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 At the end of this time, a sample was taken from the lower lumbar needle, and both needles were withdrawn.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.     

Pharmacokinetics of intravenous, intrathecal and epidural morphine and fentanyl in the goat

Intrathecal and epidural catheters and an intravenous cannula were inserted in 10 goats. After administration of either morphine 4 mg, intravenously, 1 mg intrathecally or 4 and 8 mg epidurally, or fentanyl 0.1 mg intravenously, 0.05 mg intrathecally or 0.1 and 0.2 mg epidurally, venous blood and CSF were sampled at 2, 5, 10, 15, 30 min and 1, 2, 4, 6, 8 and 24 h. The concentrations of the drugs were measured by radioimmunoassay. After administration of intravenous morphine the plasma concentration-time curve fitted a 3-compartment model (body clearance = 84 +/- 23 ml/min/kg, mean +/- s.d., N = 5), while after fentanyl the plasma concentration-time curve was best described by a 2-compartment model (body clearance = 3.9-5.8 ml/min/kg, N = 3]. After intrathecal injection the elimination rates of the opioids from CSF were 0.3 to 2.0 and 0.6 to 2.4 ml/h/kg for morphine and fentanyl, respectively (N = 3). The time to reach maximum CSF concentration after epidural administration was 0.22 +/- 0.14 h for morphine (N = 6) and 0.22 +/- 0.13 h for fentanyl (N = 8). In the same goat the CSF availability was 2.3 and 11.3% for morphine and 0.8 and 3.3% for fentanyl following epidural administration of the low and high doses, respectively. After epidural administration, morphine and fentanyl are absorbed into CSF at the same rate but the relative amount of drug absorbed may be higher for morphine than fentanyl. Bulk flow is supposed to be the principal mechanism of opioid elimination from CSF.     

A Comparison of Intrathecal Fentanyl and Sufentanil for Labor Analgesia

Background: The use of intrathecal opioids for labor analgesia continues to gain popularity, but there are limited data to guide this use. Previously, the authors established the ED50 for 60 min of labor analgesia from intrathecal sufentanil using an up-down sequential allocation study design. The current study first establishes an ED50 for intrathecal fentanyl using this same study design to establish an intrathecal potency ratio for fentanyl and sufentanil and then uses this ratio to compare the efficacy, duration of analgesia, and side effects from comparable doses of intrathecal fentanyl and sufentanil.

Methods: Seventy-five healthy nulliparous women requesting labor analgesia were enrolled in this two-part study. In phase I, 20 women received varying doses of fentanyl to establish an ED50 for 60 min of labor analgesia. In phase II, 55 women were randomized to receive either 36 [mu]g intrathecal fentanyl or 8 [mu]g sufentanil (2 times the ED50s) via a combined spinal-epidural technique and by double-blinded design. Pain relief, side effects, block height, maternal hemodynamics, and fetal heart rate were assessed throughout the study. The duration of spinal analgesia was considered to be the time from injection of study drug to the time of the patient's first request for additional analgesia.

Results: The ED50 of intrathecal fentanyl for 60 min of labor analgesia was found to be 18.2 [mu]g, and therefore, the potency ratio of intrathecal sufentanil to intrathecal fentanyl at the ED50 level is 4.4:1. The duration of spinal analgesia was significantly longer from 8 [mu]g intrathecal sufentanil than from 36 [mu]g intrathecal fentanyl (104 +/- 34 vs. 79 +/- 34 min, P = 0.009). Otherwise, patient demographics, maternal hemodynamics, duration of labor, mode of delivery, motor block, subjective leg weakness, pruritus, nausea, pinprick sensory levels, visual analog scale pain scores, fetal bradycardia, and Apgar scores were similar between groups.     

A Comparison of the 24-Gauge Sprotte® and Gertie Marx® Spinal Needles for Combined Spinal-Epidural Analgesia during Labor

Background: Prior experience with the combined spinal-epidural technique (CSE) for labor analgesia demonstrated a high (up to 14%) failure rate because of failure to obtain cerebrospinal fluid (CSF) or lack of response to appropriate doses of intrathecal sufentanil. The current study was designed to test whether a longer needle with a shorter side port (Gertie Marx(R) needle; 127 mm long) would eliminate failures to obtain CSF compared with the needle we had used previously (Sprotte(R) needle; 120 mm long).

