Portal vein thrombosis after laparoscopic colectomy: thrombolytic therapy via the superior mesenteric vein.

Portal vein thrombosis is a rare but well-reported complication after laparoscopic surgery. We present a case of portomesenteric venous thrombosis that occurred 8 days after a laparoscopic-assisted right hemicolectomy. Systemic anticoagulation failed to improve symptoms. The early postoperative state precluded the use of transarterial thrombolytic therapy. Transjugular intrahepatic catheter-directed infusion of urokinase into the superior mesenteric vein resulted in clearance of thrombus and resolution of symptoms. The published data on laparoscopy-induced splanchnic venous thrombosis and transjugular intrahepatic intramesenteric thrombolysis are discussed.

Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial.

This study was designed to assess the efficacy and safety of pregabalin-a novel alpha(2)-delta ligand with analgesic, anxiolytic, and anticonvulsant activity-for treating neuropathic pain in patients with post-herpetic neuralgia (PHN). Two hundred and thirty-eight patients were randomised into this multicentre, doubleblind, placebo-controlled trial to receive 150 (n=81), 300 mg/day (n=76) pregabalin, or placebo (n=81) for 8 weeks. Among the exclusion criteria was failure to respond to previous treatment for PHN with gabapentin at doses > or =1200 mg/day. Endpoint mean pain scores were significantly reduced in patients receiving 150 or 300 mg/day pregabalin compared with placebo. Efficacy was observed as early as week 1 and was maintained throughout the study. Significantly more patients in both pregabalin groups (150 mg, 26%; 300 mg, 28%) were responders (> or =50% decrease in mean pain score from baseline to endpoint) than in the placebo group (10%). Additionally, by week 1 and for the study's duration, 150 and 300 mg/day pregabalin significantly reduced weekly mean sleep interference scores. More pregabalin-treated patients than placebo-treated patients reported that they were 'much improved' or 'very much improved'. Health-related quality-of-life (HRQoL) measurements using the SF-36 Health Survey demonstrated improvement in the mental health domain for both pregabalin dosages, and bodily pain and vitality domains were improved in the 300 mg/day group. The most frequent adverse events were dizziness, somnolence, peripheral oedema, headache, and dry mouth. Pregabalin efficaciously treated the neuropathic pain of PHN. Additionally, pregabalin was associated with decreased sleep interference and significant improvements in HRQoL measures.

Management of chronic intractable angina - spinal opioids offer an alternative therapy.

The successful treatment of chronic intractable angina by spinally administered opioids via an Algomed drug delivery device (hereinafter called the pump) is reported in seven patients. All patients had at least two prior cardiac surgeries and the duration of minimally controlled chronic intractable angina varied from 5 to 19 years prior to spinally administered opioids. The duration of effective spinally administered analgesia to either the epidural (two cases) or intrathecal (five cases) spaces varied from 2 to 7 years. The opioid used was either morphine or fentanyl and the dose increase (either mg/year or microg/year, respectively) varied from 1.2 to 16. We suggest that bolus spinal morphine or fentanyl administered via the pump is a viable alternative for the effective control of angina when more established therapies have been found to provide insufficient pain relief.

Pharmacokinetics and pharmacodynamics of twenty-four-hourly Kapanol compared to twelve-hourly MS Contin in the treatment of severe cancer pain.

