Clearance of cerebrospinal fluid from the sacral spine through lymphatic vessels.

The pathways of circulation and clearance of cerebrospinal fluid (CSF) in the spine have yet to be elucidated. We have recently shown with dynamic in vivo imaging that routes of outflow of CSF in mice occur along cranial nerves to extracranial lymphatic vessels. Here, we use near-infrared and magnetic resonance imaging to demonstrate the flow of CSF tracers within the spinal column and reveal the major spinal pathways for outflow to lymphatic vessels in mice. We found that after intraventricular injection, a spread of CSF tracers occurs within both the central canal and the spinal subarachnoid space toward the caudal end of the spine. Outflow of CSF tracers from the spinal subarachnoid space occurred predominantly from intravertebral regions of the sacral spine to lymphatic vessels, leading to sacral and iliac LNs. Clearance of CSF from the spine to lymphatic vessels may have significance for many conditions, including multiple sclerosis and spinal cord injury.

Oxycodone concentrations in the central nervous system and cerebrospinal fluid after epidural administration to the pregnant ewe.

The main sites of the analgesic action of oxycodone are the brain and spinal cord. The present study describes the concentrations of oxycodone and its metabolites in the brain and spinal cord after epidural administration to the ewe. Twenty pregnant ewes undergoing laparotomy were randomized into two groups to receive epidural oxycodone: infusion group (n = 10, 0.1 mg·kg-1 bolus followed by continuous infusion of 0.05 mg·kg-1 ·h-1 for five days) or repeated boluses group (n = 10, 0.2 + 2x0.1 mg·kg-1 bolus followed by a 0.2 mg·kg-1 bolus every 12 hours for five days). After five days of oxycodone administration, arterial blood samples were collected, the sheep were killed, and a CSF sample and tissue samples from the cortex, thalamus, cerebellum and spinal cord were obtained for the quantification of oxycodone and its main metabolites. The median plasma and CSF concentrations of oxycodone were 9.0 and 14.2 ng·mL-1 after infusion and 0.4 and 1.1 ng·mL-1 after repeated boluses. In the infusion group, the cortex, thalamus and cerebellum oxycodone concentrations were 4-8 times higher and in the spinal cord 1310 times higher than in plasma. In the repeated boluses group, brain tissue concentrations were similar in the three areas, and in the spinal cord were 720 times higher than in plasma. Oxymorphone was the main metabolite detected, which accumulated in the brain and spinal cord tissue. In conclusion, first, accumulation of oxycodone and oxymorphone in the CNS was observed, and second, high spinal cord concentrations suggest that epidural oxycodone may provide segmental analgesia.

Computational and In Vitro Experimental Investigation of Intrathecal Drug Distribution: Parametric Study of the Effect of Injection Volume, Cerebrospinal Fluid Pulsatility, and Drug Uptake.

BACKGROUND: Intrathecal drug delivery is an attractive option to circumvent the blood-brain barrier for pain management through its increased efficacy of pain relief, reduction in adverse side effects, and cost-effectiveness. Unfortunately, there are limited guidelines for physicians to choose infusion or drug pump settings to administer therapeutic doses to specific regions of the spine or the brain. Although empiric trialing of intrathecal drugs is critical to determine the sustained side effects, currently there is no inexpensive in vitro method to guide the selection of spinal drug delivery parameters. The goal of this study is to demonstrate current computational capabilities to predict drug biodistribution while varying 3 parameters: (1) infusion settings, (2) drug chemistry, and (3) subject-specific anatomy and cerebrospinal fluid dynamics. We will discuss strategies to systematically optimize these 3 parameters to administer drug molecules to targeted tissue locations in the central nervous system. METHODS: We acquired anatomical data from magnetic resonance imaging (MRI) and velocity measurements in the spinal cerebrospinal fluid with CINE-MRI for 2 subjects. A bench-top surrogate of the subject-specific central nervous system was constructed to match measured anatomical dimensions and volumes. We generated a computational mesh for the bench-top model. Idealized simulations of tracer distribution were compared with bench-top measurements for validation. Using reconstructions from MRI data, we also introduced a subject-specific computer model for predicting drug spread for the human volunteer. RESULTS: MRI velocity measurements at 3 spinal regions of interest reasonably matched the simulated flow fields in a subject-specific computer mesh. Comparison between the idealized spine computations and bench-top tracer distribution experiments demonstrate agreement of our drug transport predictions to this physical model. Simulated multibolus drug infusion theoretically localizes drug to the cervical and thoracic region. Continuous drug pump and single bolus injection were successful to target the lumbar spine in the simulations. The parenchyma might be targeted suitably by multiple boluses followed by a flush infusion. We present potential guidelines that take into account drug specific kinetics for tissue uptake, which influence the speed of drug dispersion in the model and potentially influence tissue targeting. CONCLUSIONS: We present potential guidelines considering drug-specific kinetics of tissue uptake, which determine the speed of drug dispersion and influence tissue targeting. However, there are limitations to this analysis in that the parameters were obtained from an idealized healthy patient in a supine position. The proposed methodology could assist physicians to select clinical infusion parameters for their patients and provide guidance to optimize treatment algorithms. In silico optimization of intrathecal drug delivery therapies presents the first steps toward a possible care paradigm in the future that is specific to personalized patient anatomy and diseases.