Methods: Seventy-three parturients were randomly assigned to have a CSE performed with one of these two needles. After identifying the epidural space with an 18-gauge Touhy needle at the L2-L3 or L3-L4 interspace, the spinal needle was introduced through the Touhy needle until penetration of the dura was felt or until the needle was maximally inserted. If no CSF was obtained, the alternate needle was tried. After obtaining CSF, 10 [mu]g sufentanil diluted in 1.8 ml saline was injected. Verbal pain scores (0-10) were obtained every 5 min for 30 min.

Results: Failure to obtain CSF occurred six times in the Sprotte group compared with none in the Gertie Marx group (P < 0.05). In all six failures in the Sprotte group, the Gertie Marx needle subsequently proved successful in obtaining CSF. There were no differences in pain scores between the groups.     

Pharmacokinetics of intrathecal morphine and meperidine in humans

Two groups of surgical patients each comprising six individuals received an intrathecal injection of morphine 0.3 mg or meperidine 10 mg. Cerebrospinal fluid (CSF) and plasma were sampled frequently during a 6-h period and analyzed for morphine or meperidine. Maximum plasma morphine concentrations were found 5-10 min after injection, and averaged 4.5 +/- 1.1 ng.ml-1 (mean +/- SEM). Maximum CSF morphine concentrations were considerably higher than maximum plasma concentrations, 6410 +/- 1290 ng.ml-1. Maximum plasma concentrations of meperidine were also measured 5 or 10 min after injection and were low (36 +/- 9 ng.ml-1) compared with the maximum CSF concentrations (364 +/- 105 micrograms.ml-1). After a rapid initial decline for about 15 min after injection, the CSF concentrations decreased with a half-life of 89.8 +/- 16.1 min for morphine and 68.0 +/- 5.1 min for meperidine during the rest of the study period. The initial volume of distribution in CSF was similar for both drugs, or 22 +/- 8 ml for morphine and 18 +/- 5 ml for meperidine. After 6 h, 1.6 +/- 0.9% of the injected morphine dose and 0.41 +/- 0.09% of the meperidine dose remained in the initial volume of distribution. Large inter-individual differences in morphine and meperidine CSF kinetics existed, which may explain some of the reported individual differences in duration of effects. The disappearance of meperidine from CSF tended to be faster than that of morphine, which may be explained, in part, by the differences in lipid solubilities of the drugs.     

Chronopharmacology of Intrathecal Sufentanil for Labor Analgesia: Daily Variations in Duration of Action

Background: The pharmacokinetic and pharmacodynamic characteristics of opioids vary throughout the day, as demonstrated for oral morphine in chronic pain. However, little is known about the chronobiology of intrathecal lipid soluble opioids used for labor analgesia. The aim of this prospective study was to determine whether the duration of action of intrathecally administered sufentanil is influenced by the time of administration.

Methods: Ninety-one women in the first stage of labor were enrolled. Labor analgesia was first provided by 10 [mu]g intrathecal sufentanil. The duration of action of intrathecal sufentanil was measured and analyzed by the cosinor method to determine periodic intraday variation.

Results: Pain assessed by a visual analog score was not different among patients (70 +/- 17 mm) before the injection of intrathecal sufentanil. Rhythm analysis revealed a mean (+/- SD) duration of analgesia (mesor) of 93.0 +/- 3.8 min. A highly significant 12-h rhythm was found, with two peaks: One was near midnight (0.78 +/- 0.6 h), and the other was near noon (12.78 +/- 0.6 min) (P < 0.01). The amplitude of this 12-h component was 16.1 +/- 5.5 min.     

The CSF and plasma pharmacokinetics of sufentanil after intrathecal administration.