Twenty-four patients with severe pain related to cancer completed a randomised, double-blind, double-dummy, crossover study examining morphine pharmacokinetics and pharmacodynamics when the same 24-h morphine dose was administered using two modified release oral morphine formulations; either one dose of Kapanol (a new sustained release polymer coated pellet formulation administered in capsule form, Glaxo Wellcome group of companies) per 24 h, or MS Contin (Purdue Frederick Company, Connecticut, USA) administered at 12-h intervals. The morphine dose was optimised for each patient using an immediate release morphine solution in the lead-in period to provide the most favourable balance between pain relief and side-effects. Patients were then randomly allocated to receive their 24-h morphine dose as either Kapanol or MS Contin in period 1. Patients recorded daily measures of pain relief and morphine related side-effects (morphine pharmacodynamics) in a diary. Patients were admitted to the Pain Management Unit on the morning of day 7 (+/- 1 day) and frequent blood samples were collected for 24 h following the 10:00 h dose to fully characterise the pharmacokinetic profile for morphine and its metabolites at steady state. Morphine pharmacodynamics and the amount and timing of rescue medication (dextromoramide) were also recorded during this time. Period 2, which commenced at 10:00 h on day 8, was identical to period 1 except the modified release formulations were changed. The pharmacokinetic profile of Kapanol exhibited a significantly higher Cmin (minimum plasma morphine concentration), less fluctuation in plasma morphine concentration throughout the dosing interval, a longer Tmax (time associated with the maximum morphine concentration) and a greater time that the plasma morphine concentration was > or = 75% of Cmax (an index of the control the formulation exerts over the morphine release rate) compared to that of MS Contin. Some of these pharmacokinetic differences (e.g., Cmin and fluctuation in plasma morphine concentration) were surprising given that the dosing interval for Kapanol (24 h) was double that of MS Contin (12 h). There was no significant difference between the Kapanol and MS Contin treatment phases in any of the pharmacodynamic parameters, morphine related side-effects, the percentage of patients taking rescue medication as well as the amount or time to the first dose of rescue analgesia on day 7 in periods 1 and 2, patient or investigator assessments of global efficacy at the end of periods 1 and 2, or patient treatment preference at the end of the study. Once a day Kapanol provided the same degree of pain relief and morphine related side-effects as 12-h MS Contin.

Ketamine as an adjunct to morphine in the treatment of pain.

A double-blind multidose trial of the addition of ketamine (0-40 mg, i.m., 8 times per day) to intramuscular morphine therapy was undertaken in a 61-year-old man with chronic back pain related to osteoporosis who had received inadequate pain relief from anterior interbody fusion, dorsal column stimulation and morphine alone. The patient reported only mild side effects. Nausea, tiredness and well-being were not significantly influenced by the ketamine dose level. Visual analogue pain scores prior to each dose were not associated with the ketamine dose level, but pain scores 30 min after doses were significantly reduced in a dose-related manner. In addition, the amount of morphine used by the patient was significantly reduced as the ketamine dose increased. This patient experienced substantial benefit from the addition of ketamine to intramuscular morphine therapy.

Chronopharmacokinetic variability in plasma morphine concentrations following oral doses of morphine solution.

Twenty-six patients with severe pain associated with cancer were entered into a study where they were required to take morphine mixture for 7 days. Prior to this, their morphine dose had been optimised to provide the most favourable balance between pain relief and side effects. After 6 days of taking their optimised morphine dose at 4-hourly intervals, the patients were admitted to the Pain Management Unit such that the doses from 18:00 h on day 6 were taken under direct nursing supervision. Frequent blood samples were collected after the 10:00 h (dose 1), 14:00 h (dose 2) and 18:00 h (dose 3) on day 7. There was a significant difference between the 3 doses with respect to Cmax values for morphine with dose 3 > dose 1 > dose 2. Further, there was considerable variability in the percentage change of either dose 1 or dose 3 Cmax values relative to dose 2. The Cmax values of the active metabolite morphine-6-glucuronide (M6G), measured in 6 of the patients, for the 3 dosing intervals followed a similar trend to the parent drug, but only doses 1 and 2 differed significantly. Similar but less pronounced changes were observed in the area-under-curve parameter calculated for both morphine and M6G during the 3 dosing intervals. There were no significant differences in the Cmin or Tmax parameters for either morphine or M6G between the 3 dosing intervals. These results suggest intra-individual variation in the absorption of morphine or changes in the volume of distribution during the day.(ABSTRACT TRUNCATED AT 250 WORDS)

CT contrast evidence of injectate encapsulation after long-term epidural administration.

This case report provides radiographic evidence (CT scan with Iopamidol) to support the development of epidural injectate encapsulation in response to long-term epidural morphine injections via an implanted polyurethane catheter. The patient complained of intense low interscapular pain when the catheter was used for administration of epidural morphine for control of angina. The patient had previously enjoyed 3 months of excellent pain relief following the initiation of epidural morphine via an implanted portal device. The CT scan, with contrast dye injected via the epidural catheter, clearly showed loculation of the injectate and associated indentation of the spinal cord. It is significant to note that the dye in the encapsulated sheath occupied a significant proportion of the spinal canal extending from T7 to T9.

Comparison of intermittent bolus with continuous infusion of epidural morphine in the treatment of severe cancer pain.

