Opioid Analgesics

Dr. D. K. Brahma
Department of Pharmacology, NEIGRIHMS
Shillong, Meghalaya, Imdia
 Opioid Analgesics (against
algesia) some important
terms
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 semi-
synthetic
Opiates: Drugs derived from opium Natural or semi-
synthetic
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.
Types of Pain
Types of Pain contd.
Types of Pain contd.
 Opioids - Opium
A dark brown, resinous material
obtained from poppy (Papaver
somniferum) Capsules.
OPIUM

PHENANTHRENE BENZYLISOQUINOLINE
Morphine 9-14% Papaverine 0.8-1%
Codeine 0.5-2% Noscapine 3-10%
Thebaine 0.2-1% Narcine 0.2-0.4%
Poppy Plant - image
Poppy to Opioids
 Opium - History
Friedrich Wilhelm Serturner
A German Pharmacist
Isolated Morphine in 1803 and named it
after the Greek god of Dreams
MORPHEUS
 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
MORPHINE Analgesia
action
Two components spinal and supraspinal
Inhibits release of excitatory transmitters
from primary afferents at Substantia
gelatinosa of dorsal horn
Exerted through Interneurones gating of
pain
At supraspinal level in cortex, meidbrain and
medulla - alter processing and interpretation
and send inhibitory impulses through
descending pthway
D

E
Morphine - The Gate
Theory
 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 DYSHORIA
But in persons with pain & addicts sense of wellbeing,
pleasurable floating feelings kick
EUPHORIA
 Pharmacological actions of
Morphine (CNS) contd.
Depression: Stimulation:
1. Respiratory centre 1. CTZ sensitize CTZ
depression Both rate to vestibular and
and depth of respiration
are diminished other impulses
Dangerous in Head 2. Edinger Westphal
injury and asthmatics Nucleus miosis
1. Cough Centre
Depressed 3. Vagal centre
2. Temperature regulating Bradycardia
centre depressed 4. Hippocampal cells
3. Vasomotor centre high convulsions (inhibition
doses cause fall in BP of GABA release)
Morphine - Effects
 Pharmacological actions
of Morphine contd.
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
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
 Pharmacological actions
of Morphine contd.
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
 Morphine -
Pharmacokinetics
Absorption and Distribution:
Variable orally (usually not given orally 1 st pass metabolism,
given IM or IV)
Widely distributed liver, spleen, kidney etc.
Enters Brain slowly
Readily crosses placental barrier dependence in fetus
Metaboloism:
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)
 Morphine -
Pharmacokinetics
 Morphine Adverse
Effects
1. Respiratory Depression: Infant and Old
2. Vomiting
3. Sedation, Mental Clouding sometimes dysphoria
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
 Morphine Therapeutic
uses
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
 Morphine 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
 Morphine -
Contraindications
1. Two Extremes of Age
2. Bronchial asthma
3. Respiratory insufficiency - empysema
4. Head Injury
5. Shock Hypotension
6. Undiagnosed acute abdomen
7. BHP
8. Renal Failure, Liver diseases and hypothyrodism
9. Unstable personalities
 Opioids - Classification
1. Natural Opium Alkaloids: Morphine and Codeine
2. Semi-synthetic: Diacetylmorphine (Heroin) and
Pholcodeine
3. Synthetic Opioids:
Phenylpiperidines:
Pethidine (Mepiridine) and its congeners Diphenoxylate
and Loperamide
Fentanyl and its congeners sufentanil, remifentanil and
alfentanil
Phenyl-heptylmines: Methadone and congeners like
Propoxyphene and Dextropropoxyphene
Benzomorphans: Pentazocine
Morphinan compounds and congeners: Levorphanol and
Butorphanol
 Pethidine
Morphine Vs Pethidine:
1/10th as potent as Morphine, but Efficacy is similar
Produces as much sedation, euphoria and respiratory
depression in equianalgesic dose and similar abuse
potential
Less spasmodic action in smooth muscles less miosis,
constipation and urinary retention
Rapid but short duration of action (2-3 Hrs)
Vagolytic effect - Tachycardia
Devoid of antitussive action
Less histamine release safer in asthmatics
Better oral absorption
 Pethidine contd.
Pharmacokinetics
Well absorbed orally, bioavailability 50%
Effects appear in 10-15 min. after oral
absorption
On parenteral administration action lasts for
2-3 Hrs
Metabolized in liver mepiridinic acid and
norpethidine
Norpethidine accumulates on chronic use
Excreted in urine
 Pethidine contd.
Adverse Effects:
Similar to Morphine
Atropine like effects dry mouth, blurred vision,
tachycardia
Overdose tremors, mydriasis, delirium and convulsion due
to norpethidine accumulation
Uses:
Analgesic as substitute of Morphine
Ptreanaesthetic medication
As analgesic during labour less fetal respiratory
depression
Dose 50-100 mg IM/SC, oral 50-100 mg tabs.
 Methadone
Chemically dissimilar but similar in most of pharmacological
actions analgesic, respiratory depression etc.
High action orally as well as parenterally
Single dose effect is same with Morphine including
duration of action
Cumulation on repeated administration (t1/2 24-36 Hrs)
Highly bound to plasma protein 80 to 90%
Metabolized in liver by demethylation and cyclization
Excreted in urine
Slow action and less subjective effect abuse potential is
low
Used as substitution therapy as opioid dependence: 1:4mg
and 1:20 mg of Morphine and Pethidine respectively
Codeine is used as substitution in Methadone addiction
 Tramadol
Centrally acting analgesic
Very low action on opioid receptors (
Other mechanisms involved in analgesic action 5-HT and
NA reuptake inhibition spinal inhibition of pain
Effective both orally and IV (100mg = 10 mg Morphine)
Side effects are similar to Morphine but less prominent
Well tolerated and low abuse potential
Only Partially reversed by Naloxone
Used in chronic neuropathic pain and short diagnostic
procedures
Dose: 50-100 mg IM/IV/Oral
(Contramol)
 Opioid Receptors
Mainly 3 (three) types of receptors (mu), (kappa) and
(delta)
Subtypes: 1, 2, 1, 2, 3, 1 and 2
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
 Effects of Different Opioid Receptor Stimulation:

