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Anesth Analg 1999;89:1209
© 1999 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MANAGEMENT

Acute Decreases in Cerebrospinal Fluid Glutathione Levels after Intracerebroventricular Morphine for Cancer Pain

Leonidas C. Goudas, MD, PhD*, Agnes Langlade, MD, PhD{ddagger}, Alain Serrie, MD, PhD{ddagger}, Wayne Matson§, Paul Milbury, §, Claude Thurel, MD{ddagger}, Pierre Sandouk, MD||, and Daniel B. Carr, MD, FABPM*,{dagger}

Departments of *Anesthesia and {dagger}Medicine, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts; {ddagger}Centre de Traitement de la Douleur, Hopital Lariboisiere, Paris, France; §ESA Corporation, Chelmsford, Massachusetts; and ||INSERM, Paris, France

Address correspondence and reprint requests to Daniel B. Carr, MD, FABPM, Department of Anesthesiology, New England Medical Center, 750 Washington St., Boston, MA 02111. Address e-mail to dcarr02{at}emerald.tufts.edu


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Intracerebroventricular (ICV) morphine administration is effective for the management of refractory cancer pain. Recent preclinical observations of acute depletion of the major endogenous intracellular antioxidant glutathione (GSH) in brain and peripheral organs after ICV morphine in rodents led us to apply microchemical methods to profile the neurochemical effects of ICV morphine in three patients treated for intractable cancer pain. Assessment of morphine, morphine-6-glucuronide, and a panel of endogenous compounds and metabolites in ventricular and cisternal cerebrospinal fluid (CSF) demonstrated transient, postdose increases in morphine and morphine-6-glucuronide in ventricular and cisternal CSF, accompanied by acute decreases in CSF GSH levels. Significant changes were also observed in the CSF levels of 4-hydroxybenzoic acid, homovanillic acid, 5-hydroxyphenyllactic acid, and uric acid. These pilot clinical observations of acute central GSH depletion after ICV morphine suggest a novel mechanism for neuropsychiatric toxicity or preclinical findings, such as hyperalgesia or increased motoric activity observed in nonhuman species after central morphine administration. Because ICV morphine is a mainstay of treatment for refractory cancer pain, elucidation of a mechanism’s (or mechanisms’) mediating a potential pro-oxidant state in the central nervous system induced by ICV morphine is important.

Implications: We observed acute decreases in glutathione levels in cerebrospinal fluid sampled from patients after intracerebroventricular doses of morphine for intractable cancer pain. Such doses may, by depleting the antioxidant glutathione, render the central nervous system vulnerable to damage from oxidative stress.


   Introduction
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 Abstract
 Introduction
Methods
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 Discussion
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Initial clinical trials of direct application of opioids within the central nervous system (CNS) were followed by wide clinical acceptance of the central route of opioid administration for acute and chronic use (1–4). Among these CNS sites, the intracerebroventricular (ICV) application of morphine has proven useful in the relief of cancer pain, especially at supradiaphragmatic sites (5–7).

In contrast to numerous preclinical studies of the mechanisms of central opioid analgesia, few clinical studies have explored neurochemical sequelae of ICV morphine administration (6,8,9) and possible correlations between such neurochemical responses and side effects (10) as somnolence (11) and neuropsychiatric toxicity (12). In clinical settings, ethical and practical limits on patient recruitment, sample procurement, and analytic technology have hindered progress. Coulometric detection methods for high pressure liquid chromatography (HPLC) (10,13) permit characterization of multiple neurotransmitters and their metabolites in small volumes of cerebrospinal fluid (CSF). Such methods have been applied to investigate clinical conditions such as Huntington’s disease (14), Rett’s syndrome (15), or facial pain (16). These methods are also useful to probe CNS metabolic pathways related to biogenic amines (11,17), that, in animal studies, have long been recognized to mediate opioid analgesia.

