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.     

Pharmacokinetics and pharmacodynamics of epidural and intrathecal morphine

Spinal opiate analgesia has opened an exciting new field of research and has also rapidly gained widespread clinical acceptance. This mode of administration has obvious and definite advantages over conventional pain therapy; however, the field is still at an early stage of development. More research is clearly needed to provide methods for coping with some of the drawbacks of this method of pain relief. Important areas for future research include (1) the CSF kinetics of opiates; (2) the physiological mechanisms underlying the rostral spread of drugs within the CSF compartment; (3) a search for safer and more selective drugs; and (4) an evaluation of the extent to which pain-modulating systems at different levels in the CNS can be regulated by opiates and drugs interfering with other neurotransmitters. In this context it is essential to emphasize the importance of simultaneous study of the pharmacokinetics and the pharmacodynamic/clinical effects in providing a rational basis for a better understanding of the mechanisms of actions underlying spinal opiate analgesia.     

Analgesic and cardiorespiratory effects of epidural sufentanil and morphine in humans

Thirty patients undergoing abdominal surgery were randomly assigned postoperatively into two groups for a double-blind evaluation of the analgesic potency and cardiorespiratory effects of either 50 micrograms sufentanil or 5 mg morphine injected epidurally. After sufentanil injection, good postoperative analgesia was obtained, with a linear analog score (LAS) of less than 5 starting 5 min after injection and lasting for more than 6 hr. Linear analog scores obtained during coughing (LASC) and during movement (LASM) were less than 5 after 10 min and lasted for more than 4 hr. Respiratory rate decreased significantly for 2 hr after sufentanil injection. After morphine, pain relief started after 20 min and lasted for more than 12 hr. Respiratory rate decreased after 30 min. Sedation was greater after sufentanil than after morphine. PaCO2, which increased significantly 1 hr after sufentanil, did not change after morphine. Peak expiratory flow significantly improved for 2 hr after both sufentanil and morphine, whereas forced vital capacity improved for 4 hr after sufentanil and 8 hr after morphine administration. Forced expiratory volume did not change with either drug. It is concluded that 5 mg morphine injected epidurally provides longer lasting analgesia than does 50 micrograms sufentanil, but that in the first hours analgesia is better after sufentanil. Injection of either drug was accompanied by remarkable cardiovascular stability.     

Respiratory effects of epidural and subcutaneous morphine, meperidine, fentanyl and sufentanil in the rat

This study compared the respiratory effects of subcutaneous and epidural morphine, meperidine, fentanyl, and sufentanil in rats breathing air or 8% CO2 in air. A whole body plethysmographic technique was used to measure minute volumes of breathing. The ED50s of subcutaneously injected morphine, meperidine, fentanyl, and sufentanil in depressing the minute volume response to 8% CO2 in air were 2300 micrograms/kg, 8800 micrograms/kg, 20 micrograms/kg, and 2.3 micrograms/kg, respectively. These doses were nearly the same as the subcutaneous ED50s of these compounds in producing analgesia, found in an earlier study. Roughly equianalgesic doses of the four opiates after epidural injection, however, failed to cause any detectable respiratory effect. Fourfold greater doses increased significantly the incidence of low minute volumes with fentanyl and sufentanil, but soon after epidural injection, i.e., at the time that analgesia was produced. None of the epidurally injected opiates had a significant delayed effect on respiration. However, one of the seven rats treated epidurally with the higher dose of morphine developed depression of the minute volume response to 8% CO2 in air as late as 7 hours after the injection. We conclude that epidural injection, in contrast to subcutaneous injection, of analgesic doses of morphine, meperidine, fentanyl, and sufentanil produces no significant respiratory effects.     

Hypertension after epidural meperidine

The use of epidural opiates, unlike the use of epidural local anaesthetics, is considered to have little, if any, effect on the cardiovascular system. A 76-year-old man with a flail chest injury was given a lumber epidural injection of meperidine. During the injection he suddenly complained of feeling cold, shivered vigorously and became tachypneic. His arterial blood pressure rose from 170/70 to 300/100; his pulse rate rose to 150/min. The patient was severely hypertensive for 40 minutes until treated with intravenous phentolamine. There is increasing evidence in the literature implicating the involvement of endogenous opiates in the central control mechanisms of blood pressure control.     