Twenty-eight patients with severe pain due to cancer, who could no longer obtain acceptable pain relief from optimised doses of oral opioids, were entered into a study which compared pain relief, satisfaction with pain therapy and estimates of neuropsychological functioning during treatment with spinally administered (i.e., epidural and intrathecal) morphine as either repeated bolus doses or as a continuous infusion. These measures of efficacy and side effects were repeated every 2 weeks until either the patient died (82% of patients), withdrew from the study or were no longer able to complete the tests due to deterioration of their condition. The mean (range) duration of treatment was 169 (6-537) days for those patients receiving continuous infusion and 140 (28-378) days for those patients receiving repeated bolus doses. There was no significant difference in visual analogue pain scores, pain relief scores and satisfaction scores between the bolus and infusion groups. Furthermore, low pain scores and high pain relief scores indicated that both treatment modalities provided effective pain control. Similarly, there was no significant difference between the two groups in the various tests used to assess depression or neuropsychological function (i.e., memory, vigilance, attention and processing). There was a significantly greater degree of dose escalation in patients receiving continuous infusion compared to patients receiving repeated bolus doses. For 6 patients in the infusion group the catheter was sited in the intrathecal space, as the dose requirements by the epidural route exceeded the delivery capacity of the pump. For 4 patients in the bolus group the catheter was similarly sited, due to pain on injection and leakage/blockage.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term spinal administration of morphine in cancer and non-cancer pain: a retrospective study.

Records of 313 patients who had been treated with spinal morphine via an implanted Port-A-Cath were reviewed. In 284 cases the Port-A-Cath was implanted for epidural delivery of morphine in patients with cancer-related pain. These patients were treated for a mean of 96 (range 1-1215) days. There was a wide variation in dose requirements, minimum daily dose ranging from 0.5 to 200 mg and maximum daily dose from 1 to 3072 mg. However, there was no clear trend to increasing dose as period of epidural morphine administration increased. The most frequent complications were pain on injection (12.0% incidence), occlusion of the portal system (10.9%), infection (8.1%) and leakage of administered morphine such that it did not all reach the epidural space (2.1%). In all but 1 case infections were limited to the area around the portal or along the catheter track. All infections resolved without sequelae following removal of the portal and/or administration of antibiotics. In 17 patients Port-A-Caths were implanted for the intrathecal delivery of morphine to control cancer-related pain. These patients also exhibited wide variations in morphine dose requirements. Port-A-Caths were also implanted for delivery of spinal morphine in 12 patients with chronic pain which was not related to cancer and which failed to respond to other therapies. These patients were treated for a mean of 155 (range 2-575) days. Port-A-Caths were removed from 7 of these patients, primarily due to infection (2 cases) and inadequate pain relief and pain on injection (2 cases).

Influence of polarity on dose-response relationships of intrathecal opioids in rats.

Dose-response curves were constructed for intrathecal morphine (M), oxymorphone (OM), hydromorphone (HM), diamorphine (DM), 14-hydroxydihydromorphine (OHM), oxycodone (OC), hydrocodone (HC) and fentanyl (F). Intrathecal catheters were placed in 69 rats under halothane/N2O anaesthesia. After recovery, baseline hot plate and tail flick latencies were measured, and a dose of opioid was given. Hot plate and tail flick latencies were assessed at 5, 15, 30, 60, 90, 120 min and then hourly until they returned to within 25% of baseline. Response latencies were converted to per cent of maximum possible effect (% MPE) and the area under the % MPE X time curve was taken as the response. This measure includes information about both potency and duration of action. Each rat received 3 opioids and saline at intervals of 2-3 days. On a fifth occasion, the animal's first treatment was repeated. Each opioid was studied over an 8-fold dose range. Results of both hot plate and tail flick were best described by a model including log(dose), a component due to development of tolerance over the 5 experimental days, and an among-rat variation term. In the hot plate test, doses equieffective in producing a response (AUC) over the dose range studied were in the order OHM less than OM less than HM less than M less than F less than DM less than HC less than OC. Slopes of the log(dose)-response curves were similar for all drugs except OHM, which had a steeper slope. A model is proposed in which hot plate and tail flick latencies are prolonged while CSF concentrations of a drug are above its minimum effective concentration, and drug is cleared from the CSF by a first-order process, possibly uptake into the spinal cord and removal via the blood. This model predicts that log(dose)-response curves will be linear, as was observed, with slopes inversely proportional to the rate constant for clearance from CSF. According to this model the steeper slope of the OHM log(dose)-response may be interpreted as indicating slower clearance from CSF. OHM has the lowest octanol/pH 7.4 buffer distribution coefficient (0.34) of all opioids studied, possibly leading to a lower rate of uptake into the spinal cord.