receptor receptor receptor

Location 1 supraspinal 1 spinal Spinal
2 - spinal 3 -supraspinal supraspinal

Effects Analgesia Spinal analgesia Spinal analgesia

Respiratory Dysphoria Affective
depression Sedation behaviour
Sedation (Supraspinal)
Psychomimetic
Euphoria Physical Respiratory
Miosis dependence depression
(nalorphine Reduced GI
Physical dependence
type) motility
Agonists Loss of GICodeine,
Morphine, motility Pentazocine
Fentanyl and
pentazocine weakly
 Effects of Opioid
Receptor Stimulation
Effects of Opioid Receptor
Stimulation contd.
 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 and . and supression
of N type of Ca++ channels
Ultimately Hyperpolarization and reduced
intracellular Ca++ Reduced Neurotransmitter
release
 Endogenous Opioid
Peptides
Endorphins:
Derived from POMC
-endorphins: 2 Types - -endorphin1 and -endorphin-2
Primarilty agonist and also has action
Enkephalins:
Derive from Proenkephalin
Met-ENK and leu-ENK
Met-ENK - Primarily and agonist and leu-ENK
agonist
Dynorphins:
Derive from Prodynorphin: DYN-A and DYN-B
Potent agonist and also have and action
 Opioid Antagonists
1. Pure antagonists: Naloxone, Naltrexone and
Nalmefene
Affinity for all receptors (, and )
Can displace opioids bound to -receptors
No action on Normal person but reverses poisoning and
withdrawal symptoms in addicts
1. Mixed Agonist-antagonists: Nalorphine, Pentazocine,
Butorphanol and Nalbuphine
2. Partial/weak agonist and antagonist:
Buprenorphine
 Nalorphine
Not used anymore
Previously used as Opioid antagonist
But, antagonism is restricted to -
receptor only and agonist of -
receptor
Drawbacks - dysphoria and
psychomimetic effects
 Pentazocine
Weak -receptor antagonist, but agonist of -receptor
One of the commonly used agents, given orally and IM
Low abuse liability
Pharmacokinetics:
High 1st pass metabolism but effective orally
Half life = 3-4 Hrs
Metabolized in liver by glucoronide conjugation
Dose: orally 50-100 mg and parenterally 30-60 mg IM
Uses:Moderately severe pain in Injury, Burns, Fracture
Trauma, Cancer and Orthopaedic manuevers
(Fortwin, Fortagesic)
 Pentazocine Vs Morphine
Spinal analgesia via kappa receptor
Dose is 30 mg Vs 10 mg and low ceiling effect
Sedation and Respiratory depression at lower doses
Tachycardia and rise in BP dangerous in MI
Lesser smooth muscle spasms
Vomiting and other side effects are less
Subjective effects lower ceiling (psycomimetic effects)
Tolerance develops on repeated use, but lesser than
Morphine
Withdrawal symptoms both Morphine and Nalorphine like
Good analgesic in subjects not exposed to Morphine
Precipitate withdrawal in Morphine addicts
 Buprenorphine
Synthetic thebaine congener and highly lipid soluble
Given Sublingually or parenterally but not oral high 1 st pass
metabolism
Selective -agonist analgesic
20-30 times more potent than Morphine
Slow but longer duration of action upto 24 Hrs
Pharmacological effects are similar to Morphine
Has ceiling effect in analgesic and respiratory depression
Good analgesic for naive patients but addicts precipitates
withdrawal syndrome
Lower tolerance and physical dependence than Morphine and abuse
liability
Withdrawal syndromes are similar to Morphine
 Buprenorphine contd.
Adverse Effects:
Hypotension (Postural)
Respiratory depression (fatal in neonates) and cannot be
reversed by Naloxone
Uses:
Long lasting painful conditions cancer
Postoperative pain
Myocardial infarction
Preparations: Norphine, Tidigesic
0.3 mg/ml injections and 0.2 mg sublingual tablets
 Naloxone
Competitive antagonist of all types of opioid
receptors
But, blocks -receptors at much lower dose
Always injected IV (0.4 t0 0.8 mg) - All symptoms
of Morphine action are antagonized respiratory
stimulation
At higher doses 4-10 mg: antagonizes actions of
Nalorphine and Pentazocine dysmorphic and
psychomimetic effects are not suppressed ()
Withdrawal symptoms: 0.4 mg doses Morphine
and 4-5 mg doses Nalorphine and Pentazocine
 Naloxone contd.
Buprenorphine actions are prevented but not
reversed fully tight bond with receptors
Also acts on endogenous opioids
Antagonizes respiratory depression of Diazepam
and N2O
Uses:
Acute Morphine Poisoning (0.4 0.8 mg IV 2-3 min,
maximum 10 mg.
New Born opioid poisoning
Reverse respiratory depression intr-aoperatively
Diagnosis of Morphine addiction
Alcohol intoxication
 SAR - Opioids
(Phenolic)

(Alcoholic) Heroin
Morphine Codeine

Naloxone