Eight patients (7 men and 1 woman, 45-68 yr old) scheduled to undergo thoracotomy were given, preoperatively, 15 micrograms sufentanil in the lumbar intrathecal space for a study of cerebrospinal fluid (CSF) and plasma kinetics of sufentanil. Multiple samples of plasma and CSF from the lumbar region were obtained through indwelling catheters for 12 h and analyzed for sufentanil by radioimmunoassay. Pharmacokinetic parameters were derived by noncompartmental analysis. In plasma, the maximal concentration of sufentanil appeared after 0.65 +/- 0.17 h (mean +/- SEM). No equilibrium was reached between the sufentanil concentration in CSF and plasma, but the CSF/plasma concentration ratio declined from approximately 140 at 2 h to about 15 at 10 h. Extrapolation indicates that another 10 h would be required before the concentration in CSF would equal that in plasma. The mean residence time (MRT) of sufentanil in CSF was 0.92 +/- 0.08 h and in plasma was 6.8 +/- 0.6 h. The volume of distribution at steady state (Vss) in the subarachnoid compartment was 1.54 +/- 0.39 ml/kg, and the clearance from the CSF was 27 +/- 5 microliters.kg-1.min-1. The intrathecal administration of 15 micrograms sufentanil at the beginning of the operation did not produce analgesia that lasted into the postoperative period. Most patients had urinary retention, but none experienced any serious complications. This study demonstrates that the lipophilic opioid sufentanil undergoes rapid clearance from CSF and absorption to plasma after intrathecal administration. These pharmacokinetic characteristics are slower for the less lipophilic opioids meperidine and morphine. The rapid pharmacokinetics of sufentanil explain its rapid onset of action and short-lasting effects.     

Can continuous low current electrical stimulation distinguish insulated needle position in the epidural and intrathecal spaces in pediatric patients?

BACKGROUND: Muscle twitches elicited with electrical stimulation (6-17 mA) during epidural insertion indicate correct epidural needle placement while muscle twitches at a lower current (<1 mA) may indicate intrathecal needle placement. This study examined whether applying continuous electrical stimulation at 6 mA could indicate needle entry into the epidural space without inadvertently penetrating the intrathecal space. METHODS: After institutional review board (IRB) approval, 10 pediatric patients scheduled for lumbar puncture were studied. Following sedation with propofol, an insulated 24-gauge Pajunck unipolar needle was inserted through an 18-gauge introducer needle placed at the L4-5 interspace. The needle was first connected to a nerve stimulator (6 mA) and advanced. At the first sign of muscle twitching, needle advancement was stopped and the threshold current for motor activity was determined. The current was then turned off, the stylet was removed and the needle checked for cerebrospinal fluid (CSF). If CSF was not present, the needle was advanced into the intrathecal space (as confirmed by the presence of CSF). Ten pediatric patients (ASA II or III) aged 7.8 +/- 4.3 years (2.8-16.0 years) were studied. RESULTS: All patients had two distinguishable threshold currents as the needle advanced. The mean threshold current to elicit muscle twitch in the presumed epidural space was 3.84 +/- 0.99 mA. CSF was not present in any of the patients at this location. The mean threshold current in the intrathecal space was 0.77 +/- 0.32 mA. The average estimated distance from the first threshold location to the intrathecal space was 3 mm. All muscle twitches were at the L3-5 myotomes. Nine muscle twitches were unilateral and one was bilateral. CONCLUSIONS: Monitoring with an insulated needle with electrical stimulation at 6 mA may prevent unintentional placement of epidural needles into the intrathecal space.     

Addition of opioids alters the density and spread of intrathecal local anesthetics? Anin vitro study

PURPOSE: To determine whether the addition of opioids alters the density and spread of intrathecal local anesthetics in vitro. METHODS: In Part I, the densities of hyperbaric bupivacaine 0.75% (HB), hyperbaric lidocaine 5% (HL) and isobaric bupivacaine 0.5% (IB) with and without morphine (M), and fentanyl (F) were measured at 22 degrees C. In Part II a model was constructed utilizing a column containing a solution similar in composition to cerebrospinal fluid (CSF) at 37 degrees C. The various local anesthetic-opioid solutions, coloured with crystalline methylene blue dye, were injected at 22 degrees C into the column at a controlled rate through a spinal needle. The direction and extent of spread of the injectates were compared. RESULTS: The relative densities of the five solutions were: HB = HL > IB > M > F. The addition of fentanyl to IB reduced the density of the final solution (P < 0.05). In the model, IB alone and IB with morphine showed mainly downward spread, with the addition of fentanyl to IB resulting in upward movement (P = 0.004). The hyperbaric local anesthetics moved downward with or without opioids. CONCLUSION: The addition of fentanyl reduces the density of IB in vitro and alters its movement in simulated CSF. This may prove to be important in predicting the level of spinal block in clinical practice.     