The efficacy of transdermal fentanyl in the treatment of postoperative pain: a double-blind comparison of fentanyl and placebo systems.

Forty consenting patients scheduled for abdominal surgery were entered into a double-blind comparison of the efficacy of transdermal fentanyl (TTS-fentanyl) and placebo (TTS-placebo) in the treatment of postoperative pain. All patients were allowed supplementary pethidine (25-50 mg) if pain relief was inadequate provided that their respiratory rate was greater than 10 breaths/min and there was no pronounced CNS depression. Visual analogue pain scores (VAPS), sedation rating scores (SRS), blood samples for the determination of fentanyl concentration, blood pressure, pulse and respiratory rate were determined hourly for 48 h from the time of TTS system application. The first lot of TTS systems were removed after 24 h and a second lot were applied which remained in situ for a further 24 h. There was no significant difference between the patients in the TTS-fentanyl and TTS-placebo groups in the VAPS throughout the 0-12, 12-24, 24-36 and 36-48 h periods suggesting that the quality of pain relief was similar between the 2 groups. However, significantly less supplementary pethidine was administered to the TTS-fentanyl group in the 12-24, 24-36 and 36-48 h periods. In contrast, the amount of supplementary pethidine administered in the 0-12 h period was similar in both groups which was consistent with the long delay time (mean +/- S.D. value of 16.6 +/- 10 h) before clinically effective concentrations of fentanyl were obtained from the systems. The profile of side effects was similar in the 2 groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of fentanyl in lumbar and cervical CSF following lumbar epidural and intravenous administration.

Fentanyl (1 microgram/kg body weight) was administered intravenously and via a lumbar epidural catheter (in random order) on 2 separate occasions to 6 patients with chronic pain associated with non-terminal disease states. Frequent blood samples were collected from an indwelling intravenous catheter and CSF samples were collected via spinal needles inserted in the cervical (C7-T1 interspace) and lumbar (L3.4 interspace) regions at 0, 5, 10, 20, 30 and 45 min after fentanyl administration. The concentration of fentanyl in blood and CSF samples were quantified by a sensitive and selective gas-liquid chromatography assay. Visual analogue pain scores (VAPS) were recorded every 5 min for the first hour. Coded syringes (one containing the appropriate fentanyl dose while the other contained an equivalent volume of saline) allowed the investigator administering the fentanyl and assessing VAPS to remain blinded as to which route of administration actually contained the fentanyl. There was minimal vascular uptake of fentanyl following epidural administration. Similarly, the permeation of fentanyl into cervical and lumbar CSF following intravenous administration was minimal and erratic such that only 4 of the 60 CSF samples had detectable fentanyl concentrations. In contrast, there was a rapid penetration of fentanyl across the dura mater following lumbar epidural administration. There was significantly fentanyl in lumbar CSF samples by 10 min in 5 patients, and by 20 min in all 6 patients. The mean maximum lumbar CSF concentration was 19.1 ng/ml, while the time associated with these maximum concentrations was 22.5 min. The mean maximum cervical CSF fentanyl concentrations were 10% of the lumbar CSF concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

The transdermal administration of fentanyl in the treatment of postoperative pain: pharmacokinetics and pharmacodynamic effects.

