Opioid pharmacology - A comprehensive subject seminar on Opioids for postgraduates and beyond.

1. OPIOID PHARMACOLOGY
PG Seminar
Dr. Rohan Kolla,
PG in MD PHARMACOLOGY,
JNMC, BELGAUM

2. Outline
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Definitions
History
Endogenous Opioids
Opioid Receptors
Pharmacokinetics
Pharmacological Effect Profile
Classification of Opioids
– Pure AGONISTS
– Agonist-antagonists
– Antagonists

3. Outline (contd.)
• Clinical Pharmacology
– Therapeutic use of Opiates in Pain control
– Guidelines for Opiate Dosing
– Non analgesic therapeutic uses
– Acute Opioid toxicity
• Screening Methods

4. Etymology
• OPIOIDS ( from Greek opos, ‘juice’): is any
substance regardless of its origin or structure
that produces morphine-like effects that are
blocked by antagonists such as nalaxone.
• OPIATES: includes the natural alkaloids
derived from the resin of the opium poppy;
– some authors also include the semisynthetic
substances derived directly from these alkaloids.

5. • Narcotic (from Greek narkos, ‘I benumb’):
– any substance which induces sleep
– any substance which acts on opioid receptors
– any illicit substance
– legally - opium, opium derivatives & their
semisynthetic derivatives

6. Papaver somniferum

7. History
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Oldest drug known to mankind
Sumer – 4000 BC
Greeks; Theophrastus – 3rd century BC
Arab Physicians
Used for – asthma, bad eyesight, diarrhoea
and as a euphoriant.

8. History (contd.)
• Opium Addiction – a lifestyle statement in 17th
– 18th century
• It was the source of an important "social
problem", one of the first "public health"
concerns, known as "baby-doping" (giving a
child opium to keep them quiet).

9. • East India company
• Opium Wars: 1/3rd of adult chinese population
was addicted
• India is a major produces of legal opium
• Taliban & the Afghan War

10. History (contd.)
• Frederick Sertuner 1806: isolated the
crystalline pure substance from opium that he
named morphine ( after morpheus, the Greek
god of dreams.
• Arnold Beckett in 1950: Proposed that
morphine like compounds act by binding to
specific receptors in the brain

11. Mapping of the morphinoids
• Huda Akil
• John Leibeskind, UCLA
• Stimulus Produced Analgesia
• Periaqueductal Grey matter
• Reversed by antagonists

12. Mapping of the morphinoids
•Avram Goldstein, Stanford
•Grind and Bind technique
•Radiolabelled opioids

13. Receptors
• Solomon Snyder &
• Candace Pert, John Hopkins
• Grind and Bind technique
• Improved radiolabelling techniques
• Discovery of Mu receptors in 1973

14. Substance X
• Hans Kosterlitz &
• John Hughes, Aberdeen University, Scotland
• Pig brain soup
• Guinea Pig Ileum
• Discovery of ENKEPHALINS in 1973

15. Endogenous Opioid Systems
• An agent found within the brain that acts through
an opioid receptor is called as an endogenous
opioid.
• Principally three classes – enkephalins,
endorphins, dynorphins
• All are peptides derived from distinct large
precursor proteins - POMC, preproenkephalin,
preprodynorphin
• Common amino terminal sequence: TYR-GLY-GLYPHE-(MET OR LEU)

16. Endogenous Opioid Systems
• The distribution of cells producing these three
different types of endogenous opioids varies:
– limited to arcuate nucleus and hippocampus in case of
POMC
– in the areas of brain related to pain producing
pathways in case of preproenkephalins
– Wider distribution in case of preprodynorphins
• ENDOMORPHINS – newly discovered endogenous
opioids with atypical structures and selectivity
towards μ receptors

17. Functions of Endogenous Opioids
• Modulation of
pain perception
• Modulation of
Motor activity for
sustained periods
– “runners high”
• Autonomic
regulation
“When I’m tired, I go for a run and
feel I have more energy when I’m
done.”

