ΔK=0 M1 Excitation Strength of the Well-Deformed Nucleus

The size of a ΔK=0 M1 excitation strength has been determined for the first time in a predominantly axially deformed even-even nucleus. It has been obtained from the observation of a rare K-mixing situation between two close-lying J^{π}=1^{+} states of the nucleus ^{164}Dy with components characterized by intrinsic projection quantum numbers K=0 and K=1. Nuclear resonance fluorescence induced by quasimonochromatic linearly polarized γ-ray beams provided evidence for K mixing of the 1^{+} states at 3159.1(3) and 3173.6(3) keV in excitation energy from their γ-decay branching ratios into the ground-state band. The ΔK=0 transition strength of B(M1;0_{1}^{+}→1_{K=0}^{+})=0.008(1)µ_{N}^{2} was inferred from a mixing analysis of their M1 transition rates into the ground-state band. It is in agreement with predictions from the quasiparticle phonon nuclear model. This determination represents first experimental information on the M1 excitation strength of a nuclear quantum state with a negative R-symmetry quantum number.

Evidence for a smooth onset of deformation in the neutron-rich Kr isotopes.

The neutron-rich nuclei 94,96Kr were studied via projectile Coulomb excitation at the REX-ISOLDE facility at CERN. Level energies of the first excited 2(+) states and their absolute E2 transition strengths to the ground state are determined and discussed in the context of the E(2(1)(+)) and B(E2;2(1)(+)→0(1)(+)) systematics of the krypton chain. Contrary to previously published results no sudden onset of deformation is observed. This experimental result is supported by a new proton-neutron interacting boson model calculation based on the constrained Hartree-Fock-Bogoliubov approach using the microscopic Gogny-D1M energy density functional.

Cerebral blood flow determinations using fluorescent microspheres: variations on the sedimentation method validated.

We validate a modification of the sedimentation method for measuring fluorescent microspheres (FM) that improves the determination of regional cerebral blood flow (rCBF). Our FM method for rCBF determination is compared to the radioactive microspheres (RM) method for rCBF measurement by simultaneous injection of one radioactive and two fluorescent labeled doses, at two separate time points, into the left ventricle of a pig. The pig was killed, the brain and spinal cord removed, and divided into 92 pieces averaging 0.83 g. Our modifications to FM analysis by sedimentation includes: 2 instead of 1 week of autolysis, pellet washing with 1% Triton X-100 instead of 0.25% Tween 80, phosphate buffer addition during rinse, fluorescent dye extraction using 2-ethoxyethylacetate instead of 2-(2-ethoxyethoxy)ethyl acetate and polypropylene instead of glass tubes. Comparing rCBF using Sc46 RM, to yellow-green and orange FM, yielded mean differences of 0.026 and 0.021 ml/min per piece, respectively. Sn(113) RM compared to blue-green and scarlet FM gave mean differences of -0.010 and 0.137 ml/min per piece, respectively. All RM-FM differences, except those for scarlet FM, are within acceptable limits. This assay provides a reliable method for determining rCBF.

Centrally mediated hemodynamic effects of cocaine in rabbits: the role of local anesthetic actions and biogenic amine re-uptake blockage.

This study sought to identify the central nervous system-mediated cardiovascular effects of cocaine and to determine if these effects result from local anesthetic action or biogenic amine re-uptake blockade. New Zealand rabbits received multiple i.c.v. doses of cocaine, pseudococaine, lidocaine or desipramine while recording blood pressure and heart rate. Moderate dose cocaine produced a decrease in heart rate and mean arterial pressure while the highest dose produced increases in heart rate and blood pressure. Lidocaine and pseudococaine produced dose-dependent increases in blood pressure while desipramine produced decreases in heart rate and mean arterial pressure. In this model, the central nervous system-mediated cardiovascular effects of cocaine are dose-dependent; low doses produced cardiovascular depression while higher doses produced cardiovascular stimulation. The data also suggest that cocaine's local anesthetic effects are responsible for its central nervous system-mediated cardiovascular stimulation, while biogenic amine re-uptake blockade causes cardiovascular depression.

Effect of (hydroxypropyl)-beta-cyclodextrin on flux of morphine, fentanyl, sufentanil, and alfentanil through the spinal meninges of monkey.

