Analgesic responses to intrathecal morphine in relation to CSF concentrations of morphine-3,β-glucuronide and morphine-6,β-glucuronide

doi:10.1016/S0024-3205(99)00110-1

Life Sciences

Volume 64, Issue 19, 2 April 1999, Pages 1725-1731

https://doi.org/10.1016/S0024-3205(99)00110-1 Get rights and content

Abstract

This study was performed to determine whether variations in analgesic responses to intrathecal morphine could be explained by cerebrospinal fluid (CSF) concentrations of morphine metabolites. Twenty-four CSF samples were collected at the beginning, middle and end of treatment periods in seven cancer patients with pain of malignant origin. CSF concentrations of morphine-3,β-glucuronide (M3G) and morphine-6,β-glucuronide (M6G) metabolites were measured by gas chromatography/mass spectrometry. Analgesic responses to morphine were estimated concurrent with CSF collection using a visual analog scale representing percentages of pain relief. Effective analgesia was defined as ≥ 75% pain relief. CSF concentration of M3G and M6G in the 24 samples were 722 ± 116 ng/ml and 699 ± 158 ng/ml, respectively. CSF samples were categorized into two groups: (1) those collected during effective analgesia (N = 14), and (2) those collected during ineffective analgesia (N = 10). M6G levels detected in group 1 samples (effective analgesia) were significantly greater than those found in group 2 samples (ineffective analgesia) (978 ± 243 ng/ml vs 309 ± 68 ng/ml, P < 0.05). Intergroup differences in CSF M3G concentrations and $M3G M6G$ ratios were not significant. It is concluded that CSF M6G may be indicative of effectiveness of analgesia in cancer patients subjected to intrathecal morphine.

References (39)

K. Budd
Br. J. Anaesth.
(1989)
C. Faura et al.
Pain
(1996)
A. Wahlstrom et al.
Pain
(1988)
A. Bodenham et al.
Br. J. Anaesth.
(1989)
M.T. Smith et al.
Life Sci.
(1990)
T. Wolff et al.
Pain
(1996)
D. Bigler et al.
Pain
(1990)
C.W. Hand et al.
Lancet
(1987)
H. Samuelsson et al.
Pain
(1991)
H. Samuelsson et al.
Pain
(1993)

G.W. Pasternak et al.

Life Sci.

(1987)

J.O. Miners et al.

Biochem. Pharmacol.

(1988)

J.O. Miners et al.

Biochem. Pharmacol.

(1990)

S. Kalman et al.

Reg. Anesth.

(1997)

B.C. Yoburn et al.

Pharmacol. Biochem. Behav.

(1989)

R.K. Portenoy et al.

Pain

(1990)

S. Arner et al.

Pain

(1988)

B. Onofrio et al.

B.M. Onofrio et al.

J. Neurosurg.

(1990)

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Glucuronidation is a major drug-metabolizing reaction in humans. A pharmacological effect of glucuronide metabolites is frequently neglected and the value of therapeutic drug monitoring has been questioned. However, this may not always be true.
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Analgesic responses to intrathecal morphine in relation to CSF concentrations of morphine-3,β-glucuronide and morphine-6,β-glucuronide

Abstract

Br. J. Anaesth.

Pain

Pain

Br. J. Anaesth.

Life Sci.

Pain

Pain

Lancet

Pain

Pain

Life Sci.

Biochem. Pharmacol.

Biochem. Pharmacol.

Reg. Anesth.

Pharmacol. Biochem. Behav.

Pain

Pain

J. Neurosurg.