This document discusses drugs used for pain management, including analgesics, anti-inflammatory drugs, and adjunctive medications. It covers the pathways of pain and inflammation, describing how nociceptive and neuropathic pain arise. It details the mechanisms of common drug classes like opioids, NSAIDs, anticonvulsants, and muscle relaxants. Key topics include the arachidonic acid cascade, prostaglandin functions, COX enzyme inhibition, and the differences between non-selective and COX-2 selective NSAIDs. Adverse effects, drug interactions, and considerations for specific pain types are also addressed.

1. DRUGS AFFECTING PAIN
ANALGESICS , ANTI
INFLAMATORY AND
ADJUNCTIVE DRUG
KHALED SHURRAB
10/MAY/2018

2. PAIN PATHWAY
OPIOIDS,
ALPHA2 AGONISTS
ANTICONVULSANT, TCA
TCA, SSRI, SNRI
LA, OPIOID,
NSAIDS
LA, OPIOIDS
LA, NSAIDS, PCT,
CAPSISLCIN

3. PAIN PATHWAY

4. TYPES OF PAIN
Nociceptive pain: Nociceptive
pain is caused by the activation
of nociceptors in the body by
noxious or potentially harmful
stimuli.
2 types : somatic, visceral
Neuropathic pain: arises from
damage to the nervous system
itself, central or peripheral,
either from disease, injury, or
pinching.
Other pain: ex. Fibromyalgia,
Psychogenic,

6. DRUG USED IN PAIN
MANAGEMENT
 Opioid analgesics
 NSAIDS
 Adjuvant drugs
• Muscle relaxant
• TCA
• ANTICONVASANT
• CORTICOSTEROIDS
• OTHERS

7. WHAT HAPPENS WHEN
THERE IS TISSUE INJURY?
Membrane phospholipids
Cell wall
injury
Releases
Arachidonic Acid
Phospholipase A2
COX-1 & COX-2 that is induced with
injury and inflammation, cancer
PGH2 (Prostaglandin H2)
PGD2
Inhibit platlet agregation
and vasodilator
TXA2
Thromboticm
vasoconstriction
PGE2
Vasodilator,
hyperalgesia
PGI2
Inhibit platlet agregation
and vasodilator,
hyperalgesia
PGF2
Bronchoconstrictor,
myometrial contraction
Prostaglandins- PGE2 as the most significant Thromboxane

8. ARACHIDONIC ACID CASCADE
Phospholipid from cell membrane
Arachidonic Acid
PGH2 5-HPETE
Leukotrienes
LipoxygenaseCyclo-oxygenase
ProstaglandinsThromboxane
These inflammatory mediators activate the nociceptors on the Aδ
and c fibres and result in pain and sensitization

9. ARACHIDONIC ACID CASCADE
NSAIDs / COX-2
inhibitors
Reduce Prostaglandins and Thromboxane, resulting in
reduced pain
Phospholipid from cell membrane
Arachidonic Acid
PGH2 5-HPETE
Leukotrienes
LipoxygenaseCyclo-oxygenase
ProstaglandinsThromboxane

10. MAIN FUNCTIONS OF
PG

11. MAIN DRUG AFFECTING
INFLAMMATORY
PATHWAY

14. NSAIDS
 Salicylate from the bark of the willow tree
 used to treat fever and rheumatism
 Salicylate is a pro drug of NSAIDS
 All NSAIDS has acidic parent group except cox2 selective
 Salicylic acid was found to be irritant to the gastric
mucosa, so acetylsalicylic acid was synthesized

15. NSAIDS
 They act through inhibition of the two isoforms
of the enzyme cyclooxygenase (COX) – i.e. COX-
1 and COX-2
 NSAIDs that act on both the enzymes are known
as non-selective NSAIDs (ns-NSAIDs)
 NSAIDs which act predominantly on the COX-2
enzyme are known as specific COX-2 inhibitors

16. NSAIDS
MECHANISM OF ACTION

17. THE TWO ISOFORMS
OF COX
 COX-1 is a normal constituent in the body for homeostasis,
such as in:
• Gastric mucosa – gastric cytoprotection
• Kidney – Sodium and water balance / renal perfusion
• Platelets – for aggregation
 COX-2 is induced in the presence of injury and inflammation
 COX-2 is also a normal constituent in the many organs such
as: Kidney, brain, endothelium, ovary and uterus

18. THE TWO ISOFORMS
OF COX
ns-NSAIDs
Acetylsalicylic acid (aspirin)
• Tablet, suppository
Ibuprofen
• Tablet, suspension for children
Indomethacin
• Tablet
Diclofenac
• Oral tablet, suppositories,
parenteral form available
Mefenamic acid
• Oral tablets
Celecoxib
• Oral capsules
Etoricoxib
• Oral tablets
Parecoxib
• parenteral
COX-2 specific
inhibitors

19. INDICATIONS
 Both the ns-NSAIDs and s-NSAIDs have the same
efficacy in postoperative analgesia
– Sole analgesia for day surgery
– Along with opioids for major surgery
 Musculo-skeletal pain – e.g. back pain, joints,
muscle sprains etc.
– Osteoarthritis
– Rheumatoid arthritis
 Fever

