This document provides an overview of analgesics, including both opioid and non-opioid analgesics. It discusses various opioid analgesics like morphine, codeine, fentanyl and pentazocin. It describes their mechanisms of action, indications, routes of administration, side effects and contraindications. It also discusses non-opioid analgesics like paracetamol, acetylsalicylic acid and analgin, and describes their mechanisms of action as inhibitors of prostaglandin synthesis. The document classifies different types of pain and summarizes the history and development of commonly used opioid analgesics.

1. “ANALGESICS”
Presented by:
Dr. Manish Chandila
JR-2

2. PAIN
What is pain?
• A protective mechanism to warn of damage or the
presence of disease
• Part of the normal healing process

3. 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

4. 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

5. 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

6. Major Sources of Pain
Source Area Involved Characteristics Treatment
Somatic body
framework
throbbing,
stabbing
narcotics,
NSAIDS
Visceral kidneys,
intestines,
liver
aching,
throbbing,
sharp, crampy
narcotics,
NSAIDS
Neuropathic Nerves burning,
numbing,
tingling
narcotics,
NSAIDS,
antidepressants,
anticonvulsants

7. 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

8. 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

9. Friedrich Wilhelm Adam
Sertürner, a German
pharmacist, isolated
Morphine from opium,
in 1805.
Morpheus
is the Greek god of
dreams and sleep.

10. 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

11. 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

12. Morphine CNS
Depressant effects
• Analgesia
• Indifference to surroundings
• Mood and subjective effects
• Depression of respiration
• Cough centre
• Temperature regulating centre
• Vasomotor centre
Stimulate effects
• CTZ (nausea, vimiting)
• Edinger Wesphal nucleus
(III nerve –producing miosis)
• Vagal centre (bradycardia)
• Certain cortical areas and
hippocampal

13. 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)

14. 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

15. 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.

16. 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

17. 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

18. 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

19. 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

20. Addiction
•Physical dependence
•Physiological dependence
•Withdrawal reactions

21. Tolerance and Dependence

22. 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”

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. Triad in case poisoning
with morphine
Acute miosis
(Pinpoint
pupils)
Cheyne Stokes
respiration
deep tendon
reflexes
increased

32. 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)

33. NON-OPIOID
ANALGESICS

34. Pharmacodynamic Effects
•Analgesic
•Antipyretic
•Anti-inflammatory
(except paracetamol)

35. 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

37. Effects of COX Inhibition
by Most NSAIDS
COX-1
Gastric ulcers
Bleeding
Acute renal failure
COX-2
Reduce inflammation
Reduce pain
Reduce fever
NSAIDs : anti-platelet—decreases ability of blood to clot

38. 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

39. 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

40. Applications in Dentistry
• Toothache
• Post extraction pain
• Periodontitis
• Neuritis
• Stomatitis
• Arthritis
• Local usage as keratoplatic agents for hyperkeratosis, hyperesthesia

41. 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

42. 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

43. Paracetamol
•Tablets
•Suppositories
•Syrups
•Soluble tablets
•Capsules

44. PARACETAMOL

45. Pharmacokinetics: Paracetamol
Metabolism: major and minor pathways
Half-life: 1-3 hours
Time to peak concentration: 10-60 min
Treatment for overdose: Acetylcysteine

46. 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

47. 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

48. 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

49. Analgin
(metamizol-sodium)

50. Baralgin (maxigan, spazgan, spazmalgon,
trigan)
metamizol-sodium +pitophenon hydrochloride+pheniverinium
bromide
Ampoules
tablets
suppositories
Analgesic
and
spasmolytic
activity

51. Traditional and selective COX-2
inhibitors

52. 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

53. 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

54. 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

55. 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

56. THANK YOU!!