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 effectsOpiate--- a substance derived from

opium and has morphine-like effects

MAIN USES OF MORPHINEMAIN 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 : N+V, DROWSINESS

(initial) DELIRIUM (CONFUSION)

COMMON : CONSTIPATION(on- going) SEDATION

OCCASIONAL : DRY MOUTH

URINARY RETENTION PRURITIS HALLUCINATION RESPIRATORY DEPRESSION

2

1

34

05

6

HO OH

M3G M6G• MAJOR METABOLITE POTENT -AGONIST

• WEAK -ANTAGONIST (x 9 MORPHINE)• ADRS

UGT2B7UGT1A1

UGT2B7

UGT = UDP - GLUCURONOSYLTRANSFERASE

N CH3

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

AUC (nmol/L.h) 370 1319

BW=70 kg; Dose= 1 mg

AUC from zero to infinity

R. Osborne et al., Lancet,April 9,1988

1 2 43 5 6 7 8

60

100

20

80

40

TIME (h)

M6G (0.5 mg, IV)V

AS

Cancer pain N = 5 x ± SE IV OVER 5 MIN

R. Osborne et al Lancet, April 9, 1988

20

40

60

80

100

10 20 30 60 100 140 180M (10 mg,

IV)

INSENSITIVE (6)

SENSITIVE (4)

MM6GM3G

CS

F M

6G

(n

g/m

l)

MAJOR EFFECTS OF MORPHINE METABOLITES

M6G(-agonist)

M3G(-antagonist)

• SEDATION• ANALGESIA• CONSTIPATION• RESPIRATORY DEPRESSION

• DELIRIUM• HALLUCINATION• INCOHERENCE• TREMOR

M

M6G M3G

TOXICITY

UGT2B7UGT1A1

UGT2B7

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

CAU TAUHis Tyr

1 2 3 4 5 6

1816

(736) (149) (132) (88) (220) (721)

GAC GCCAsp Ala

816

bpPromoter

GENETIC ANOMALIES UNDERLINE THE CAUSE OF SEVERE ADVERSE REACTIONS TO MORPHINE

PATIENT DISEASE M3G ADRS GENETIC CAUSE

M6G

Appendicitis 10:1 N + V Point mutation in exon 2,6

Burn 25:1 Delirium Point mutation in + Tremor exon 2,6

Renal stone 30:1 Tremor Insertion of an extra

+ Hallucination TA in the promoter;

Point mutation in exon 6

Low back pain 40:1 N + V Gene deletion + Hallucination

+ Seizure

The M3G:M6G ratio was obtained from AUC 0.5-8h after morphine (5 mg, IM).

UGT2BT

40.4 3.4 9.2 12.8 15.6

35.2Xanthopsia

10.0 8.4

Hallucinationn+v

NORMAL M3G/M6G RATIOS ARE 3-5

M3G AUC0

M6G AUC

0

M

M3G M6G

UGT1A1UGT2BT

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)

MORPHINE-INDUCEDHISTAMINE RELEASE IN SENSITIVE PATIENTS

* P < 0.05

PLA

SM

A

CO

NC

(n

g/m

l)

20

10

*

*

8

0

1

2

3

4

5

CONTROL INSENSITIVE SENSITIVE

MORPHINE

(Base, pKa = 7.9)

NALOXONE

M – OPIOIDRECEPTOR

MASTCELL

ANALGESIA

HISTAMINE

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)