Levels of morphine and metabolites in CSF during respiratory depression after intraventricular morphine injection.

We report a case of respiratory depression after intracerebroventricular morphine administration of a dose inadvertently 10 times greater than the typical daily dose. At the time of the respiratory dysfunction, the concentrations of morphine and its metabolites in cerebrospinal fluid (CSF) and plasma samples were determined. On comparison of these results with previous clinical studies in which there was no respiratory depression, no relationship was found between the occurrence of respiratory depression and the concentration of morphine or its metabolites in the CSF. The occurrence and characteristics of respiratory depression may be related to the concentrations of morphine and its metabolites in bulbar tissue.

Morphine-3-glucuronide: silent regulator of morphine actions.

To assess whether stoichiometric manipulation of morphine (M) metabolism can enhance analgesia or slow the development of M tolerance we co-administered M-3- glucuronide (M3G) during single or repeated doses of morphine in rats. Although M3G itself lacked analgesic activity, co-injection of M3G with M increased and prolonged analgesia beyond that seen with M. In addition, diminution of the acute analgesic effect of M after 3 once-daily doses of M did not occur after daily co-injection of M3G and M. Thus the traditional view that tolerance to the effects of M is due solely to effects mediated through opioid receptors must be broadened to include the contributions of enzyme induction or stoichiometric equilibration of M3G in this process.

Enhanced potency of intravenous, but not intrathecal, morphine and morphine-6-glucuronide after burn trauma.

We examined the analgesic effect of morphine (M) and its metabolite morphine-6-glucuronide (M6G) in a rat model of acute thermal trauma. M or M6G were given by intrathecal (IT) or intravenous (i.v.) routes after brief burn or sham burn delivered during inhalational anesthesia. In the sham group, M6G was significantly less potent than M when given i.v., yet tended to be more potent than M when given IT. For both drugs, thermal injury increased i.v. potency, yet decreased (for M) or displayed a trend to decrease (for M6G) It potency. The increased potency seen with i.v. but not IT opioid administration may reflect pharmacokinetic (e.g., diminished clearance) and/or pharmacodynamic responses (e.g., activation of peripheral opioid receptors) after thermal injury.

Presence of morphine metabolites in human cerebrospinal fluid after intracerebroventricular administration of morphine.

After intracerebroventricular administration of morphine in four cancer patients, cerebrospinal fluid (CSF) was analyzed by two morphine radioimmunoassays (RIA), liquid chromatography (LC) and radioreceptor assay (RRA) to evaluate the presence of morphine metabolites. Immunoreactive morphine-like substances were detected by differential RIA's. The maximum concentrations of these compounds were achieved 3 hours after drug administration. These concentrations, according to the specificity of the antiserum, represent a mixture of several metabolites in which only morphine 3-glucuronide(M 3-G) and morphine 6-glucuronide (M 6-G) were identified by LC, and M 6-G by LC-RRA. These results confirm that brain is able to metabolize morphine to inactive (M 3-G) or more potent (M 6-G) derivatives.

[Treatment of acute postoperative pain]. / Traitement des douleurs aiguës post-opératoires.

Postoperative pain is a subjective experience involving sensations and perceptions, which may be the result of tissue damage after surgery. Various analgesic drugs and techniques can be used to relief postoperative pain. They must be adapted to the surgery and to the patient. Moreover, adequate management of postoperative pain need to be organized. This include medical attitudes, clinical orientations, disciplinary involvements, consultative protocols and program education.

[Patient-controlled analgesia. Benefits, risks, methods of monitoring]. / Analgésie contrôlée par le patient. Bénéfices, risques, modalités de surveillance.

Patient-controlled analgesia refers to a relatively new approach to morphine delivery in which patients are allowed to self-administer small doses of an opioid, to achieve adequate relief of postoperative pain. The main benefit is to reduce fluctuations in opioid plasma concentrations. A matter for worry remains the occurrence of side effects, especially ventilatory depression. In order to guarantee the efficacy and safety of this technique, the education of patients and nurses is essential. Protocols are required, specifying the use of this technique (prescription, patient monitoring, treatment of side effects).

[Propacetamol: from basic action to clinical utilization]. / Le propacétamol: des données fondamentales à l'utilisation clinique.

OBJECTIVE: To review pharmacology and therapeutic use of propacetamol, an injectable prodrug of acetaminophen (paracetamol). DATA SOURCES: Extraction from the Medline database of French and English articles on pharmacology and clinical use of propacetamol. STUDY SELECTION: Articles providing new data into the mechanisms of the analgesic action of paracetamol. Selection of controlled studies (original articles and abstracts of oral communications on therapeutic trials with propacetamol as a single agent or part of balanced analgesia protocols). Case reports and letters to the editor were not considered in this analysis. DATA EXTRACTION: Clinical articles were selected for advantages and adverse effects of propacetamol. Articles dealing with mechanisms of action of propacetamol and paracetamol were selected for the more recent data, excluding those reporting outdated theories not confirmed or abandoned. DATA SYNTHESIS AND CONCLUSION: Mechanisms of action of paracetamol differ from those of NSAIDs, giving account of a low risk of adverse renal, gastrointestinal and haematological effects. Thanks to their high therapeutic index, prescription of propacetamol and paracetamol is quite simple and safe. Main indications of both drugs are painful conditions, especially but not exclusively in the postoperative period, not requiring opioids and also in combination with other analgesic drug and/or techniques (balanced or multimodal analgesia). Because of cost, IV propacetamol is changed for oral paracetamol as soon as possible.

