Morphine
Chemical
Exogenous opioid agonist of PHENANTHRENE CLASS
Intermediate onset, long acting
Naturally occurring → 1° alkaloid of poppy
The prototype opioid agonist to which all other opioids are compared
Use
- Analgesia
- Premed
- Palliative analgesia
Presentation
ORAL: morphine sulphate capsules 5 – 100mg
PARENTERAL: clear, colourless solution, 10mg/mL
Physical properties
- pKa 7.9 → 76% ionised at pH 7.4
- Partition coefficient 1.4 → poor lipid solubility
Dose / Route
ORAL
- Poor OBA 30% → due to high 1st pass metabolism; used for slow release preparation → MS CONTIN (i.e. morphine sulphate controlled release)
- When converting parenteral → oral = x 3
PARENTERAL
- Subcut (palliative), IM, IV
- 1mg/kg
- PCA 1 – 2mg q5mins
EPIDURAL
- 2 – 4mg gives 24hr of analgesia
- Poor lipid solubility ∴ may take 60 mins before enters CSF for onset
INTRATHECAL
- 100 – 300mcg
- Rapid onset s/c deposited in CSF, but prolonged action 24hr & risk respiratory depression
Onset
15 – 30mins (IV)
40 – 90 mins (IM)
Delayed because poor lipid solubility à long time to cross BBB
DoA
3 – 4hrs
MoA
µOP agonist (x100 less affinity for κOP)
- µOP located throughout CNS
- µOP concentrated in periaqueductal grey matter near 4th ventricle & substantia gelatinosa of dorsal horn of SC
Gi GPCR
- Closure of voltage sensitive Ca2+ channel on presynaptic membrane → ↓intrac Ca2+
- Post synaptic stimulation of K efflux → hyperpolarisation
- Inhibition of AC → ↓cAMP
OVERALL
- ↓cell membrane excitability
- ↓transmission nociceptive signals
µ1 → supraspinal analgesia
µ2 → spinal analgesia
PD
CNS
- Analgesia
- Sedation
- Miosis
RESP
- Ventilatory depression
- ↓CO2 responsiveness
- ↓RR & MV
- Blunts airway reflexes
CVS
- ↓SVR 2° histamine & ↓symp tone
- ↓HR due to stimulation of vagal nuclei in medulla
- May directly depress AV node conduction
GI
- N&V
- Biliary colic
- Constipation
- Delayed gastric emptying
IMMUNO
- Histamine release
- Reactivation of herpes with neuraxial administration
PK
A
Poor OBA 30%
High 1st pass metabolism
D
Large 3.2L/kg
(v H2O soluble)
PPB 35%
Crosses placenta + immature neonatal BBB = neonatal depression
At peak plasma [ ] only <0.1% dose has entered CNS
Peak [ ] in biophase occurs 15 – 30 mins following IV admin
Poor CNS penetration because:
- 76% ionised at pH7.4
- Poor lipid soluble of UNIONISED %
- PPB
- Rapid conjugation with glucuronic acid
M
Hepatic biotransformation
MAJOR ROUTE OF ELIMINATION
High HER 0.7
∴ high 1st pass metabolism → only 30% oral dose reaches circulation
INTRAHEPATIC GLUCURONIDATION
- Main metabolism pathway
- Conjugated with glucuronic acid
- M3G (>80%)
- M6G (<10%)
- M6G still active & more potent at µOP
EXTRAHEPATIC GLUCURONIDATION
- Esp in kidneys
DEALKYL (methyl) ATION
- Demethylated to normorphine
- <5% of dose
- Small amount CODEINE made this way
CLEARANCE
- 15mL/kg/min
- M plasma clearance exceeds Hepatic Plasma Flow
- ∴ HBF = rate limiting step for M elimination & extrahepatic metabolism must be occurring
E
<5% dose excreted unchanged
t ½ B = 180 mins; short elimination ½ life consistent with DoA 3 – 4hrs
Response Variability
Age
Neonate <4wks
- ↓conjugating capacity of liver
- Immature BBB
- ↑sensitivity to M
- Crosses placenta
- Avoid/use cautiously
Elderly
- ↓VD
- ↓clearance
- ∴ ↑ sensitivity
Cirrhosis
- ↓PPB
- Elim unaffected 2° ↑kidney glucuronidation
Renal failure
- ↓PPB
- ↓ VD
- ↑t ½
- Accumulation of M3G & M6G
- ∴ prolonged DoA & M6G accumulation
Drug Interactions
MAOI: inhibit formation of glucuronide conjugates
∴ ↓metabolism = ↑ effects/DoA
Contraindicated
- Resp disease = resp D, bronchospasm
- Neuro Sx
- CO2 retention
- Sedation clouds GCS assessment
- ↑CBF 2° ↑CO2
- Altered pupillary response
- Elderly/neonates/pregnancy
- Renal/hepatic disease
- Previous HSV infection with neuraxial admin
Adverse Effects
Muscle rigidity
Ouch! Muscle spasm, colic, constipation
Resp depression
Pruritus
Histamine release & ↓BP
IDC for urinary retention
N & V
Euphoria/sedation/confusion
Illicit → tolerance/depression
Viral reactivation (neuraxial)