Previous studies have demonstrated that (hydroxypropyl)-beta-cyclodextrin behaves as a slow-release reservoir when used as a vehicle for intrathecal administration of opioids. The goal of the current investigation was to determine if (hydroxypropyl)-beta-cyclodextrin might serve as a slow-release vehicle for epidural opioid administration as well. An in vitro diffusion cell model was used to determine the flux of morphine, fentanyl, alfentanil, and sufentanil through the spinal meninges of Macaque nemestrina monkeys in the absence or presence of varying concentrations of (hydroxypropyl)-beta-cyclodextrin. No concentration of cyclodextrin slowed the flux of any of the opioids through the meninges, indicating that (hydroxypropyl)-beta-cyclodextrin will not behave as a slow-release reservoir for these opioids in the epidural space. This finding suggests that the rate-limiting step in opioid transfer was diffusion through the meninges not dissociation of the opioid cyclodextrin complex. However, (hydroxypropyl)-beta-cyclodextrin significantly increased the flux of sufentanil through the meninges. Since sufentanil's hydrophobicity has previously been shown to impede its meningeal flux, this finding suggests that cyclodextrin effectively decreases sufentanil's hydrophobicity by formation of inclusion complexes in the aqueous environments of the spinal meninges.

Intravenous lidocaine decreases but cocaine does not alter the rate of cerebrospinal fluid formation in anesthetized rabbits.

Considering that adrenergic stimulation was reported to decrease the rate of cerebrospinal fluid (CSF) formation (Vf), it was hypothesized that cocaine might exert a similar effect. Accordingly, the present study was designed to examine the effects of low, moderate, and high doses of cocaine on Vf and resistance to reabsorption of CSF (Ra). Because cocaine possesses both adrenergic-stimulating and local anesthetic properties, the present study examined the effects of lidocaine, a local anesthetic without adrenergic-stimulating properties, as a comparison treatment to cocaine. New Zealand white rabbits (n = 17) weighing 3.5-4.3 kg were anesthetized with halothane. A needle was inserted into the left lateral cerebral ventricle and a catheter was inserted into the cisterna magna to permit ventriculocisternal perfusion with mock CSF labeled with blue dextran. A1 each of four experimental conditions, control and three doses of cocaine or lidocaine, fluid volumes and concentrations of blue dextran in timed samples of cisternal outflow were used to determine Vf and the rate of reabsorption of CSF (Va). In turn, Va at normal and elevated CSF pressures (+6 cmH2O) were used to determine Ra. For both the cocaine group (n = 9) and the lidocaine group (n = 8) the three drug doses were 0.5 mg.kg-1 followed by 1.0 microgram.kg-1.min-1, 1.5 mg.kg-1 followed by 3.0 micrograms.kg-1.min-1, and 4.5 mg.kg-1 followed by 9.0 micrograms.kg-1.min-1 i.v. Cocaine caused no significant change of Vf or Ra. In the lidocaine group there was a dose/time-related decrease of Vf (although the slope relating Vf to dose/time was not significantly different from that in the cocaine group), but no significant change of Ra. It is concluded that during halothane anesthesia cocaine does not decrease Vf, a finding not consistent with previous reports that adrenergic stimulation decreases Vf. Decrease of Vf with lidocaine is consistent with previous reports of similar dose-related effects of thiopental, etomidate, midazolam, and fentanyl on Vf.

Effect of Staphylococcus aureus bacteria and bacterial toxins on meningeal permeability in vitro.

BACKGROUND AND OBJECTIVES: Epidural catheterization is associated with a significant bacterial colonization rate and occasionally frank infection. During epidural space infection, decreased analgesia despite increased epidural opioid doses has been described. One possible explanation for this observation is that bacterial infection decreases meningeal permeability. The purpose of the study was to determine whether Staphylococcus aureus bacteria, the most common organism causing epidural space infection, or S. aureus toxins alter meningeal permeability. METHODS: Spinal meninges of M. nemestrina monkeys were mounted in a previously established in vitro diffusion cell model and exposed to S. aureus toxins A, B, and F. Simultaneous transmeningeal fluxes of mannitol and sufentanil were measured before and after toxin exposure and compared to controls. In a second series of experiments, diffusion cells were inoculated with live S. aureus bacteria in suspension and the permeability of sufentanil was investigated. RESULTS: Staphylococcus aureus toxin-A increased the transmeningeal flux of mannitol but not sufentanil. Toxins B and F did not alter the meningeal permeability of either drug. Inoculation with live S. aureus bacteria increased the transmeningeal flux of sufentanil by 115+/-21% (P = .032). CONCLUSIONS: These data demonstrate that S. aureus alpha-toxin and live S. aureus bacteria can increase meningeal permeability. Thus, clinical observations of decreased epidural analgesia in the face of bacterial infection cannot be explained by decreased meningeal permeability.

