Opioid Analgesics

• Opioids: Any drug which binds to the opioid receptors

(Pharmacologically related) in the CNS
• 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.
 Opioids - Opium
• A dark brown, resinous material obtained from poppy
(Papaver somniferum) Capsules.
OPIUM

BENZYLISOQUINOLINE
•Papaverine 0.8-1%
PHENANTHRENE •Noscapine 3-10%
•Morphine 9-14% •Narcine 0.2-0.4%
•Codeine 0.5-2%
•Thebaine 0.2-1%
 Opioid System
• 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
 Effects of Different Opioid Receptor Stimulation:

μ receptor κ receptor δ receptor

Location μ1 – supraspinal κ1 – spinal Spinal
μ2 - spinal κ3 -supraspinal supraspinal

Effects Analgesia Spinal analgesia Spinal analgesia

Respiratory Dysphoria Affective
depression Sedation behaviour
Sedation Psychomimetic (Supraspinal)
Euphoria Respiratory
Physical
Miosis dependence depression
(nalorphine Reduced GI
Physical dependence
type) motility
Loss of GI motility

Agonists Morphine, Codein,

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

They are synthesized from large, inactive precursor proteins called

prepropeptides, which are cleaved into several active peptides
 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
 Morphine -
Pharmacokinetics
• Absorption and Distribution:
• Variable orally (usually not given orally – 1stpass 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)
 MORPHINE – Analgesia
action
• Two components – spinal and
supraspinal
• Inhibits release of excitatory D
transmitters from primary
afferents – at Substantia
gelatinosa of dorsal horn
• Exerted through Interneurones –
gating of pain
• At supraspinal level in cortex, E
meidbrain and medulla - alter
processing and interpretation and
send inhibitory impulses through
descending pthway
 MORPHINE (Pharmacological
actions) - CNS
• Analgesia:
• Strong analgesic
• Degree of analgesia increases with dose
• Nociceptive pain is better relieved than
Neuropathic pain
• Associated reactions to pain are also relieved
– apprehension, fear and autonomic effects
 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

• 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
 Pharmacological actions of
Morphine (CNS) – contd.
• Depression: • Stimulation:
1. Respiratory centre 1. CTZ – sensitize CTZ
depression – Both rate
and depth of respiration
to vestibular and
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
3. Vasomotor centre – high
doses cause fall in BP
 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 (retention)
• Bronchi - Bronchospasm
 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
 Adverse
Respiratory depression
Inhibition of the bulb-pontine breathing center (mediated by µ
receptors)

Sedation
Linked to direct action on the CNS.
Sedation and respiratory depression are directly related:
worsening of a state of sedation can be an early indicator of
the development of a state of respiratory depression.

Nausea - vomiting
By activation of the vomiting center at the bulbar level

Miosis
It is mediated by µ e kappa receptors present in the nucleus of
the oculomotor nerve (important for recognizing respiratory
depression from opiate overdose)
Itching and hives Incidence of 10-38%, generalized or localized to the
trunk, legs, nose (linked to the release of histamine from mast cells at
the injection site)

Constipation by increasing the muscle tone of the duodenum by reducing

the peristaltic contractions of the small intestine and the normal reflex
of defecation.

Tolerance: It develops very rapidly due to the analgesic effect and

respiratory depression, less so from the constipating effect.

Physical addiction: need for increasing amounts to produce the desired

effect (syndrome of withdrawal upon cessation)

Psychic dependence: overwhelming desire to repeat the use of a

particular drug to produce pleasure or avoid discomfort
 Pethidine
• Morphine Vs Pethidine:
– 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)
– Devoid of antitussive action
– Better oral absorption
 Pethidine
• 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.
• Adverse Effects:
• Similar to Morphine
• Atropine like effects – dry mouth, blurred vision,
tachycardia
• Overdose – tremors, mydriasis, delirium and convulsion due
to norpethidine accumulation
 FENTANYL
It is a pure agonist for opioid receptors, possessing a high
affinity for µ receptors
It has an analgesic action 75-125 times greater than morphine
High speed of action iv (30 sec.) And limited duration of action
(30-60 min).

High lipophilicity which guarantees the release of the drug

through the skin by an external system
IV, IM, epidural, intrathecal, transdermal and transmucosal
administration: Minor side effects related to "bolus effect"
Catabolism is entirely hepatic (no active metabolites)
Hepatic clearance on the first pass is 70%
Congeneres alfentanil, sufentanil and remifentanil
Remifentanil is not metabolised by the liver but by tissue and
plasma esterases

reversed by Naloxone (µ receptor antagonist)

 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
 Pentazocine
• Weak α-receptor antagonist, but agonist of κ-receptor
• One of the commonly used agents, given orally and IM
• Low abuse liability
• Pharmacokinetics:
– High 1stpass 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
 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
 Buprenorphine
• Synthetic thebaine congener and highly lipid soluble
• Given Sublingually or parenterally but not oral – high 1st pass
metabolism
• Partial/weak μ agonist and κ antagonist

• 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
withdrawal syndrome
• Good analgesic for naive patients but addicts – precipitates

• Lower tolerance and physical dependence than Morphine and abuse

liability
• Withdrawal syndromes are similar to Morphine
Buprenorphine
• Preparations: Norphine, Tidigesic
• 0.3 mg/ml injections and 0.2 mg sublingual tablets
• Uses:
– Long lasting painful conditions – cancer
– Postoperative pain
– Myocardial infarction
• Adverse Effects:
– Hypotension (Postural)
– Respiratory depression (fatal in neonates) and cannot be
reversed by Naloxone
 Antagonists
1. Pure antagonists: Naloxone, Naltrexone and
Nalmefene
• Affinity for all receptors (μ, δ and κ)
• Can displace opioids bound to α-receptors
• No action on Normal person but reverses poisoning and
withdrawal symptoms in addicts
2. Mixed Agonist-antagonists: Nalorphine, Pentazocine,
Butorphanol and Nalbuphine
3. Partial/weak μ agonist and κ antagonist:
Buprenorphine
 Naloxone
• Competitive antagonist of all types of opioid
receptors
• But, blocks μ-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 (δ)
• Withdrawal symptoms: 0.4 mg doses – Morphine
and 4-5 mg doses – Nalorphine and Pentazocine
 Naloxone
• 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