18. OPIOID RECEPTORS
• μ, κ and δ; the three opioid receptors
• Rhodopsin family of GPCRs
• Disributed through the brain & spinal cord; and
also outside the CNS – vascular tissues, cardia,
airway/lung, gut and cells of the immune system.
• IUPHAR – MOP, KOP & DOP
• Opiate receptor-like protein (ORL1 or NOP) with
an endogenous ligand ‘nociceptin/orphanin(F/Q)’

19. OPIOID RECEPTORS (contd.)
• Upon activation of the receptors , Gi/Gs
coupling occurs leading to a large no. of
intracellular events:
– Inhibition of adenylyl cyclase activity
– Reduced opening of voltage-gated Ca2+ channels
– Stimulation of K+ current through GIRKs
(G protein-activated inwardly rectifying K+ channels)
– Activation of PKC & PLCβ

20. Pharmacokinetics

21. Absorption
• Modestly absorbed through GI tract -oral,
rectal,
• Depends on lipophilicity
• High first pass metabolism
• Morphine - ~25% bioavailability by oral route
• Codeine & oxycodone – low FPM
• Well absorbed through SC & IM routes
• Nasal Insufflation – rapid rise in blood levels

22. Distribution
• 1/3rd of morphine is plasma protein bound
• They achieve high concentrations in highly
perfused tissues – brain, liver, kidneys &
spleen
• In chronic administration – this buildup can
take place & opioids are found in the plasma
long after their dosage has been stopped

23. Metabolism
• In liver
Morphine  morphine-6-glucuronide, morphine-3glucuronide
These have significant activity themselves.
• CYP3A4 & CYP2D6 are involved in
biotransformation of morphine congeners like
heroin, codeine, fentanyl etc
Ex: Increased & Decreased activity of CYP2D6

24. Excretion
• In kidneys,
M6G & M3G are excreted by glomerular filtration.
CRF can cause elevated levels of these metabolites
& lead to adverse effects – seizures, CNS
depression

25. Pharmacodynamic effect
profile of Clinically Used
Opioids

26. Central Nervous System
effects

27. Analgesia
• When given to patients in pain:
less intense, tolerable and they feel more
comfortable with relief of distress
• When given to normal patients:
frankly unpleasant with drowsiness, difficulty
in mentation, lessened physical activity and
apathy

28. Analgesia – Different pain states
• Acute nociception: activation of small
high threshhold sensory afferents, Aδ & C
fibres  Spinothalamic tracts anterior
cingulate cortex ( limbic system).
• Examples: hot plates, needle prick,
incisions

29. Analgesia – Different pain states
• Tissue Injury:
Ex: Burns,
abrasion, joint
inflammation,
musculoskelet
al injury

30. Analgesia – Different pain states
• Nerve Injury:
Activation of Aβ
Ex: Nerve
compression,
chemotherapy,
diabetes, etc

31. Analgesia – Mechanism
• Supraspinal
Action

32. Analgesia – Mechanism
• Spinal Opiate
Action

33. Analgesia - Mechanism
Peripheral Mechanism:
• Basic tenet of Opiate pharmacology has been
that these drugs act centrally
• Recently, in conditions of inflammation it has
been found that opioids act directly even on
the peripheral terminals of small primary
afferents.

34. Mood alterations & Rewarding
properties
• Pathways – Mesocorticolimbic Dopamine
system
Opiates increase DA release in the Nucleus Accumbens.

35. Mood
alterations &
Rewarding
properties

36. CNS depression – Respiration
• Respiratory depression: primary cause of morbidity
secondary to opioid therapy.
• All phases of respiratory activity – rate, minute volume,
tidal exchange;  aperiodic & irregular breathing
1. Direct depression of rhythm generation in
ventrolateral medulla
2. Desensitization of brainstem chemoreceptors which
normally respond to rising PCO 2
3. Also desensitize the carotid & aortic chemosensors
which usually respond to hypoxia.