Sciatic nerve blockade improves early postoperative analgesia after open repair of calcaneus fractures.

OBJECTIVE: To determine the effectiveness of analgesia, with or without sciatic nerve blockade, after open repair of calcaneus fracture. DESIGN: Randomized, prospective trial involving 30 patients divided into 3 groups of 10, all having open repair of calcaneus fractures. Group 1 used morphine patient-controlled analgesia alone. Groups 2 and 3 had morphine patient-controlled analgesia and a "one-shot" bupivacaine sciatic nerve blockade, either presurgically (group 2) or postsurgically (group 3). SETTING: Harborview Medical Center operating rooms and orthopedic floors. OUTCOME MEASURES: Morphine use over 24 hours, visual analogue scale pain scores, and sciatic nerve blockade duration. RESULTS: In the absence of sciatic nerve blockade, initial postoperative pain was marked, even with a mean recovery room dose of intravenous morphine more than 30 mg. Sciatic nerve blockade with bupivacaine had a mean duration of 14 hours and substantially reduced pain for the first 24 postoperative hours. Presurgical blockade confers no advantage over postsurgical blockade. CONCLUSION: Sciatic nerve blockade confers significant benefit over morphine alone for analgesia after open repair of calcaneus fractures. Postsurgical sciatic nerve blockade provides the longest possible postoperative block duration.

Cyclosporine-A-mediated inhibition of p-glycoprotein increases methylprednisolone entry into the central nervous system.

STUDY DESIGN: Prospective, randomized, pharmacokinetic study. OBJECTIVE: To determine if cyclosporine-A-mediated inhibition of p-glycoprotein would increase methylprednisolone entry into the central nervous system thereby permitting a reduction in the systemic methylprednisolone dose. SETTING: Department of Anesthesiology, University of Washington, Seattle, USA. METHODS: Microdialysis probes were used to obtain cerebrospinal fluid and gluteal muscle extracellular fluid samples for measurement of methylprednisolone concentration in pigs. At time zero, a methylprednisolone bolus was given and an infusion started. At 210 min, after reaching a stable methylprednisolone concentration, a cyclosporine-A bolus was given (either 10 or 30 mg/kg) and microdialysis samples collected until 420 min. Plasma samples were collected at 10, 30 min and then every 30 min until the study's end. RESULTS: Cyclosporine-A bolus produced a dose-dependant increase in methylprednisolone concentration in plasma, muscle and cerebrospinal fluid. Importantly, the magnitude of the increase in cerebrospinal fluid was significantly greater than the increase in plasma and muscle. CONCLUSIONS: The relatively greater increase in cerebrospinal fluid concentrations of methylprednisolone is consistent with increased penetration of the blood-brain barrier secondary to cyclosporine-mediated p-glycoprotein inhibition. Theoretically, increased methylprednisolone entry into the central nervous system should allow a reduction in the systemic methylprednisolone dose and a consequent decrease in glucocorticoid-mediated side effects.

Effect of postinjury intravenous or intrathecal methylprednisolone on spinal cord excitatory amino-acid release, nitric oxide generation, PGE2 synthesis, and myeloperoxidase content in a pig model of acute spinal cord injury.

STUDY DESIGN: Prospective, randomized, in vivo acute spinal cord injury in pigs. SETTING: Department of Anesthesiology, University of Washington, Seattle, WA, USA. OBJECTIVES: To determine whether postinjury methylprednisolone could reduce the generation of known mediators of secondary neurological injury. METHODS: Intrathecal microdialysis probes were used to sample cerebrospinal fluid (CSF) for measurement of PGE(2), glutamate, and citrulline (a byproduct of nitric oxide generation), before and after spinal cord injury in anesthetized pigs. The spinal cord was removed at the end of the study for measurement of myeloperoxidase and methylprednisolone concentrations. Animals were randomly allocated to receive intravenous methylprednisolone (30 mg/kg bolus then 3.4 mg/kg/h), intrathecal methylprednisolone (5 mg bolus then 5 mg/h), or saline, beginning 30 min after the spinal cord was injured by using a modification of the Allen weight drop technique. RESULTS: Spinal cord injury significantly increased the amount of glutamate, PGE(2), myeloperoxidase, and citrulline, recovered from the CSF dialysates. However, neither intravenous nor intrathecal methylprednisolone administered after injury had any effect on the magnitude of the increase in any of the measured biochemicals. Intrathecal methylprednisolone administration produced a spinal cord methylprednisolone concentration that was eight times greater, and a plasma concentration that was 32 times less, than that achieved with intravenous administration. CONCLUSIONS: Contrary to earlier animal studies in which methylprednisolone was administered either before or immediately after spinal cord injury, we found no effect of intravenous or intrathecal methylprednisolone on any of the parameters measured when administered 30 min postinjury.

