Michael J. Cousins

Variables of patient‐controlled analgesia 1. bolus size

The efficacy of a range of demand doses of morphine for patient‐controlled analgesia was studied. Patients who self–administered the smallest dose (0.5 mg) were frequently unable to achieve good pain control; patients who received the largest dose (2 mg) had a high incidence of ventilatory depression. A dose of 1 mg was the best increment under the conditions of this study but the relationship between increment and lockout interval requires consideration.

Local anaesthetics and their current clinical use.

The development of local anaesthetics from the single agent of the last centu ry, cocaine, through the first three decades of this century with the proliferation of the ester -caines, to the beginning in the 1940s and subsequent growth of the amide-caines of the present , is a fascinating phase in the saga of anaesthesia. Agents that have survived th is evolutionary process have done so because they possess peculiar properties which justify their place in the range of agents used in contemporary medicine. Hence, the range of agents currently available offers great versatility. This , combined with a sound knowledge of the clinical pharmacology of the individual local anaesthetics, enables the achievement of effective and safe regional block for a wide range of local anaesthetic techniques. Currently , the local anaesthetic procedures most commonly employed are infiltration techniques, some topical applications and a considerable range of peripheral nerve blocks. The remainder, i.e. major plexus and central neural blockade techniques (table 0 , are , in most situations , the province of the specialist anaesthetist for reasons outlined below. It is beyond the scope of this article to describe how to perform blocks. The realm of how to is documented in specialised texts of which those by Eriksson (1969) and Moore (1971) are essential reading. I. Backgroundto the Use of LocalAnaesthetic Agents

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

&NA; 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 < 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: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;changes in pain scores estimated by patients using the visual analogue pain scale (VAPS);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.

Strong analgesics in severe pain

While opium has been used for centuries to control pain, it was not until the mid-I920s that the structure of the principal active alkaloid, morphine, was established. Extensive research programmes followed, concentrating on modifications to the morphine nucleus to produce a range of semisynthetic and synthetic analogues. The product of this research, which is still in progress, is the present range of agonist (i.e. morphine-like), mixed agonist/antagonist [i.e. which have both morphinelike (agonist) and naloxone-like (antagonist) activity) and antagonist opioid analgesicagents. The aim throughout these studies has been to develop a drug which has the analgesic qualities of morphine without the undesirable effects, e.g. respiratory depression, nausea, vomiting, abuse potential, and addiction liability. While the large sums of money invested in the search for the ideal opioid have resulted in some promising new potent opioids, invariably there are still significant deficiencies. This article reviews the available opioid analgesics and outlines alternative methods of using existing well established opioid agonists to significantly improve pain control. It is appropriate that we define what is classified as pain. The International Association for the Study of Pain (IASP) recently defined it as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.

Halothane Hepatitis: What’s New?

There is no longer any doubt that liver dysfunction following surgery and anaesthesia may sometimes be attributable to the inhalational anaesthetic agent halothane [J -6]. This potential cause of postoperative jaundice is a very minor one compared with shock, blood transfusion, concurrent bacterial and viral infection, nonspecific depression of immune response, various hepatotoxic drugs and other factors [6,12]. However, recent studies have helped to clarify the role of halothane in postoperative jaundice [J -6, 8-11.17-22].

Changes in rat hepatic microsomal mixed function oxidase activity following exposure to halothane under various oxygen concentrations.

This study demonstrates that the exposure of phenobarbitone-treated rats to halothane at an oxygen concentration of either 10% or 14% results in marked decreases in cytochrome P-450 content and aminopyrine demethylase activity in animals sacrificed from 1 to 48 hr post-exposure. The alterations observed in the hepatic mixed function oxidase system were accompanied by increases in serum alanine aminotransferase (ALT), ornithine carbamyl transferase (OCT) and changes in liver pathology. However, the minor changes in cytochrome P-450 content and aminopyrine demethylase activity observed following exposure of enzyme-induced rats to halothane under normoxic conditions (i.e. 21% oxygen) were not of a sufficient magnitude to lead to hepatic cell necrosis. Halothane administration in the absence of phenobarbitone pretreatment (i.e. 21% oxygen) or during hypoxia alone (i.e. either 10% or 14% oxygen) did not result in any systematic changes in the parameters assayed. The results suggest that cytochrome P-450 may catalyse its own inactivation by virtue of greater free radical production under conditions which favour the non-oxygen dependent metabolism of halothane. The impairment in microsomal function as evidenced by decreases in cytochrome P-450 and aminopyrine demethylase activity are considered to occur as a primary consequence of the reductive metabolism of halothane. Data are presented which support the concept of the initiation of hepatic damage occurring during the period of anaesthesia with halothane.