A comparison of intrathecal fentanyl and sufentanil for labor analgesia

BACKGROUND: The use of intrathecal opioids for labor analgesia continues to gain popularity, but there are limited data to guide this use. Previously, the authors established the ED50 for 60 min of labor analgesia from intrathecal sufentanil using an up-down sequential allocation study design. The current study first establishes an ED50 for intrathecal fentanyl using this same study design to establish an intrathecal potency ratio for fentanyl and sufentanil and then uses this ratio to compare the efficacy, duration of analgesia, and side effects from comparable doses of intrathecal fentanyl and sufentanil. METHODS: Seventy-five healthy nulliparous women requesting labor analgesia were enrolled in this two-part study. In phase I, 20 women received varying doses of fentanyl to establish an ED50 for 60 min of labor analgesia. In phase II, 55 women were randomized to receive either 36 microg intrathecal fentanyl or 8 microg sufentanil (2 times the ED50s) via a combined spinal-epidural technique and by double-blinded design. Pain relief, side effects, block height, maternal hemodynamics, and fetal heart rate were assessed throughout the study. The duration of spinal analgesia was considered to be the time from injection of study drug to the time of the patient's first request for additional analgesia. RESULTS: The ED50 of intrathecal fentanyl for 60 min of labor analgesia was found to be 18.2 microg, and therefore, the potency ratio of intrathecal sufentanil to intrathecal fentanyl at the ED50 level is 4.4:1. The duration of spinal analgesia was significantly longer from 8 microg intrathecal sufentanil than from 36 microg intrathecal fentanyl (104 +/- 34 vs. 79 +/- 34 min, P = 0.009). Otherwise, patient demographics, maternal hemodynamics, duration of labor, mode of delivery, motor block, subjective leg weakness, pruritus, nausea, pinprick sensory levels, visual analog scale pain scores, fetal bradycardia, and Apgar scores were similar between groups. CONCLUSION: The relative potency of intrathecal sufentanil to fentanyl for labor analgesia is 4.4:1. When using intrathecal opioids alone for early labor analgesia, 8 microg sufentanil produces labor analgesia lasting approximately 25 min longer than from 36 microg fentanyl, without a statistically significant increase in side effects. However, when making a choice between fentanyl and sufentanil, one must consider other important factors, such as the higher cost of sufentanil and the greater risk of dosing error due to the higher potency of sufentanil compared with fentanyl.     

Cardiorespiratory effects and kinetics of intrathecally injected D-Ala2-D-Leu5-enkephalin and morphine in unanesthetized dogs

In unanesthetized dogs prepared with chronic tracheostomies and chronically implanted intrathecal (IT) catheters having openings in the cisterna magna and lumbar region, lumbar IT injection of D-Ala2-D-Leu5-enkephalin (DADL, 1-10 mg) and morphine (3-30 mg) produced a dose-dependent depression of the slope of the CO2 response function (minute expired volume [VE] vs. end-tidal [ET] CO2) as investigated by a modified Read rebreathing technique. The maximum depression occurred less than 3 h after IT injection of either agent and lasted as long as 12 h. The depression was totally reversed by naloxone (0.4 mg/kg, iv). Naloxone alone had no effect on ventilatory function. After 10 mg DADL, there was no significant change in heart rate (HR), mean arterial pressure (MAP), mean pulmonary artery pressure (MPAP), cardiac output (CO), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), or PaO2 during the 3 h postinjection. In contrast, PaCO2 was significantly elevated and pH significantly decreased (P less than 0.05). Naloxone administration after high-dose IT DADL resulted in a doubling of MABP, MPBP, CO, and SVR that lasted approximately 20 min. In concurrently measured cisternal cerebrospinal fluid (CSF) levels, both morphine and DADL displayed peak levels by 30-60 min. The lumbar CSF clearance curves for both agents were fitted with a two-compartment intravenous bolus model. The t 1/2 alpha was 13.8 +/- 3.6 min for DADL and 9.4 +/- 1.6 min for morphine (mean +/- SE). The t 1/2 beta was 101.3 +/- 17.7 min for DADL and 116.7 +/- 27.9 min for morphine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Arterial and ventricular CSF pharmacokinetics after intrathecal meperidine in humans

In order to investigate the mechanisms leading to respiratory depression after lumbar administration of opioids, plasma and ventricular CSF pharmacokinetics of intrathecal meperidine (1 mg.kg-1) were studied in five head-injured patients undergoing surgery for lower limb fracture. Meperidine was detected both in the plasma (arterial catheter) and in the ventricular CSF (intracranial catheter) soon after intrathecal administration: 45 +/- 17 min and 100 +/- 14 min, respectively. The maximal plasma concentration was 341 +/- 133 ng.ml-1, whereas, in ventricular CSF, it was 64.5 +/- 14.9 ng.ml-1. The ventricular CSF-plasma ratio increased with time (r = 0.82) from 0.18 +/- 0.04 at the first hour to 0.38 +/- 0.1 at 16th hour. It is concluded that the putative risk of respiratory depression appears to be mainly related to the absorption into the systemic circulation and to redistribution back into CSF.     