Flux of morphine, fentanyl, and alfentanil through rabbit arteries in vivo. Evidence supporting a vascular route for redistribution of opioids between the epidural space and the spinal cord.

BACKGROUND: It has been suggested that opioids may move from the epidural space to the spinal cord by way of the spinal radicular arteries. However, there are no data that address this proposed mechanism. The goal of the current study was to determine whether the radicular arterial supply of the spinal cord is a viable route for movement of opioids between the epidural space and spinal cord. METHODS: The carotid and femoral arteries of anesthetized rabbits were exposed, ligated distally, and cannulated proximal to the ligature. A fluid reservoir was placed around the study vessel and filled with saline buffered to pH = 7.4 or 9.0. The study drug (morphine, fentanyl, or alfentanil) and a radiolabeled tracer were added to the reservoir. Blood was collected as it flowed through the arterial segment bathed by the fluid reservoir and analyzed by scintillation counting to determine how much drug diffused through the arterial wall per minute. RESULTS: Relative flux rates through the carotid artery at pH = 7.4 were alfentanil flux > fentanyl > morphine. Increasing the pH to 9.0 resulted in a significant decrease in fentanyl's flux, but no significant change in alfentanil's or morphine's flux. In addition, the data demonstrate a biphasic relationship between octanol:buffer distribution coefficient and transarterial flux rates. CONCLUSIONS: Because the critical step in transporting drug via radicular arteries is diffusion through the radicular artery wall, these data support the idea that drugs may gain direct access to the spinal cord by diffusing into the radicular arteries as they traverse the epidural space en route to the spinal cord.

Radicular artery blood flow does not redistribute fentanyl from the epidural space to the spinal cord.

BACKGROUND: Epidural opioids must redistribute to the spinal cord to produce analgesia. It has been suggested that opioids may reach the spinal cord via the radicular arterial blood supply. This study was designed to test this hypothesis. METHODS: Microdialysis probes were placed in the lumbar and thoracic spinal cord of six anesthetized pigs and a ligature placed around the thoracic aorta. At t = 0, fentanyl (300 micrograms) was injected into the epidural space and the spinal cord and plasma were sampled over 90 min to determine resultant spinal cord dialysate fentanyl concentrations. At t = 90, the thoracic aorta was occluded to eliminate distal radicular artery blood flow and fentanyl was again injected into the epidural space. The spinal cord was sampled for an additional 90 min to determine spinal cord dialysate fentanyl concentrations. At t = 90 min the aortic cross-clamp was released and spinal cord samples were collected for another 30 min. RESULTS: There was no difference in lumbar spinal cord dialysate concentrations of fentanyl between the control and cross-clamp conditions over the first 20 min after epidural administration. Between 20 and 90 min, lumbar spinal cord fentanyl concentrations were significantly greater during aortic cross-clamp. Fentanyl was not detected in the thoracic cord. CONCLUSIONS: Radicular artery blood supply does not redistribute fentanyl from the epidural space to the spinal cord in this model. However, radicular artery blood flow does play a role in clearing fentanyl from the spinal cord.

Effect of intracerebroventricular picrotoxin and muscimol on intravenous bupivacaine toxicity. Evidence supporting central nervous system involvement in bupivacaine cardiovascular toxicity.

