Pharmacology of Opioids

1. Opioids
Clinical Pharmacology
&
Pain Management

2. Opioid Analgesics (against-algesia
• Analgesics: Are the Drugs which selectively
relieves pain by acting in the CNS or on
peripheral pain mechanisms, without
significantly altering the consciousness –
Opioids and NSAIDS
• Opioids: Any drug which binds to the opioid
receptors (Pharmacologically related) in the
CNS and antagonized by Naloxone. They may
be – Natural, Synthetic and semisynthetic

3. • Opiates: Drugs derived from opium – Natural
or semisynthetic
• Narcotics: Drugs derived from opium or opium
like compounds, with potent analgesic effects
associated with significant alteration of mood
and behavior, and with the potential for
dependence and tolerance following repeated
administration.

4. PAIN
“An unpleasant sensory and emotional
experience associated with actual or
potential tissue damage, or described in
terms of such damage"

6. Hyman SE, Cassem NH. Pain. In: Scientific American Medicine. Vol XIX. 1996: Chap 11.
Ascending pathwaysPeripheral
nerves
Descending pathway
Ventroposterolateral
thalamic nucleus
Intralaminar thalamic
nucleus
Somatosensory
cortex
Limbic forebrain system
Periaqueductal gray area
Rostroventral medulla
Neuroanatomy of Pain Pathways

7. Mechanisms of Action of Opioids
Basic and Clinical Pharmacology. 8th ed. 2001.
Primary
afferent
Presynaptic
terminal
Postsynaptic
neuron
Spinal pain-
transmission
neuron
, d, k receptors cause
 Ca++
 Transmitter release
 receptors cause
 K+, IPSP{
{

8. Peripheral Nerve Terminal
Sympathetic
Terminal
Nociceptor
Platelets
Mast cell
histamine
5-HT
TBX
PGE2
NPY
SP
CGRP
NKA
BK
IL
Blood
Vessel

9. Peripheral Nerve Terminal
NociceptorEP1
BK2
MOR
+cAMP
+PI, +Ca
-cAMP,
-Ca
PGE2
BK
-endorphin,
Mu agonists

11. Classified pain according to specific
characteristics:
• Region of the body involved (e.g. abdomen,
lower limbs),
• System whose dysfunction may be causing the
pain (e.g., nervous, gastrointestinal),
• Duration and pattern of occurrence,
• Intensity and time since onset, and
• Cause

12. Types of Pain

13. Nociceptive pain
• Nociceptive pain is caused by stimulation of sensory
nerve fibers that respond to stimuli approaching or
exceeding harmful intensity (nociceptors), and may
be classified according to the mode of noxious
stimulation.
• The most common categories are "thermal" (e.g.
heat or cold), "mechanical" (e.g. crushing, tearing,
shearing, etc.) and "chemical" (e.g. iodine in a cut or
chemicals released during inflammation).

15. • Nociceptive pain may also be divided into
–"visceral” (ischemia and inflammation)
–"deep somatic” (ligaments, tendons, bones,
blood vessels, fasciae and muscles)
–"superficial somatic" (minor wounds and
minor (first degree) burns)

16. Neuropathic pain
• Neuropathic pain is caused by damage or
disease affecting any part of the nervous
system involved in bodily feelings (the
somatosensory system).
• Peripheral neuropathic pain is often described
as "burning", "tingling", "electrical",
"stabbing", or "pins and needles”.

18. Inflammatory pain stimuli

19. Managements

24. Opioids

25. Opioids - Opium
• A dark brown, resinous material obtained
from poppy (Papaver somniferum) Capsules.
PHENANTHRENE
• Morphine 9-14%
• Codeine 0.5-2%
• Thebaine 0.2-1%
BENZYLISOQUINOLINE
Papaverine 0.8-1%
Noscapine 3-10%
Narcine 0.2-0.4%

26. Poppy Plant

27. Poppy to Opioids

28. Opium - History
• Friedrich Wilhelm Serturner
• – A German Pharmacist
• – Isolated Morphine in 1803 and named it
after the Greek god of Dreams “MORPHEUS”

