A retrospective study on the use of oral morphine in cancer pain

The authors report a retrospective study of 390 cancer pain patients tested with oral morphine during a four-month period. Initial pain scores were reduced to one half after one week of treatment and then maintained throughout the study period. Mean daily dosages of morphine were lower in those patients 65 years and older. No significant changes in performance in relation to therapy were noted except for an increase in hours of sleep. An accurate titration of dosage and continued control of side effects are the main requirements of this method of administration. The presence of side effects and the cause of interruption of treatment are reported.     

Comparison of circulatory and respiratory responses between supplementary epidural buprenorphine and eptazocine administration during and immediately after total intravenous anesthesia

Opioid supplements are often required in total intravenous anesthesia (TIVA). Most ϰ-opiate receptors are found in the spinal cord, wherea μ-opiate receptors are widespread throughout the brain and spinal cord. Buprenorphine has a strong μ-action with a minute ϰ-action, while eptazocine stimulates ϰ-receptors only. From these, epidural eptazocine is expected to exert strong spinal analgesia by ϰ-stimulation without μ-action, which produces circulatory and respiratory depression. Therefore, the clinical effects of epidural opioids on circulation, respiration, and analgesia were compared. Continuous epidural administration of eptazocine or buprenorphine was combined with TIVA in patients scheduled for elective abdominal surgery. Epidural opioid administration was continued throughout and for 72h after anesthesia. A significant analgesic effect (P<0.01) of epidural eptazocine without circulatory and respiratory depression was observed. With epidural buprenorphine, circulatory and respiratory depression during and immediately after anesthesia were significant (P<0.05). These results suggest that medullary μ-stimulation by an epidural opioid induces circulatory (hypervagotonicity and hypervagosensitivity) and respiratory depression, while ϰ-stimulation produces only minimal effects on circulatory and respiratory systems.     

胆囊收缩素－B受体拮抗剂的镇痛作用

用小鼠热水缩尾法研究了高选择性的ＣＣＫ－Ｂ受体拮抗剂ＰＤ１３４３０８的镇痛效应。ＰＤ１３４３０８在小鼠产生的镇痛有剂量依赖关系。阿片受体拮抗剂对抗其镇痛作用，表明阿片受体系统参与介导ＰＤ１３４３０８的镇痛。ＰＤ１３４３０８能加强吗啡的镇痛作用，但对α２受体激动剂可乐定的镇痛作用没有影响，表明ＣＣＫ－Ｂ受体拮抗剂对阿片受体系统作用有选择性。脑啡肽酶抑制剂ＳＣＨ３２６１５加强ＰＤ１３４３０８的镇痛作用，说明ＰＤ１３４３０８可能是通过增加内源性阿片物质产生镇痛作用的。另外，ＰＤ１３４３０８还参与吗啡镇痛耐受性的形成。     

ACEA-1328, AN NMDA RECEPTOR ANTAGONIST, INCREASES THE POTENCY OF MORPHINE AND U50,488H IN THE TAIL FLICK TEST IN MICE

The effect of 5-nitro-6,7-dimethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1328), a competitive and systemically bioavailable NMDA receptor/glycine site antagonist, was examined on opioid-induced antinociception in the tail flick test. Swiss Webster mice were injected with ACEA-1328 either alone or in combination with morphine or (±)-trans-U-50488 methanesulfonate (U50,488H), a μ- and a κ-opioid receptor agonist, respectively, and tested for antinociception. Systemic administration of ACEA-1328 alone increased the tail flick latencies with an ED₅₀of approximately 45 mg kg⁻¹. Concurrent administration of ACEA-1328 with morphine, or U50,488H, at doses that did not affect tail flick latencies, potentiated the antinociceptive effect of the opioid analgesics and vice versa. Naloxone, an opioid receptor antagonist, while not modifying the effect of ACEA-1328, did block the augmentation, suggesting that opioid receptors might be involved in the latter effect. 5-Aza-7-chloro-4-hydroxy-3-(m-phenoxyphenyl)quinoline-2(1H)-one (ACEA-0762), a selective NMDA receptor/glycine site antagonist, also showed enhancement of the antinociceptive effect of morphine and U50,488H. However, concurrent administration of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX), a selective non-NMDA receptor antagonist, with morphine did not alter the antinociceptive potency of the opioid analgesic. Overall, the data suggest that ACEA-1328 may increase the potency of the opioid analgesics by antagonising the glycine site associated with the NMDA receptor.     

