1Department of Anaesthesia, The Toronto Western Hospital and University of Toronto, Toronto, Ontario, Canada. 2Department of Anaesthesia and Critical Care, University of Chicago, Chicago IL, USA*Corresponding author: Department of Anaesthesia, Intensive Care and Pain Management,Cork University Hospital, Wilton, Cork City, Ireland
Accepted for publication: August 15, 2000
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Abstract |
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Br J Anaesth 2001; 86: 1202
Keywords: anaesthetic techniques, epidural; pharmacokinetics, methylnaltrexone; rabbit
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Introduction |
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Methylnaltrexone (MNTX) is a quaternary opioid antagonist with limited ability to cross the bloodbrain barrier. In man, intravenous MNTX has been shown to reverse morphine-induced delayed gastric emptying2 and to reverse constipation due to chronic methadone use3 without affecting centrally mediated analgesia. We postulated that if MNTX does not cross the dura it might have potential to reverse peripherally mediated side-effects of epidural opioids without affecting analgesia. Therefore, the purpose of this study was to describe the pharmacokinetics of epidurally administered MNTX and to test the hypothesis that epidurally administered MNTX does not penetrate the dura into the subarachnoid space (SAS).
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Methods and results |
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A midline skin incision was made over the shaved back of the neck covering the occipital bone and cervical dorsum. The atlanto-occipital membrane was identified and a 22 g cannula was inserted in the base of the skull covering the cisterna magna, cephalad to the occipitalatlas junction. Spontaneous CSF flow was obtained and allowed to drain freely. The cannula was immobilized with dental cement. MNTX 0.66 mg kg1 (Mallinckrodt Specialty Chemicals, St Louis, MO, USA) was administered in 1ml of normal saline via the epidural catheter and blood and CSF samples were taken 0, 3, 6, 10, 15, 20, 40, 60, 120 and 180 min after drug administration. The epidural dose of MNTX was chosen on the basis of previous results,2 3 with the aim of administering a relatively high dose of MNTX. Animals were euthanized after 3 h by pentobarbital overdose. Blood samples were centrifuged, separated immediately and the serum and CSF sample was frozen at 80°C for later analysis by high-performance liquid chromatography. Using the modified procedure from the method of Kim et al.,4 standard curves of MNTX were run for each set of samples. The lower limit of detection was 2 ng ml1. Pharmacokinetic parameters for MNTX were calculated using WinNonlinTM (2.1 Scientific Consulting, Mountain View, CA, USA).
Seven rabbits were enrolled in the study, but data from two were excluded due to difficulty in CSF or blood sampling techniques. Results are expressed as mean (SD) unless stated otherwise. The mean weight of the animals was 3.5 (0.3) kg. The serum drug concentration time profile for each animal fitted a biexpontential function. Therefore, the disposition of epidural MNTX could be described by a two-compartment model in which the drug is eliminated from the central compartment. The mean serum and CSF MNTX concentrations determined during the duration of the study are shown in Fig. 1. There were minimal amounts of MNTX detected in the CSF at up to 20 min and none thereafter. The following pharmacokinetic data were calculated: area under the curve [AUC0240 11920 (3892) ng min1 ml1], peak concentration [Cmax 215 (35) ng1 ml1], time to maximum concentration (Tmax 10 min), total volume of distribution [Vz 5199 (1199) ml kg1], total body clearance [CL 86 (26) ml min1 kg1] and ß half-life [T ß 74.96 (35) min1]
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Comment |
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After epidural administration of MNTX 0.66 mg kg1, peak serum values were greater than 200 ng ml1. These systemic drug levels may possibly be of therapeutic significance. In patients on chronic opioid therapy who received i.v. MNTX in doses up to 0.35 mg kg 1 over 1 min, rapid laxation was induced without evidence of withdrawal or diminished analgesia. Peak plasma levels of 162 (237) ng ml 1 were observed without side-effects in that group.3
In conclusion, epidurally administered MNTX does not appear to gain significant access to the CSF. Further studies are warranted as epidurally administered MNTX may have potential to reverse epidural opioid-mediated side-effects whilst preserving analgesia.
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Acknowledgements |
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References |
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2 Murphy DB, Sutton JA, Prescott LF, et al. Opioid-induced delay in gastric emptying: a peripheral mechanism in humans. Anesthesiology 1997; 87: 76570[ISI][Medline]
3 Yuan CS, Foss JF, OConnor M et al. Methylnaltrexone for reversal of constipation due to chronic methadone use: a randomized controlled trial. J Am Med Assoc 2000; 283: 36772
4 Kim C, Cheng R, Corrigall WA, et al. Assay for methylnaltrexone in rat brain region by serum high performance liquid chromatography with colorimetric electrochemical detection. Chromatographia 1989; 28: 35963[ISI]
5 Brose WG, Tanelian DL, Brodsky JB, et al. CSF and blood pharmacokinetics of hydromorphone and morphine following lumbar epidural administration. Pain 1991; 45: 115[ISI][Medline]
6 Brown DR, Goldberg LI. The use of quaternary narcotic antagonists in opiate research. Neuropharmacology 1985; 24: 18191[ISI][Medline]