29. MORPHINE (Pharmacological
actions) - CNS
• Analgesia:
• Strong analgesic
• Visceral pain is relieved better than somatic pain
• Degree of analgesia increases with dose
• Nociceptive pain is better relieved than Neuretic pain
• Associated reactions to pain are also relieved
apprehension, fear and autonomic effects
• Tolerance to pain is better

30. MORPHINE – Analgesia
action
• Two components – spinal and supraspinal
• Inhibits release of excitatory transmitters from
primary afferents – at Substantia gelatinosa of
dorsal horn
• Exerted through Interneurons – gating of pain
• At supraspinal level in cortex, midbrain and
medulla - alter processing and interpretation
and send inhibitory impulses through
descending pathway

31. Morphine - The Gate
Theory

32. Pharmacological actions of
Morphine (CNS) – contd.
• Sedation:
– Drowsiness and indifference to surroundings
– Inability to concentrate and extravagant imagination – colorful day
dream
– Apparent excitement
– Larger doses produce sleep – EEG resembles normal sleep
• Mood effects:
– In Normal persons calming effect, mental clouding, feeling of
detachment, lack of initiative etc. - unpleasant in absence of pain
– Sometimes DYSPHORIA
– But in persons with pain & addicts sense of wellbeing, pleasurable
floating feelings – kick
– EUPHORIA

33. Pharmacological actions of
Morphine (CNS) – contd.
• Depression:
1. Respiratory centre
depression – Both rate and
depth of respiration are
diminished
– Dangerous in Head injury
and asthmatics
1. Cough Centre –
Depressed
2. Temperature regulating
centre – depressed
3. Vasomotor centre – high
doses cause fall in BP
• Stimulation:
1. CTZ – sensitize CTZ to
vestibular and other
impulses
2. Edinger Westphal Nucleus
– miosis
3. Vagal centre –
Bradycardia
4. Hippocampal cells –
convulsions (inhibition of
GABA release)

34. Morphine - Effects

35. Neuro-endocrine:
• GnRH and CRH are inhibited – FSH, LH and
ACTH levels are lowered – only short term –
tolerance develops
• Decrease in levels of Sex hormone and
corticosteroids, but no infertility
• Increases ADH release – oliguria

36. CVS
NO DIRECT EFFECT ON HEART
• Vasodilatation – histamine release, depression
of vasomotor centre and directly on blood
vessels decreasing the tone
• Cardiac work reduction due to consistent
vasodilatation

37. GIT: CONSTIPATION
–Due to direct action on intestine reducing
propulsive movement, spasm of sphincters,
decrease in all GIT secretions
• Smooth Muscles:
• Billiary Tract: Billiary colic – closure of sph.
of Oddi
• Bladder: Urinary urgency but difficulty
• Bronchi - Bronchospasm

38. Morphine -
Pharmacokinetics
Absorption and Distribution:
– Variable orally (usually not given orally – 1st pass metabolism, given
IM or IV)
– Widely distributed – liver, spleen, kidney etc.
– Enters Brain slowly
– Readily crosses placental barrier – dependence in fetus
Metabolism:
– In Liver by glucoronidation – water soluble metabolites
– Morphine-6- Glucoronide – analgesic – in renal failure prolong
analgesia
– Morphine-3-glucoronide – No analgesia – neuroexcitatory
Excretion:
– Via Urine, Plasma t1/2 = 2-3 Hrs
– Action lasts for 4-6 Hrs
– Completely eliminated in 24 Hrs
– Preparation: 10, 15, and 20 mg. (IV: 2 – 10 mg)

39. ADR
1. Respiratory Depression: Infant and Old
2. Vomiting
3. Sedation, Mental Clouding – sometimes dysphoria H
4. Hypotensive effect
5. Rise in Intracranial Pressure
6. Apnoea: Newborn
7. Urinary retention
8. Idiosyncrasy and allergy
9. Acute Morphine Poisoning: occurs if >50 mg (Lethal dose – 250
mg), Gastric lavage with KMNO4, Specific antidote: Naloxone: 0.4
to 0.8 mg IV repeatedly in 2-3 minutes till respiration picks up
10. Tolerance and dependence

40. Indications
Analgesic:
1. Long Bone Fracture
2. Myocardial Infarction
3. Terminal stages of cancer
4. Burn patients
5. Postoperative patients
6. Visceral pains – pulmonary embolism, pleurisy, acute
pericarditis
7. Biliary colic and renal colic
8. Obstetric analgesia
9. Segmental analgesia

