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MORPHINE: New Findings of an Old Drug
By
Amnuay Thithapandha, Ph.D.
Professor, Office of Academic Affairs
Faculty of Medicine Ramathibodi Hospital
Mahidol University
Among the remedies which it has
pleased Almighty God to give to man
to relieve his sufferings, none is so
universal and so efficacious as opium.
Sydenham (1680)
In 1806, F. Serturner (a German
pharmacist) reported the isolation of a
pure substance from opium that he named
MORPHINE, after Morpheus (Greek god
of dreams)
CONFUSING TERMINOLOGY
Narcotic ( Greek = stupor ) ---- used only in
a legal context
Opioid--- any substance (synthetic
or semisynthetic) that has
morphine-like effects
Opiate--- a substance derived from
opium and has morphine-like
effects
MAIN USES OF MORPHINE
1. SEVERE PAIN
•
POST-OPERATIVE
•
TRAUMATIC
2. CANCER PAIN (terminal)
3. BURN PAIN
4. TO INTERRUPT THE PAIN CYCLE
Remember : “Severe Pain Can Kill”
(F.J. Brescia et al., J Clinical Oncol 10 : 149, 1992;
G.K. Groulay & D.A. Cherry, Clin J Pain 7:347,1991 )
MORPHINE : KINETICS
•
ORAL BIOAVAILABILITY = 20 %
HALF – LIFE ( PO, IM ,SC , IV ) = 2 – 3 h
CONJUGATED IN LIVER & EXCRETED VIA
KIDNEY ( 90 % OR MORE )
M6G = Active metabolite (9X)
M3G = Toxic metabolite
IN PATIENTS WITH DEHYDRATION, RENAL
FAILURE OR HEPATIC INSUFFICIENCY
 REDUCE DOSE
 INCREASE DOSING INTERNVAL
 USE ONLY PRN IF OLIGURIA OR ANURIA IS
PRESENT
ADVERSE EFFECTS OF MORPHINE
COMMON :
(initial)
N+V, DROWSINESS
DELIRIUM (CONFUSION)
COMMON :
CONSTIPATION
(on- going)
SEDATION
OCCASIONAL :
DRY MOUTH
URINARY RETENTION
PRURITIS
HALLUCINATION
RESPIRATORY DEPRESSION
N CH3
1
2
3
HO
4
0
UGT2B7
UGT1A1
M3G
• MAJOR METABOLITE
• WEAK
• ADRS
m -ANTAGONIST
5
6
OH
UGT2B7
M6G
POTENT
m-AGONIST
(x 9 MORPHINE)
UGT = UDP - GLUCURONOSYLTRANSFERASE
INTRAVENOUS M6G: PHARMACOKINETICS
Renal Function
Normal
Impaired
Creatinine clearance (ml/min)
84
19
M6G clearance (ml/min)
89
26
Volume of distribution (L)
14.7
16.4
Elimination half-life(h)
1.9
7.4
370
1319
AUC (nmol/L.h)
BW=70 kg; Dose= 1 mg
AUC from zero to infinity
R. Osborne et al., Lancet,April 9,1988
M6G (0.5 mg, IV)
100
80
Cancer pain
N=5
± SE
OVER 5 MIN
x
IV
R. Osborne et al
Lancet, April 9, 1988
VAS
60
40
20
TIME (h)
1
2
3
4
5
6
7
8
100
M
80
CSF M6G (ng/ml)
M6G
M3G
60
40
SENSITIVE (4)
20
INSENSITIVE (6)
10
M
(10 mg, IV)
20 30
60
100
140
180
MAJOR EFFECTS OF
MORPHINE METABOLITES
M3G
(m-antagonist)
M6G
(m-agonist)
•
•
•
•
SEDATION
ANALGESIA
CONSTIPATION
RESPIRATORY DEPRESSION
UGT2B7
M
•
•
•
•
DELIRIUM
HALLUCINATION
INCOHERENCE
TREMOR
UGT1A1
UGT2B7
M6G
M3G
TOXICITY
Case: MORPHINE REACTIONS
Sirima Triamruktakul, a 45-year-old woman
weighing 56 Kg, was admitted to the emergency room
because of low back pain. The pain intensity was such
that she could not mobilize and felt desperate. She was
given a small dose of morphine (5 mg, IM) but did not
obtain any pain relief even at 1 hour after the drug
administration. In fact, she manifested signs of tremor
and hallucination which became apparent at only half
an hour after the opioid. Diazepam (5 mg, IV) was needed
to ameliorate these adverse reactions.
Case: MORPHINE REACTIONS (CONT)
Three months later she was readmitted with the same
complaint. Morphine (5 mg, IM) was tried on her again
with the same signs of its adverse reactions. Blood
samples were taken serially from 0.5,1,2,3,4,6 and 8 hours.
When morphine and its metabolites were analyzed, it was
found that she could make little M6G but an unusually large
M3G profile was noted.
45 yr
UGT 2B7
1
bp
Promoter
2
(736)
4
5
(149) (132) (88) (220)
816
CAU
His
3
TAU
Tyr
6
(721)
1816
GAC
Asp
GCC
Ala
GENETIC ANOMALIES UNDERLINE THE CAUSE OF
SEVERE ADVERSE REACTIONS TO MORPHINE
PATIENT DISEASE
M3G
M6G
ADRS
Appendicitis 10:1
N+V
Burn
25:1
Renal stone
30:1
Delirium
+ Tremor
Tremor
+ Hallucination
Low back pain 40:1
N+V
GENETIC CAUSE
Point mutation in
exon 2,6
Point mutation in
exon 2,6
Insertion of an extra
TA in the promoter;
Point mutation in
exon 6
Gene deletion
+ Hallucination
+ Seizure
The M3G:M6G ratio was obtained from AUC 0.5-8h after
morphine (5 mg, IM).
AUCa0
10.0
40.4
M3G
M6G AUCa0
8.4
3.4
9.2
12.8
15.6
Hallucination
n+v
NORMAL M3G/M6G
RATIOS ARE 3-5
35.2
Xanthopsia
M
UGT1A1
UGT2BT
M3G
UGT2BT
M6G
Nose itching and pruritis caused by
morphine are due to histamine release
and are antagonized by hydroxyzine
or naloxone. In the presence of the
antagonist, however, plasma
histamine level in the sensitive
individuals remains elevated.
A.Thithapandha, Toxicol. Appl. Pharmacol., 2007(in press)
PLASMA CONC (ng/ml)
5
4
MORPHINE-INDUCED
HISTAMINE RELEASE IN
SENSITIVE PATIENTS
3
8
* P < 0.05
*
2
1
0
*
20
CONTROL
10
INSENSITIVE
SENSITIVE
MORPHINE
(Base, pKa = 7.9)
NALOXONE
M – OPIOID
RECEPTOR
MAST
CELL
HISTAMINE
ANALGESIA
HYDROXYZINE
ITCHING
No patient should ever wish for death
because of a physician’s reluctance to
use adequate amounts of effective
opioids.
Gutstein and Akil
(Goodman & Gilman, 11th edition, 2006)