20. HOW NSAID FIGHT
PAIN nociception
perception

21. HOW NSAID FIGHT
FEVER

22. SIDE EFFECTS /
ADVERSE EFFECTS

23. GASTROINTESTINAL
EFFECTS
 The risk of erosions, ulcers and bleeding is higher with
ns-NSAIDs compared to Coxibs.
 This risk with ns-NSAIDs is also variable with some being
less than others.
 Risk is greater
– In elderly patients
– Those who are also taking aspirin
 Risk can be reduced by adding a proton-pump inhibitor
(e.g. omeprazole) to ns-NSAIDs.
– H2 receptor blockers are not very effective.

24. HOW NSAID AFFECT
THE STOMACH
 All ns-NSAID are acidic in nature
 2 mechanism to protect
• S-NSAID
• Short half life ns-NSAID

25. RENAL EFFECTS
 Both COX-1 & 2 are constituent enzymes in the kidney
– Maintain renal perfusion and sodium/water balance
 Both ns-NSAIDs and s-NSAID can cause
– Hypertension, odema
– Decrease in creatinine clearance that may be
significant in patients with impaired renal function or
transient hypotension / hypovolaemia in the
postoperative period

27. CARDIOVASCULAR EFFECTS
 Some studies have shown that there was a higher risk
of thrombotic cardiovascular events (stroke, heart attack)
when on s-NSAIDs when compared to ns-NSAIDs such
as naproxen
 Other studies have shown that the cardiovascular
events are similar
 Nevertheless, current recommendations are that s-NSAIDs
should not be used in patients with active cardiovascular
disease and a known thrombotic condition

28. WHY?

29. EFFECT ON PLATELETS
 ns-NSAIDs are able to prevent platelet aggregation as
platelets do not have COX-2. There is therefore a potential
for bleeding with ns-NSAIDs
 s-NSAIDs do not prevent platelet aggregation
 ns-NSAIDs should be used with caution in patients who
are already on aspirin

30. OTHERS
 Some ns-NSAIDs can precipitate asthma is aspirin
sensitive asthmatic patients.
 `Coxibs are well tolerated by patients who have aspirin
sensitive asthma
 WHY?

31. SELECTIVITY SCHEME

32. DIFFERENT GROUPS
OF NSAIDS

37. IMPORTANT NOTES
PARACETAMOL TOXICITY

39. IMPORTANT NOTES

40. OPIOIDS
Opioids on the WHO essential drug list
• Morphine
• Codeine
• Tramadol
Natural
• Morphine
• Codeine
Semi-Synthetic
• Hydromorphone
• Oxycodone
• Diacetylmorphine
(heroin)
• Naloxone
(antagonist)
Fully Synthetic
• Pethidine
(meperidine)
• Tramadol
• Nalbuphine
• Methadone
• Pentazocine
• Fentanyl
• Alfentanil
• Sufentanil
• Remifentanil

41. OPIOIDS CAN BE CLASSIFIED AS:
 Strong opioids used for severe pain
– Morphine, Oxycodone, Pethidine, Fentanyl
 Weak Opioids used for moderate pain
– Codeine, Tramadol

42. MECHANISM OF ACTION
 Opioids act by binding to opioid receptors
(complex proteins embedded within the cell
membrane of neurons)
Opioid receptors are found in the brain
and in the dorsal horn of the spinal cord
There are three different
opioid receptors - µ, δ, κ
µ - most relevant as all
clinically used opioids exert
their action via the
µ -opioid receptor

43. MECHANISM OF ACTION
 Opioids bind to opioid receptors
 Leading to reduction in excitability of
neurons and inhibition of pain signals
 Resulting in reduction of pain
perception

44. MORPHINE
 Is the most widely used opioid for the
control of severe pain
 It can be given by all the routes of
administration.
 It is well absorbed when given orally
and has a bio-availability of around 30-
35%.

45. METABOLISM
The principle pathway of metabolism is
conjugation with glucuronic acid in
hepatic and extra-hepatic (kidney) sites
Morphine -3 and morphine -6
glucuronides that are excreted mainly by
the kidneys
Morphine should be used with caution in
patients with hepatic and renal
impairment.

46. CODEINE PHOSPHATE
– WEAK OPIOID
 Oral tablet 15mg; 30 mg
 Is well absorbed and there is no first pass metabolism
in the liver
 Codeine is metabolized to morphine; which accounts for
its analgesic effect
 60 mg of codeine has an equi-analgesic effect
of 650 mg aspirin
 Has an anti-tussive effect and is often used in cough
mixtures
 Is available in combination with paracetamol
 Cause minimal sedation, nausea, vomiting and
constipation

47. TRAMADOL – WEAK
OPIOID
 This is also known as an “atypical opioid”
 It has a dual mechanism of action:
• weak opioid receptor binding properties
• Inhibits the reuptake of serotonin and noradrenaline at the
descending inhibitory pathway
 It is available
• Oral capsule
• Injection – 50 mg / ml – in 2 ml ampoules
 Due to its weak opioid activity it is not placed in the
same schedule as the strong opioids such as morphine