Recently, we observed acute depletion of the major endogenous intracellular antioxidant, reduced glutathione (GSH), in brain and peripheral organs after ICV morphine administration in rats (18). Because such oxidative stress may contribute to adverse effects of ICV morphine, the aim of the present study was to characterize (17) neurochemical responses to therapeutic ICV injections of morphine in patients with refractory cancer pain. We were able to measure 30 compounds in CSF (Table 1), along with morphine and its major analgesic metabolite, morphine-6-glucuronide (M6G), simultaneously in 2-mL CSF samples withdrawn during placement and therapeutic use of ICV cannulae for morphine delivery. Separate measurement of CSF levels of morphine and M6G was accomplished by radioimmunoassay to validate HPLC assays for morphine.


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  		Table 1. Concentrations of Endogenous Compounds in Ventricular and Cisternal CSF Samples from Patients Treated for Intractable Cancer Pain
 

   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Written, informed consent was provided by three patients suffering from cancer-related pain. At the time of the initial pain consultation, these patients were judged to be in the terminal phase and not candidates for further radiotherapy, chemotherapy, or surgical resection of tumor. Each patient had a supradiaphragmatic malignancy. Patient 1 had recurrent laryngeal carcinoma after laryngectomy; Patient 2, lung cancer unresponsive to prior radiotherapy; and Patient 3, unresectable lung cancer with superior sulcus syndrome. In each case, analgesia was inadequate despite increasing oral morphine dosage to the point of unacceptable side effects, and so ICV morphine therapy was suggested as an appropriate clinical alternative.

Oral morphine was discontinued on the day of the placement of the central catheter. Under local anesthesia, an Ommaya reservoir was implanted with the distal catheter tip in the frontal horn of the right lateral ventricle. After Ommaya reservoir placement, a thin catheter was inserted into the cisterna magna to sample CSF for 24–48 h, after which it was withdrawn. An initial ICV dose of morphine hydrochloride (0.3 mg) was given when pain first recurred after catheter placement and was repeated each time the patient requested it or every 24 h (whichever was sooner). Pain intensity was monitored on a 10-cm visual analog scale. Before the first ICV dose of morphine, 2-mL aliquots of cisternal and ICV CSF were withdrawn at 1, 3, 6, and (if pain still had not recurred) 12 and 24 h after catheter placement. CSF was again withdrawn at similar time points after each ICV morphine injection. Plasma samples were collected in EDTA vacuum-containing blood withdrawal tubes. Both plasma and CSF samples were centrifuged at 3000 g for 10 min to clear red cells and other particulate matter, then frozen at -70°C until thawed once for analysis.

To characterize morphine, M6G, and other analytes in CSF, we used coulometric HPLC to measure multiple analytes simultaneously (11,19). Each CSF sample (50 µL) was assayed in duplicate, using a 16-channel coulometric electrode array (ESA CouloChem, Bedford, MA), and separation was achieved using a gradient mobile phase (10,13). The sensitivity limits ranged between 1 and 5 pg and were compound-dependent. Levels of morphine-3-glucuronide and oxidized glutathione could not be reliably measured using the present methods and, so, are not reported.

For each patient, cisternal and ventricular concentrations of each substance were analyzed separately after pooling into three data sets. The first set (PRE) consists of the mean concentrations of each compound in all ICV and cisternal CSF samples collected from immediately after placement of the ICV cannula until just before the first request for morphine administration. The second set (POST1) consists of concentrations of each compound in all ICV and cisternal CSF samples collected from immediately after the first morphine administration until just before the second request for morphine administration. For Patients 1 and 2, a third set (POST2) consists of mean concentrations of each compound in all ICV CSF and cisternal samples collected immediately after the second morphine administration until the end of the study, 48 h after the initial ICV dose of morphine. By merging data from multiple time points in this manner, given the limited number of cases studied, the statistical significance of aggregate differences between concentrations of analytes before and after administration of morphine was strengthened, even though their detailed patterns of change across separate time points were obscured. In an exploratory analysis, data were analyzed using one-way analysis of variance followed by a post hoc Dunnett test for comparison with levels before morphine administration (PRE, considered as control). For selected compounds whose concentrations changed significantly, correlation analyses were performed (Pearson’s correlation coefficient) with respect to morphine and M6G. Data in graphs and tables are expressed as mean ± SD. A P < 0.05 was considered significant.


