JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS
AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
A&A International Anesthesia Research Society
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (19)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Goudas, L. C.
Right arrow Articles by Carr, D. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Goudas, L. C.
Right arrow Articles by Carr, D. B.
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
Top
 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
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
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.


View this table:
[in this window]
[in a new window]
  		Table 1. Concentrations of Endogenous Compounds in Ventricular and Cisternal CSF Samples from Patients Treated for Intractable Cancer Pain
 

   Methods
Top
 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
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
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.



View larger version (14K):
[in this window]
[in a new window]
  		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).



View larger version (36K):
[in this window]
[in a new window]
  		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
Top
 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
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Bruera E, Macmillan K, Hanson J, MacDonald N. The cognitive effects of the administration of narcotic analgesics in patients with cancer pain. Pain 1989;39:13–6.[Web of Science][Medline]
  2. Cousins MJ, Mather LE. Intrathecal and epidural administration of opioids. Anesthesiology 1984;61:276–310.[Web of Science][Medline]
  3. Rawal N, Sjostrand VH, Dahlstrom B, et al. Epidural morphine for postoperative pain relief: a comparative study with intramuscular narcotic and intercostal nerve block. Anesth Analg 1982;61:93–8.[Abstract/Free Full Text]
  4. Poletti CE, Cohen AM, Todd DP, Sweet WH. Cancer pain relieved by long-term epidural morphine with permanent indwelling systems for self-administration. J Neurosurg 1981;55:581–4.[Web of Science][Medline]
  5. Cramond T, Stuart G. Intraventricular morphine for intractable pain of advanced cancer. Symptom Manage 1993;8:465–73.
  6. Lobato RD, Madrid JL, Fatela LV, et al. Intraventricular morphine administration for intractable cancer pain: rationale, methods, clinical results. Acta Anaesthesiol Scand 1987;85 (Suppl):68–74.
  7. Ballantyne JC, Carr DB, Berkey CS, et al. Comparative efficacy of epidural, subarachnoid, and intracerebroventricular opioids in patients with pain due to cancer. Regional Anesthesia 1996;21:542–56.[Web of Science][Medline]
  8. Ceccherelli F, Costa C, Ischia S, et al. Cerebral tryptophan metabolism in humans in relation to malignant pain. Funct Neurol 1989;4:341–53.[Medline]
  9. Hyppa MT, Scheinin H, Alaranta H, et al. Neurotransmission and the experience of low back pain: no association between CSF monoamine metabolites and pain. Pain 1985;21:57–65.[Web of Science][Medline]
  10. Matson WR, Gamache P, Beal MF, et al. EC array sensor: concepts and data. Life Sci 1987;41:905–8.[Web of Science][Medline]
  11. Langlade A, Serrie A, Sandouk P, et al. Levels of morphine and metabolites in CSF during respiratory depression after intracerebroventricular morphine injection. Pain 1991;44:175–8.[Web of Science][Medline]
  12. Wood MM, Cousins MJ. Iatrogenic neurotoxicity in cancer patients. Pain 1989;39:1–3.[Web of Science][Medline]
  13. Matson WR, Langlais P, Volicer L, et al. N-electrode three-dimensional liquid chromatography with electrochemical detection for determination of neurotransmitters. Clin Chem 1984;30:1477–88.[Abstract/Free Full Text]
  14. Beal MF, Matson WR, Swartz KJ, et al. Kynurenine pathway measurements in Huntington’s disease striatum: evidence for reduced formation of kynurenic acid. Neurochem 1990;55:1327–39.
  15. Uldall P, Hansen FJ, Tonnby B. Lamotrigine in Rett syndrome. Neuropediatrics 1993;24:339–40.[Web of Science][Medline]
  16. Bouckoms AJ, Sweet WH, Poletti C, et al. Monoamines in the brain cerebrospinal fluid of facial pain patients. Progress 1993;39:201–8.
  17. Akil H, Liebeskind JC. Monoaminergic mechanisms of stimulation-produced analgesia. Brain Res 1975;84:279–96.[Web of Science][Medline]
