Gunnar Nordberg

Antinociceptive and ventilatory effects of the morphine metabolites: morphine-6-glucuronide and morphine-3-glucuronide

Morphine and its major metabolites, morphine-3-glucuronide and morphine-6-glucuronide, were given intracerebroventricularly (i.c.v.) to rats. The antinociceptive effects were assessed in the tail-flick and hot-plate tests as well as the writhing test. Ventilatory effects were studied in halothane-anaesthetized rats. Based on calculated ED50 values, morphine-6-glucuronide was approximately 200 times more potent that morphine itself in the tail-flick and hot-plate tests. In the writhing test the difference in ED50 was approximately 9-fold. Morphine and morphine-6-glucuronide administered i.c.v. induced dose-related decreases in minute ventilation in the dose range 2.7 x 10(-9)-1.3 x 10(-7) mol. The dose-response curve for minute ventilation was steeper for morphine-6-glucuronide than for morphine. Morphine-6-glucuronide was approximately 10 times more potent than morphine in depressing minute ventilation. Morphine-6-glucuronide reduced both tidal volume and respiratory frequency, while morphine reduced only the tidal volume. Morphine-3-glucuronide, in contrast, increased both tidal volume and respiratory frequency, causing an increase in minute ventilation. Apnoea was elicited after the highest doses of morphine-6-glucuronide but not of morphine. The potency difference for depression of minute ventilation between morphine-6-glucuronide and morphine corresponded well to the difference in the writhing test but not to the potency difference in the tail-flick or hot-plate tests. The ventilatory depression induced by morphine and morphine-6-glucuronide was readily reversed by naloxone, while the hyperventilation caused by morphine-3-glucuronide was slightly potentiated by the opioid antagonist. Naloxone pretreatment completely blocked the ventilatory depression induced by morphine-6-glucuronide. These results show that the potent ventilatory depression induced by morphine-6-glucuronide is related to its antinociceptive effects in rats. Furthermore, the fact that morphine-3-glucuronide stimulated ventilation and that morphine had a more shallow ventilatory dose-response curve compared to morphine-6-glucuronide may indicate that morphine-3-glucuronide is a functional antagonist of the depressive effects of morphine and morphine-6-glucuronide on ventilation.

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 · kg−1 and 1.06 · 0.17 ml · kg−1, respectively; and the clearance from CSF was 2.81 · 0.41 μl · kg−1 · min−1 and 3.41 · 0.55 μl · kg−1 · 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.

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.

The analgesic efficacy and adverse effects of continuous epidural sufentanil and bupivacaine infusion after thoracotomy

We investigated analgesia and the adverse effects of epidural sufentanil infusion in a double-blind randomized study of 37 patients undergoing thoracic surgery. Sufentanil 1 micro gram/mL was administered at a thoracic (Ts, n = 12) or lumbar level (Ls, n = 11), or combined with bupivacaine 1 mg/mL at a thoracic level (Tsb, n = 14). Postoperatively, the epidural infusion rate was titrated (4-20 mL/h) according to the visual analog pain scale when assessed during function (VAS-F) or the occurrence of side effects. When epidural analgesia failed, nonsteroidal antiinflammatory drugs (NSAIDs) were given. VAS-F was lowest in the Tsb group (Tsb < Ts = Ls) despite its having both the lowest rate of epidural infusion (Tsb < Ts < Ls) and need of additional NSAIDs (Tsb < Ts = Ls). Sedation (Tsb < Ts < Ls) and hypercapnia (Tsb = Ts < Ls) occurred most frequently in the Ls group. Vital capacity (VC) was reduced in all groups by 43%-58% (Ls > Ts) and had recovered only partially at 24 h after discontinuation of the epidural infusion. The slopes of the ventilatory response (minute ventilation [VE], inspiratory flow, and mouth occlusion pressure at 0.1 s [P0.1]) to 7% CO2 decreased during treatment in Ls, Ts, and Tsb groups at the most by 73%, 55%, and 52% (not significant [NS] between groups), 59%, 45%, and 38% (NS between groups), and 81%, 43%, and 18% (Ls > Tsb), respectively. Twenty-four hours after discontinuation of the epidural infusion, there was a complete recovery of the VE, inspiratory flow, and P0.1 response to CO2 in the Tsb group only. The study shows that, after thoracotomy, epidural sufentanil analgesia is optimal when tailored to the site of nociceptive input and combined with bupivacaine. (Anesth Analg 1996;83:394-400)