41. Other Therapeutic uses
• Preanaesthetic Medication
• Balanced anaesthesia and surgical analgesia
• Acute Left ventricular failure – Cardiac asthma
• Cough – not used but Codeine is used
• Diarrhoea – colostomy – Loperamide,
Diphenoxylate

42. Contraindications
1. Two Extremes of Age
2. Bronchial asthma
3. Respiratory insufficiency - emphysema
4. Head Injury
5. Shock – Hypotension
6. Undiagnosed acute abdomen
7. BHP
8. Renal Failure, Liver diseases and hypothyroidism
9. Unstable personalities

43. Opioid Receptors
• Mainly 3 (three) types of receptors – μ (mu), κ (kappa)
and δ (delta)
• Subtypes: μ1, μ2, κ1, κ2, κ3, δ1 and δ2
• Location: Peripheral Nerve endings, SG in spinal chord,
Periaqueductal gray (PAG) in midbrain and Brain stem
(medulla, hypothalumus and also amygdala
• Opioids are – agonists, partial agonist or competitive
antagonists of these receptors
• Overall effect depends on nature of interaction and
affinity to these
• Morphine is agonist of all but affinity is higher for mu

44. Effects of Different Opioid Receptor
Stimulation
Receptors μ receptor κ receptor δ receptor
Locations μ1 – supraspinal
μ2 - spinal
κ1 – spinal
κ3 -supraspinal
Spinal
Supraspinal
Effects Analgesia
Respiratory
depression
Sedation
Euphoria
Miosis
Physical
dependence
Loss of GI motility
Spinal analgesia
Dysphoria
Sedation
Psychomimetic
Physical
dependence
Spinal analgesia
Affective
behaviour
(Supraspinal)
Respiratory
depression
Reduced GI
Motility
Agonists Morphine, Codeine,
Fentanyl and
pentazocine weakly

45. Effects of Opioid
Receptor Stimulation

46. Effects of Opioid
Receptor Stimulation

47. Opioid Receptors –
Intracellular mechanism
• All are G-protein coupled receptors
• Located on prejunctional neurones
• Inhibits release of transmitters – NA, DA, 5-HT,
GABA and Glutamate
• Activation reduces intracellular cAMP formation -
Opening of K+ channel via μ and δ and supression
of N type of Ca++ channels
• Ultimately Hyperpolarization and reduced
intracellular Ca++ Reduced Neurotransmitter
release

48. CLASSIFICATION OF OPIOIDS
Natural opium
alkaloids (opiates)
Semi-synthetic
opiates
Synthetic opioids
 Morphine
 Codeine
 Diacetylmorphine
(Heroin)
 Pholcodeine
 Ethylmorphine
 Hydromorphone*
 Oxymorphone*
 Hydrocodone*
 Oxycodone*
 Pethidine (Meperidine)
 Fentanyl
 Methadone
 Dextropropoxyphene
 Tramadol
 Tapentadol
 Dextromoramide*
 Dipipanone*
 Alfentanil*
 Sufentanil*
 Remifentanil*

49. Codeine
• It is another form of natural alkaloid of opium.
• It is partial agonist at μ opioid receptor with a low
ceiling effect.
• The potency and efficacy is less than morphine; 300 mg
of codeine is similar to 30 mg of morphine.
• It is indicated in mild to moderate pain, diarrhoea and
for dry cough [in low dose of 10-30 mg].
• The oral absorption is better than morphine.
• Parenteral preparation of codeine is not available.
• The most common side effect is constipation.

50. SEMISYNTHETIC OPIATES

51. Diacetylmorphine (Heroin)
• This drug is not used therapeutically
worldwide except in United Kingdom.
• It is highly addicting drug and notorious for
illicit drug trafficking.
• It is three times more potent and fast acting
than morphine.
• Being lipid soluble, it crosses the BBB and
produces euphoria; hence having more
addictive property than morphine

52. Pholcodeine, Ethylmorphine
• These drugs are having similar properties as
codeine.
• These drugs are mainly used as antitussives
and spasmodic.
• They have low incidence of constipation as a
side effect.

