Opioid analgesics are the important group of medications used in pain management. The present seminar has been prepared by referring to standard textbooks of pharmacology and presented point wise for easy understanding.
2. • A boy aged 14 years is brought to the hospital
emergency with crush injury of both lower legs.
• An eye witness who brought the boy told that a
bus had run over his legs about 20 min. ago.
• The legs were crushed but he had not bled much.
He also told that initially the boy was shrieking in
pain, but had fainted on way to the hospital.
• Preliminary examination reveals that the patient is
in a semiconscious state, looks pale, the pulse is
fast, low volume and collapsing.
• Both legs have sustained multiple fractures, the
skin and soft tissues have lacerated from which
blood is oozing, but there is no active bleeding.
• There is no apparent head injury.
3. • Should any medicine be administered
immediately, before even completing a thorough
physical examination?
• If so, which drug, by what route, and why?
12. OPIOID RECEPTORS
• μ, δ, and κ (MOR, DOR, and KOR)
• Rhodopsin family of GPCRs (GRAFS classification)
• Transducer mechanisms: Gi/Go proteins
14. OPIOID RECEPTORS
• μ, δ, and κ (MOR, DOR, and KOR)
• Rhodopsin family of GPCRs
• Transducer mechanisms: Gi/Go proteins
• μ and κ: reduce intracellular cAMP formation
and open K+ channels (mainly)
• δ: suppresses voltage gated N type Ca2+
channels (mainly)
• Neuronal hyperpolarization and reduced
availability of intracellular Ca2+ → decreased
neurotransmitter release
19. Internalization
• μ and δ receptors: endocytic, β-arrestin-
mediated
• κ receptors: do not internalize
20. Desensitization
• Acute tolerance or desensitization
• Receptor specific
• Phosphorylation of the receptors resulting in
an uncoupling of the receptor from its G-
protein and/or internalization
21. Tolerance
• Decrease in the apparent effectiveness of a drug
• With continuous or repeated agonist
administration (days to weeks)
• Following removal of the agonist, disappears
over several weeks
• Right shift in the dose-effect curve
• Cross-tolerance is not consistent or complete
23. Dependence
“a state of adaptation manifested by
receptor/drug class-specific withdrawal
syndrome produced by cessation of drug
exposure (e.g., by drug abstinence) or
administration of an antagonist”
24. Dependence
Withdrawal is manifested by
• Agitation
• Hyperalgesia
• Hyperthermia
• Hypertension
• Diarrhea
• Pupillary dilation
• Release of virtually all pituitary
and adrenomedullary hormones
Affective symptoms
• Dysphoria
• Anxiety
• Depression
somatomotor and
autonomic outflow
25. Addiction
“a behavioral pattern characterized by
compulsive use of a drug”
• Driving force: rewarding effects of opiates
• Avoidance and alleviation of withdrawal
symptoms
31. Analgesia
• Dose related
• Peripheral vs neuritic
• Visceral vs somatic
• Dull poorly localised vs sharp shooting
localised
• Pain associated components
• Spinal & supraspinal
• Peripheral action of opioid
32. Sites of action of
Morphine.
A: Direct action of
opioids on inflamed
or damaged
peripheral tissues.
B: Inhibition also
occurs in the spinal
cord.
C: Possible sites of
action in the
thalamus.
33. The pain-inhibitory
neuron is indirectly
activated by opioids,
which inhibits an
inhibitory (GABAergic)
interneuron.
37. CASE STUDY
A 60-year-old man with a history of moderate chronic
obstructive pulmonary disease presents in the
emergency department with a broken hip suffered in
an automobile accident. He complains of severe pain.
• What is the most appropriate immediate treatment
for his pain?
• Are any special precautions needed?
39. Codeine
• Methyl-morphine
• Partial agonist at μ opioid receptor with a low
ceiling effect
• More selective cough suppressant
• Degree of analgesia is comparable to aspirin
• Demethylation by CYP2D6 morphine
• Constipation is a prominent side effect Rx of
diarrhea
• Abuse liability is low
40. Heroin
• Diacetylmorphine 6-monoacetylmorphine
morphine
• Euphorient especially on i.v. injection and highly
addicting
• Sedative, emetic and hypotensive actions are less
prominent
• Banned in most countries except U.K
41. LEVORPHANOL
• Opioid agonist of the morphinan series
• Pharmacological effects parallel those of
morphine
• Less nausea and vomiting
• Metabolized less rapidly than morphine long
acting (t1/2 of 12-16 hr)
• D-isomer (dextrorphan)
– Devoid of analgesic action
– Has inhibitory effects at NMDA receptors
42. Pethidine (Meperidine)
• Synthesized as an atropine substitute in 1939
• μ opioid receptor agonist and its actions are blocked
by naloxone
• Special features:
1. Analgesic potency
2. Onset of action
3. Cough
4. Spasmodic action on
smooth muscles
5. Sedation and euphoria
6. Tachycardia
7. Histamine release
8. Local anaesthesia
9. Norpethidine & Serotonin
syndrome
10. Preferred opioid
analgesic during labour
43. DIPHENOXYLATE
• Meperidine congener
• Definite constipating effect in humans
• Even its salts are virtually insoluble in aqueous
solution less abuse potential
• Diphenoxylate hydrochloride is available only
in combination with atropine sulfate
• Difenoxin, a metabolite of diphenoxylate,
– marketed in a fixed dose with atropine
44. LOPERAMIDE
• A piperidine derivative
• Antidiarrheal effect:
o slows GI motility by effects on the circular and
