Acute effects of vitamin B6 and fixed combinations of vitamin B1, B6, B12 on nociceptive activity evoked in the rat thalamus: Dose-response relationship and combinations with morphine and paracetamol

Summary Nociceptive activity was elicited in neurones of the thalamus by supramaximal electrical stimulation of afferent C fibres in the sural nerve of rats under urethane anesthesia. The fixed combination of vitamin B₁, B₆, B₁₂ (Neurobion^®) as well as of vitamin B₆ administered by i.p. injection dose-dependently reduced the evoked nociceptive activity. The ED₅₀ of Neurobion^® is 4.6 ml/kg (at 100 min after injection) and that of vitamin B₆ is 189mg/kg (at 90 min after injection). The minimum effective doses of Neurobion^® and vitamin B₆ are 0.5 ml/kg and 40 mg/kg, respectively. When Neurobion^® or vitamin B₆ were given at their minimum effective doses, and the minimum effective doses of morphine (0.025 mg/kg) or paracetamol (5 mg/kg) were injected i.v. 80 min later, i.e., when the maximum effect of higher doses of Neurobion^® or vitamin B₆was about to develop, no supraadditive effect developed. It is concluded that the antinociceptive effect caused by a single injection of Neurobion^® is largely due to vitamin B₆. Vitamin B₁₂ may contribute to this effect, whereas vitamin B₁ alone exhibited only a slight effect on nociception. Moreover, it appears that Neurobion^® produces its antinociceptive effect after a single injection and after repeated administration during several days by different mechanisms so that the effect of analgesic agents is not enhanced following a single injection of Neurobion^® but may be enhanced after repeated administration of the compound.     

Report of the symposium

Summary The past decades have seen considerable shifts of emphasis in surgical care. The recognition that pus was not laudable, was followed by a realisation that not all complications were inevitable and that prophylaxis could effectively reduce the incidence of most common problems in the post-operative period. As anaesthesia has become safer, it has been possible to embark on more intricate and prolonged procedures and for sufficient time to be available to ensure adequate intraoperative care.These two phenomena have firstly increased the complexity of management in the post-operative period, and have brought this aspect of surgical care more obviously to the limelight. However, many separate disciplines are involved in the care of the patient post-operatively, and the Symposium was organised¹ to bring the different groups together to identify the areas of recent development in the different specialities and to integrate the overall care of the individual patient.Abbreviations ARDS adult respiratory distress syndrome - DIC disseminated intravascular clotting     

Intra-articular morphine versus bupivacaine for postoperative analgesia following knee arthroscopy

In a prospective, double blind, randomized study, 30 ASA I patients were allocated to three groups depending on the drug injected intra-articularly, in an attempt to establish the best postoperative analgesic protocol following knee arthroscopy. Group 1 received 3 mg of preservative-free morphine in 25 ml saline; group 2, 5 mg of preservative-free morphine in 25 ml saline; and group 3, 25 ml 0.25% bupivacaine. The degree of postoperative pain was evaluated by visual analogue scale and the need for additional analgesics at 1, 2, 3, 8 and 24 h. We conclude that bupivacaine 0.25% provides analgesia of early onset and of short duration. While 3 mg-preservative free morphine provides moderate postoperative analgesia with peak effect during the eighth postoperative hour, 5 mg preservative-free morphine provides effective and long lasting (more than 24 h) pain relief. No side effects were noted.     

Tourniquet inflation after intra-articular morphine and bupivacaine administration following knee arthroscopy

We performed a randomized doubled-blind study to evaluate whether there was a benefit in delay in tourniquet deflation with intra-articular administration of morphine and bupivacaine following operative arthroscopic surgery. In 34 patients the tourniquet was deflated immediately and in 38 patients the tourniquet remained inflated for 10 min following injection. The analgesic efficacy was assessed using pain scores and the amount of supplementary analgesia required. The results demonstrate no benefit in delay in tourniquet deflation.     

Agonistic behaviour in rats: evidence for non-involvement of opioid mechanisms

It has recently been proposed that a stress-activated, endogenous analgesia mechanism would be adaptive in situations in which pain perception might otherwise disrupt effective behavioural performance. In a semi-natural test situation, the current study examined two predictions arising from this hypothesis: (1) in a manner analogous to other stressors, agonistic experience should produce analgesia and, if naloxone-sensitive opioid mechanisms are implicated, then (2) pretreatment with naloxone should block the development of this response and alter the displayed behaviour patterns. Neither prediction was substantiated by the data. Experience of an agonistic encounter failed to produce analgesia in either resident or intruder animals. Furthermore, naloxone hydrochloride (1-25 mg/kg) was also without effect on patterns of offense or defense. Data are discussed in relation to the critical nature of the stimulus factors involved in the activation of endogenous analgesic mechanisms and the postulated involvement of such mechanisms in biologically-adaptive behaviours.     

Naloxone injections into the periaqueductal grey area and arcuate nucleus block analgesia in defeated mice

In a situation of social conflict, mice that are defeated by an opponent exhibit a marked analgesia. Microinjections of naloxone (1 or 10 g) into the periaqueductal grey area (PAG) or into the region of the arcuate nucleus prior to the defeat prevented the emergence of analgesia. Microinjections of morphine (5 g) into these sites had previously been shown to produce profound analgesia. Mice whose adrenals were removed rapidly developed analgesia when attacked by a stimulus animal. Injection of naloxone into PAG also antagonized defeat-induced analgesia in adrenalectomized mice. These observations indicate that sites and processes in the brain rather than in the periphery are responsible for the development of analgesia in mice that are subjected to social defeat.     

Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing

Spinopetal pathways may be activated by a variety of brainstem manipulations including microinjections of morphine which are known to modulate spinal nociceptive processing. Based on the ability of these manipulations to release spinal noradrenalin; the ability to reverse the antinociceptive effects by intrathecal adrenergic antagonists and the fact that intrathecal injections of noradrenalin mimic the antinociceptive effect, it appears that the descending modulation may be mediated by descending noradrenergic systems. Examination of the spinal receptor systems with intrathecally administered agents indicates that spinal alpha, but not beta adrenergic receptor agonists produce a powerful analgesia as measured on a variety of reflex and operant measures in mouse, rat, cat, primate and man. On the basis of agonist and antagonist structure-activity relationships it appears that a significant effect can be produced in the absence of any detectable effect on motor function by the occupation of spinal alpha 2 receptors. Distinguishable alpha 1 receptors also appear "analgetically-coupled," but their effects are uniformly contaminated by signs of cutaneous hyperreflexia at doses required to produce analgesia. The ordering of potency with which intrathecal adrenergic antagonists reverse the effects of intrathecal noradrenalin is indistinguishable from that of the reversal by these intrathecal agents of the antinociceptive effects evoked by brainstem morphine. This suggests that the population of spinal receptors acted upon by exogenously administered adrenergic agonists and endogenously released noradrenaline have indistinguishable characteristics.     

Benzodiazepine ligands,nociception and ‘defeat’ analgesia in male mice

Recent studies have indicated that defeat experience induces acute non-opioid analgesia in intruder mice. To investigate the potential involvement of benzodiazepine receptors in this biologically-relevant form of environmentally-induced antinociception, we initially assessed the effects of some benzodiazepine ligands on basal nociception (tail-flick assay). Chlordiazepoxide (5–30 mg/kg), midazolam (0.625–5 mg/kg), diazepam (0.5–4 mg/kg), Ro15-1788 (5–80 mg/kg) and CGS8216 (5 mg/kg) were found to be ineffective in altering basal nociception. However, higher doses of CGS8216 (10–20 mg/kg) induced significant analgesia, an effect also observed with the -carboline derivatives FG7142 (5–20 mg/kg) and DMCM (1–2 mg/kg). Time-course analyses revealed that the onset of CGS8216 analgesia was slower than for FG7142 and DMCM, but that all three drugs produced long-lasting elevations in tailflick latencies. The analgesic effects of FG7142 and DMCM were completely reversed by Ro15-1788 (20 mg/kg) and by chlordiazepoxide (20 mg/kg), suggesting mediation by benzodiazepine receptor mechanisms. Although CGS8216 analgesia was also reversed by Ro15-1788, it was unaffected by chlordiazepoxide; however, diazepam (5 mg/kg) did significantly attenuate the reaction. Further studies indicated that the antinociceptive consequences of defeat experience were dose-dependently blocked by Ro15-1788 (10–40 mg/kg) and by diazepam (0.5–2 mg/kg). Surprisingly, however, neither chlordiazepoxide (5–20 mg/kg) nor midazolam (1.25–2.5 mg/kg) blocked defeat analgesia under present test conditions. Although several issues remain unresolved, present findings would not be inconsistent with the proposal that stimuli associated with the acute stress of defeat experience release an endogenous ligand which acts in an inverse agonist-like manner at benzodiazepine sites.     

Species differences in the relative analgesic potencies of some classical opiates and opioid peptides

The analgesic ED₅₀ values of some classical morphine congeners (morphine, methadone, fentanyl, azidomorphine) in the rat and mouse tail-flick tests were found to be similar. However, several synthetic derivatives of the natural enkephalins were more potent in mice than in rats. (These analogs contain d-amino acid in position 2 and d- or l-sulfonic (or phosphonic) acid residue in position 5). -Endorpin, d-Met², Pro⁵-enkephalinamide and two partial agonists showed intermediate interspecies relative potencies. According to the data obtained, similar opiate receptors might mediate the analgesic action of classical opiates in rats and in mice. However, the opiate receptors responsible for the antinociceptive effects of the above mentioned enkephalin analogues must be dissimilar in the two species examined. The results are discussed in terms of the role of - and -receptors in mediation of the analgesic effect induced by different types of opioids.     

2021年ACOG关于产后阶梯式多模式药物镇痛的建议及要点解读

产后疼痛是困扰产妇的常见问题,如治疗不当可能会导致阿片类药物滥用、产后抑郁和疼痛长期存在等不良后果。因此,美国妇产科医师学会（American College of Obstetricians and Gynecologists,ACOG）于2021年9月提出了针对产后疼痛的临床共识,专门对产后疼痛的一般管理、阴道分娩、剖宫产术后、母乳喂养时及出院后疼痛的处置给出了治疗建议与指导,强调了阶梯式多模式药物镇痛方法与个体化用药原则。推荐临床用药可遵循“非阿片类镇痛药（如对乙酰氨基酚和非甾体抗炎药）—弱阿片类药物—强阿片类药物（必要时）”阶梯式给药原则,并可合理联合用药。对此进行简要介绍与要点解读。