53. Synthetic opioids

54. Pethidine (Meperidine)
• It acts on the μ opioid receptors like morphine.
• It is well absorbed orally, metabolized in liver and
excreted through urine with a plasma t ½ of 2-3
hours.
• It is indicated for the management of pain, as
preanaesthetic and even as post anesthetic
medication to treat shivering.
• Overdose of pethidine may lead to mydriasis,
delirium, tremor, and convulsions.
• It is given in a dose of 50–100 mg IV/IM/SC.

55. Difference between Pethidine and
Morphine
Properties Pethidine Morphine
Analgesic Less More
Onset of action Rapid Slow
Duration of action Less More
Action on smooth muscles Less More
Cough centre No effect Depresses
Effect on biliary spasm Less More
Effects on Asthma Can be given [less histamine
release]
Contraindicated
Effects on CVS Tachycardia [due to
antimuscarinic effects]
Bradycardia
Effects on CNS Same Same

56. Fentanyl
• It is more potent synthetic opioids than morphine.
• It has potent analgesic and respiratory depressant effect.
• It is highly lipid soluble and easily crosses BBB; produces
analgesic effects within 5 minutes after IV injection. Hence,
exclusively used in anaesthesia.
• It has shorter duration of action [≤40 minutes] due to
redistribution.
• The transdermal preparations are mostly used in patients with
cancer, terminal illness or other types of chronic pain.
• Transdermal patch is available in a concentration of 12 μg/hour,
25-μg/hour, 50-μg/hour, 75-μg/ hour or 100-μg per hour; the
patch is changed after 3 days.
• Patient may experience nausea, vomiting and pruritus during
recovery phase.

57. Methadone
• It is a synthetic opioid, having similar pharmacological properties
as morphine.
• It has similar analgesic, emetic, antitussive, constipating and
respiratory depressant actions to morphine.
• The plasma t ½ is 25-52 hours with 4-6 hour duration of action
after IM injection.
• It is used as a substitution therapy in opioids dependence: 1 mg
of oral methadone can be substituted for 4 mg of morphine, 2
mg of heroin and 20 mg of pethidine.
• Methadone maintenance therapy in opioid addicts: 10–40
mg/day, given orally over long term to produce high degree of
tolerance so that pleasurable effects of IV doses of morphine or
heroin are not perceived and the addicts gives up the habit.
• It is used as analgesic in a dose of 2.5–10 mg oral or IM.

58. Tramadol
• Tramadol has low affinity for μ opioid receptors and very
low affinity for κ and δ receptors.
• It is an atypical opioid because, in addition to actions at
opioids receptors, it also inhibits reuptake of
noradrenaline and 5-HT; thus inhibits the pain at spinal
level also.
• 50 mg of IM tramadol provides analgesic effects equal to 5
mg of morphine IM.
• It is given in a dose of 50–100 mg oral/IM/slow IV infusion
(children 1–2 mg/ kg) 4–6 hourly. More specifically the
safer dose is 37.5 mg.
• It is metabolized in liver and excreted through kidneys with
plasma t ½ of 6 hours.

59. Tramadol
• It is indicated in mild to moderate short lasting
pain after therapeutic or surgical procedures.
• It can also be used in chronic painful conditions
such as cancer related pain but not effective in
severe pain.
• The abuse potential is very low; therefore, it is
also used as a part of opioids de-addiction
therapy.
• Tramadol may increase the risk of ‘serotonin
syndrome’; hence, concomitant therapy of
tramadol and SSRI should be avoided

60. OPIOID ANTAGONISTS

61. OPIOID ANTAGONISTS
Agonistic-
antagonists (κ
analgesics)
Partial/weak μ
agonist + κ
antagonist
Pure antagonists
 Nalorphine
 Pentazocine
 Butorphanol
 Buprenorphine  Naloxone
 Naltrexone
 Nalmefene

62. Pentazocine
• It has potent κ-agonist and weak μ-antagonistic
property.
• t ½ of 3-4 hours.
• It is indicated in postoperative pain, burns and pain due
to trauma.
• It is given in a dose of 30-60 mg IM/SC and 50-100 mg
orally.
• It is contraindicated in patients with
– hypertension, myocardial infarction (sympathetic stimulant
action),
– head injury (increased ICT),
– epilepsy (lowers seizure threshold) &
– psychotic patients (psychosomatic effects).