   Results
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 Introduction
 Methods
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Discussion
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Baseline plasma levels of morphine and M6G determined by HPLC and EDTA were low and fell slowly after discontinuation of oral morphine at the start of our observations (Figure 1). Concentrations of morphine and M6G then followed the expected pattern of transient log-order rises in ventricles and cisternae after each therapeutic ICV morphine injection. Although M6G concentrations in the ventricular and cisternal CSF were measurable before ICV morphine administration, small transient increases of M6G after two ICV morphine injections in Patients 2 and 3 took place as concentrations of morphine declined, which suggests that local glucuronidation of morphine within brain structures is a possible route of morphine biotransformation.



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  		Figure 1. Concentrations by high pressure liquid chromatography and electrochemical detection of morphine in the ventricles (•) and cisternae ({circ}) and morphine-6-glucuronide (M6G) in the ventricles ({blacktriangleup}) and cisternae ({triangleup}) across time in three patients. The arrows indicate the time of intracerebroventricular morphine injection. A logarithmic scale is used for concentrations to display both morphine and M6G. Arrows indicate ICV administration of morphine: twice for Patients 1 and 2, and once for Patient 3.

 
Of the 30 endogenous neuromodulators or endogenous compounds assessed in ventricular and cisternal CSF, significant changes were observed in the concentrations of GSH (Figure 2) and the monoamine metabolites 4-hydroxybenzoic acid (4-HBAC), homovanillic acid, 5-hydroxyphenyllactic acid, and uric acid (Table 1).



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  		Figure 2. Reduced glutathione (GSH) concentrations by high pressure liquid chromatography and electrochemical detection (mean ± SD) in ventricular and cisternal cerebrospinal fluid in three patients. GSH concentrations before the first administration of morphine (PRE) were compared with the average of concentrations after the first morphine dose and until the second morphine dose (POST1) or the average of concentrations in all samples following the second morphine injection until the end of the study (POST2). Comparisons were performed within each patient separately using one-way analysis of variance followed by the Dunett test. *P < 0.01.

 
GSH concentrations in the ventricular or cisternal CSF decreased after morphine administration, although not significantly, in each patient after every injection (Figure 2). Concentrations of GSH before morphine administration were significantly higher after the first morphine injection (POST1) and the second injection (POST 2) in both cisternal (P = 0.006) and ventricular (P = 0.00004) samples in Patient 1 and in ventricular (P = 0.00263) but not cisternal CSF in Patient 2.

In view of the significant decreases of GSH observed in two of the three patients (Figure 2), Pearson’s correlation coefficients were calculated between morphine and M6G concentrations and the corresponding GSH concentrations across all time points in all three patients. Weakly negative, but significant, correlations were demonstrated between concentrations of morphine and GSH in ventricular CSF (r = -0.3664, P = 0.0331, n = 34) and between M6G and GSH in ventricular CSF (r = -0.49055, P = 0.00277, n = 35), which suggests that morphine and M6G may be at least partially responsible for the observed decreases of the endogenous antioxidant.

Significant changes in ventricular and/or cisternal CSF concentrations of 5-hydroxyphenyllactic (Patients 1 and 2), 4-HBAC (Patient 1), homovanillic acid, and finally uric acid (Patients 1 and 2) were demonstrated after morphine administration and are shown in Table 1.


   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Morphine is the opioid of choice via both systemic and central routes for the control of moderate to severe cancer pain (20–22). Morphine and other opioids can produce neuropsychiatric dysfunction that may, in its subtlest forms, only be evident in specific testing (12). Opioid interactions with major neurotransmitter families are innumerable, but scarce evidence to date has elucidated specific mechanisms that may underlie opioid-induced neuropsychiatric dysfunction or dysfunction of peripheral organs, such as the kidney. Morphine may be either glucuronidated or dehydrogenated at the 6-position to yield M6G or morphinone, respectively. Morphine-induced depletion of hepatic GSH has been shown by several laboratories to be caused, in part, by formation of morphinone-GSH conjugates (23–26). Previously, glucuronidation of morphine was felt to occur exclusively in the liver, but this reaction is now recognized within the CNS as well (27–29). In previous laboratory investigations, we demonstrated that ICV morphine depletes GSH in the caudate nucleus of rats within hours after injection and concurrently induces a state of motoric hyperactivity (18). Although the effect of acute or chronic morphine administered directly to the brain on caudate concentrations of GSH has not been evaluated in human subjects, behavioral responses with a significant motoric component and/or seizures have occasionally been observed after systemic or intraspinal doses of morphine in patients suffering from cancer pain (30,31).