48. TRAMADOL
 It is well absorbed when given orally
 Time to effect is around 30 minutes and can last
5 - 6 hours
 Sedation is minimal
 Can cause nausea, vomiting, dizziness
 Abuse potential is minimal
 Is used as a weak opioid, however as it has a dual
mechanism of action – its analgesic efficacy is
superior to codeine – Maximum daily dose is 400
mg

49. METABOLISM
 Tramadol is metabolized by the liver
and excreted
by the kidneys
 Tramadol has an active metabolite
(O-desmethyltramadol) – that is also
excreted
by the kidney
 The daily dose should be reduced in the
presence of chronic renal failure

50. OPIOID RELATED SIDE
EFFECTS
 Gastrointestinal
• Nausea and vomiting
• Constipation
 Sedation
 Respiratory depression in overdose
 Pruritus
 Cough suppression (anti-tussive)

51. OPIOIDS AND
TOLERANCE
 Patients can develop tolerance when opioids are
used
for an extended period
 Tolerance is defined as reduction of the
pharmacological
effect of an opioid:
 When the same dose produces a lesser effect
 Increasing doses of drug is required to produce
the same effect
 The mechanisms of the development of tolerance
are complex

52. PHYSICAL DEPENDENCE
AND ADDICTION
 Physical dependence is a state of adaptation by the
body with extended use of an opioid
 It is manifested by withdrawal symptoms with abrupt
cessation of the opioid, rapid dose reduction or
administration of an opioid antagonist
 Addiction to opioids is drug seeking behaviour
where the person is looking for opioids for its
euphoric action rather than pain relief alone

53. NEUROPATHIC PAIN
 Is defined as pain that arises as a result
of injury or disease of the
somatosensory system
 Neuropathic pain is not responsive to
NSAIDs.
 Poorly responsive to Opioids

54. DRUGS USED FOR
TREATING NEUROPATHIC
PAIN
 Amitriptyline
 Carbamazepine
 Gabapentinoids (not on the WHO essential drug list)
 Opioids
 SSNRIs

55. AMITRIPTYLINE
 Is a tri-cyclic anti-depressant drug
 Used more for the management of neuropathic pain
than for symptoms of depression
 Low dose amitryptyline is a first line drug for
neuropathic pain
Mechanism of action
 Inhibits the reuptake of noradrenaline and serotonin (thus
increasing these two neurotransmitters) at the descending
inhibitory pathway

56. CARBAMAZEPINE
 Is an antiepileptic drug
 It is currently the drug of choice for the management of
pain in patients with trigeminal neuralgia
Mechanism of action
 It blocks the frequency and use of the voltage-gated neuronal
sodium channels
 Limits repetitive firing action of action potentials
 There is a proliferation of sodium channels when there is
nerve injury – thus the efficacy of carbamazepine in patients
with neuropathic pain

57. OTHER DRUGS
(MISCELLANEOUS
CATEGORY)
Steroids
• Dexamethasone , Prednisone ,hydrocortison, triamcinolon

58. MUSCLE RELAXANT
commonly indicated for the treatment of two different
types of conditions:
• spasticity from upper motor neuron syndromes
• muscular pain or spasms
Muscle relaxants make up a heterogeneous group of
drugs that mainly exert their pharmacologic effect
centrally at the level of the spinal cord, the brainstem,
or the cerebrum, and that have an insignificant, if any
effect, at the muscle fiber level.
Their centrally mediated mechanism of action can
exert a clinically significant peripheral therapeutic
effect.

60.  It possesses a fairly long half-life of approximately 18
hours and can continue to accumulate for up to 4 days
when administered at a frequency of three times per day.
 potent anticholinergic properties
 The initial starting dose should be 5 mg three times per
day on as needed basis and can be titrated up to 10 mg
three times per day

61. CARISOPRODOL
 Carisoprodol is still a commonly prescribed muscle
relaxant
 dispensed with caution owing to the potentially addictive
properties of its main metabolite, meprobamate.
 It is not recommended for use in the pediatric age
population.
 This drug is metabolized in the liver with meprobamate as
its main metabolite.
 It is mainly excreted through the kidneys.
 The usual adult dosage is 350 mg four times per day.

63. TIZANIDINE
 Tizanidine is a centrally acting muscle relaxant that, through its
alpha-2 adrenergic agonist properties,
 prevent the release of excitatory amino acids by suppressing
polysynaptic excitation of spinal cord interneurons.
 Metabolism is through the liver,
 excretion is 60% through the kidneys and 20% through the feces.
 Tizanidine should be administered through a gradual upward
titration from an initial dose of 2 to 4 mg at bedtime up to the
maximum of 8 mg three times per day.
 The bedtime dose can provide an analgesic effect as well as improve
quality of sleep owing to the commonly occurring sedating side
effect.
 Other common side effects are daytime drowsiness, hypotension,
weakness, and dry mouth.

67. JUST RELAX