37. Effect on Cough
• Direct inhibitory effect on the cough centre of
medulla
• Without loss protective glottic function
• There is no relation between the suppression
of cough & respiratory depression.
• Centrally acting antitussives –
dextromethorphan, codeine, pholcodeine

38. Effect on Nausea & Emesis
• Direct stimulation of CTZ
• A vestibular component is also involved
• Apomorphine – a congener of morphine is
highly emetic but has no action on opioid
receptors
• 5HT3 receptor antagonists are used for opioid
induced nausea & vomiting

39. Seizure & Convulsions
Some opioids at a slightly higher doses can
produce epileptogenic activity
• Meperidine
• Frank seizures & myoclonus
• Several mechanisms
– Inhibition of inhibitory interneurons
– Direct stimulatory effects
– Actions mediated by non-opioid receptors by their
metabolites

40. Other effects
• Temperature regulation: Slight fall in body
temperature
– In withdrawal, there will be rise
• Miosis: Parasympathetic pathways by
inhibition of GABAergic transmission
– very last action to develop tolerance
• Motor tone: high doses increase the muscle
tone  chest wall rigidity, increased
propensity to myoclonus

41. Peripheral effects

42. Neuroendocrine Effects
• Broadly Opioids block the release of many
hormones of the HPA axis.
A. Adrenal & sex steroid hormones: general
decrease in the release of testosterone,
DHEA, cortisol and also the gonadotrophins
from the pituitary
– Direct effect on pituicytes & also a indirect effect
on hypothalamic neurons  decreased releasing
hormones

43. Neuroendocrine Effects
• endocrinopathies, Hypogonadotrophic
hypogonadism, decreased libido, menstrual
irregularities, effect on secondary sexual
characteristics!
B. Prolactin: increased secretion due to loss of
inhibitory control of dopamine
C. Oxytocin & Vasopressin: KOR agonists inhibit
the release of both the hormones

44. Cardiovascular Effects
• Peripheral vasodilatation, reduced peripheral
resistance and inhibition of baroreceptor reflexes
– orthostatic hypotension
– histamine release
– Blunting of reflex vasoconstriction in response to PCO2
• Coronary Artery Disease:
– Decreasing preload, inotropy and chronotropy
– Decrease in O2 consumption, left ventricular enddiastolic volume & cardiac work

45. Cardiovascular Effects – (contd.)
• This protective effect is partly mediated by
increase in the centrally mediated vagal
outflow.
• Can aggravate hypovolemic shock
• Respiratory depression  CO2 retention 
cerebral vasodilatation  increase in ICT
• Can be arrhythmogenic

46. Effect on GI Tract
• Opioid receptors – dense distribution in the
enteric plexuses
• Stomach:
– delays gastric emptying
– also decreases the secretion of HCl
• Intestine:
– diminishes propulsive activity in both SI & LI
– Intestinal secretions are reduced by inhibitpry
effects on secretomotor neurons

47. Effect on other smooth muscle
Ureter & Urinary Bladder
• Inhibition of urinary voiding reflex
• Increase in the tone of external sphincter  increase in
the volume of the bladder
Uterus
• Restores the tone of hyperactive bladder secondary to
oxytocics
Biliary Tract
• Sphincter of Oddi contracts – hence some pts with
biliary colic will experience more pain when morphine
is given

48. Effect on Immune system
• Opioid receptors are present on different cells
of the immune system like neutrophils, natural
killer cells – direct modulation of their
function
• Suppression of HPA axis
• In toto, the appear to suppress the immune
function, but in the presence of pain
syndromes they appear to improve
immunity!!

49. Clinical Pharmacology

50. Classification
• Receptor Affinity
A. Opioid Agonists: Morphine, Codeine,
Meperidine, Fentanyl, Methadone, Tramadol
B. Opioid Agonist/Antagonist & Partial Agonist:
Pentazocine, Nalbuphine, Butorphanol,
Buprenorphine
C. Opioid Antagoinists: Nalorphine, Naloxone,
Naltrexone, Naltrindole, Nalmefene,

51. Pethidine (Meperidine)
• Potent MOR agonist
• Used in post op pain, chronic pain of severe
degree & post anesthetic shivering
• Its metabolite normeperidine is epileptogenic
• It can block neuronal uptake of 5HT3 – can cause
serotonin syndrome if used with MAO inhibitors
& SSRIs
• Concurrent use of Antihistaminics & TCAs can
cause additive CNS depression

52. Levorphanol
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Morphinian series
Agonist at MOR, DOR & KOR
T1/2 – 12 hours
Action & uses similar to morphine.

