ANALGESICS
 Analgesics are drugs that relieve pain due to multiple causes.
Classification of Analgesics
Nonopioid Analgesics
Opioid Analgesics
 Nonsteroidal anti-inflammatory drugs.
 Morphine.
 Paracetamol.
 Synthetic opioids.
Used in mild to moderate pain
(see NSAIDs)
Used in moderate to severe
pain
Opioid (Narcotic) Analgesics

Opioids are drugs with morphine-like effects.
Sources
1. Plant: morphine - codeine (termed opiates; natural alkaloids; products of
opium poppy).
2. Synthetic: fentanyl - methadone - heroin - pethidine….
3. Endogenous: endorphins - enkephalins - dynorphins (opiopeptides)
released in the body, acting on opioid receptors, producing morphine-like
effects.
Classification of Opioids
Opioid Analgesics
(see below)
Opioid Antitussives
Opioid Antidiarrheals
(Less addictive than
(Less addictive than
morphine)
morphine)
 Codeine
 Loperamide
Mechanism of Action
1. Opioid receptors, mu (mediate most effects of opioids), kappa & delta, are
Gi protein-coupled receptors present in the CNS and periphery (e.g. GIT).
2. Opioids (directly or through release of opiopeptides) activate receptors in:
 Afferent pain-conducting fibers  peripheral analgesia.
 Spinal cord  spinal analgesia.
 Brain stem1, thalamus & cerebral cortex  supraspinal analgesia.
 Limbic system  euphoria &  emotional response to pain
(patient may still feel the pain but the feeling is not unpleasant).
3. Activation of receptors  neuronal inhibition through:
a. Inhibition of Ca2+ entry   release of excitatory neurotransmitters
including substance P.
b. Stimulation of K+ outflux  hyperpolarization of neuronal membrane.
1
Activation of opioid receptors in midbrain activation of inhibitory descending pathways to
raphe nuclei in medulla to dorsal horn of spinal cord→ transmission in pain pathways
ascending from spinal cord to thalamus, limbic & somatosensory cortex.
Actions, Uses, Adverse Effects & Contraindications (CI) of Morphine
Uses
Actions
1. Analgesic in:
 Acute trauma.
 Chronic visceral pain
 Postoperative pain
 Cancer pain
 Myocardial infarction
I. Main Effects
A. Analgesia
 Pain perception &
emotional response to
pain
2. In anesthesia
 Preanaesthesia
 CV surgery
C. Euphoria(or dysphoria)
B. Sedation
Adverse Effects & CI
 Masks pain
CI: acute undiagnosed
abdomen
 Sedation - Narcosis
 Drug dependence
II. Inhibitory Effects
3. Acute pulmonary
edema in LVF:
 ↓preload & after load
 Respiratory distress
A.  VMC → venular &
arterial VD
 Hypotension
B. Respiratory center
 Respiratory depression
& asphyxia neonatorum
depression→ CO2 →
Cerebral VD & increased
intracranial tension
4. Antitussive
Replaced by
Codeine
Dextromethorphan
(less addictive)
C.  Cough center
D.  Uterine tone  delayed  Delayed labor
labor
III. Stimulatory Effects
A.  Oculomotor nucleus
 miosis
B.  CTZ  vomiting
5. Antidiarrheal
Loperamide
Diphenoxylate
(less addictive, more
widely used)
  Intracranial tension
CI: head injury
C. Urinary & GI Tracts
 tone of wall &
sphincters (spasmogenic)
but  peristalsis  stools
stagnate & harden due to
fluid absorption.
D. Histamine release
 Miosis
 Nausea - vomiting
 Urine Retention
(CI: enlarged prostate
 Biliary colic(CI
 Constipation
 Hypotension – itching bronchospasm(CI: asthma)
Other CI: extremes of age - hypothyroidism - liver dysfunction ( opioid metabolism)
Tolerance develops to all effects except constipation and miosis.
Classification of Opioid Analgesics
1. Strong
A. Pure Agonists
2. Moderate
3. Weak
Codeine
Propoxyphene
(Oral)
(Oral)
 Morphine
 Analgesic plus
 Analgesic plus
 Methadone
paracetamol or
paracetamol or
 Pethidine
aspirin in
aspirin in mild
 Heroin
moderate pain.
to moderate
 Fentanyl(& subgroup)
B. Partial agonists
 Antitussive.
pain.
 Buprenorphine
I. Pure Agonists
1. Morphine (see table).
Given IV - IM - SC - epidurally - orally (extensive 1st pass metabolism).
2. Pethidine [IM - Oral]
 Used in acute moderate & severe pain e.g, trauma, postoperative
pain, biliary colic or labor pain.
Pethidine differs from morphine in:
1. Less biliary colic- less constipation- less urinary retention (shorter
acting).