Minaxolone, clinical effects and pharmacokinetics

Minaxolone, infused at a constant rate of 0·01 mg/kg/min produced drowsiness followed by a sleep‐like state from which subjects could be easily awakened. After the infusion was stopped, initial recovery was rapid, and completed within 45 minutes. The ability to produce this state rapidly and reversibly would have great value in outpatient surgery, short operative procedures and for basal sedation during procedures performed under regional anaesthesia. In common with many intravenous induction agents, involuntary skeletal muscle movement and twitching during the latter part of the infusion regimen was observed in some subjects. The rapid recovery was consistent with the pharmacokinetic characteristics of Minaxolone, i.e. high total body clearance (near or even exceeding that of indocyanine green) and rapid redistribution. However, renal clearance of unchanged Minaxolone was negligible.

A rapid gas-liquid chromatographic determination of antipyrine clearance in the rat

The assay procedure described in this paper allows the calculation of pharmacokinetic data of antipyrine disposition to be obtained from a single animal with minimal disturbance in hematocrit. A sample volume (100 microliters) allows the repeated use of the same rat for studies of hepatic drug metabolism. The lower limit of sensitivity is 5 micrograms/ml, with a range of linearity extending to 100 micrograms/ml. This allows for various dosing regimens. The GLC assay is rapid and accurate as shown by comparison with previously published values for the half-life of antipyrine in rats.

The analgesic efficacy of a serotonin reiftake blocker, zimelidine, in the treatment of chronic benign pain

NVOLVE:ENT It: THE MODULATION OF PAIN AND,2F ENDOGENOUS20PxIATE ACTIVITY INxMAN. J.C. Miller A. Roby , C. Maulet and A. Gerard . Departments of Physiology , Fat. Med. Saint-Antoine, Paris 12 and 2 Pharmuka Group, 92231 Gennevilliers (France). Aim of investigation : The use of 5-HT uptake inhibitor in pain therapy is a well known fact, but the mechanisms by which this group of drug relieves pain is unclear. This report gives some electrophysiological evidences that Indalpine or LM 5008 < 4-(2-(3-indolylj-ethyl)-piperidine>, a selective 5-HT uptake inhibitor can induce an increase in both pain threshold and nociceptive reflex threshold in a naloxone-reversible fashion via a supraspinal descending pathway. Methods : The threshold of both nociceptive reflex and pain sensation evokedipsilateral sural nerve stimulation was determined in 6 volunteers, before and after a 3 days IndalPine treatment (75mg/day; per OS) or with placebo (double-blind; cross-over). 10 minutes after the beginning of each session, subjects received (double-blind) either naloxone (0.02 mg/kg) or saline, i.v. ; a new collection of data was then performed. Results : Indalpine produced a very significant increase in the threshold of both parameters studied. This increase was partially but significantly reversed by naloxone while saline remained without any effect. In contrast, the placebo treatment did not induce any change in these parameters, compared to contra values. Furthermore, in 2 paraplegic patients with chronic spinal cord section, indalpine did not change the nociceptive reflex thresh. Conclusion : These results show that the indalpine-induced analgesia would mainly acts via some supraspinal endogenous morphine-like system which inhibits nociceptive transmission at a spinal level through a serotoninergic descending pathway. These data could be of interest in the research of pain therapy, because they show the possibility to stimulate some analgesic opiate system without the need of exogenous narcotic.