Evaluation of the route dependency of the pharmacokinetics and neuro-pharmacokinetics of tramadol and its main metabolites in rats.

Tramadol hydrochloride is a centrally acting analgesic used for the treatment of moderate-to-severe pain. It has three main metabolites: O-desmethyltramadol (M1), N-desmethyltramadol (M2), and N,O-didesmethyltramadol (M5). Because of the frequent use of tramadol by patients and drug abusers, the ability to determine the parent drug and its metabolites in plasma and cerebrospinal fluid is of great importance. In the present study, a pharmacokinetic approach was applied using two groups of five male Wistar rats administered a 20mg/kg dose of tramadol via intravenous (i.v.) or intraperitoneal (i.p.) routes. Plasma and CSF samples were collected at 5-360min following tramadol administration. Our results demonstrate that the plasma values of Cmax (C0 in i.v. group) and area under the curve (AUC)0-t for tramadol were 23,314.40±6944.85 vs. 3187.39±760.25ng/mL (Cmax) and 871.15±165.98 vs. 414.04±149.25µg·min/mL in the i.v. and i.p. groups, respectively (p<0.05). However, there were no significant differences between i.v. and i.p. plasma values for tramadol metabolites (p>0.05). Tramadol rapidly penetrated the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) (5.00±0.00 vs. 10.00±5.77min in i.v. and i.p. groups, respectively). Tramadol and its metabolites (M1 and M2) were present to a lesser extent in the cerebrospinal fluid (CSF) than in the plasma. M5 hardly penetrated the CSF, owing to its high polarity. There was no significant difference between the AUC0-t of tramadol in plasma (414.04±149.25µg·min/mL) and CSF (221.81±83.02µg·min/mL) in the i.p. group. In addition, the amounts of metabolites (M1 and M2) in the CSF showed no significant differences following both routes of administration. There were also no significant differences among the Kp,uu,CSF(0-360) (0.51±0.12 vs. 0.63±0.04) and Kp,uu,CSF(0-∞) (0.61±0.10 vs. 0.62±0.02) for i.v. and i.p. pathways, respectively (p>0.05). Drug targeting efficiency (DTE) values of tramadol after i.p. injection were more than unity for all scheduled time points. Considering the main analgesic effect of M1, it is hypothesized that both routes of administration may produce the same amount of analgesia.

Quantitative determination of fentanyl in newborn pig plasma and cerebrospinal fluid samples by HPLC-MS/MS.

In this study, a selective and sensitive high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method requiring low sample volume (≤100 µL) was developed and validated for the quantitative determination of the opioid drug fentanyl in plasma and cerebrospinal fluid (CSF). A protein precipitation extraction with acetonitrile was used for plasma samples whereas CSF samples were injected directly on the HPLC column. Fentanyl and (13) C6 -fentanyl (Internal Standard) were analyzed in an electrospray ionization source in positive mode, with multiple reaction monitoring (MRM) of the transitions m/z 337.0/188.0 and m/z 337.0/105.0 for quantification and confirmation of fentanyl, and m/z 343.0/188.0 for (13) C6 -fentanyl. The respective lowest limits of quantification for plasma and CSF were 0.2 and 0.25 ng/mL. Intra- and inter-assay precision and accuracy did not exceed 15%, in accordance with bioanalytical validation guidelines. The described analytical method was proven to be robust and was successfully applied to the determination of fentanyl in plasma and CSF samples from a pharmacokinetic and pharmacodynamic study in newborn piglets receiving intravenous fentanyl (5 µg/kg bolus immediately followed by a 90-min infusion of 3 µg/kg/h).