A transdermal formulation of fentanyl (TTS-fentanyl, Alza Corp., Palo Alto, CA) was evaluated in 13 surgical patients after an abdominal operation. An intraoperative dose of fentanyl (100-200 micrograms i.v.) was administered at the same time as the TTS-fentanyl systems (50-125 micrograms/h) were applied to the antero-lateral chest wall. The TTS-fentanyl systems remained in situ for 24 h and were then removed and a second lot of systems were applied to the contra-lateral chest wall. There was a mean (S.D.) delay time of 12.7 (9.6) h before minimum effective blood fentanyl concentrations (MEC) were obtained from the systems and pseudo-steady state was reached between 36 and 48 h. There was a decay time of 16.1 (7.1) h after the systems were removed for the blood fentanyl concentration to decrease to less than the mean MEC for the control of postoperative pain. There was marked variability between patients in the actual hourly fentanyl dose rate determined from the residual amount of fentanyl remaining in the system and the duration of application. Significantly more supplementary pethidine was administered for inadequate postoperative analgesia between 0 and 12 h compared to the 12-24, 24-36 and 36-48 h periods; this was consistent with the observed delay time. Three patients required a reduction in the hourly fentanyl dose rate because of bradypnoea while 1 patient required an increase in dose because of inadequate pain relief. Nausea was the most frequently reported side effect (85% of patients) while bradypnoea, drowsiness, unpleasant dreams and headache were also reported. These effects were due to the combined effects of a sustained blood fentanyl concentration and the intermittent supplementary pethidine doses. Side effects due to the topical formulation were transient and included erythema (8 patients) and a minor rash (2 patients) in the area occluded by the systems. The TTS-fentanyl systems provided a significant contribution to postoperative pain control but, at the TTS dose rates used, supplementary doses of pethidine were required by all patients probably to control 'incident' pain.

Estimation of methadone clearance: application in the management of cancer pain.

The long half-life and wide inter-patient variability in clearance of methadone make this drug difficult to use optimally. If a patient's methadone clearance is known, however, dose regimens can be devised to maintain any desired blood concentration and hence, since the effect of methadone is related to its concentration in the blood, pain relief. We investigated methods for determining methadone clearance. In 25 patients, clearance was estimated by monitoring blood methadone concentrations following an intravenous infusion. Estimates of clearance adequate for clinical purposes could be obtained by assaying only 10-12 blood samples collected over 30 h following the infusion. The blood sampling schedules were such that it was not necessary to collect samples during the night, so the procedure could be done on an outpatient basis. An advantage of this procedure is that it also allows estimation of the blood methadone concentration required to relieve pain. We also conducted a retrospective study of data from 185 patients whose methadone clearance we had determined, to identify factors which may give rise to the large inter-patient variation in clearance. Clearance tended to be high in patients taking phenytoin, spironolactone, verapamil or oestrogens, and low in patients taking amitriptyline. Patients with malignant disease as opposed to chronic benign pain, and patients 65 years of age or older, tended to have low clearance. Clearance was positively associated with haematocrit. An equation was constructed allowing methadone clearance to be predicted from knowledge of these factors. The predicted clearance, however, showed only a moderately strong correlation with measured clearance (r = 0.75), indicating that factors not investigated also had a major influence on methadone clearance.

The influence of drug polarity on the absorption of opioid drugs into CSF and subsequent cephalad migration following lumbar epidural administration: application to morphine and pethidine.

This study examines the influence of drug polarity on the rate and extent of drug absorption into cerebrospinal fluid (CSF) following lumbar epidural administration. Twelve patients with pain secondary to cancer were simultaneously administered both morphine (10 mg) and pethidine (50 mg) in 10 ml of normal saline via an epidural catheter inserted in the lumbar region (usually L2,3) and attached to a subcutaneously implanted portal reservoir. Frequent blood samples were collected to characterise the vascular uptake of both opioids. In addition, a single CSF sample was collected in each patient from the C7-T1 interspace at one of the following times: 10, 30, 60, 120, 180 and 240 min. There was a rapid vascular uptake of morphine from the epidural space with a mean (+/- S.D.) peak concentration of 173 +/- 80 ng/ml (range 52-345 ng/ml) and a time-to-peak concentration of 8 +/- 6 min (range 2-17 min). In contrast, the vascular uptake of pethidine was more variable with a mean (+/- S.D.) concentration of 274 +/- 294 ng/ml (range 80-1113 ng/ml) and the time-to-peak concentration was 21 +/- 26 min (range 2-75 min). There was a rapid absorption of pethidine across the dura mater into the CSF with peak CSF concentrations between 1400 and 1650 ng/ml occurring between 10 and 60 min in samples collected cephalad (C7-T1 interspace) from the administration point in the lumbar region. However, the peak morphine concentration in CSF was delayed relative to the pethidine peak and occurred at 120 min.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparative study of the efficacy and pharmacokinetics of oral methadone and morphine in the treatment of severe pain in patients with cancer.