BACKGROUND: The authors have previously shown that administration of bupivacaine into the cerebral ventricles of rabbits results in CNS-mediated cardiac dysrhythmias and that these CNS-mediated dysrhythmias could be terminated by CNS administration of a drug (midazolam) that enhances GABAergic activity. The goal of the current investigation was to determine whether the CNS-mediated cardiotoxicity that occurs after direct CNS administration of bupivacaine contributes to bupivacaine's cardiovascular toxicity following intravenous administration. METHODS: Three groups of rabbits were pretreated by intracerebroventricular administration of mock CSF (control), muscimol (a GABA agonist), or picrotoxin (a GABA chloride channel blocker). A fourth group received intravenous hexamethonium as a pretreatment. After pretreatment, all groups received intravenous bupivacaine at 1.5 mg.kg-1.min-1 and the bupivacaine dose and plasma concentration at the onset of dysrhythmias and cardiovascular collapse were determined. It was hypothesized that pretreatment with muscimol and hexamethonium would increase the threshold for cardiac dysrhythmias, while pretreatment with picrotoxin would decrease the threshold for dysrhythmias. RESULTS: The bupivacaine plasma concentration required to produce cardiac dysrhythmias was significantly greater in the muscimol and hexamethonium groups compared to control. The bupivacaine plasma concentration at the onset of dysrhythmias was not different from control in the picrotoxin group. The bupivacaine plasma concentration that produced cardiovascular collapse did not differ from control in any of the groups. CONCLUSIONS: It was concluded that the data generally support the hypothesis that bupivacaine-mediated cardiac dysrhythmias are, at least in part, mediated by CNS actions of the drug.

The spinal nerve root sleeve is not a preferred route for redistribution of drugs from the epidural space to the spinal cord.

It has been frequently suggested that the spinal nerve root sleeve is a preferred route for redistribution of drugs from the epidural space to the spinal cord. To determine if this supposition is true, the authors measured the rate at which morphine, fentanyl, and lidocaine diffuse through dog and monkey meningeal specimens with and without a root sleeve. Two meningeal specimens of intact dura-arachnoid-pia mater were removed from each animal and placed in separate temperature-controlled diffusion cells. One specimen included a spinal nerve root sleeve; the other did not. The permeability of the tissues to each drug was then determined by placing the study drug in one of the reservoirs of the diffusion cell and measuring the rate at which the drug diffused through the tissue and accumulated in the second reservoir. There was no difference in permeability between specimens with and without a nerve root sleeve for any drug in either species. Lidocaine was found to diffuse through the tissue significantly faster than fentanyl in both the dog and monkey even though fentanyl is nearly 48 times more lipid soluble than lidocaine. Morphine diffused through the tissue significantly slower than both lidocaine and fentanyl. The authors conclude that the spinal nerve root sleeve is not a preferred route of entry for drugs moving from the epidural space to the spinal cord. In addition, despite hypotheses to the contrary, lipid solubility does not appear to be the overriding determinant of meningeal permeability.

Progression of first degree heart block to high-grade second degree block during spinal anaesthesia.

A case is presented in which a patient with pre-existing first degree heart block developed high-grade second degree heart block during spinal anaesthesia. Progression of the block was associated with blockade of cardiac sympathetic neurons induced by spinal anaesthesia. This suggests that patients with pre-existing heart block may be at increased risk for development of higher grade block during spinal anaesthesia.

Physical and chemical properties of drug molecules governing their diffusion through the spinal meninges.

Drugs administered into the epidural space for selective spinal analgesia must diffuse through the spinal meninges to gain access to their sites of action in the spinal cord. Therefore, knowledge of the physical and chemical properties of drug molecules that govern their diffusion through the meninges is important for understanding the pharmacokinetics of epidural analgesia. To determine the physicochemical properties of drug molecules that govern the rate at which drugs diffuse through the spinal meninges, the authors measured the permeability coefficient of eight different drug molecules through the spinal meninges of the monkey using a previously established in vitro model. We previously reported permeability measurements for four of the molecules used in this study; the other four molecules' permeability measurements are new. The measured permeability coefficient was then correlated with the drugs' molecular weight, molecular surface area, molecular volume, length of the major molecular axis, and octanol:buffer distribution coefficient. We found no relationship between the drugs' permeability coefficients and any measure of drug mass, molecular shape, or molecular size. There was, however, a biphasic relationship between the octanol: buffer distribution coefficient and the drugs' measured permeability coefficients. Drugs that were either very hydrophilic or very hydrophobic had permeability coefficients that were significantly less than drugs of intermediate hydrophobicity. These data suggest that it should be possible to design novel analgesics for which meningeal permeability is maximal.

Effect of epinephrine on lidocaine clearance in vivo: a microdialysis study in humans.