Effects of intracisternal tramadol on cerebral and spinal neuronal cells in rat.

BACKGROUND: The aim was to investigate whether tramadol had toxic effect on cerebral neurons and/or spinal cord neurons when it was administered into the cerebrospinal fluid. Due to lipid peroxidation (LPO) and myeloperoxidation (MPO) levels are not specific predictors of neuronal damage, these biochemical markers of tissue damage were evaluated together with the histopathological findings of apoptosis. METHODS: Forty eight Wistar rats were anesthetized and the right femoral artery was cannulated. Mean arterial pressures, and heart rates, arterial carbon dioxide tension, arterial oxygen tension, blood pH were recorded. When the free cerebrospinal fluid flow was seen; 0.04 mL normal saline (Group Sham) or diluted tramadol in 0.04 mL volume (Group T1, T2, T0.5 and T0.1) was administered within 30 seconds from the posterior craniocervical junction of rats. For the Control Group, the free cerebrospinal fluid flow was seen but nothing was injected in it. After 7 days, following the sacrification of the rats, brain tissue, cervical and lumber segments of spinal cord were collected for the histopathological and biochemical examination. RESULTS: There was not a statistically significant difference among all groups regarding the brain LPO levels (P=0.485). The LPO levels of the cervical segment of spinal cord and the lumbar segment of spinal cord were also similar (P=0.146, P=0.939, respectively). The mean MPO levels of the cervical and the lumbar segments of spinal cord were similar among all groups (P=0.693, P=0.377, respectively). There were not any statistically significant difference regarding the total number of red neurons of the brain tissue and the cervical and lumbar segments of spinal cord among all groups (P=0.264, P=0.202, P=0.780, respectively). CONCLUSION: Tramadol had no neurotoxic effect on brain and on spinal cord tissue when administered by the intracisternal route in cerebrospinal fluid in rats.

Enhancement by grapefruit juice of morphine antinociception.

The aim of this study was to investigate the effect of grapefruit juice intake on the antinociception of morphine in rats. The antinociception of morphine (30 mg/kg, per os (p.o.)) was significantly enhanced by the oral administration of grapefruit juice (2 ml/rat). Further, the effect of grapefruit juice was examined in morphine-tolerant rats. The repeated administration of morphine (100 mg/kg p.o.) for 5 d caused a marked decrease in the antinociception, indicating the development of morphine-tolerance. In the morphine-tolerant rats, oral administration of grapefruit juice potentiated significantly the antinociceptive effect of morphine. To examine the pharmacokinetics of morphine after the repeated treatment with morphine for 5 d, microdialysis probes were implanted into the jugular vein and spinal intrathecal space in rats. The morphine concentrations in the blood and intrathecal cerebrospinal fluid (CSF) were gradually decreased by the repeated treatment with morphine. The grapefruit juice treatment significantly increased the blood concentration of morphine in morphine-tolerant rats. These results suggest that oral administration of grapefruit juice enhances the morphine antinociception by increasing the intestinal absorption of this agent.

Pharmacokinetics of tramadol in rat plasma and cerebrospinal fluid after intranasal administration.

We have evaluated the potential of intranasal administration of tramadol. The pharmacokinetic behaviour of tramadol in rat plasma and cerebrospinal fluid (CSF) after intranasal administration was determined and compared with those after intravenous and oral administration. Serial plasma and CSF samples were collected for 6 h, and the drug concentrations were assayed by an HPLC-fluorescence method. The plasma absolute bioavailability values of tramadol after intranasal and oral administration were 73.8% and 32.4%, respectively, in conscious rats. The Cmax (maximum concentration) value after the intranasal dose was lower (P<0.05), and the MRT (mean retention time) was longer (P<0.05) than the values obtained after intravenous administration. A pharmacokinetic study of tramadol in plasma and CSF was undertaken in anaesthetized rats. The absolute bioavailability values in plasma and CSF after intranasal administration were 66.7% and 87.3%, respectively. The Cmax values in plasma and CSF after a nasal dose were lower (P<0.05) than after the intravenous dose. The values of Cmax and AUC0-->6 h in plasma and CSF after intranasal administration were higher than after the oral dose. The mean drug-targeting efficiency after intranasal administration was significantly greater than after the oral dose. In conclusion, intranasal administration of tramadol appeared to be a promising alternative to the traditional administration modes for this drug.