longitudinal muscles of the intestine
o reduces of GI secretion
• Does not penetrate well into the brain due to the
exporting activity of P-glycoprotein
45. FENTANYL
• Synthetic opioid related to the phenylpiperidines
• 80–100 times more potent than morphine
• Very important drugs in anesthetic practice
because
1. Relatively short time to peak analgesic effect
2. Rapid termination of effect after small
bolus doses
3. Cardiovascular safety
4. Capacity to significantly reduce the dosing
requirement for the volatile agents
46. METHADONE
• Long-acting MOR agonist
• Pharmacological properties qualitatively similar to those
of morphine
• L-methadone -> 8-50 times more potent than D-isomer
& has analgesic activity
• D-methadone -> possesses antitussive activity
-> Lacks respiratory depressant action and addiction
liability
• Cumulates in tissues on repeated administration —
duration of action is progressively lengthened
• Abuse potential is rated lower than morphine
• Used primarily as substitution therapy for opioid
dependence
47. PROPOXYPHENE
• Long-acting MOR agonist, strucurally related to
methadone
• Pharmacological properties qualitatively similar to those
of morphine
• D-propoxyphene -> 8-50 times more potent than L-
isomer & has analgesic activity
• L-propoxyphene -> possesses antitussive activity
• Marketed only in combination with paracetamol ± other
drugs
48. TRAMADOL
• Synthetic codeine analog that is a weak μ agonist
• Inhibits reuptake of NA and 5-HT
Increases 5-HT release
Thus activates monoaminergic spinal inhibition
of pain
• less respiratory depression, sedation,
constipation, urinary retention and rise in
intrabiliary pressure
• ‘serotonin syndrome’
49. TAPENTADOL.
• Structurally & mechanistically similar to tramadol
• Displays a mild opioid activity
• Possesses monoamine reuptake inhibitor activity
• Considered similar to tramadol in activity,
efficacy and side-effect profile
• NUCYNTA
51. Nalorphine (Nalbuphine)
• N-allyl-normorphine
• first opioid antagonist introduced in 1951
• KOR agonist-MOR antagonist
• not used clinically because of dysphoric and
psychotomimetic effects.
52. Pentazocine
• Synthesized as part of a deliberate effort to
develop an effective analgesic with little or no
abuse potential
• Weak μ antagonist and strong κ agonist
• Analgesia - spinal (κ1)
• Lower ceiling Sedation and respiratory depression
• Tachycardia and rise in BP-sympathetic stimulation
• Biliary spasm and constipation – less prominent
• Low dose – pleasurable; high dose- unpleasurable
(σ mediated)
53. Recognised by post-addicts as an opiate
Tolerance, psychological and physical
dependence
‘Drug seeking’
Withdrawal syndrome has features of both
morphine and nalorphine abstinence
Uses: Postoperative and moderately severe pain
in burns, trauma, fracture & cancer
Combination of pentazocine with naloxone
reduces the potential misuse of tablets
54. Butorphanol
• KOR agonist and MOR antagonist
• Actions similar to pentazocine
• Dysphoric & Psychotomimetic effects are not
prominent (weaker σ agonist)
• Recognised by post-addicts as an barbiturate
Tolerance, physical dependence and withdrawal
(mild)
• Can neither substitute for, nor antagonize
morphine (weak interaction with µ receptors)
• postoperative and other short-lasting (e.g. renal
colic) painful conditions
56. • It substitutes for morphine at low levels of
morphine dependence
• Precipitates withdrawal in highly morphine
dependent subjects
• Long-lasting painful conditions requiring an
opioid analgesic (cancer pain)
• Premedication, postoperative pain, in myocardial
infarction and in the treatment of morphine
dependence.
• Naloxone (high dose) can prevent buprenorphine
effect but does not reverse it - not used during
labour
57. Naloxone
• It is N-alylnor-oxymorphone
• Competitive antagonist on all types of opioid
receptors
• No
– Agonistic action
– Autonomic action
– Physical/psychological dependence
• Antagonizes all actions of morphine
• Antagonizes the agonistic actions of nalorphine,
pentazocine @higher doses
58. • Naloxone also blocks the actions of endogenous
opioid peptides
– blocks placebo, acupuncture and stress-induced
analgesia
• Naloxone partly antagonizes respiratory
depression produced by certain nonopioids,
e.g. N2O, diazepam
59. • Uses:
– drug of choice for morphine poisoning (0.4–0.8 mg
i.v. every 2– 3 min: max 10 mg)
– reversing neonatal asphyxia due to opioid use during
labour
– overdose with other opioids and agonistantagonists
(except buprenorphine)
– diagnosis of opioid dependence
60. Naltrexone
• chemically related to naloxone
• more potent than naloxone
• orally active and having a long duration
of action
• ‘opioid blockade’ therapy of post addicts
• Alcohol craving is also reduced by naltrexone
– approved for prevention of relapse of heavy drinking
61. Methyl naltrexone
• derivative of naltrexone
• does not penetrate the blood-brain barrier
• effectively blocks peripheral action of μ opioids
• used to reverse constipation in
– cancer patients receiving chronic opioid
analgesia
– those taking methadone maintenance
therapy.
62. References :-
• Goodman & Gilman’s The Pharmacological Basis of
Therapeutics; 12th edition.
• Basic & Clinical Pharmacology – Katzung ; 13th edition.
• Essentials of Medical Pharmacology - KD Tripathi; 6th edition.