The effect of age on the pharmacokinetics of the opioid antagonist nalmefene

1 The disposition of nalmefene was evaluated in young and elderly normal healthy volunteers. Subjects received either a single 1  mg ( n =18 young; n =11 elderly) or 2  mg ( n =8 young; n =15 elderly) intravenous bolus dose of nalmefene.
2 Following the administration of nalmefene, the initial plasma concentrations were significantly higher in elderly vs young subjects. The higher concentrations were the result of the 30 to 40% smaller central compartment apparent volume of distribution that was observed in the elderly subjects as compared with the young volunteers (2.8±1.1 vs 3.9±1.1  l  kg⁻¹ for 1  mg dose). The elderly volunteers also had a significantly shorter distributional half-life ( t1/2λ1 ) than young volunteers (0.7±0.7 vs 1.3±0.8  h for 1  mg dose). No significant differences between groups were observed for the elimination half-life, clearance or steady-state apparent volume of distribution.
3 Although transiently higher nalmefene plasma concentrations were observed in the elderly immediately following drug administration, there was no association between this observation and adverse events. We conclude that no dosage alteration is warranted in elderly patients.     

Interaction of Nucleoside Analogues with the Sodium–Nucleoside Transport System in Brush Border Membrane Vesicles from Human Kidney

The therapeutic efficacy of nucleosides and nucleoside analogues as antitumor, antiviral, antiparasitic, and antiarrhythmic agents has been well documented. Pharmacokinetic studies suggest that many of these compounds are actively transported in the kidney. The goal of this study was to determine if therapeutically relevant nucleosides or analogues interact with the recently characterized Na⁺-driven nucleoside transport system of the brush border membrane of the human kidney. Brush border membrane vesicles (BBMV) were prepared from human kidney by divalent cation precipitation and differential centrifugation. The initial Na⁺-driven ³H-uridine uptake into vesicles was determined by rapid filtration. The effect of several naturally occurring nucleosides (cytidine, thymidine, adenosine), a pyrimidine base (uracil), a nucleotide (UMP), and several synthetic nucleoside analogues [zidovudine (AZT), cytarabine (Ara-C), and dideoxycytidine (ddC)] on Na⁺–uridine transport was determined. At a concentration of 100 µM the naturally occurring nucleosides, uracil, and UMP significantly inhibited Na+-uridine transport, whereas the three synthetic nucleoside analogues did not. Adenosine competitively inhibited Na+-uridine uptake with a K _i of 26.4 µM (determined by constructing a Dixon plot). These data suggest that naturally occurring nucleosides are substrates of the Na⁺–nucleoside transport system in the renal brush border membrane, whereas synthetic nucleoside analogues with modifications on the ribose ring are not. The K _i of adenosine is higher than clinically observed concentrations and suggests that the system may play a physiologic role in the disposition of this nucleoside.     

Histamine turnover in the brain of morphine-dependent mice

Summary The turnover of brain histamine was examined in mice implanted subcutaneously with a morphine pellet (50 mg free base). The numbers of naloxone-precipitated jumpings and body shakes were maximum 2 and 3 days after implantation, respectively. The brain tele-methylhistamine level significantly increased (50% to 115%) during 12 h3 days after implantation of a morphine pellet, whereas the histamine level remained unchanged. The accumulation of tele-methylhistamine by pargyline treatment was significantly enhanced when pargyline was administered 12 h after implantation, suggesting an enhancement of histamine turnover. However, a similar degree of the tele-methylhistamine accumulation was induced by pargyline during 1–5 days after implantation, as compared with the accumulation in the control mice implanted with a placebo pellet. In mice undergoing morphine withdrawal by either the removal of morphine pellet or the treatment with naloxone 3 days after implantation, the degree of the pargyline-induced telemethylhistamine accumulation or the (S)--fluoromethylhistidine (-FMH)-induced histamine decrease was similar to that observed in the placebo pellet-control mice. The numbers of naloxone-precipitated jumpings and body shakes occurring in mice 3 days after implantation were not significantly affected by any of l-histidine, -FMH or metoprine. These results suggest that turnover of histamine in the brain is enhanced by acute morphine treatment and returns to the normal rate in the stage of chronic treatment and remains unchanged during the state of withdrawal. Send offprint requests to K. Saeki     

The death drive exemplified in a case of alcohol dependence

• ? When Freud first advanced the death drive it was considered a highly controversial theoretical idea. However, with the passage of time it has been slowly gaining support in certain psychoanalytical quarters.
• ? This paper aims to demonstrate the clinical usefulness of this theory in accordance with the Freudian and Kleinian model.
• ? Although the case history to be discussed is a severe case of alcohol dependence which had, previously, been unresponsive to treatment, many other maladies, both mental and physical, can be better understood in the context of the death drive being the principal motivating factor.

     

Opioid peptides selective for mu- and delta-opiate receptors reduce calcium-dependent action potential duration by increasing potassium conductance

We suggest that both mu- and delta-opiate receptors on dorsal root ganglion neuron somata are coupled to voltage- and/or calcium-dependent potassium channels since opioid peptide decreases of calcium-dependent action potential duration were: (1) not associated with a change of resting membrane potential or conductance; (2) accompanied by an increase in action potential after-hyperpolarization, and (3) blocked by intracellular injection of the potassium channel blocker cesium [18]. In contrast, norepinephrine [4] and cadmium [9], which have been reported to act on voltage-dependent calcium rather than potassium channels, shortened action potential duration and decreased after-hyperpolarization amplitude, an action not blocked by intracellular iontophoresis of cesium.