Comparison of drug concentrations in postmortem cerebrospinal fluid and blood specimens.

The concentration of drugs and metabolites in cerebrospinal fluid (CSF) and blood were determined in 282 autopsied cases using liquid-liquid extraction techniques and gas chromatographic analyses. All drugs were confirmed in one matrix by gas chromatography-mass spectrometry. CSF/blood ratios were used to compare the two biological fluids. Classes of drugs evaluated in this study included: benzodiazepines, anticonvulsants, sedatives, opioids, antidepressants, anesthetics, and antihistamines. The majority of the drugs tested were readily detected in CSF specimens. The average CSF/blood ratio for most drugs was in the range of 0.05-0.50. Interpretation of these results is difficult because protein binding, half-life, hydrophobic properties, and pKa of a drug, in addition to survival time after drug use, influence the CSF/blood ratio. While CSF specimens do provide a viable alternative testing matrix when blood specimens are not available, they should not be used to estimate blood drug concentrations.

Comparative measurement of spinal CSF microdialysate concentrations and concomitant antinociception of morphine and morphine-6beta-glucuronide in rats.

Morphine-6beta-glucuronide (M6G) is well known as a potent active metabolite in humans. To clarify concentration-antinociceptive effect relationships for morphine and M6G, we evaluated comparatively the pharmacokinetics and antinociceptive effects of morphine and M6G. The spinal CSF concentration and antinociception were simultaneously measured by using the combination of a microdialysis method and the formalin test in conscious rats after the s.c. administration of morphine (0.3-3 mg/kg) and M6G (0.1-3 mg/kg). The plasma concentration of M6G after s.c. administration was higher than that of morphine, as shown by the 2.1 times greater value of area under the concentration-time curve (AUC(plasma)). The spinal CSF concentrations of morphine and M6G increased dose-dependently. The AUC(CSF) of M6G was 1.6-1.8 times higher than that of morphine at each dose. Administration of morphine and M6G dose-dependently suppressed the flinching behavior induced by formalin injection. The ED(50) values for M6G were 3 times lower than those of morphine, although the spinal CSF concentration versus antinociceptive effect curves of morphine and M6G were very similar, with similar EC(50) values. These results suggest that the antinociceptive potencies of morphine and M6G, evaluated by simultaneous measurements of spinal CSF drug concentration and antinociception, are equivalent. Simultaneous measurement of spinal CSF concentration and antinociception by using microdialysis should be useful for elucidating the relationship between pharmacokinetics and pharmacodynamics of various opioids.

Opiate pharmacology of intrathecal granulomas.

BACKGROUND: Chronic intrathecal morphine infusion produces intradural granulomas. The authors examined a variety of opioids infused intrathecal for analgesic activity and toxicity. METHODS: Two sets of experiments were undertaken in dogs with chronic intrathecal catheters: (1) Six-hour intrathecal infusions were used to determine the full analgesic dose and the maximum tolerated dose. (2) To establish toxicity, the maximum tolerated dose was given for up to 28 days by continuous intrathecal infusion. Drugs examined were morphine sulfate, hydromorphone, D/L-methadone, L-methadone, D-methadone, fentanyl, [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO), naloxone, or saline. RESULTS ANALGESIA AND TOLERABILITY: Six-hour intrathecal infusion of agonists resulted in a time-dependent increase in thermal escape latency. At higher concentrations, dose-limiting motor dysfunction and sedation occurred, and hypersensitivity occurred. The concentrations, in mg/ml, for full analgesic dose/maximum tolerated dose were as follows: morphine, 0.9/12.0; hydromorphone, 1.0/3.0; D/L-methadone, 2.8/3; L-methadone, 1.0/> 1.0; fentanyl, 0.3/2.0; DAMGO, 0.1/> 2.0; D-methadone, > 1/> 1; naloxone, > 10/> 10. SPINAL PATHOLOGY: Chronic intrathecal infusion of the maximum tolerated dose revealed 100% intradural granuloma formation after morphine, hydromorphone, L-methadone, and naloxone. DAMGO induced a mass in only a single animal (one of three). D/L- and D-methadone produced intradural granulomas but were also associated with parenchymal necrosis. Saline and fentanyl animals displayed no granulomas. CONCLUSIONS: Intrathecal opiate-induced granulomas are not strictly dependent on opioid receptor activation. Therefore, opiates at equianalgesic doses present different risks for granuloma formation. Importantly, D/L- and D-methadone also resulted in parenchymal necrosis, an affect associated with the N-methyl-D-aspartate antagonist action of the D-isomer.