Loss of intrathecal morphine analgesia in terminal cancer patients is associated with high levels of excitatory amino acids in the CSF

PURPOSE: To examine excitatory amino acid (EAA) levels in the cerebrospinal fluid (CSF) of patients on long-term morphine treatment for terminal cancer pain relief and to correlate these with morphine's analgesic effect. METHODS: Fourteen terminal cancer patients suffering severe pain and requiring long-term opioid treatment for pain relief were included. An intrathecal (IT) catheter was implanted at the L(3-4)/L(4-5) level and advanced 10 cm in a cephalad direction. IT morphine injection was started at 100 microgram q 12 hr with a daily incremental dose of 50 microgram until the effective dose was reached. The CSF was sampled (2 mL) as follows: 1) before the first IT morphine injection, 2) when the effective dose of morphine was reached, 3) when loss of morphine's analgesic effect at the effective dose (pain visual analogue scale > 5), and 4) after consecutive increases of the morphine dose (50 microgram, IT, daily) for satisfactory pain relief and up to double the effective dose. The concentrations of glutamate and aspartate in the CSF were determined. RESULTS: CSF levels of glutamate and aspartate at the effective dose of morphine were lower than the baseline levels and increased when pain intensity increased and when morphine's analgesic effect was lost. CONCLUSION: Long-term IT morphine administration was accompanied by an increase of EAA level in the CSF that was associated with a loss of morphine's analgesic effect.     

Body habitus does not influence spread of sensory blockade after the intrathecal injection of a hypobaric solution in term parturients

PURPOSE: To determine if the extent of sensory blockade after the intrathecal injection of hypobaric fentanyl (25 micro g) and bupicavaine (2.5 mg) in the sitting position in term parturients is influenced by body habitus. METHODS: A prospective observational study in 245 term parturients who received intrathecal fentanyl and bupivacaine plus an epidural test dose to initiate labour analgesia at an academic university hospital. The highest sensory blockade to ice and pinprick was determined at 15 and 30 min after the intrathecal injection. Correlations between sensory blockade and parturient height, weight and body mass index (BMI) were determined. RESULTS: There was no association between highest sensory blockade and parturients' height. Increasing weight and BMI were associated with increased cephalad sensory blockade at 15 min, but not at 30 min. The estimated difference in sensory level between women at the extremes of BMI, based on our linear regression model, was less than one dermatome. CONCLUSION: Height did not influence the extent of sensory analgesia after initiation of intrathecal labour analgesia using a hypobaric solution injected with the parturient in the sitting position. Weight and BMI were associated with a non-clinically significant increase in the cephalic spread of analgesia, suggesting that dose adjustments based on body habitus in this population are not necessary.     

A comparison of the 24-gauge Sprotte and Gertie Marx spinal needles for combined spinal-epidural analgesia during labor

BACKGROUND: Prior experience with the combined spinal-epidural technique (CSE) for labor analgesia demonstrated a high (up to 14%) failure rate because of failure to obtain cerebrospinal fluid (CSF) or lack of response to appropriate doses of intrathecal sufentanil. The current study was designed to test whether a longer needle with a shorter side port (Gertie Marx needle; 127 mm long) would eliminate failures to obtain CSF compared with the needle we had used previously (Sprotte needle; 120 mm long). METHODS: Seventy-three parturients were randomly assigned to have a CSE performed with one of these two needles. After identifying the epidural space with an 18-gauge Touhy needle at the L2-L3 or L3-L4 interspace, the spinal needle was introduced through the Touhy needle until penetration of the dura was felt or until the needle was maximally inserted. If no CSF was obtained, the alternate needle was tried. After obtaining CSF, 10 microg sufentanil diluted in 1.8 ml saline was injected. Verbal pain scores (0-10) were obtained every 5 min for 30 min. RESULTS: Failure to obtain CSF occurred six times in the Sprotte group compared with none in the Gertie Marx group (P < 0.05). In all six failures in the Sprotte group, the Gertie Marx needle subsequently proved successful in obtaining CSF. There were no differences in pain scores between the groups. CONCLUSIONS: The extra length of the 127-mm Gertie Marx needle resulted in a higher success rate for obtaining CSF when used in the CSE technique. Side port design was not a factor influencing success in this clinical setting.     