BACKGROUND: Local anesthetic nerve block prolonged by epinephrine is thought to result from local vasoconstriction and consequent decreased local anesthetic clearance from the injection site. However, no study has yet confirmed this directly in humans by measuring tissue concentrations of local anesthetic over time. In addition, recent studies have shown that the alpha2-adrenergic receptor agonist, clonidine, also prolongs nerve block without altering local anesthetic clearance. Because epinephrine is also an alpha2-adrenergic receptor agonist, it is possible that epinephrine prolongs local anesthetic block by a pharmacodynamic mechanism and not a pharmacokinetic one. This study was designed to address this issue. METHODS: Microdialysis probes were placed adjacent to the superficial peroneal nerve in both feet of eight volunteers. Plain lidocaine (1%) was injected along one peroneal nerve and lidocaine with epinephrine (2.5 microg/ml) was injected along the other nerve in a double-blinded, randomized manner. The concentration of lidocaine in tissue was measured at 5-min intervals, and sensory block and cutaneous blood flow were assessed by laser Doppler at 10-min intervals for 5 h. The resulting data for lidocaine concentration versus time were fit to a two-compartment model using modeling software. RESULTS: Epinephrine prolonged sensory block by decreasing local blood flow and slowing clearance. There was no evidence of a pharmacodynamic effect of epinephrine. CONCLUSION: Although epinephrine activates alpha2-adrenergic receptors, its mechanism for prolonging the duration of local anesthetic block rests on its ability to decrease local anesthetic clearance and not on a pharmacodynamically mediated potentiation of local anesthetic effect.

Palmitoyl carnitine increases the transmeningeal flux of hydrophilic but not hydrophobic compounds in vitro.

BACKGROUND: Increasing drug penetration through the spinal meninges should improve epidural analgesia/anesthesia by increasing the rate and extent to which epidurally administered drugs redistribute to the spinal cord. Palmitoyl carnitine has been shown to improve drug penetration through the intestinal mucosa. The purpose of this study was to determine whether palmitoyl carnitine improves drug penetration through the spinal meninges. METHODS: The transmeningeal flux of morphine, mannitol, bupivacaine, and sufentanil was determined through the spinal meninges of Macacca nemestrina monkeys before and after addition of palmitoyl carnitine. Flux was determined using a previously established in vitro diffusion cell method. RESULTS: Palmitoyl carnitine significantly increased the transmeningeal flux of mannitol, morphine, and bupivacaine by 942 +/- 102%, 401 +/- 43%, and 12 +/- 4%, respectively. However, palmitoyl carnitine had no significant effect on the transmeningeal flux of sufentanil. The penetration-enhancing effect of palmitoyl carnitine was shown to depend on the dose of palmitoyl carnitine added and on the octanol:buffer distribution coefficient of the study drugs but not on the concentration of the study drug. CONCLUSIONS: The mechanism by which palmitoyl carnitine increases transmeningeal flux is unclear but may be a result of palmitoyl carnitine's ability to decrease packing order of lipid bilayers in the arachnoid mater cell membranes. Regardless of the mechanism, palmitoyl carnitine's ability to selectively increase the transmeningeal flux of hydrophilic compounds in vitro offers the possibility of improving the spinal bioavailability of this group of epidurally administered drugs in vivo.

Morphine and alfentanil permeability through the spinal dura, arachnoid, and pia mater of dogs and monkeys.

Little information exists about which spinal meninx is the principal permeability barrier between the epidural space and the spinal cord or about what physicochemical properties of drug molecules govern their meningeal permeability. To better understand these aspects of epidural pharmacokinetics, the authors measured the permeability of morphine and alfentanil through the different components of the spinal meninges-dura mater, arachnoid mater, and pia mater-of dogs and monkeys in vitro. Live meningeal tissue from either species (dura mater alone, pia mater alone, or intact dura-arachnoid-pia) was placed between two fluid reservoirs of a temperature-controlled diffusion cell. The permeability of the tissues to each opioid was determined by placing the opioid in one of the reservoirs of the diffusion cell and measuring the rate at which the drug diffused through the tissue and appeared in the second reservoir. The arachnoid mater was found to be the major meningeal diffusion barrier between the epidural space and the spinal cord. Alfentanil was 3.7 times more permeable than morphine through all three meninges, suggesting that increased lipid solubility increases meningeal permeability. However, neither lipid solubility nor molecular weight adequately explained the difference in permeability between morphine and alfentanil. The authors conclude that this in vitro model has significant utility for studies aimed at predicting in vivo meningeal permeability and hence the potency and rapidity of action of any opioid administered by the epidural route.