Enhancement of systemic and CNS delivery of meptazinol hydrochloride by intranasal administration to rats.

AIM: To investigate the extent of systemic absorption and uptake of meptazinol (MEP) hydrochloride in cerebrospinal fluid (CSF) after intranasal administration on rats and compare with oral administration. METHODS: CSF samples were collected by a serial sampling method. The concentration of MEP in the biological samples was measured by HPLC with fluorescence detector. RESULTS: Rapid and significant levels of MEP in plasma and CSF can be achieved after nasal administration whereas the oral administration resulted in considerably lower drug concentrations. AUC in plasma and CSF from the nasal route are 7.375 and 15.6 folds compared with those of the oral route, respectively. CONCLUSION: Intranasal MEP is able to show quick absorption and improve the bioavailability, which could be a promising alternative to oral administration.

Disposition of morphine in plasma and cerebrospinal fluid varies during neonatal development in pigs.

The pharmacological effects of morphine are mediated via the central nervous system (CNS) but its clearance from the CNS in neonates has not been investigated. We have proposed that neonatal development of the blood-brain barrier affected CNS clearance mechanisms and CNS exposure to morphine. Male piglets (n = 5) aged one, three and six weeks were given morphine sulfate (0.5 mg kg(-1), i.v.). Serial blood and cerebrospinal fluid (CSF) samples were withdrawn over 360 min after morphine administration. Morphine concentration was measured by radioimmunoassay. A three-compartment model was fitted to individual data. Estimated parameters were reported as median and range. The peak morphine concentrations in plasma were not significantly different in the one-, three- or six-week-old piglets. Plasma clearance at one week (4.5, 3.8-8.6 mL min(-1) kg(-1)) was significantly lower than at three weeks (30.0, 19.1- 39.0 mL min(-1) kg(-1)) and six weeks (37.0, 29.7-82.8 mL min(-1) kg(-1)). The peak morphine concentration in CSF at one week (59.84, 31-67 ng mL(-1)) was higher than at three weeks (18.8, 17.7-25 ng mL(-1)) and six weeks (24.51, 16.5-84 ng mL(-1)), while CSF clearance was lower at one week (1.0, 0.18-9 mL min(-1) kg(-1)) compared with three weeks (6.2, 2.3-9.3 mL min(-1) kg(-1)) and six weeks (3.95, 1.3-85.7 mL min(-1) kg(-1)). Apparent plasma:CSF transfer ratio at one week was greater than at three and six weeks. The reduced plasma and CSF morphine clearance in early infancy resulted in elevated systemic and central morphine exposure in neonatal pigs.

Effects of morphine and endomorphins on the polysynaptic reflex in the isolated rat spinal cord.

At the spinal level, mu-opioids exert their actions on nociceptive primary afferent neurons both pre- and postsynaptically. In the present study, we used an in vitro isolated neonatal rat (11-15 days old) spinal cord preparation to examine the effects of morphine and the endogenous mu-opioid ligands endomorphin-1 (EM-1) and endomorphin-2 (EM-2) on the polysynaptic reflex (PSR) of dorsal root-ventral root (DR-VR) reflex. The actions of mu-opioids on spinal nociception were investigated by quantification of the firing frequency and the mean amplitude of the PSR evoked by stimuli with 20 x threshold intensity. EM-1 decreased the mean amplitude of PSR, whereas EM-2 and morphine decreased the firing frequency. The pattern of the effects elicited by morphine was the same as that for EM-2, except at high concentration. Naloxonazine, a selective mu(1) opioid receptor antagonist, had no significant effect on PSR by itself, but blocked the inhibition of PSR firing frequency or amplitude induced by EM-1, -2 and morphine. This may suggest that EM-1, EM-2 and morphine modulate spinal nociception differently and act mainly at the mu(1)-opioid receptors. Although they all act via mu(1)-opioid receptors, their different effects on the PSR may suggest the existence of different subtypes of the mu(1)-opioid receptor. The present data is also consistent with a further hypothesis, namely, that morphine and EM-2 activate a subtype of mu(1)-opioid receptor presynaptically, while EM-1 acts mainly through another subtype postsynaptically. However, since other reports indicate that EM-2, but not EM-1, could stimulate the release of enkephalins or dynorphin, presynaptic delta and kappa receptors may be also involved indirectly in the different regulation by mu-opioids at the spinal level.

