea
Cough suppression
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
Morpheus
is the Greek god of
dreams and sleep.

Friedrich Wilhelm Adam


Sertrner, a German
pharmacist, isolated
Morphine from opium,
in 1805.
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
Opioid receptors
group of G-protein coupled receptors with
opioids as ligands.
The endogenous opioids are dynorphins,
enkephalins, endorphins, endomorphins and
nociceptin.

Subtypes of opiod receptors:


mu, delta, kappa, epsilon, sigma
Opiod Receptor Activation

Response Mu-1 Mu-2 Kappa Delta Sigma

Analgesia

Respiratory
depression
Euphoria

Dysphoria

Decrease GI
motility
Physical
Dependence
Mania,
hallucination
Morphine CNS
Depressant effects Stimulate effects
Analgesia CTZ (nausea, vimiting)
Indifference to surroundings Edinger Wesphal nucleus
Mood and subjective effects (III nerve producing miosis)
Depression of respiration Vagal centre (bradycardia)
Cough centre Certain cortical areas and
Temperature regulating hippocampal
centre
Vasomotor centre
Morphine can be used as an
analgesic to relieve:
pain in myocardial infarction
pain associated with surgical conditions, pre- and
postoperatively (pre-anesthetic medication, balanced
anesthesia, surgical analgesia)
pain associated with trauma, burns
severe chronic pain, e.g., cancer
pain from kidney stones, renal colic, ureterolithiasis, etc
(pain may be valuable for diagnosis: should not be relived by
analgesic unless proper assessment of the patient has been done)
traumas of thorax accompanied by cough (morphine depresses
central links of coughing reflexes)
Applications in Dentistry

Narcotic (opioid) analgesics are extremely


effective in reducing acute dental and
postoperative pain.
The narcotic analgesics have established a
niche for the treatment of pain in those
situations where the NSAIDs are less effective.
Hydrocodone, oxycodone, codeine, and
occasionally meperidine are the narcotics used
to treat dental pain.
MORPHINE HYDROCHLORIDE
routes of administration
subcutaneously and intramuscularly
(analgesic action after 10-15 min)
oral administration presystemic elimination
( 20-60 % enters general blood circulation)
sublingually quick absorption
i.v. is indicated even in emergency
Epidural or intrathecal ( into the spinal canal ) injection
produces segmental analgesia lasting 12 hours without
affecting other sensory, motor or autonomic modalities
Duration of analgesic action 4-6 hours
Maximum single dose of morphine is 0,02 g,
maximum daily dose 0,05 g
Side effects of morphine
Respiratory depression
Vomiting (excitation of starting zone of vomiting
center)
bradycardia (increasing of tone of n. vagus nuclei)
spasm of sphincters of gastro-intestinal tract
accompanied by constipations
increasing of tone of smooth musculature of
urinary and bile-excreting tracts (retentions of
urination, bile stasis)
Decreasing of BP
CONTRAINDICATIONS FOR ADMINISTRATION
OF MORPHINE
acute respiratory depression
renal failure (due to accumulation of the metabolites morphine-3-
glucuronide and morphine-6-glucuronide)
chemical toxicity (potentially lethal in low tolerance subjects)
raised intracranial pressure, including head injury (risk of worsening
respiratory depression)
Biliary colic

Precaution
pain that accompanies chronic inflammatory pain
children before the age of 2 years
Tolerance
Tolerance is a diminished responsiveness to the drugs action
that is seen with many compounds
Tolerance can be demonstrated by a decreased effect from a
constant dose of drug or by an increase in the minimum drug
dose required to produce a given level of effect
Physiological tolerance involves changes in the binding of a
drug to receptors or changes in receptor transductional
processes related to the drug of action
This type of tolerance occurs in opioids
Addiction
Physical dependence
Physiological dependence
Withdrawal reactions
Tolerance and Dependence
Withdrawl Reactions
Acute Action Withdrawl Sign
Analgesia Pain and irritability
Respiratory Depression Hyperventilation
Euphoria Dysphoria and depression
Relaxation and sleep Restlessness and insomnia
Tranquilization Fearfulness and hostility
Decreased blood pressure Increased blood pressure
Constipation Diarrhea
Pupillary constriction Pupillary dilation
Hypothermia Hyperthermia
Drying of secretions Lacrimation, runny nose
Reduced sex drive Spontaneous ejaculation
Flushed and warm skin Chilliness and gooseflesh
Fentanyl
synthetic opioid analgesic of short action
analgesic activity is 300 times higher
than of morphine
analgesic effect after intravenous
introduction after 1-3 min, lasts for
15-30 min
used with neuroleptic droperidol
(complex drug talamonal) for
neuroleptanalgesia
fentanyl transdermal system
should be used for long-
term (chronic) pain
requiring continuous
narcotic pain
Is designed to release the
drug into the skin at a
constant rate ranging
from 25 to 100
micrograms/h,
Codeine
opium alkaloid
analgesic action is not strong, but
anticough effect is considerable
administered as an anticough drug of
central action
combination with non opiod analgesics
(eg. Paracetamol) is supra-additive
Acute poisoning with opioid analgesics
Respiratory Depression
Euphoria
Relaxation and sleep
Tranquilization
Decreased blood pressure
Constipation
Pupillary constriction
Hypothermia
Drying of secretions
Flushed and warm skin
Triad in case
poisoning with
morphine
Acute miosis
(Pinpoint
pupils)