53. Loperamide & Diphenoxylate
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Piperidine derivatives
Approved for treatment of diarrhoeas
It slows GI motility
Also may act by decreasing secretions
Loperamide has very less central effects
because of the activity of P-glycoprotein
• Diphenoxylate is available in FDC with
atropine

54. Fentanyl & Its Congeners
• Fentanyl, Alfentanil, Sufentanil & remifentanil
• They are used as anesthetic adjuvants and
inducing agents
• Short ‘time to peak’ analgesic effect
• Rapid termination of effect if used in bolus
• MAC-sparing effect on gaseous anesthetics
• Can cause muscle rigidity
• But very minimal effect on myocardial
parameters

55. Fentanyl & Its Congeners
• Uses:
– Inducing agents especially in cardiovascular
operations – high dose fentanyl & sufentanil
– Short procedures – remifentanil
– Chronic analgesia – epidural
– Cancer pain – transdermal patches

56. Methadone
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Long acting MOR agonist
Racemic mixture – L isomer is more potent
Similar to morphine but enhanced duration
Can cause prolongation of QT interval –series
cardiac arrhythmias
Propoxyphene: Similar to methadone

57. Tramadol
• Synthetic codeine analogue
• Weak MOR agonist
• Used in the treatment of mild to moderate
pain
• Epileptogenic
Tapentadol

58. Pentazocine
• KOR agonist and a weak antagonist/partial
agonist at MOR receptors
• Effects similar to morphine – analgesia,
sedation, respiratory depression.
• At high doses – dysphoric & psychotomimetic
effects
• Tachycardia & increase in BP
• Can precipitate withdrawal in morphine
dependant patients

59. Nalbuphine
• KOR agonist with
competitive antagonistic
activity at MOR
• Analgesia is similar
• Respiratory depression
exhibits ceiling effect – so
relatively safe drug
Butorphanol
• Morphinian compound
• Similar to Nalbuphine

60. Buprenorphine
• Highly lipophilic partial agonist at MOR
• 20-50 times more affinity to MOR than
morphine
• Used in analgesia & management of Opioid
dependence

61. Opioid Antagonists
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Nalorphine,
Naloxone,
Naltrexone,
Naltrindole,
Nalmefene
They have very little effect if given alone. They produce
their effects only when given with agonists or in some
cases the endogenous opioid system is activated

62. Opioid Antagonists
Effect in the absence of Agonists
• Mild hyperalgesia
• Reverse the hypotension associated with
different forms of shock to some extent
• Mild dysphoria
• Neuroendocrine effects

63. Opioid Antagonists
Effect in the presence of Agonists
• Effect on Acute opioid actions:
– Increase in respiratory rate & depth
– Reversal of dysphoric & psychotomimetic effects
– Overshoot phenomenon
– Rebound release of catecholamines 
tachycardia, hypertension, ventricular arrhythmias

64. Opioid Antagonists
Effect in the presence of Agonists
• Effect on Opioid dependant patients:
– Moderate to severe withdrawal
– Depends on the dose of the antagonist and also
on the degree and duration of dependence
– Methylnaltrexone & Alvimopan can reverse the GI
effects of opioid dependence without pptting
central withdrawal syndrome.

65. Opioid Antagonists - Uses
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Acute toxicity /overdosage
Management of constipation
Management of abuse syndromes
Trauma – shock, stroke, brain trauma

66. Centrally acting antitussives
• Codeine, hydrocodone & oxycodone
• Dextromethorphan:
– Analog of codeine
– Elevates the threshold of
– Fewer subjective & GI side effects
• Pentoxyverine & Caramiphen

67. Therapeutic Uses of OPIOIDS
Analgesia
• Most potent pain-relieving drugs available
• Adequate pain relief
• Many guidelines are available – WHO,
American pain Society, Federation of State
medical board

70. Therapeutic Uses – Routes of administration
1.
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3.
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5.
6.
7.
8.
Patient controlled analgesia
Spinal Delivery
Local drug action
Rectal administration
Inhalation
Oral transmucosal administration
Transnasal Administration
Transdermal & Iontophoretic
Administration

