Pain is a complex experience involving both sensory and emotional components. There are various scales used to measure pain. The main options for pain treatment are analgesics which can be opioids or non-opioids. Opioids include natural, semi-synthetic, and synthetic compounds that act on opioid receptors in the brain to reduce pain perception and emotional response to pain. Non-opioids like NSAIDs inhibit prostaglandin synthesis to reduce inflammation and pain. Common NSAIDs include aspirin, ibuprofen, and paracetamol.

1. CNS Pharmacology
Opioid and non-opioid
analgesics

2. Pain definition
• An unpleasant sensory and emotional experience associated with
actual or potential tissue damage
• Pain is whatever the experiencing person says it is and exists
whenever he or she says it does
• Pain is whatever the patient thinks it is at the present time
• Dual nature of pain:
• Pain perception
• Pain reaction

3. PAIN SCALES

4. Pain treatment options
Analgesics
• Kill pain
LA
• Kill all
sensations
GA
• Kill
consciousness

5. ANALGESICS
PAIN KILLERS
A. Opioids
 Natural opiates (Alkaloids contained in the resin of the opium poppy
including morphine, codeine and thebaine)
 Semi-synthetic Opiates (Created from the natural opioids such as
hydromorphone, oxycodone and diacetylmorphine (heroin))
 Fully synthetic opioids (Fentanyl, methadone and tramadol)
 Endogenous opioid peptides (Proudced naturally in the body, such as
endorphins, enkephalins, dynorphins and endomorphins)
B. Non-opioids (Non-Steroid AntiInflamatory Drugs and
paracetamol)
 COX inhibitors: paracetamol, acethylsalycilic acid, ibuprophen,
diclophenac…
“Sedare dolorem - divinum opus est”
“Smiriti bol - božansko je delo”

6. Opium Poppy

7. History of opium
 Opioids have been the mainstay of pain treatment for thousand of
years, and they remain so today
 The search for a safe, orally active, and non-addictive analgesic
based on the opiate structure is one of the oldest fields in medicinal
chemistry
 The opiates are perhaps the oldest drugs known to humanity
 The first undisputed reference to opium is found in the writings of Theophrastus in
the third century B.C.
 The use of opium was recorded in China over 2000 years ago, and was known in
Mesopotamia before that
 Its use in medicine is quoted in a twelfth-century prescription:
• Take opium ,mandragora, and henbane in equal parts and mix with water. When you
want to saw or cut a man, dip a rag in this and put it to his nostrils. He will sleep so
deep that you may do what you wish.

8. Opioids

9. Pain signal

10. Opioid receptors subtypes
Endogenous opioids

12. Mechanis of action

13. Opioids

14. METABOLISM
• Morphine
• Morphine-3-glucuronide (M3G) – neuroexcitory properties
• Morphine-6-glucuronide (M&G) – an active metabolite
• Meperidine (pethidine)
• Normeperidine – seizures
• Codeine
• CYP2D6 – codeine demethylated to morphine

15. Opioid effects
1. Analgesia – both sensory and affective (emotional) components.
2. Euphoria/dysphoria
3. Sedation
4. Respiratory depression/broncho constriction (depression of the
ventilatory response to CO2)
5. Cough suppression
6. Constipation (decrease in propulsive movements, contractions of
sphincters, decrease secretions, inattention to defeacation reflex)
7. Miosis (stimulation of III nerve nucleus)
8. Pruritus

16. Opioid effects
9. Hypotension/bradycardia (excl. Meperidne)
10. Vomiting
11. Disruption of sleep architecture
12. Temperature regulation- hyper/hypothermia
13. Biliary colic
14. Antidiuretic action/reduction in renal blood flow
15. Endocrine (FSH, LH, ACTH levels are lowered, GH levels are raised)
16. Prolongation of labour
17. Difficulty in urination

17. INDICATIONS
• Pain (traumatic, visceral, ischemic –MI, postoperative, burn, cancer
pain, renal colic…)
• Preanesthetic medication
• Acute pulmonary edema
• Cough
• Diarrhoea

18. Routes of administration
• Oral
• IV, IM, SC
• Epidural/subarachnoid
• Rectal
• Intra nasal (butorphanol)
• Buccal/trans mucosal
• Transdermal
• PCA (Patient controlled analgesia)

19. Adverse effects

20. Tolerance
• Pharmacokinetic (increase metabolism)
• Pharmacodiynamic (receptor recycling, receptor
uncoupling)
• NMDA receptor antagonists – recouple receptors to their target
ion channels
• Opioid rotation

21. Degrees of tolerance

22. CONTRAINDICATIONS AND CAUTIONS
• Pure agonists with weak partial agonists
• Head injuries
• Pregnancy
• Impaired pulmonary function
• Impaired hepatic and renal function
• Endocrine diseases
• Undiagnosed acute abdomen
• Elderly males