Tramadol concentrations in blood and in cerebrospinal fluid in a neonate.

Based on blood and cerebrospinal fluid samples collected in a full-term neonate, the penetration of tramadol in the central nervous system is described. Following intravenous administration of tramadol, a lag time of about 4 h was observed until full blood-brain equilibration was achieved. This pharmacokinetic observation is in line with a recent pharmacodynamic evaluation of the central opioid effects of tramadol in adults.

Impact of peripheral elimination on the concentration-effect relationship of remifentanil in anaesthetized dogs.

BACKGROUND: This study elucidates the impact of sampling site when estimating pharmacokinetic-pharmacodynamic (PK-PD) parameters of drugs such as remifentanil that undergo tissue extraction in the biophase. The interrelationship between the concentrations of remifentanil predicted for the effect compartment and those measured in arterial, venous, and cerebrospinal fluid were investigated under steady-state conditions. METHODS: Following induction of anaesthesia with pentobarbital, an arterial cannula (femoral) and two venous catheters (jugular and femoral) were inserted. Electrodes were placed for EEG recording of theta wave activity. Each dog received two consecutive 5-min infusions for the PK-PD study and a bolus followed by a 60-min infusion was started for the steady-state study. Cerebrospinal fluid, arterial and venous blood samples were drawn simultaneously after 30, 40, and 50 min. At the end of the infusion, arterial blood samples were collected for pharmacokinetic analysis. RESULTS: Remifentanil PK-PD parameters based on theta wave activity were as follows: apparent volume of distribution at steady-state (V(ss)) (231+/-37 ml kg(-1)), total body clearance (Cl) (63+/-16 ml min(-1) kg(-1)), terminal elimination half-life (t(1/2 beta)) (7.71 min), effect compartment concentration at 50% of maximal observed effect (EC(50)) (21+/-13 ng ml(-1)), and equilibration rate constant between plasma and effect compartment (k(e0)) (0.48+/-0.24 min). The mean steady-state cerebrospinal fluid concentration of 236 ng ml(-1) represented 52 and 74% of that in arterial and venous blood, respectively. CONCLUSIONS: Our study re-emphasizes the importance of a sampling site when performing PK-PD modelling for drugs undergoing elimination from the effect compartment. For a drug undergoing tissue elimination such as remifentanil, venous rather than arterial concentrations will reflect more exactly the effect compartment concentrations, under steady-state conditions.

Epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidural opioids (part 1): differences among opioids.

BACKGROUND: The pharmacokinetics of epidurally administered drugs has been the subject of many studies, yet drug concentration in the epidural space has never been measured. This study was undertaken to characterize the epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidurally administered opioids on the basis of measurement of drug concentration in each of these compartments after epidural administration. METHODS: Morphine plus alfentanil, fentanyl, or sufentanil were administered epidurally in anesthetized pigs. Microdialysis was used to sample the epidural space and the cerebrospinal fluid for measurement of opioid concentration over time. Plasma samples were obtained from the central venous plasma and the epidural venous plasma. These data were used to calculate relevant pharmacokinetic parameters, including mean residence time, elimination half-lives, areas under the concentration versus time curves, clearance, and volume of distribution for each opioid in each compartment. RESULTS: Some of the more important findings were that the cerebrospinal fluid and plasma pharmacokinetics of the opioids did not parallel their epidural pharmacokinetics and that their hydrophobic character governed multiple aspects of their lumbar epidural pharmacokinetics. CONCLUSIONS: The findings indicate that the spinal pharmacokinetics of these drugs are complex and, in some ways, counterintuitive. Also, the bioavailability of opioids in the cerebrospinal fluid and epidural space is determined primarily by their hydrophobicity, with less hydrophobic drugs having greater bioavailability.

Epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidural opioids (part 2): effect of epinephrine.