[Quality assurance for the assessment of postoperative pain: proposal of procedures and questionnaires]. / Démarche assurance-qualité pour la prise en charge des douleurs postopératoires: proposition d'un outil de réalisation d'enquêtes.

OBJECTIVES: This study presents a tool including survey questionnaires and a specific data-processing software for the data processing, allowing health care providers to assess the quality of postoperative pain management in surgical wards. STUDY DESIGN: Descriptive study. METHODS: A committee including anesthesiologists, nurses and epidemiologists had elaborated and tested three survey questionnaires to assess patients, nurses and medical staff satisfaction respectively. Specific data processing software was issued out of the final questionnaires. It allowed a quick analysis of items possibly, explaining inadequate postoperative pain management. After this adjustment, this tool was used in three different surgical wards, named A, B, C. RESULTS: The rate of answer (of investigated persons) being over 50%, data resulting from the survey performed in the surgical wards A and B were considered valid. The items which could explain insufficient pain relief were classified into 4 levels: patients assertion (ex: more than 50% of patients experienced persistent postoperative pain); practices evaluation (ex: 42 to 72% health care providers declared being aware of analgesic procedures); behavior's evaluation (ex: 19 to 34% of health care providers considered persistent postoperative pain to be useful for monitoring); and surgical wards potential (ex: 21 to 61% of health care providers took a specific course on pain management). Pros and cons of this tool were carefully examined and subsequent strategies defined. CONCLUSIONS: This survey's device should allow health care providers to assess the quality of postoperative pain management in surgical wards. Its validation is currently developed to improve its use, and keep the most performing indicators, showing an adequate postoperative pain management.

[Optimal use of the administration of morphine derivatives]. / Optimisation de l'administration des morphiniques.

During the postoperative period, the efficacy of opioid treatment is different among patients. Indeed, an extreme variability exists between patients, concerning their analgesic requirement and their sensibility to opioids. To improve opioid analgesia, some empiric considerations must be observed: 1) Techniques of opioid administration must allow to titrate analgesic requirement. Patient Controlled Analgesia represents a real improvement and should be developed. 2) Occurrence of side effects must be avoided. The combination of different analgesics must be prescribed systematically, if there is no contraindication. 3) Opoid side effects must be appropriately treated, in order to improve the quality of analgesia. These simple measures require regular evaluation of opioid analgesia, and treatment of the side effects.

[Patient-controlled analgesia and postoperative pain]. / Analgésie contrôlée par le patient et douleurs postopératoires.

Patient controlled analgesia improves titration of analgesic drugs, minimizing individual pharmacodynamic differences between patients, during the postoperative period. We describe the efficacy and the safety of intravenous PCA, based on the follow-up of 300 patients, recovering from upper and lower abdominal surgery. Successful use of PCA requires the choice of two important parameters: the PCA bolus and the lock-out period. In our experience, we only prescribed morphine, with a PCA bolus of 0.5 or 1 mg and a lock-out period of 5 or 10 minutes. Nurses were educated to change the syringes and to assess analgesia and the respiratory function. Patients were mostly hospitalized in surgical wards and only 16% of patients were treated in an intensive care unit. Patient's acceptance proved to be excellent and only 4 patients were not satisfied with PCA therapy. The incidence of respiratory depression was low (0.02%) and only one patient required naloxone. The side effects were dysphoria, nausea, pruritus and urinary retention; their incidence was low.

[Influence of medicolegal aspects on the management of the treatment of chronic backache]. / Influence des aspects médico-légaux sur la conduite du traitement des lombalgies chroniques.

After reviewing the different legal definitions in which low back pain is determined to represent a compensable injury, authors evoke the difficulties to prove the reality and the degree of impairment. They recommend to solve conflicting medico legal rules and disability before using other pain relief technics.

Meta-analysis of the efficacy of extradural clonidine to relieve postoperative pain: an impossible task.