The present data are the first to support the hypothesis that morphine-induced GSH depletion may occur not simply in hepatic or renal sites but also in sites within the CNS. Clearly, for ethical and logistical reasons, it is unlikely that in vivo clinical GSH investigations will ever involve sampling of brain tissue, for which CSF can be at best only an indirect index. Experimental preclinical studies of pathological conditions such as stroke, however, have identified decreases in several free radical scavengers such as GSH, ascorbic acid, cysteine, and methionine in brain tissue after focal ischemic injury. Agents such as superoxide dismutase, {alpha}-tocopherol, 21-aminosteroid lipid peroxidation inhibitors, and GSH, which all "scavenge" free radicals, have been reported to exert neuroprotective effects in ischemia. Because acetaminophen is frequently administered on a chronic basis along with opioid analgesics, it is possible that the combination of morphine and acetaminophen may render patients with cancer doubly vulnerable to GSH depletion.

4-HBAC is a common final pathway for many neurotransmitter families, and therefore the significance of its increase after morphine administration is unclear.

Serotonergic and adrenergic pathways are involved in pain modulation both in relation to opioid and nonopioid analgesia (32,33). Despite a wealth of basic research, our weakly negative findings concerning the correlations between grouped metabolites within the serotonin system and morphine are consistent with an inconclusive clinical literature. Ceccherelli et al. (8) found that CSF levels of 5-hydroxy indole acetic acid in patients suffering from cancer pain treated with nonopioid drugs were higher than in patients without pain, but observed no significant differences in tryptophan or serotonin. Lobato et al. (6) found no change in 5-HIAA concentrations in spinal CSF after ventricular morphine administration. Hyppa et al. (9) demonstrated no relationship between 5-HIAA levels in CSF and pain intensity in patients suffering from low back pain. Bouckoms et al. (16), using an electrochemical HPLC method identical to ours, found that trigeminal cisternal levels of 5-HIAA in patients with intractable facial pain were approximately half those of controls.

The noradrenergic system also modulates nociception. Wigdor and Wilcox (34) have suggested that the descending noradrenergic system is at least as important as the descending serotonergic system in the spinal and surpaspinal antinociceptive effects of systemically administered morphine. Directly administered to the spinal cord, norepinephrine produces a profound analgesic effect that is mediated by {alpha} receptors. In humans, intrathecal or epidural clonidine administration produces analgesia (35,36). In the present study, no single determinant of the noradrenergic pathway was individually correlated positively with morphine or M6G levels in CSF, and a multiple regression equation also was of little predictive significance.

In summary, we applied a microanalytic method in an exploratory study of neurochemical findings during intermittent ICV administration of morphine. Although it proved feasible to perform such an analysis, as in other limited studies to date, we could find no clear-cut patterns of response to morphine therapy among compounds belonging to catecholaminergic, serotonergic, or purinergic families. Unexpectedly, however, we observed significant and consistent negative correlations between morphine and GSH, as well as morphine and M6G, findings that might be explained by a GSH-depleting effect of morphinone taking place within the CNS. Because we did not have morphinone standards available for the present analyses, this explanation is speculative. If further studies indicate that morphinone concentrations increase and/or GSH levels decline in the CNS during morphine administration, then coadministration of free radical scavengers along with morphine might have therapeutic potential.


   Acknowledgments
 
We thank Patricia Osgood, PhD, for helpful comments on this manuscript, Arthur Kazianis, Ma, and Iwona Maszczynska, BPharm, for technical assistance, and Professors Richard Kitz, MD, and E. Echter, MD, for encouragement of these studies.


   Footnotes
 
These studies were supported by the Richard Saltonstall Charitable Foundation (to DBC and LCG), the Evenor Armington Fund (to DBC and LCG) and grant DA06284–08A1 from National Institute Health/National Institute of Drug Abuse (to DBC and LCG).


   References
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 Introduction
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 References
 

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Accepted for publication June 22, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press