OPIOID DRUGS

OPIOID DRUGS

• Substances obtained from crude extracts of Papaver somniferum (poppy plant).

Main clinical uses:

• Used as analgesic agents – 
• Relieves visceral, dull & constant pain, more effectively than inflammatory pain.

Opioid receptors:

Three receptors – 

• µ, κ and δ receptors.

µ receptor – 

• Opioids produce dependence, mainly euphoric action.           

κ receptors – 

• Mediates psychomimetic effects, mainly dysphoria action.

Actions of receptors: 

µ receptors	κ receptors	δ receptors
Sedation	Dysphoria (Psychomimetic effects)	Spinal analgesia
Analgesia	Constipation	Modulation of hormone
Euphoria	Analgesia	NT release
Miosis
Truncal rigidity
Respiratory depression

Opioid drugs:

Pure opioids	Mixed agonist-antagonist drugs	Opioid antagonists
Morphine – Prototype opioid; Acts as agonistic activity on µ, κ and δ receptors	Buprenorphine	Naloxone
Methadone	Butorphanol	Naltrexone
Pethidine	Nalbuphine	Nalmefene
Codeine	Pentazocine	Methylnaltrexone
Heroin	Dezocine	Alvimopan
Oxycodone	Tramadol (Partial agonist)	Naloxegol
Hydrocodone
Other important drugs: Propoxyphene,  Hydromorphone,  Oxymorphone,  Levorphanol,  Meperidine

Endogenous peptides:

• Endorphins, dynorphins, enkephalins & Nociceptin.
• Acts on opioid receptors producing analgesic effects.
• Endorphins act on µ receptor; Dynorphins acts on κ receptor; Enkephalins acts on δ receptors.
• Nociceptin – Acts on nociceptin/orphanin FQ (N/OFQ) or orphanin-like-receptors  (ORL).

Route of administration:

• Morphine – Administered by oral, rectal, i.v., i.m., intrathecal or epidural routes.
• Fentanyl – Applied as transdermal patch; also administered by buccal transmucosal route.
• Butorphanol – Only opioid available in nasal formulation.

1. PURE OPIOIDS:

Drugs included:

• Morphine, methadone, pethidine, levorphanol, codeine, hydrocodone, oxycodone, propoxyphene & Heroin (diacetylmorphine).
• Highly lipid soluble drugs – Fentanyl, alfentanyl & sufentanil.
• Strong opioid agonists – Morphine, hydromorphone & oxymorphone.
• Heroin (diacetylmorphine) – Potent & fast acting opioid; with high risk of abuse potential.

Actions of opioid:

CNS actions:

Morphine: 

• Acts on µ, κ and δ receptors.
• Produce marked sedation.
• Spinal & supraspinal analgesia. 
• Producerespiratory depression, cough suppression & miosis.
• Main feature for opioid poisoning diagnosis – Pinpoint pupil.

Pethidine & Fentanyl – 

• Produces less sedation.

Highly lipid soluble drugs (fentanyl, alfentanil & sufentanil) – 

• Causes truncal rigidity on rapid i.v. infusion.
• Results in nausea & vomiting – By cetirizine stimulation.

Peripheral effects:

• No direct effect on heart, except pethidine & pentazocine.
• Increases heart rate.
• Decreases BP – Due to vasomotor system depression & histamine release.
• Constipation – Due to decreased motility & increased GIT tone.

Alvimopan – 

• Peripheral opioid antagonist.
• Mainly for paralytic ileus.
• Bacause of increased intrabiliary pressure by constricting biliary smooth muscle.

Uses of pure opioids:

Morphine (i.v.) – 

• Useful in myocardial infarction, acute pulmonary edema & pre-anesthetic medication.

Codeine, pholcodine, dextromethorphan & noscapine – 

• Effective cough suppressants. 

Loperamide & diphenoxylate – 

• Used for non-infective diarrhea treatment.

Highly lipid soluble drugs (fentanyl, alfentanil, sufentanil) – 

• Used as adjuncts to other anesthetic agents.

Pethidine – 

• Used to reduce shivering after anesthesia Its action on α₂ receptor.

Dextromethorphan – 

• Devoid of constipating action, unlike other drugs.

Contraindications of opioids:

• Used cautiously in patients with pulmonary, hepatic or renal dysfunction.
• Cautious use in infants & elderly.
• In hypothyroidism – Show exaggerated response to opioids.
• In pregnancy – Prolonged opioid use → Causes in-utero physical dependence of fetus & precipitates severe withdrawal symptoms after birth.

Morphine –

• Absolute contraindication in head injury.
• Due to increased intracranial tension, respiratory depression & causes CO retention.
• Interferes with neurological function assessment – Masks important pupillary signs – Mainly causes miosis.
• In extremes of age i.e., very young and elderly persons.
• In bronchial asthma because it can cause respiratory depression and worsen the condition.
• In biliary colic – By increasing intrabiliary pressure worsens pain of biliary colic.

Pethidine & pentazocine – 

• In MI.

Important points on individual drugs:

Methadone – 

• Long-acting opioid analgesic.
• Administered by oral, i.v., s.c. & rectal routes.
• Potent agonistic actions at µ receptors; blocks NMDA receptors & monoamines reuptake.
• Relieves neuropathic & cancer pain – Uncontrolled with morphine.
• Due to its long t1/2, development of dependence & very slow tolerance – Hence, useful for opioid abuse treatment & opioid rotation therapy.

Pethidine & pentazocine – 

• Possess anticholinergic activity → Causes tachycardia.
• Relatively safer in biliary colic – Due to anticholinergic properties.
• Accumulation of active metabolite of pethidine (norpethidine) can produce seizures.

Propoxyphene – 

• Least potent & least efficacious analgesic agent.

Diphenoxylate, difenoxin (its active metabolite) & loperamide – 

• Useful for diarrhea.

Nalbuphine – 

• Shows ceiling effect to its respiratory depressant action.
• Buprenorphine dissociates slowly from µ receptors & is resistant to naloxone reversal.
• Butorphanol, pentazocine & dezocine – 
• Has psychomimetic effects with κ-agonistic activity.

Ziconotide:

• Intrathecal analgesia.
• Acts by blocking voltage-gated N-type Ca2+ channels.

Tramadol – 

• Weak µ-receptor agonist.
• Inhibits NA & 5-HT reuptake.
• At high doses – seizures.
• Analgesic action abolished by 5-HT antagonists (ondansetron).

Tapentadol (new drug) – 

• µ-receptor agonistic action & NA reuptake inhibiting action.
• Opioid tolerance: Develops all opioids actions except constipation, convulsions & pupil constriction.

MIXED AGONISTS-ANTAGONIST DRUGS:

Drugs included:

• Buprenorphine
• Nalbuphine
• Pentazocine
• Dezocine
• Butorphanol

Drugs & receptors:

• Nalbuphine, pentazocine & dezocine: κ-agonists and µ-receptor antagonists
• Buprenorphine: Partial agonist at µ receptor; Mild κ- and δ-antagonistic property.
• Butorphanol – Predominant κ-agonist

Uses:

• Analgesic.
• As methadone alternative – For opioid withdrawal management.
• Nalbuphine, pentazocine & dezocine – Produces psychomimetic effects with hallucinations, nightmares & anxiety.
• Butorphanol – Produces equivalent analgesia; more sedative than morphine.