The pharmacokinetics of continuous epidural sufentanil and bupivacaine infusion after thoracotomy

In a double-blind, randomized study in patients undergoing thoracic surgery the plasma and cerebrospinal fluid (CSF) pharmacokinetics of epidural sufentanil were studied by using radioimmunoassay analysis. Sufentanil was given as an infusion (1 micro gram/mL) at the lumbar (Ls; n = 11), or thoracic (Ts; n = 12) level, or epidural sufentanil combined with bupivacaine (1 mg/mL) at the thoracic level (Tsb; n = 14). Postoperatively, the infusion was adjusted to optimize analgesia. During the infusion, the sufentanil plasma concentrations were related to the rate of epidural infusion and unrelated both to the epidural infusion regimen and to the postoperative pain scores. The elimination half-life in plasma (mean +/- SEM) was 9.9 +/- 1.7 h (Ls), 8.6 +/- 0.7 h (Ts), and 11.7 +/- 2.2 h (Tsb). The distribution volume was 15.2 +/- 3.5 L/kg (Ls), 14.8 +/- 2.4 L/kg (Ts), and 12.9 +/- 1.2 L/kg (Tsb). Total sufentanil clearance was 17.8 +/- 1.4 and 16.9 +/- 2.0 mL centered dot kg-1 centered dot min-1 (Ls), 22.9 +/- 3.5 and 20.0 +/- 2.6 mL centered dot kg-1 centered dot min-1 (Ts), and 22.4 +/- 3.0 and 14.5 +/- 1.3 mL centered dot kg-1 centered dot min-1 (Tsb). The terminal elimination half-life of sufentanil in CSF was 7.2 +/- 0.6 h. During steady state the CSF concentrations were not homogeneously distributed and they were higher than those in plasma. These pharmacokinetic findings support the concept that epidural sufentanil analgesia is optimal when administered segmentally and tailored to the surgical incision. (Anesth Analg 1996;83:401-6)

The cerebrospinal fluid and plasma pharmacokinetics of sufentanil after thoracic or lumbar epidural administration.

The cerebrospinal fluid (CSF) and plasma pharmacokinetics of sufentanil were studied in 29 adult patients undergoing thoracotomy under general anesthesia.Sufentanil, 75 micro gram, diluted in 10 mL saline, was given preoperatively in either the lumbar or thoracic epidural space to 14 and 15 patients, respectively. Lumbar CSF and plasma were frequently sampled for 10 h and analyzed for sufentanil concentration by radioimmunoassay. In plasma, the area under the concentration curve (AUC) did not differ between the groups. The fraction of the lumbar epidural dose found in CSF was calculated to be 2.7%. The time to peak CSF sufentanil concentration differed (P < 0.01) after epidural administration in the lumbar (0.76 +/- 0.50 h) and thoracic (2.1 +/- 1.4 h) region. In the lumbar group, the AUC and Cmax values in CSF were 19 (P < 0.01) and 45 (P < 0.01) times higher than in plasma, and 4.7 (P < 0.01) and 8.2 (P < 0.001) times higher than in CSF in the thoracic group. The decline in sufentanil concentration was more rapid in CSF than plasma; in the lumbar group the CSF/plasma concentration-ratio was eight and five at 6 and 10 h, respectively, after sufentanil administration. This study shows that after epidural administration sufentanil concentrations are higher in CSF than in plasma, and are highly localized within CSF to the site of administration. (Anesth Analg 1995;80:724-9)

CSF and plasma morphine concentrations in cancer patients during chronic epidural morphine therapy and its relation to pain relief

