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 Used in moderate to severe

(see NSAIDs) 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 Opioid Antitussives Opioid Antidiarrheals

(Less addictive than (Less addictive than
(see below)
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 Adverse Effects & CI

1. Analgesic in: I. Main Effects  Masks pain

 Acute trauma. A. Analgesia CI: acute undiagnosed
 Chronic visceral pain  Pain perception &
abdomen
 Postoperative pain emotional response to
 Cancer pain pain
 Myocardial infarction  Sedation - Narcosis
B. Sedation
C. Euphoria(or dysphoria)  Drug dependence
2. In anesthesia
 Preanaesthesia
 CV surgery
II. Inhibitory Effects
3. Acute pulmonary A.  VMC → venular &  Hypotension
edema in LVF: arterial VD
 ↓preload & after load
 Respiratory distress B. Respiratory center  Respiratory depression
depression→ CO2 → & asphyxia neonatorum

Cerebral VD & increased   Intracranial tension

intracranial tension CI: head injury
4. Antitussive
Replaced by C.  Cough center
Codeine
Dextromethorphan D.  Uterine tone  delayed  Delayed labor
labor
(less addictive)

III. Stimulatory Effects

A.  Oculomotor nucleus  Miosis
 miosis
B.  CTZ  vomiting  Nausea - vomiting

5. Antidiarrheal C. Urinary & GI Tracts  Urine Retention

Loperamide  tone of wall & (CI: enlarged prostate
Diphenoxylate sphincters (spasmogenic)  Biliary colic(CI
(less addictive, more but  peristalsis  stools
stagnate & harden due to  Constipation
widely used) fluid absorption.
 Hypotension – itching -
D. Histamine release
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 2. Moderate 3. Weak

A. Pure Agonists Codeine Propoxyphene
 Morphine (Oral) (Oral)
 Fentanyl(& subgroup)  Analgesic plus  Analgesic plus
 Methadone paracetamol or paracetamol or
 Pethidine aspirin in aspirin in mild
 Heroin moderate pain. to moderate
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