“ANALGESICS”

Presented by:

Dr. Manish Chandila

JR-2
 PAIN

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-opioid 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
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
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 cont’d

•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

Sertürner, 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 opireceptors:
mu, delta, kappa, epsilon, sigma
 Morphine CNS

Depressant effects Stimulate effects

• Analgesia
• Indifference to surroundings
• Mood and subjective effects
• Depression of respiration
• Cough centre
• Temperature regulating centre
• Vasomotor centre
• CTZ (nausea, vimiting)
• Edinger Wesphal nucleus
(III nerve –producing miosis)
• Vagal centre (bradycardia)
• Certain cortical areas and
hippocampal
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)
 Acute left-ventricular cardiac failure
(cardiac asthma)
 Reduce preload on heard due to vasodilatation
 Tending to shift blood from pulmonary to systemic circuit;
relieves pulmonary congestion and edema
 Allays air hunger by depressing respiratory centre
 Cuts down sympathetic stimulation by calming the patient
 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 drug’s

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
• 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”
OMNOPON
• contains mixture if opium alkaloids
(48-50% morphine)
• does not cause spasms of smooth musculature,
as it contains alkaloids of isoquinoline raw
• is used for analgesia according to all the
indications of morphine hydrochloride, for
example, colics
Promedol (trimeperidine)
• produces similar effects to other opioids, such
as analgesia and sedation, along with side
effects such as nausea, itching, vomiting and
respiratory depression which may be harmful or
fatal.
• duration of analgesic action - 3-4 hours
• moderate spasmolytic influence on smooth
musculature of internal organs
• stimulation of rhythmic contractions of uterus
• can be used for analgesia
• in case of pain syndrome connected with
spasms of smooth musculature
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
Pentazocin
 agonist-antagonist of opioid receptors
 comparatively with morphine, it is a bit less
dangerous in the aspect of addiction development
 indicated in case of pain of medium intensity in
such conditions like other opioid analgesics. In case
of strong pain its administration is limited as in case
of increasing of dose of the drug excitation appears
 it can cause increasing of blood pressure and
tachycardia that’s why it’s not advised to use in case
of acute myocardium infarction
 if it is administered for people with narcotic
addiction manifestations of abstinence develop
Buprenorphine
• Partly agonist of mu-opioid receptors
• Acts longer than morphine (approximately 6 hours)
• Analgesic activity is higher than of morphine, that’s why it’s
used in doses of 0,3-0,6 mg
• In case of breathing depression, which it causes, naloxon is less
effective since buprenorphine is slowly released from the
connection with mu-receptors
• Indicated for pain decreasing in the same situations as other
narcotic analgesics
• May be used for detoxication and supporting treatment of
individuals who is addicted to heroine
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
 suspension of 20-30 g of activated charcoal
 salt laxative agents (sodium sulfate)
 forced diuresis
 atropine sulfate
 inhalation of carbogen (5-7 % СО2 and 93-95 % O2)
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-platelet—decreases 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
Applications in Dentistry

• Toothache
• Post extraction pain
• Periodontitis
• Neuritis
• Stomatitis
• Arthritis
• Local usage as keratoplatic agents for hyperkeratosis, hyperesthesia
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, production of met-hemoglobin
 Paracetamol (Acetaminophen)
N-Acetyl-P-Aminophenol

Classification: analgesic, antipyretic, misc.

not an NSAID

Mechanism: inhibits prostaglandin synthesis

via CNS inhibition of COX (not peripheral)-
doesn’t promote ulcers, bleeding or renal failure;
peripherally blocks generation of pain impulses,
inhibits hypothalamic heat-regulation center
 Paracetamol
• Tablets
• Suppositories
• Syrups
• Soluble tablets
• 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 (liver’s 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 Reye’s 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 μ-opioid receptor

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

2. 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!!