Eighteen patients suffering from cancer were entered into a study of the pharmacokinetics and efficacy of methadone and morphine in pain control. All patients had both clinical and radiological evidence of metastatic spread of their cancer and there were no significant differences in age, weight and sites of the primary cancer between the methadone (n = 9) and morphine (n = 9) groups. Blood opioid concentration, visual analogue pain scores (VAPS) and end-tidal percent carbon dioxide were measured before and after both an intravenous and oral dose of either methadone or morphine. Terminal half-lives (mean +/- S.D.) were 30.4 +/- 16.3 h and 2.7 +/- 1.2 h respectively for methadone and morphine while the clearance values (mean +/- S.D.) were 0.19 +/- 0.13 l/min and 1.16 +/- 0.47 l/min. The long half-life of methadone was associated with prolonged pain relief. However, the large variation in the half-life of methadone necessitated careful adjustment of the dosing interval in individual patients. There were pronounced differences in oral bioavailability between the two opioids: methadone, 79 +/- 11.7%, compared to morphine, 26 +/- 13% (mean +/- S.D.). Of greater clinical significance was the variability in these bioavailability estimates with a coefficient of variation of 15% for methadone compared to 50% for morphine. The combined effects of low and variable oral bioavailability for morphine may result in sub-therapeutic doses being administered as practitioners may be inhibited by the size of the effective oral morphine dose and may be confused by the variability in this dose compared to intramuscular doses. The initial oral dose of morphine varied from 15 mg 4 hourly to 150 mg 3 hourly, while the initial dose for methadone varied from 15 mg on alternate nights to 20 mg twice daily. There was no rapid escalation of daily opioid dose for either methadone or morphine when adequate pain control was provided rapidly at the start of treatment by the technique described in this study.

A controlled study of a serotonin reuptake blocker, zimelidine, in the treatment of chronic pain.

Zimelidine inhibits the central neuronal reuptake of serotonin and has undergone clinical evaluation as an antidepressant. Twenty patients with chronic pain of non-malignant origin (mean duration 15.8 years) were entered into a double blind cross-over study of the analgesic efficacy of zimelidine and placebo. The duration of each treatment phase was 6 weeks and there was a comprehensive assessment of each patient prior to the commencement and at the completion of the study, during a brief period of hospitalisation. Zimelidine was superior (P less than 0.05) to placebo with respect to pain relief based on a global assessment (by the clinical investigators) performed at the completion of each treatment phase. However, there was no significant difference in analgesic efficacy between the zimelidine and placebo treatment phases based on the following criteria: (a) changes in the minimum effective blood concentration of pethidine necessary to provide pain relief in each patient, measured during a pethidine infusion of 1.67 mg/min for 60 min; (b) changes in pain scores estimated by patients using the visual analogue pain scale (VAPS); (c) changes in patients' estimates of pain intensity associated with various daily activities. Significant pain relief was apparent within 2-3 days in those patients who had a beneficial effect, which contrasts with the documented 3-4 weeks for maximal antidepressant effects. The results of this study suggest that serotonin reuptake blockers do not provide consistent pain relief in patients with chronic pain, but may contribute an analgesic effect in the treatment of some patients.

Cephalad migration of morphine in CSF following lumbar epidural administration in patients with cancer pain.

This study examines the cephalad migration of morphine in CSF following lumbar epidural administration in cancer patients with pain. Fourteen cancer patients were administered 10 mg of morphine in 10 ml of normal saline via an epidural catheter inserted in the lumbar region (usually L2.3) and attached to a subcutaneously implanted portal for drug administration. There was a rapid vascular uptake of morphine from the epidural space with a mean (+/- S.D.) peak blood concentration of 110 +/- 32 ng/ml (range 76-182 ng/ml and the mean time associated with this peak blood concentration was 5.1 +/- 2.3 min (range 2-10 min). A cervical CSF sample was obtained from the C7-T1 interspace in each patient at one of the following times from the completion of the epidural morphine dose: 10, 30, 60, 120, 180, 240 or 360 min. There was a delay of at least 60 min before morphine was detected in significant concentrations (approximately 300 ng/ml) in the cervical CSF samples and peak CSF concentrations occurred after approximately 3 h. The results of this study are compatable with the hypothesis that the delayed onset of respiratory depression sometimes observed following epidural morphine in opioid naive patients results from significant amounts of morphine reaching the respiratory centre in the brain-stem as a consequence of passive CSF flow in a rostral direction from the lumbar region.