&NA; Seventeen patients with advanced cancer pain, treated with chronic epidural morphine, were studied. Minimum plasma and CSF morphine concentrations (Cssmin) were determined at pharmacokinetic steady state. A linear relationship was found between epidural morphine dose and concentrations obtained in plasma (r = 0.92) as well as CSF (r = 0.90). The line for best fit was much steeper for CSF than for plasma. The CSF/plasma concentration gradient of morphine at Cssmin was 132 ± 31 (mean ± S.E.M.). Large interindividual variations of morphine concentrations in CSF were found. It is suggested that the variations are due to substantial differences in transdural morphine diffusion between individuals. No correlation was found between pain relief, evaluated with a visual analog scale, and CSF morphine concentrations at pharmacokinetic steady state, when calculated in 9 patients. Mean duration of treatment was 104 days (range 14–366) and the daily dose was increased from 18 ± 2 to 87 ± 31 mg/day (mean ± S.E.M.). A total of 39 epidural catheters were inserted in 14 patients. The catheters were patent for 2–223 days with a mean of 38 days. When re‐examined later during treatment, 2 out of 8 patients demonstrated decreased CSF morphine concentrations in spite of increased doses given. One patient with extremely high dose demand is reported on separately and data supporting the concept of a combined spinal and systemic brain morphine effect in such cases are presented. Side effects were not a major problem but the possibility of infectious complications should be considered during chronic epidural morphine therapy.

Opioid Receptors: Types, Distribution, and Pharmacological Profiles

Although the use of opium can be traced back to the ancient Sumerians [1] and the receptor theory of drug actions was proposed at the turn of the century [2], the actual postulation and demonstration of distinct receptor binding sites for morphine and other opiates was first made in 1973 through the work of Pert and Snyder [3], Simon et al. [4], and Terenius [5]. Several prior decades of studies of opiate pharmacology had outlined but not formulated the idea of specific binding sites. Such studies included, e.g., demonstration of rigid structural requirements for drug action, stereospecificity, and dose-dependent actions, as well as the existence of specific antagonists [6].

Evidence for a spinal antinociceptive effect of adenosine in the rat

R.W. Foote*, D. Rbmer and R. Achini*, Preclinical Research Department, Sandoz Ltd., CH 4002 Easel, Switzerland Aim of Investiqation: The medical need is high for a potent non-narcotic analgesic which lacks gastro-intestinal and liver toxicity. Compounds having a pharmacodynamic profile resembling the antipyretic-analgesics (lacking anti-inflammatory properties) were selected vith the intention of avoiding the side effects frequently found with non-steroidal anti-inflammatory drugs. Ue describe the preclinical results for a new antipyretic-analgesic FX 205-754 (FX). Methods: Acetylsalicylic acid (ASA), paracetamol (P, acetamenophen) and FX were tested in the !;rithing, pav pressure, arthritic pain and gout knee pain moclels and in y5ast-induced pyrexia as veil as the carrageenin-induced pav edema test. Acute hepatotoxicity was determined in tile mouse by measurement of plasma transaminases and toxicity to the gastric mucosa of rats was monitored. The ex vivo generation of prostanoids was measured from three tissues taken from rabbits which had received oral doses of the compounds. Results: FX vas several times mure potent in the rat as an antinociceptive agent, at least equally potent as an antipyretic, and caused no gastric lesions or increases in transaminases compared with ASA or P. FX had effects on the prostanoid systems which differed from both ASA and P. Conclusions: In animal experiments FX has been shovn to be a very well tolerated antipy,retic-analgesic. Its pharmacodynamic profile is clearly different from that of ASA and P.

CSF AND plasma morphine concentrations during chronic epidural therapy

Pharmacology,Sahlgrens University Hospital,S-413 45 Gijteborg Sweden. Aim of Investigation: Only limited information exists about morphine concetrations obtained during chronic spinal therapy. This study examines the CSF and plasma cont. in order to evaluate the dose-concentration relationship. Methodes: 21 cancer patients treated with intermittent doses of epidural morphine were examined. Duration ranged between 14-366 days. 33 samples were obtained at minimum steady state cont. ( Css min ) and analysed by gas chromatography with electron capture detection. Results: Plasma Css min were significantly related to the epidural dose (r=0.9 p<O.Ol). For CSF Css min, the degree of relationship was lower but still significant (r=0.58 p<O.Ol). Repeated CSF recordings will be presented from 11 patients. Conclusions: The plasma morphine cont. can be predicted from the epidural dose during chronic therapy.In contrast, the CSF cont. can not be predicted from the dose only. Other possible influences on the CSF concentration are discussed,based on X-ray pictures presented.