The addition of fentanyl does not alter the extent of spread of intrathecal isobaric bupivacaine in clinical practice

PURPOSE: Fentanyl is commonly added to intrathecal local anesthetic solutions. In vitro data has shown fentanyl to render isobaric local anesthetics hypobaric, and alter the spread in artificial cerebrospinal fluid. This study examined whether the addition of fentanyl to isobaric bupivacaine with morphine leads to a clinically important alteration in the extent of spread of anesthesia. METHODS: Forty-four ASA I-III patients undergoing lower limb orthopedic procedures completed this double-blind, placebo-controlled trial. Patients were randomized into one of two groups, receiving intrathecal bupivacaine 15 mg and preservative-free morphine 200 microg without (Control group), or with the addition of fentanyl 0.02 mg (Fentanyl group). Patients were maintained at a slight head-up tilt. Variables studied over three hours included sensory level to cold and pinprick, motor blockade (Bromage scale), and circulatory data. RESULTS: No differences existed between the Fentanyl and Control groups with respect to highest level of block for cold: T4 (T2-T5) vs T3.5 (T3-T8) respectively (median, 95% confidence interval) or pinprick: T4 (T3-T6) vs T4.5 (T3-T8). Similarly, there was no difference in the time taken to reach maximum block height to cold (20 +/- 9 vs 23 +/- 13 min, mean +/- SD) or pinprick (20 +/- 9 vs 24 +/- 13 min). CONCLUSION: The addition of fentanyl 0.02 mg to 0.5% bupivacaine with morphine does not affect the maximal block height or time to maximal block in clinical practice.     

Pharmacokinetic aspects of intrathecal morphine analgesia

Fifteen patients undergoing thoracotomy were given 0.25 or 0.50 mg morphine intrathecally (L2-L3 or L3-L4) for an analgetic and pharmacokinetic study. Administration of morphine at the end of the operation resulted in a highly variable duration of analgesia ranging from 1-20.5 and 1-40 h for the 0.25 and 0.50 mg groups, respectively. Calculation of cumulative consumption pattern of additional analgesics given im indicated a dose-related analgesia lasting around 12 h. Morphine concentrations in the CSF were high and dose dependent. Thus, at 1 h, CSF concentrations (means +/- SEM) were 4,228 +/- 361 ng/ml and 10,447 +/- 1,538 ng/ml for the 0.25 and 0.50-mg groups, respectively. The plasma concentrations generally were very low, i.e., under 1 ng/ml. For the 0.50 and 0.25 mg groups, the terminal elimination half-life in CSF was 175 +/- 9 min and 196 +/- 13 min, respectively: the volume of CSF distribution was 0.88 +/- 0.16 ml X kg-1 and 1.06 +/- 0.17 ml X kg-1, respectively: and the clearance from CSF was 2.81 +/- 0.41 microliter X kg-1 X min-1 and 3.41 +/- 0.55 microliter X kg-1 X min-1, respectively (means +/- SEM). The study indicates that the significant pharmacokinetic parameter related to the long duration of analgesia after intrathecal morphine administration probably is the high CSF concentrations found, since the rate of elimination from CSF is similar to what is reported for morphine in plasma. Furthermore, modulation of nociceptive input in the thoracic region also may be achieved by lumbar administration, but a slower onset should be anticipated.     

Analgesic Effect of Low-dose Intrathecal Morphine after Spinal Fusion in Children

Background: This study was designed to assess the postoperative analgesic effect of low-dose intrathecal morphine after scoliosis surgery in children.

Methods: Thirty children, 9-19 yr of age, scheduled for spinal fusion, were randomly allocated into three groups to receive a single dose of 0 (saline injection), 2, or 5 [mu]g/kg intrathecal morphine. After surgery, a patient-controlled analgesia device (PCA) provided free access to additional intravenous morphine. Children were monitored for 24 h in the postanesthesia care unit.