Clonidine, an alpha2 adrenoceptor agonist, has anti-hypertensive and anti-nociceptive effects. It is commonly used in association with local anaesthetics and opioids to enhance the quality and duration of extradural analgesia in the postoperative period, and to decrease the incidence of side effects. As a sole analgesic, it has seldom been used to relieve postoperative pain. The dose of extradural clonidine to achieve good pain relief without deleterious side effects remains undetermined. In order to address this problem, we performed a computer search via two well-known databases, Medline and Excerpta Medica, covering the period from 1985 to September 1997. One hundred and fifty-nine articles were retrieved of which 38 dealt with extradural clonidine and postoperative pain. All but 16 studies suffered from serious design flaws, such as lack of controls and/or randomization, or inadequate statistical analysis. The data from these studies were difficult to interpret because of the tremendous variation in variables, especially dose of clonidine, level of extradural injection, time of administration, type of anaesthesia, type of surgery, and reference and rescue drugs. The simultaneous extradural use of local anaesthetics and opioids further hindered data interpretation, and precluded any meta-analysis. Proposals for a standard study design are made to help comparison between studies involving extradural clonidine and postoperative pain.

Acute decreases in cerebrospinal fluid glutathione levels after intracerebroventricular morphine for cancer pain.

UNLABELLED: Intracerebroventricular (ICV) morphine administration is effective for the management of refractory cancer pain. Recent preclinical observations of acute depletion of the major endogenous intracellular antioxidant glutathione (GSH) in brain and peripheral organs after ICV morphine in rodents led us to apply microchemical methods to profile the neurochemical effects of ICV morphine in three patients treated for intractable cancer pain. Assessment of morphine, morphine-6-glucuronide, and a panel of endogenous compounds and metabolites in ventricular and cisternal cerebrospinal fluid (CSF) demonstrated transient, postdose increases in morphine and morphine-6-glucuronide in ventricular and cistemal CSF, accompanied by acute decreases in CSF GSH levels. Significant changes were also observed in the CSF levels of 4-hydroxybenzoic acid, homovanillic acid, 5-hydroxyphenyllactic acid, and uric acid. These pilot clinical observations of acute central GSH depletion after ICV morphine suggest a novel mechanism for neuropsychiatric toxicity or preclinical findings, such as hyperalgesia or increased motoric activity observed in nonhuman species after central morphine administration. Because ICV morphine is a mainstay of treatment for refractory cancer pain, elucidation of a mechanism's (or mechanisms') mediating a potential pro-oxidant state in the central nervous system induced by ICV morphine is important. IMPLICATIONS: We observed acute decreases in glutathione levels in cerebrospinal fluid sampled from patients after intracerebroventricular doses of morphine for intractable cancer pain. Such doses may, by depleting the antioxidant glutathione, render the central nervous system vulnerable to damage from oxidative stress.

[Abortion induced by mifepristone and sulprostone combination: attempting analgesia with acetominophen or dipropyline]. / Interruptions volontaires de grossesse induites par l'association mifepristone-sulprostone: essai d'antalgie par le paracetamol ou la dipropyline.

PIP: 45 women undergoing 1st trimester abortions induced by RU-486 were divided into 3 groups for a double-blind randomized vs. placebo trail of analgesia following sulprostone administration. 600 mg of RU-486 was administered orally 36-48 hours before admission to the hospital. After admission, 10 women received 600 mg of acetaminophen, 14 received 80 mg of dipropyline, and 14 received a placebo. 500 mcg of sulprostone was injected about 30 minutes later. The study excluded method failures, expulsions occurring before hospital admission, deviations from the protocol, and delays to expulsion greater than 8 hours. There was no significant difference between the 3 groups in maximal pain, but the placebo group appeared to experience less discomfort than the other two. The delay to expulsion was significantly longer in the acetaminophen group than in the other two. The relatively lower amount of pain in the placebo group was probably due to the reduced proportion of nulliparas in it compared to the other 2 groups. 6 women in the acetaminophen group, 9 in the dipropyline group, and only 5 in the placebo group were nulliparas. Comparing nulliparas with mothers within groups, the maximal pain was significantly less intense among mothers than among nulliparas in the placebo group and to a lesser extent in the dipropyline group but not in the acetaminophen group. Based on these results it is recommended that a systematic study be made of analgesia for RU-486 and sulprostone-induced abortions. An antispasmodic effect on the cervical fibers should be sought more than analgesia per se.^ieng

Local increases of subcutaneous beta-endorphin immunoactivity at the site of thermal injury.

To examine interactions between exogenous opioid analgesia and endogenous opioid generation at a site of burn-induced tissue injury, we measured beta-endorphin (BE) and corticosterone (C) in aliquots of plasma and wound fluid withdrawn from subcutaneous wire mesh chambers beneath the site of a 3-5% surface area burn. After brief inhalational anesthesia at the time of thermal injury, rats received morphine (4 mg/kg, single dose), fentanyl (0.02 mg/kg hourly for 4 h), or no opioid. Systemic hormone responses and behavioral changes were minimal as expected for the minimal percentage burn. In all three groups intrachamber BE and C rose above baseline at 1, 2 and 4 h postburn, then returned to baseline at 24 h. Systemic opioid treatment produced analgesia (by tail flick latency testing) but did not reduce intrachamber hormone responses. Thus local BE and C responses at the site of thermal injury are regulated differently from systemic pituitary-adrenal responses.