63. Difference between pantazocine and
morphine
Properties Pentazocine Morphine
Analgesia Spinal level [less
potent]
Spinal & supraspinal
level [more potent]
Sedation Less More
Biliary spasm Less More
Vomiting Less More
Respiratory
depression
Less More
CVS effects Tachycardia Bradycardia
Addictive property Higher at low dose;
low at high dose
More common [any
dose]

64. Butorphanol
• It is more potent than pentazocine (1 mg
butorphanol = 15 mg pentazocine).
• It has potent κ-agonist and weak or partial
antagonist to μ receptors.
• It is used as analgesic; having similar action to
buprenorphine.
• It is given in a dose of 1–4 mg IM/IV for
postoperative and other painful conditions for short-
term use only.
• It should be avoided in patients with cardiac
ischemia.

65. PARTIAL/WEAK μ-AGONIST + κ-
ANTAGONIST
• Buprenorphine
– It is a synthetic derivative of thebaine.
– It is 25-50 times more potent than morphine, [0.4 mg of
buprenorphine produces similar effects as 10-20 mg of
morphine on IM injection].
– It is well absorbed by most routes.
– It is indicated in chronic pain conditions like cancer-
induced pain, postoperative pain, myocardial infarction,
morphine dependence & opioids withdrawal.
– Depresses the respiratory centre; hence should be avoided
during labour.
– It is given in a dose of 0.3–0.6 mg IM, SC or slow IV, and
sublingual dose is 0.2–0.4mg 6–8 hourly.

66. PURE OPIOIDS ANTAGONISTS
Naloxone, Naltrexone, Nalmefene
• Naloxone
– It is non-selective competitive antagonist of opioid receptors,
but it has more affinity for μ receptors than κ or δ receptors.
– It does not produce any subjective or autonomic effect on
normal individuals and it does not produce any
physical/psychological dependence.
– It also blocks the action of endogenous opioids such as
endorphins and enkephalins.
– It is ineffective for the management of buprenorphine
overdose: Buprenorphine actions are prevented but not
reversed fully – tight bond with receptors

67. Indications & Doses
• Morphine Poisoning: Naloxone [drug of choice] given
in a dose of 0.4–0.8 mg IV, inhibits all actions of
morphine and stimulates respiratory centre.
• Diagnosis of Morphine addiction
• Alcohol intoxication
• For reversal of neonatal asphyxia due to opioid use
during labour: 10 μ g/kg in the umbilical cord.
• Opioid overdose: Naloxone given in a dose of 4–10 mg
inhibits the action of nalorphine, pentazocine, etc.
• Reverse respiratory depression intraoperatively.

68. Naltrexone
• It is also a pure opioid antagonist chemically related to
naloxone.
• It is more potent than naloxone.
• Due to better oral bioavailability and longer duration of
action, it may be given in post-drug addict individuals as
‘opioid blockade’ therapy.
• It is given in a dose of 50 mg/day in drug addict individuals
to reduce craving.
• Before initiation of therapy, the patient should be opioid
free for at least 7-10 days.
– The therapy is started orally with 25 mg initially under
supervision, then 50 mg daily till the patient stabilizes.
– Then, 100 mg three times a week.

69. • The de-addiction treatment with naltrexone should ideally
begin in a residential setting in order to prevent withdrawal
symptoms. But, it can be prescribed in outpatient medical
settings also.
• It is also used to prevent alcohol craving in chronic
alcoholics.
• The common side effect are nausea, headache and
hepatotoxicity (on prolong use).
• It blocks opioids from binding to their receptors and
thereby prevents their euphoric and other effects.
• Recently, a long-acting injectable version of naltrexone
(depot form) has been approved to treat opioid addiction.

70. Endogenous Opioid Peptides
Endorphins:
• Derived from POMC
• ß-endorphins: 2 Types - ß-endorphin1 and ß-endorphin-2
• Primarilty μ agonist and also has δ action
Enkephalins:
• Derive from Proenkephalin
• Met-ENK and leu-ENK
• Met-ENK - Primarily μ and δ agonist and leu-ENK – δ agonist
Dynorphins:
• Derive from Prodynorphin: DYN-A and DYN-B
• Potent κ agonist and also have μ and δ action