23. OPIOID ANTAGONISTS
 Naloxone – short acting – treatment of opioid over
dosage, testing of dependence, shock (increase
BP)
 Naltrexon – oral, long acting, management of
opioid, alcohol, nicotine dependence
 Nalmefene – IV, long acting
 Methylnaltrexone bromide – constipation in
patients with late sage advanced illness
 Alvimopan – postoperative ileusfollowing bowel
resection surgery

24. ATYPICAL OPIOIDS
• Tapentadol
• Moderate µ agonist, strong inhibitor of NE reuptake (NET)
• Analgesia, moderate pain
• Duration 4-6 h
• Toxicity: hedache, nausea and vomiting, possible dependence, serotonin
syndrome with SSRI
• Tramadol
• weak µ agonist, moderate SSRI, weak inhibitor of NE reuptake (NET)
• moderate pain, chronic pain syndromes
• Duration 4-6 h
• Toxicity: seizures, risk of serotonin syndrome

25. ANTIPYRETIC-
ANALGESIC AND
ANTIINFLAMMATORY
DRUGS

26. Phospholipase
Arachidonic acid
Cyclooxygenase Lipoxygenases
Steroids
-----
NSAIDs -----
Prostaglandins
PGE2
PGF2α PGI2
pyrexia vasodilation
algesic
PMNs
Lymphokines
-----
Lipoxygenase inhititors
The events of the inflammtory response and mechanisms of anti-flammatory

28. Non-steroidal anti-inflammatory
drugs (NSAIDs)
NSAIDs have three major actions, all of which are due mainly to the
inhibition of arachidonic acid cyclo-oxygenase in inflammatory cells (the
COX-2 isoenzyme), and the resultant decrease in prostanoid synthesis:
(1) The decrease in vasodilator prostaglandins (PGE2, PGI2) means less
vasodilatation and, indirectly, less oedema.
(2) The inhibition of activity of adhesion molecule.
(3) Accumulation of inflammatory cells is also reduced.

29. • COX:
• COX-1: constitutive enzyme: is involved in tissue homeostasis.
• COX-2: inducible enzyme: is responsible for the production of the
prostanoid mediators of inflammation.

30. Non-steroidal anti-inflammatory
drugs (NSAIDs)
• An analgesic effect: decreased prostaglandin
generation means less sensitisation of nociceptive
nerve endings to inflammatory mediators such as
bradykinin and 5-hydroxytryptamine.
• Relief of headache is probably due to decreased
prostaglandin-mediated vasodilatation.

31. Non-steroidal anti-inflammatory drugs
(NSAIDs)
• An antipyretic effect: this is partly due to a decrease
in the mediator prostaglandin that is responsible for
elevating the hypothalamic set-point for temperature
control in fever.
• Endogenous pyogen(IL-1,TNF,IFN, IL-6)
BBB CNS(PEG, Na+/Ca2+, cAMP,CRH)
fever

32. Classification
Non-selective COX inhibitor
Selective COX2 inhibitor
selection
chemcial
constitution

33. Non-steroidal anti-inflammatory
drugs (NSAIDs)
• Some important examples are aspirin, ibuprofen,
naproxen, indomethacin, paracetamol. (The last agent
has analgesic and antipyretic effects but little anti-
inflammatory action).

34. The Salicylates: Aspirin
• Aspirin (acetylsalicylic acid) was first
isolated in 1829 by Leroux from willow
bark.
• It can cause irreversible inactivation
of cyclo-oxygenase, acting on both
COX-1 and COX-2.

35. Aspirin
• Salicylates are given orally and are rapidly
absorbed; 75% metabolized in the liver.
• Excretion: 85% in alkaline urine
5% in acid urine

36. Pharmacologic effects of ASA
1. Antipyretic action: is rapidly effective in febrile patients, yet has little
effect on normal body temperature.
2. Anti-inflammatory effects: the primary clinical application is in the
treatment of musculoskeletal disorders, such as rheumatoid arthritis,
osteoarthritis and ankylosing spondylitis.
3. Analgesia -relief of pain occurs through both peripheral and central
mechanisms.
4. low-dose aspirin reduces thromboembolic events in coronary and
cerebral circulation
5. Uricosuric effect in high dose by preventing tubular reabsorption of
uric acid (low dose has opposite effect)

37. Adverse effects

38. ASA effects on acid-base balance
(a) High doses result in medullary stimulation,
leading to hyperventilation and a respiratory
alkalosis. Compensation rapidly occurs because the
kidneys are able to increase the excretion of
bicarbonate, producing a compensated metabolic
acidosis.
(b) Toxic doses or very prolonged administration can
depress the medullary resulting in an
uncompensated respiratory acidosis.

39. Gastrointestinal effects
(a) It can cause epigastric distress, nausea, and vomiting by
irritating the gastric mucosal lining and stimulating the
chemoreceptor trigger zone in the CNS.
(b) It may cause a dose-related gastric ulceration, bleeding,
and erosive gastritis because of inhibiting the formation of
PGE2, which inhibits gastric acid secretion and has a
cytoprotective effect. Salicylate-induced gastric bleeding is
painless and may lead to an iron deficiency anemia.