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.     

Pharmacokinetics of meperidine in spinal anaesthesia

Five male patients undergoing haemorrhoidectomy received intrathecal meperidine 1 mg X kg-1 as the sole anaesthetic agent. Plasma concentration-time profiles were investigated. The peak plasma concentration of meperidine was 175 +/- 78.8 ng X ml-1 (mean +/- SD) and this occurred 90 minutes after intrathecal injection. The plasma concentrations generally were lower than those necessary for systemic analgesic effects. The terminal elimination half life of meperidine (t 1/2 beta) in the plasma was 198 minutes. Intrathecal meperidine produced good surgical anaesthesia in all patients studied. The mean duration of sensory and motor block was 77 +/- 18.8 and 47 +/- 7.4 minutes respectively. Four patients did not require any analgesic supplement during the postoperative period. No patient developed clinically evident respiratory depression or neurological sequelae. The pharmacokinetic data suggests that intrathecal meperidine provides prolonged postoperative analgesia through a regional effect on opioid receptors in the spinal cord.     

Lumbar epidural morphine in humans and supraspinal analgesia to experimental heat pain

BACKGROUND: Epidural administration of morphine is a common analgesic technique to manage pain. Morphine spreads from the epidural space to the cerebrospinal fluid and then rostrally, causing side effects mediated by the brain stem. However, data on the rostral spread of morphine-mediated analgesia are sparse. This study examined the rostral spread of analgesic effects on heat and electrical pain after epidural administration of morphine. METHODS: In a randomized, double-blinded, placebo-controlled, crossover study, 5 mg morphine or saline placebo were injected into the lumbar epidural space in nine healthy volunteers. Correct needle placement was confirmed with fluoroscopy. Analgesia to experimental nociceptive heat and electrical stimuli was measured at lumbar (L4), thoracic (T10), cervical (C2), and trigeminal (V2) levels before and 2, 5, 10, and 24 h after epidural injection. Plasma samples for assaying morphine concentrations were drawn before and after each analgesic evaluation. RESULTS: Epidural morphine significantly attenuated experimental heat pain at all dermatomes tested compared with saline placebo. Analgesic effects were significant at L4 after 2, 5, and 10 h, at T10 after 5, 10, and 24 h, and at V2 after 10 h. Electrical pain was attenuated at the lumbar and thoracic but not at the cervical dermatome. Analgesic effects were significant at L4 after 2, 5, and 10 h and at T10 after 5 and 10 h. Morphine plasma concentrations were below the detection limit (1 ng/ml) in eight of the nine subjects 10 h after epidural injection. CONCLUSIONS: Lumbar epidural injection of morphine attenuated cutaneous heat pain up to the trigeminal dermatome during a 24-h observation period. In a clinical context, this implies that some types of pain may be attenuated up to the supraspinal level after lumbar epidural administration of morphine.     

Oxyhemoglobin saturation following cesarean section in patients receiving epidural morphine, PCA, or im meperidine analgesia

The frequency and severity of oxyhemoglobin desaturation was compared in 49 patients receiving epidural morphine, 5 mg (n = 21); patient-controlled analgesia (PCA) using meperidine (n = 20); or intramuscular (im) meperidine (n = 8) for postoperative analgesia following elective cesarean section performed with epidural anesthesia. Oxygen saturation (SpO2) was monitored for 24 h using a pulse oximeter; data were continuously collected and stored every 30 s via an interface connected to a computer. For analysis purposes, SpO2 was divided into five categories: 96-100%, 91-95%, 86-90%, 81-85%, and less than or equal to 80%. Although SpO2 remained above 95% for the majority of the monitored period, patients in all groups experienced periods of desaturation. PCA patients spent the longest cumulative time with SpO2 between 91 and 95%, 231 +/- 49 min (mean +/- SEM), compared with only 112 +/- 30 min and 152 +/- 42 min for the epidural and im groups, respectively (P less than 0.05 vs. epidural group). PCA patients also spent longest with SpO2 at 86-90% (19 +/- 10 min, vs. 6 +/- 3 and 0.5 +/- 0.3 min for the epidural and im groups, respectively), although this difference was not statistically significant. Severe desaturation episodes, defined as SpO2 less than or equal to 85% for more than 30 s, occurred in 71% of patients in the epidural group, 30% in the PCA group, and 63% in the im group (P less than 0.05 PCA vs. epidural and im).(ABSTRACT TRUNCATED AT 250 WORDS)     