BACKGROUND: The ability of epinephrine to improve the efficacy of epidurally administered drugs is assumed to result from local vasoconstriction and a consequent decrease in drug clearance. However, because drug concentration in the epidural space has never been measured, our understanding of the effect of epinephrine on epidural pharmacokinetics is incomplete. This study was designed to characterize the effect of epinephrine on the epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidurally administered opioids. METHODS: Morphine plus alfentanil, fentanyl, or sufentanil was administered epidurally with and without epinephrine (1:200,000) to pigs. Opioid concentration was subsequently measured in the epidural space, central venous plasma, and epidural venous plasma, and these data were used to calculate relevant pharmacokinetic parameters. RESULTS: The pharmacokinetic effects of epinephrine varied by opioid and by sampling site. For example, in the lumbar epidural space, epinephrine increased the mean residence time of morphine but decreased that of fentanyl and sufentanil. Epinephrine had no effect on the terminal elimination half-life of morphine in the epidural space, but it decreased that of fentanyl and sufentanil. In contrast, in the lumbar intrathecal space, epinephrine had no effect on the pharmacokinetics of alfentanil, fentanyl, or sufentanil, but it increased the area under the concentration-time curve of morphine and decreased its elimination half-life. CONCLUSIONS: The findings indicate that the effects of epinephrine on the spinal pharmacokinetics of these opioids are complex and often antithetical across compartments and opioids. In addition, the data clearly indicate that the pharmacokinetic effects of epinephrine in spinal "compartments" cannot be predicted from measurements of drug concentration in plasma, as has been assumed for decades.

Cephalad movement of morphine and fentanyl in humans after intrathecal injection.

BACKGROUND: Despite decades of use, controversy remains regarding the extent and time course of cephalad spread of opioids in cerebrospinal fluid (CSF) after intrathecal injection. The purpose of this study was to examine differences between two often used opioids, morphine and fentanyl, in distribution in the CSF after intrathecal injection. METHODS: Eight healthy volunteers received intrathecal injection of morphine (50 microg) plus fentanyl (50 microg) at a lower lumbar interspace. CSF was sampled through a needle in an upper lumbar interspace for 60-120 min. At the end of this time, a sample was taken from the lower lumbar needle, and both needles were withdrawn. CSF volume was determined by magnetic resonance imaging. Pharmacokinetic modeling was performed with NONMEM. RESULTS: Morphine and fentanyl peaked in CSF at the cephalad needle at similar times (41 +/- 13 min for fentanyl, 57 +/- 12 min for morphine). The ratio of morphine to fentanyl in CSF at the cephalad needle increased with time, surpassing 2:1 by 36 min and 4:1 by 103 min. CSF concentrations did not correlate with weight, height, or lumbosacral CSF volume. The concentrations of morphine and fentanyl at both sampling sites were well described by a simple pharmacokinetic model. The individual model parameters did not correlate with the distance between the needles, CSF volume, patient height, or patient weight. CONCLUSIONS: Fentanyl is cleared more rapidly from CSF than morphine, although their initial distribution in the first hour after injection does not differ greatly. The pharmacokinetic model demonstrates that mixing is the primary determinant of early concentrations and is highly variable among individuals.

Safety of chronic intrathecal morphine infusion in a sheep model.

BACKGROUND: The safety of chronically administered intrathecal morphine has been questioned. Therefore, the authors examined the behavioral and neurologic effects and neurotoxicity of continuous intrathecal morphine administration in sheep. METHODS: Groups of three sheep were implanted with intrathecal infusion systems for the continuous administration of morphine (3, 6, 9, 12, or 18 mg/day) or saline at a fixed infusion rate of 1.92 ml/day beginning approximately 7 days after implantation. Sheep were examined daily for any changes in behavior or neurologic function. After 28-30 days, the animals were humanely killed. Cerebrospinal fluid samples were collected and analyzed for protein, erythrocytes and leukocytes, and morphine content. The spinal cord and meninges with the catheter in situ was removed en bloc and fixed in formalin for histologic analysis. RESULTS: Unilateral hind-leg gait deficits were observed in two of three animals in each of the 12- and 18-mg/day dose groups. Gross and microscopic evaluation of spinal cord tissue from these animals revealed intradural-extramedullary inflammatory masses that compressed the spinal cord at the catheter-tip and mid-catheter areas. This inflammation was ipsilateral to extremities that exhibited gait deficits and had acute and chronic cellular components. CONCLUSIONS: The toxicity of intrathecal morphine seems to be dependent on the amount of morphine infused, although the effects of dose versus concentration cannot be clearly distinguished in this study. Intrathecal morphine doses of 12- 18 mg/day produced inflammatory masses extending from the catheter tip down the length of the catheter within the subarachnoid space. Doses of 6-9 mg/day produced mild-to-moderate inflammation 5 cm cranial to the catheter tip. A dose of 3 mg/day produced no neurotoxicity and spinal histopathologic changes that were equivalent to those observed in the saline-treated animals.