71. Therapeutic Uses – Other uses
• Dyspnoea- Acute LVF & Acute
Pulmonary edema
– Pink puffers
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Cough
Diarrhoea
Shivering
Anaesthetic adjuvants

72. Contraindications & Cautions
• Use of pure agonists with weak partial
agonists
• Use in patients with head injuries
• Use in pregnancy
• Use in impaired pulmonary reserve
• Use in patients with impaired hepatic &/or
renal function
• Use in patients with endocrine disease

73. Toxicity, Tolerence & Dependence

74. Tolerance
• When large doses are given at short intervals
• Analgesia, sedation & respiratory depression
are the commonest effects to develop
tolerance
• Respiratory depression  60mg & 200mg
• Tolerance does not develop to miotic,
convulsant & constipatory effects
• Cross tolerance – partial & incomplete 
opioid rotation

75. PhysicalDependence
• Dependence refers to a state of adaptation
manifested by receptor/drug class-specific
withdrawal syndrome produced by cessation
of drug exposure.
• Signs & symptoms – rhinorrhoea, yawning,
chills, piloerection, hyperventilation,
hyperthermia, diarrhoea, hostility & anxiety
• Antagonist precipitated withdrawal

76. Psyschological Dependence
• Reason for opioid abuse:
– Euphoria, indifference to stimuli, sedation, abdominal
experiences similar to intense orgasm
– Reinforced by physical dependance
• Therapy:
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Methadone
Clonidine
Transcutaneous electrical stimulation
Buprenorphine
Naltrexone

77. Toxicity & Overdosage
• Clinical overdosage, accidental
overdosage or suicidal
• Signs & symptoms:
– Triad of coma, pinpont pupils & depressed
respiration
– Anuria, frank convulsions in children
– Noncardiogenic pulmonary edema

78. Treatment of Opioid toxicity &
Overdosage
• Ventilatory support
• DOC – IV Naloxone 0.01mg/kg
• Treatment should be such that reversal should
occur without precipitation of withdrawal
• If the poisoning is due to methadone the pts
may slip back into coma as antagonist have
short half lives

79. Screening Methods

80. Acute pain
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1.
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3.
4.
MODELS USING THERMAL STIMULUS
Hot plate method
Tail –Flick method
MODELS USING ELECTRICAL STIMULUS
Tooth pulp test
Monkey shock titration test
MODELS USING CHEMICAL STIMULUS
Formalin test
Writhing test
Rat sigmoid colon model
Inflammatory uterine pain model

81. • MODELS USING MECHANICAL STIMULUS
1. Haffner’s tail clip method
2. Randall Selitto test
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Chronic pain
1. Neuropathic pain models
2. Vincristine-induced Neuropathy model
3. Diabetic neuropathy model
4. Persistent postthoracotomy pain model
5. Rat model of incisional pain

82. Cancer pain
• Rat model of bone cancer pain
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In Vitro Methods
1. 3H-Naloxone binding assay
2. µ Opiate receptor binding assay
3. Assay to study cannabinoids activity

83. References
1. Essentials of Medical Pharmacological, K D. Tripathi,
6th ed
2. Pharmacology and Pharmacotherapeutics, R S.
Satoskar, S D. Bhandarkar, Nirmala N. Rege, 21st ed.
3. Goodman & Gilman’s The Pharmacological Basis of
Therapeutics, 12th ed
4. Rang & Dale’s Pharmacology 6th ed,
5. Basic & Clinical Pharmacology, Katzung’s, 11th ed.
6. Principles of Pharmacology: The Pathophysiologic
Basis of Drug Therapy, Golan, LippinCott’s
7. Harrison’s Principles of Internal Medicine, 17th ed.

84. References
8. Anatomy of a scientific Discovery, Jeff
Goldberg, Bantam Books.

85. Thank you!
“Religion is the opium of the masses.” –
Karl Marx

86. Mechanisms of tolerance
• Receptor disposition
• Adaptation of intracellular signalling
mechanisms in the opioid receptor bearing
neurons
• System level counteradaptation
• Fractional occupancy requirements

87. Structure Activity Relationship
• Message – Address concept
• Message: a protonated nitrogen, a phenolic
ring, a hydrophobic domain.