Distribution of morphine and meperidine after intrathecal administration in rat and mouse

Morphine and meperidine distribution in the neuroaxis were studied in rats after intrathecal injection through catheters ending at the lumbar level. 14C-Morphine and 3H-meperidine were injected with pharmacologic doses of each drug. Radioactivity was measured in spinal cord segments at different times. At 14 min the segment with maximum morphine concentration (T11-12) contained 8.6 +/- 2.4 (mean +/- SD) pmol/mg, a value 215 times higher than would be observed if distribution in the body were homogeneous. The ratio between concentration in the most rostral segment (C3-4) and in the segment with maximal concentration was 0.21 +/- 0.10. At 14 min the segment with maximum meperidine concentration (T9-10) contained 161.4 +/- 33.9 pmol/mg wet tissue, a value 75 times higher than would be seen with even distribution in the body. The ratio (C3-4 vs. T9-10) was 0.10 +/- 0.04 at this time. The distribution of 14C-morphine in the whole central nervous system (CNS) was studied in mice by whole body autoradiography after intrathecal injections of 5 microliters at the L5-6 level. High levels of radioactivity were detected in the whole spinal cord and in brain regions close to the basal cisterns until 2 h after injection. At 4 h only the caudal part of the spinal cord had detectable levels of radioactivity. The per cent of the injected dose of morphine that was recovered from the spinal cord was 26.5 +/- 4.5 at 14 min, 19.9 +/- 8.8 at 44 min, and 4.5 +/- 1.7 at 179 min after injection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bupivacaine decreases epidural meperidine requirements after abdominal surgery

Purpose

The purpose of this study was to determine the optimal of three concentrations of bupivacaine (0.0%. 0.05%. 0.10%) to add to an epidural infusion of mependine (1 mg· ml¹) for postoperative pain relief.

Methods

In this prospective, double blind study. 60 patients undergoing abdominal surgery with general anaesthesia were randomized into three groups to receive for postoperative epidural analgesia: 1) 1 mg· ml¹ mependine (0% group). 2) bupivacaine 0.05% and 1 mgml mependine (0.05% group). 3) bupivacaine 0.10% and 1 mg· ml mependine (0 10% group). Postoperatively, the epidural infusion rate was titrated to produce adequate analgesia and pain was assessed at rest and on movement.

Results

There were no differences in demographic data, average pain scores or side effects among the three groups. However, there was improvement of pain relief at rest over time in the three groups (P< 0.05). Postoperative epidural analgesic infusion rates increased over time for the three groups (P< 0.05) and were lower in the 0.10% group (mean of 10.0 ml· hr^?1 than in the 0% group (mean of 12.6 ml·hr¹) (P< 0.05). More than half of the 0% group had serum mependine concentrations >400 g· L^?1 to control moderate postoperative pain.

Conclusion

Although analgesia was identical among groups, the lower serum concentrations of mependine support the addition of bupivacaine 0.10% to mependine when administered as a continuous infusion following abdominal surgery.     

Patient-controlled epidural analgesia after Caesarean section using meperidine

Purpose

To determine the effects of the addition of a background infusion to patient-controlled epidural analgesia (PCEA) using mependine for analgesia after Caesarean section.

Methods

In a randomized, double-blind study. we assigned 40 patients having elective Caesarean section to receive postoperative analgesia by patient-controlled epidural analgesia (PCEA) using mependme 5 mg · ml^?1 with (group Pi) or without (group Po) a background infusion of 10 mg · hr^?1. The PCEA settings (20 mg bolus. 10 mm lockout interval, four-hour maximum dose 150 mg) were otherwise identical. We compared pain at rest, pain on coughing, side effects, number of PCEA demands, drug consumption and patient satisfaction between groups in the first 24 hr after surgery.

Results

Total consumption of mependme was greater in group Pi (median 390 mg) than in group Po (median 240 mg; P = 0.017) and the number of PCEA demands was greater in group Po (median 12) than in group Pi (median 7.5;P = 0.012). Analgesia, side effects and patient satisfaction was similar between groups.

Conclusion

Addition of a background infusion to PCEA using mependine after Caesarean section has no clinical benefit.