40. Hepatic effects
(a) dose-dependent hepatic damage. Usually,
asymptomatic, elevated plasma transaminase
levels are the key indication of hepatic insult.
(b) more severe and associated with
encephalopathy seen in Reye’s syndrome.
Use of salicylates in children with chickenpox or
influenze is contraindicated.

41. Hematologic effects
(1) It inhibits the platelet aggregation by decreasing the production
of TXA2.
(2) In doses greater than 6g/d, aspirin may reduce plasma
prothrombin levels.

42. Other effects of ASA
1. Renal effects: It can result in salt and water retention
because of decreasing renal blood flow.
2. Metabolic effects: It can produce hyperglycemia and
glycosuria in large doses.
3. Endocrine effects: In very large doses, it can
stimulate steroid secretion by the adrenal cortex.

43. Therapeutic uses
(1) Aspirin is used in restricted situation for the
symptomatic relief of fever. Because of an increased
incidence of Reye’s syndrome in children who
previously were given aspirin for the relief of viral
fevers, it is now recommended that a child with any
fever be given paracetamol instead, if medication is
required.
(2) It is useful as analgesics for certain categories of
pain, such as headache, arthritis, dysmenorrhea.

44. Therapeutic uses
(3) It remains the standard, first-line drug in the therapy of
rheumatoid arthritis, and can provide relief of symptoms in acute
rheumatic fever.
(4) small daily doses of aspirin for prophylaxis of thromboembolism,
stroke, or myocardial infarction because of its antiplatelet activity.

45. Adverse effects
(1) Salicylism: usually occurs with repeated
administration of large doses. Characteristic findings
include:
----headache, mental confusion, lassitude, and
drowsiness.
----tinnitus and difficulty in hearing.
----hyperthermia, sweating, thirst, hyperventilation,
vomiting, and diarrhea.
(2) Bronchospasm in ‘aspirin-sensitive’ asthmatics.

46. Adverse effects
(3) Gastrointestinal disturbances.
(4) Prolongation of bleed time or reduced prothrombin level.
(5) Other: skin eruption, hepatic effects, Reye’s syndrome.

47. Treatment of Aspirin poisoning
(1) Inducing emesis or administering gastric lavage.
(2) Appropriate infusion measures to correct abnormal
electrolyte balance and dehydration.
(3) Alkalinization of the urine.
(4) Dialysis as required.

48. Paracetamol
Pharmacologic effects:
Paracetamol has analgesic and antipyretic
actions but only weak anti-inflammatory effects.
• It appears to be an inhibitor of PG synthesis in the
brain, thus accounting for its analgesic and
antipyretic activity.
• It is much less effective than aspirin as an inhibitor
of the peripherally located PG biosynthetic enzyme
system that plays such an important role in
inflammation.

49. Paracetamol
Pharmacologic effects:
• It exerts little or no pharmacologic effect on the
cardiovascular, respiratory, or gastrointestinal
systems, on acid-base regulation, or on platelet
function.

50. Therapeutic uses
• Paracetamol provides an effective alternative when
aspirin is contraindicated (e.g., in patients with peptic
ulcer or hemophilia) and when the anti-inflammtory
action of aspirin is not required.

51. Adverse effects
• At therapeutic doses, paracetamol is well tolerated;
however, adverse effects include:
-----Skin rash and drug fever.
-----Rare instances of blood dyscrasias.
-----Renal tubular necrosis and renal failure.
-----Hypoglycemic coma
• At overdose, it can result in severe hepatotoxicity,
resulting in centrilobular hepatic necrosis.

52. Indomethacin
• Pharmacologic effects :
(1) Inhibit COX nonselectively .
(2) Inhibit phospholipase A and C.
(3) Reduce PMN migration.
(4) Decrease T cell and B cell proliferation.
(10-40 time more potent anti-inflammatory than aspirin)

53. Indomethacin
• Therapeutic uses:
Because of its toxicity and side effect, it is not
routinely used for analgesia or antipyresis.
The major uses of indomethacin are in the treatment
of rheumatoid arthritis, ankylosing spondylitis,
osteoarthritis, and acute gout.

54. Indomethacin
• Adverse effect:
(1) Gastrointestinal complaint:
(2) CNS effects: 25%-50%
(3) Hematologic reactions:
(4) Hypersensitivity reactions: asthma (aspirin-
sensitive patients may exhibit cross-reactions to
indomethacin).

55. Naproxen and Ibuprofen
• They have prominent anti-inflammatory action.
• Therapeutic uses: rheumatoid arthritis, osteoarthritis,
ankylosing spondylitis, acute tendinitis, dysmenorrhea,
et al.
• Adverse effect: gastrointestinal effects, dermatologic
problems, thrombocytopenia.
☆ apply to long-term treatment because they are
better-tolerated.

56. Selective COX-2 inhibitor
Celecoxib, Meloxicam and Rofenxib
• more selective for COX-2 than for COX-1.
• GIT adverse effects are slighter than other NSADs.
• Cardiovascular side effects are more common!!!