Cheyne Stokes
respiration

deep tendon
reflexes
increased
Treatment of acute poisoning
Naloxon (antagonist of opioid receptors)
intravenously - 0,4-1,2 mg
general dose of naloxon should not overcome 10 mg
stomach lavage (for morphine enterohepatic circulation
is typical) with 0,05-0,1% solution of potassium
permanganate and 0,5 % tannin solution
NON-OPIOID
ANALGESICS
Pharmacodynamic Effects

Analgesic
Antipyretic
Anti-inflammatory
(except paracetamol)
Mechanism of action of non-opioid analgesics

depression of cyclooxygenases activity


decreasing of prostaglandins synthesis in
peripheral tissues and in central nervous system
decreasing of sensitivity of nervous endings and
depression of transmission of nociceptive impulses
on the level of CNS structures
pain-relieving action of non-opioid analgesics is
partly connected with their anti-inflammatory
activity
Effects of COX Inhibition
by Most NSAIDS

COX-1 COX-2

Gastric ulcers Reduce inflammation

Bleeding Reduce pain

Acute renal failure Reduce fever

NSAIDs : anti-plateletdecreases ability of blood to clot


COX Enzyme:Prostaglandin Effects
COX-1: beneficial COX-2: harmful

Peripheral injury Inflammation


site
Brain Modulate pain
perception
Promote fever
(hypothalamus)
Stomach protect mucosa
Platelets aggregation

Kidney vasodilation
Indications for administration of non-
narcotic analgesics
headache
toothache
backache
neuralgias
pulled muscles
joint pain
dysmenorrhea
for potentiating of their action combinations
paracetamol with codeine,
metamizol with dimedrol, metamizol with codeine
Paracetamol
(Acetaminophen)
analgesic and antipyretic drug
maximal effect if the drug is introduced
orally after 2 hours, lasts approximately
for 4 hours
in case of durable administration of big
doses damaging of liver and kidneys
Paracetamol (Acetaminophen)
N-Acetyl-P-Aminophenol

Classification: analgesic, antipyretic

Mechanism: inhibits prostaglandin synthesis


via CNS inhibition of COX (not peripheral)-
doesnt promote ulcers, bleeding or renal failure;
peripherally blocks generation of pain impulses,
inhibits hypothalamic heat-regulation center
Paracetamol

Tablets
Suppositories
Syrups
Capsules
PARACETAMOL
Pharmacokinetics: paracetamol

Metabolism: major and minor pathways


Half-life: 1-3 hours
Time to peak concentration: 10-60 min

Treatment for overdose: Acetylcysteine


Paracetamol Liver Metabolism

1. Major pathway Majority of drug is


metabolized to produce a non-toxic metabolite
2. Minor pathway Produces a highly reactive
intermediate (acetylimidoquinone) that
conjugates with glutathione and is inactivated.

At toxic paracetamol levels, minor pathway


metabolism cannot keep up (livers supply of
glutathione is limited), causing an increase in the
reactive intermediate which leads to hepatic toxicity
and necrosis
Acetylsalicylic acid
Blocks irreversibly COX
As antipyretic and analgesic
drug 0,25 and 0,5 g per time
As an anti-inflammatory 3-4 g
per day (for arthritis,
myocarditis, pleuritis, bronchitis
etc.
As platelets inhibitor - for
prophylaxis of thrombus-
formation (in case of ischemic
heart disease, thrombophlebitis
etc.) daily dose 80-100 mg
Pharmacokinetics: ASA
Absorption: from stomach and intestine
Distribution: readily, into most fluids/tissues
Metabolism : primarily hepatic
ASA contraindicated for use in children with viral
fever can lead to Reyes Syndrome
Fatal overdose is possible

Similar pharmacokinetics for ibuprofen and related NSAIDs


Analgin
(metamizol-sodium)
Baralgin (maxigan, spazgan,
spazmalgon, trigan)
metamizol-sodium +pitophenon
hydrochloride+pheniverinium bromide

Ampoules
tablets
suppositories

Analgesic and
spasmolytic
activity
Traditional and selective COX-2
inhibitors
Ketorolak (ketanov)
according to analgesic activity it
prevails over effect of acetylsalicylic
acid, indometacin and equals to
opioid analgesics
moderate anti-inflammatory,
antipyretic and anti-aggregate effects
high effectiveness in case of pain in
postoperative period, in oncology,
during child delivery, traumas, colic
i/m, i/v, orally
NOT indicated
for chronic pain syndrome
Ketoprophen (ketonal)
strong analgesic, anti-inflammatory and
antipyretic agent
administered in case of arthroses and
arthritis, ancilizing spondilitis, pain of
different genesis (after surgeries, in case
of traumas, painful menstruations etc.)
administered orally, intramuscularly, in
forms of suppositories and ointments
TRAMADOL
Analgesic activity is similar to the activity
of morphine
Abuse potential is low
Less respiratory depression
Hemodynamic effects are minimal
In case of intravenous administration effect
develops after 5-10 min, if administered
orally after 30-40 min, action lasts for
3-5 hours.

Tramadol possesses agonist actions at the -opioid receptor


and affects reuptake at the noradrenergic and serotonergic systems
ADMINISTRATION OF TRAMADOL
surgery, traumatology, gynecology,
neurology, urology, oncology

For all kinds of acute and chronic pain of


moderate and considerable intensity,
including
neuralgias, postoperative, traumatic pain
diagnostic and therapeutic interventions
oncologic pathology
Thank you!

QUESTIONS?!