Results: The three groups were similar for age, weight, duration of surgery, and time to extubation. The time to first PCA demand was dose-dependently delayed by intrathecal morphine. The first 24 h of PCA morphine consumption was 49 +/- 17, 19 +/- 10, and 12 +/- 12 mg (mean +/- SD) in the saline, 2 [mu]g/kg morphine, and 5 [mu]g/kg morphine groups, respectively. Pain scores at rest were significantly lower over the whole study period after 2 and 5 [mu]g/kg intrathecal morphine than after saline, but there was no difference between intrathecal doses. Pain scores while coughing and the incidence of side effects were similar in the three groups.     

Comparative Spinal Distribution and Clearance Kinetics of Intrathecally Administered Morphine, Fentanyl, Alfentanil, and Sufentanil

Background: Despite widespread use, little is known about the comparative pharmacokinetics of intrathecally administered opioids. The present study was designed to characterize the rate and extent of opioid distribution within cerebrospinal fluid, spinal cord, epidural space, and systemic circulation after intrathecal injection.

Methods: Equal doses of morphine and alfentanil, fentanyl, or sufentanil were administered intrathecally (L3) to anesthetized pigs. Microdialysis probes were used to sample cerebrospinal fluid at L2, T11, T7, T3, and the epidural space at L2 every 5-10 min for 4 h. At the end of the experiment, spinal cord and epidural fat tissue were sampled, and each probe's recovery was determined in vitro. Using SAAM II pharmacokinetic modeling software (SAAM Institute, University of Washington, Seattle, WA), the data were fit to a 16-compartment model that was divided into four spinal levels, each of which consisted of a caternary arrangement of four compartments representing the spinal cord, cerebrospinal fluid, epidural space, and epidural fat.

Results: Model simulations revealed that the integral exposure (area under the curve divided by dose) of the spinal cord (i.e., effect compartment) to the opioids was highest for morphine because of its low spinal cord distribution volume and slow clearance into plasma. The integral exposure of the spinal cord to the other opioids was relatively low, but for different reasons: alfentanil has a high clearance from spinal cord into plasma, fentanyl distributes rapidly into the epidural space and fat, and sufentanil has a high spinal cord volume of distribution.     

Pharmacokinetics of epidural morphine and meperidine in humans

Five groups of surgical patients, each comprising six individuals, received epidural doses of morphine or meperidine, and the plasma and CSF kinetics were studied. Three groups received epidural doses of morphine 3 mg in 1 or 10 ml or meperidine 30 mg in 1 ml. Cerebrospinal fluid (CSF) and central venous blood opioid concentrations were measured intermittently for 6 h after injection. Two groups received epidural doses of morphine 3 mg in 1 ml or meperidine 30 mg in 1 ml, and opioid CSF concentrations were determined over a 24-h period. Morphine appeared rapidly in plasma, and maximum plasma concentrations were usually detected 5 min after injection and averaged 33 ng.ml-1 in the 1-ml volume group and 40 ng.ml-1 in the 10-ml volume group. The terminal plasma half-life averaged 91 +/- 34 min and 87 +/- 27 min, respectively (mean +/- SEM). Maximal plasma concentrations of meperidine were usually detected 10 or 15 min post-injection and averaged 196 +/- 29 ng.ml-1. The terminal plasma half-life averaged 124 +/- 26 min. Morphine crossed the dura relatively slowly, and the absorption half-life across the dura averaged 22 min. Maximal CSF concentrations were usually seen 60-90 min post-injection. In contrast, meperidine crossed the dura quickly, with an absorption half-life averaging 7.6 +/- 2.0 min. Maximal CSF concentrations were seen 15 or 30 min post-injection. Morphine and meperidine concentrations remained several times higher in the CSF than in the plasma. The fraction of the opioid dose crossing the dura was calculated to be 3.6% for morphine and 3.7% for meperidine. There were no significant differences in the kinetics of morphine administered in 1 or in 10 ml when CSF was sampled close to the site of lumbar epidural injection. The CSF concentration-time curves of both drugs decreased biexponentially after the initial rise due to diffusion across the dura. The early half-life in CSF averaged 73.3 +/- 11.5 min for morphine and 71.3 +/- 3.1 min for meperidine, and the late half-life averaged 369 +/- 113 min for morphine and 982 +/- 449 min for meperidine. Dose-normalized morphine and meperidine CSF concentrations after epidural administration showed that meperidine concentrations were down to one-fourth the corresponding morphine concentrations from the 2nd to the 15th h after administration, which may partly explain the longer duration of analgesia from morphine.(ABSTRACT TRUNCATED AT 400 WORDS)