  18. Goudas LC, Carr DB, Maszczynska I, et al. Differential effect of central versus parenteral administration of morphine sulfate on regional concentrations of reduced glutathione in rat brain. Pharmacology 1997;54:92–7.[Web of Science][Medline]
  19. Sandouk P, Schermann JM, Bourdon R. Combined liquid-solid chromatography and radioimmunoassay for determination of morphine in human fluids. Pharmacol Meth 1984;11:227–37.
  20. Carr DB. The WHO concept of cancer pain treatment: a guideline prototype and its context. In: Chrubasick J, Cousins M, Martin E, eds. Advances in pain therapy I. Berlin:Springer-Verlag, 1992:8–17.
  21. Carr DB, Jacox AK, Chapman CR, et al. Acute pain management: operative or medical procedures and trauma. Clinical practice guideline no. 1. Rockville, MD:Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health & Human Service, 1992.
  22. Jacox AK, Carr DB, Payne R, et al. Management of cancer pain. Clinical practice guideline no 9. Rockville, MD :Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health & Human Service, 1992.
  23. Nagamatsu K, Ohno Y, Ikebuchi H, et al. Morphine metabolism in isolated rat hepatocytes and its implications for hepatotoxicity. Biochem Pharmacol 1986;35:3543–8.[Web of Science][Medline]
  24. Nagamatsu K, Kido Y, Terao T, et al. Protective effect of sulfhydryl compounds on acute toxicity of morphinone. Exp Ther 1982;221:708–14.
  25. Nagamatsu K, Kido Y, Terao T, et al. Studies on the mechanism of covalent binding of morphine metabolites to proteins in mouse. Drug Metab Dispos 1983;11:190–4.[Abstract]
  26. Nagamatsu K, Hasegawa A. Covalent binding of morphine to isolated rat hepatocytes. Pharmacol 1992;43:2631–5.
  27. Viani A, Temellini A, Tusini G, Pacifici GM. Human brain sulphotransferase and glucuronyltransferase. Human Exp Toxicol 1990;9:65–9.[Web of Science][Medline]
  28. Wahlstrom A, Winblad B, Bixo M, Rane A. Human brain metabolism of morphine and naloxone. Pain 1988;35:121–7.[Web of Science][Medline]
  29. Wahlstrom A, Lundin LG, Ask B, Rane A. The sensitivity to noxious heat in relation to brain and liver opioid glucuronidation in inbred strains of mice. Pain 1989;38:71–5.[Web of Science][Medline]
  30. Sjogren P, Jonsson T, Jensen NH, et al. Hyperalgesia and myoclonus in terminal cancer patients treated with continuous intravenous morphine. Pain 1993;55:93–7.[Web of Science][Medline]
  31. Parkinson SK, Bailey SL, Little WL, Mueller JB. Myoclonic seizure activity with chronic high-dose spinal opioid administration. Anesthesiology 1990;72:743–5.[Web of Science][Medline]
  32. Jordan LM, Kenshalo DR, Martin RT, Willis WD. Two populations of spinothalamic tract neurons with opposite responses to 5HT. Brain Res 1979;164:342–6.[Web of Science][Medline]
  33. Griersmith BT, Duggan AW. Prolonged depression of spinal transmission of nociceptive information by 5HT administered in the substantia gelatinosa: antagonism by methysergide. Brain Res 1980;187:231–6.[Web of Science][Medline]
  34. Wigdor S, Wilcox GL. Central and systemic morphine-induced antinociception in mice: contribution of descending serotonergic and noradrenergic pathways. Ther 1987;242:90–5.
  35. Goudas LC. Clonidine. Curr Opin Anaesthesiol 1995;8:455–60.
  36. Filos KS, Goudas LC, Patroni O, Polyzou V. Intrathecal clonidine as a sole analgesic for pain relief after cesarean section. Anesthesiology 1992;77:267–74.[Web of Science][Medline]
Accepted for publication June 22, 1999.




This article has been cited by other articles:


Home page
 Hum Exp ToxicolHome page
D. Calderon-Guzman, N. Osnaya-Brizuela, R. Garcia-Alvarez, E. Hernandez-Garcia, and H. Juarez-Olguin
Oxidative stress induced by morphine in brain of rats fed with a protein deficient diet
Human and Experimental Toxicology, September 1, 2009; 28(9): 577 - 582.
[Abstract] [PDF]

Home page
 Am J Health Syst PharmHome page
S. A. Strassels, E. Mcnicol, and R. Suleman
Postoperative pain management: A practical review, part 2
Am. J. Health Syst. Pharm., October 1, 2005; 62(19): 2019 - 2025.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (19)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Goudas, L. C.
Right arrow Articles by Carr, D. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Goudas, L. C.
Right arrow Articles by Carr, D. B.

Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press