2. Less respiratory depressant in neonates2 & does not delay labor
 preferred during labor ( risk of asphyxia neonatorum).
3. Atropine-like action: dry mouth, blurred vision, ….....
4.  Risk of convulsions (with high dose or in renal failure due to
accumulation of the pethidine metabolite, norpethidine).
2
Morphine metabolism (conjugation ) is deficient in newborns  longer depressant effect on
respiration.
3. Methadone [Oral]
Uses
1. Treatment of opioid addicts (detoxification & maintenance):
 Orally-active & long acting, thus, it is used to replace morphine or
heroin in addicts. Gradual withdrawal of methadone is associated with
less severe & smoother withdrawal symptoms.
2. Analgesic in severe chronic pain (efficacy equal to morphine).
4. Fentanyl
 More potent than morphine with rapid onset & shorter action
(preferred in anesthesia).
 High anesthetic doses→ chest wall rigidity↓ thoracic compliance 
ventillation.
Uses (IV– epidural- spinal - transdermal patch – pt. controlled infusion)
1. Analgesic in severe pain e.g. perioperative, labor & cancer pain.
2. In anesthesia (for its analgesic & sedative effects):
 Preanesthetic medication.
 IV anesthetic in cardiovascular surgery (safer).
 Conscious sedation - neuroleptanalgesia – neuroleptanesthesia.
Conscious Sedation & Neuroleptanalgesia
(Amnesia, sedation & analgesia without complete loss of consciousness)
Uses: minor procedures or for diagnostic purposes (e.g. endoscopy).
Conscious Sedation
 IV benzodiazepine (e.g. midazolam) - opioid analgesic (e.g. fentanyl).
 Easily reversed by flumazenil & naloxone (advantage).
Neuroleptanalgesia
 Neuroleptic (e.g. droperidol) plus opioid analgesic (e.g. fentanyl).
 Converted to neuroleptanesthesia by adding 65% nitrous oxide in O2.
Fentanyl subgroup
 Sufentanil is more potent than fentanyl.
 Remifentanil (IV infusion): ultrashort acting as it is metabolized by
blood & tissue esterases →less ventillatory depression.
5. Heroin
 Diacetylmorphine converted to morphine in CNS.
 Rapid onset (greater lipid solubility  crosses BBB more than morphine)
& short duration   risk of abuse (not used clinically in most countries).
Tramadol
 Analgesic acting by inhibiting uptake of 5- HT and NA.
 Weak Mu agonist (only partially antagonized by naloxone).
 Less constipation, respiratory depression & addiction than morphine.
 ↑ Risk of convulsions.
Uses (oral, IM, IV)
 Analgesic in postoperative & chronic moderate pain - neuropathic pain.
II. Partial Agonists
Buprenorphine (partial Mu receptor agonist)
Advantages over Pure Agonists
1. Less addiction (less euphoria  less craving).
2. Respiratory depression is not  by  dose (ceiling due to antagonist effect)
but if it occurs, it is not easily reversed as it binds with  affinity to
receptors.
Uses (parentral, sublingual)
1. Analgesic in severe pain.
2. Treatment of opioid addicts (long-acting, slowly dissociates from
receptors) as an alternative to methadone (sublingual).
Drug Interactions of Opioids
1. Opioids + other CNS depressants (sedatives, alcohol, antidepressants &
antipsychotics)  additive CNS depression.
2. Pethidine + MAOIs  hyperpyrexia- respiratory depression - convulsions3.
3. Partial agonist + pure agonist  withdrawal syndrome &  analgesic
effect.
Acute Morphine Toxicity
 Coma.
 Respiratory depression.
 Pin pointed pupil (diagnostic).
Treatment
 Support respiration.
 Naloxone (IV): opioid antagonist, repeated when necessary.
3
Inhibition of pethidine metabolism by MAOI  norpethidine formation by another metabolic
pathway.
Pure Opioid Antagonists
Naloxone
Naltrexone
IV & short-acting
Oral & long-acting
Management of acute toxicity
Maintenance therapy in addicts
1. Acute opioid toxicity:
1. Opioid abuse
Repeated as necessary to avoid
Blocks euphoria of opioids
relapse into coma since duration
→ loss of desire to take
of action is shorter than opioids.
drug (prevents relapse).
2. Asphyxia neonatorum
2. Alcohol abuse
Respiratory stimulant in opioid-
↓ Craving in chronic
induced respiratory depression
alcoholics.
in newborns.
N.B.:
 Addicts should be closely monitored during reversal of acute opioid
toxicity with naloxone to avoid precipitation of withdrawal symptoms.
 Naltrexone should be given to opioid addicts after full detoxification,
otherwise it would precipitate a withdrawal syndrome