Morphine prescribed for analgesia has caused drug-related deaths at an estimated incidence of 0.3% to 4%. Morphine has pharmacological properties that make it particularly difficult to assess the causality of morphine administration with a patient's death, such as its slow transfer between plasma and central nervous sites of action and the existence of the active metabolite morphine-6-glucuronide with opioid agonistic effects, Furthermore, there is no well-defined toxic dose or plasma/blood concentration for morphine. Dosing is often adjusted for adequate pain relief. Here, we summarize reported deaths associated with morphine therapy, including associated morphine exposure and modulating patient factors such as pharmacogenetics, concomitant medications, or comorbidities. In addition, we systematically analyzed published numerical information on the stability of concentrations of morphine and its relevant metabolites in biological samples collected postmortem. A medicolegal case is presented in which the causality of morphine administration with death was in dispute and pharmacokinetic modeling was applied to infer the administered dose. The results of this analytical review suggest that (i) inference from postmortem blood concentrations to the morphine dose administered has low validity and (ii) causality between a patient's death and the morphine dose administered remains a highly context-dependent and collaborative assessment among experts from different medical specialties.

This article addresses postoperative analgesia in patients with end-stage liver disease who have undergone liver transplantation (LT). Postoperative analgesia determines how patients perceive LT. Although important, this topic is underrepresented in the current literature. With an increased frequency of fast tracking in LT, efficient intra- and postoperative analgesia are undergoing changes. We herein review the current literature, compare the benefits and disadvantages of the therapeutic options, and make recommendations based on the current literature and clinical experience.

The kidney plays a major role in pharmacokinetics and pharmacodynamics of drugs; therefore, medication errors can result from failure to properly adjust medications in patients with CKD. It is the responsibility of all health-care providers to work collectively when reviewing medications, initiating new medications, and adjusting doses of current medications. Awareness of appropriate dosing recommendations can significantly decrease medication error-associated morbidity, mortality, and cost.

The present study was designed to study the impact of intermittent hemodialysis on the disposition of the partial agonist buprenorphine and its metabolite norbuprenorphine during therapy with transdermal buprenorphine in chronic pain patients with end-stage kidney disease. Ten patients (mean age 63 years) who had received transdermal buprenorphine for at least 1 week, were asked to provide blood samples immediately before and after hemodialysis. Blood samples were analysed for buprenorphine and its metabolite norbuprenorphine. The median buprenorphine plasma concentrations were found to be 0.16 ng/ml before and 0.23 ng/ml after hemodialysis. A significant correlation between plasma levels and administered doses was observed (Spearman R=0.74; P<0.05). In three patients norbuprenorphine plasma levels were detected. No differences in pain relief before and after hemodialysis were observed. This investigation shows no elevated buprenorphine and norbuprenorphine plasma levels in patients with renal insufficiency receiving transdermal buprenorphine up to 70 microg/h. Furthermore, hemodialysis did not affect buprenorphine plasma levels, leading to stable analgesic effects during the therapy.

Opioid use in patients with renal impairment can lead to increased adverse effects. Opioids differ in their effect in renal impairment in both efficacy and tolerability. This systematic literature review forms the basis of guidelines for opioid use in renal impairment and cancer pain as part of the European Palliative Care Research Collaborative's opioid guidelines project.

The objective of this study was to identify and assess the quality of evidence for the safe and effective use of opioids for the relief of cancer pain in patients with renal impairment and to produce guidelines.

The Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MedLine, EMBASE and CINAHL were systematically searched in addition to hand searching of relevant journals.

Studies were included if they reported a clinical outcome relevant to the use of selected opioids in cancer-related pain and renal impairment. The selected opioids were morphine, diamorphine, codeine, dextropropoxyphene, dihydrocodeine, oxycodone, hydromorphone, buprenorphine, tramadol, alfentanil, fentanyl, sufentanil, remifentanil, pethidine and methadone. No direct comparator was required for inclusion. Studies assessing the long-term efficacy of opioids during dialysis were excluded.

This is a narrative systematic review and no meta-analysis was performed. The Grading of RECOMMENDATIONS Assessment, Development and Evaluation (GRADE) approach was used to assess the quality of the studies and to formulate guidelines.

Fifteen original articles were identified. Eight prospective and seven retrospective clinical studies were identified but no randomized controlled trials. No results were found for diamorphine, codeine, dihydrocodeine, buprenorphine, tramadol, dextropropoxyphene, methadone or remifentanil.

All of the studies identified have a significant risk of bias inherent in the study methodology and there is additional significant risk of publication bias. Overall evidence is of very low quality. The direct clinical evidence in cancer-related pain and renal impairment is insufficient to allow formulation of guidelines but is suggestive of significant differences in risk between opioids.

RECOMMENDATIONS regarding opioid use in renal impairment and cancer pain are made on the basis of pharmacokinetic data, extrapolation from non-cancer pain studies and from clinical experience. The risk of opioid use in renal impairment is stratified according to the activity of opioid metabolites, potential for accumulation and reports of successful or harmful use. Fentanyl, alfentanil and methadone are identified, with caveats, as the least likely to cause harm when used appropriately. Morphine may be associated with toxicity in patients with renal impairment. Unwanted side effects with morphine may be satisfactorily dealt with by either increasing the dosing interval or reducing the 24 hour dose or by switching to an alternative opioid.

Morphine-6-glucuronide, the active metabolite of morphine, and to a lesser extent morphine itself are known to accumulate in patients with renal failure. A number of cases on non-lethal morphine toxicity in patients with renal impairment report high plasma concentrations of morphine-6-glucuronide, suggesting that this metabolite achieves sufficiently high brain concentrations to cause long-lasting respiratory depression, despite its poor central nervous system penetration. We report a lethal morphine intoxication in a 61-year-old man with sickle cell disease and renal impairment, and we measured concentrations of morphine and morphine-6-glucuronide in blood, brain and cerebrospinal fluid. There were no measurable concentrations of morphine-6-glucuronide in cerebrospinal fluid or brain tissue, despite high blood concentrations. In contrast, the relatively high morphine concentration in the brain suggests that morphine itself was responsible for the cardiorespiratory arrest in this patient. Given the fatal outcome, we recommend to avoid repeated or continuous morphine administration in renal failure.

Opioid analgesics have an established role in the management of postoperative pain and cancer pain, and are gaining acceptance for the management of moderate to severe chronic noncancer pain, most notably chronic low back pain and osteoarthritis, that does not respond to other interventions. Many patients with chronic pain have co-morbid medical conditions that may complicate opioid therapy. Selecting the appropriate opioid requires knowledge of how individual opioids differ with respect to metabolism and interaction with concurrent medications, as well as the reasons why specific medical conditions may influence their efficacy and tolerability. Polypharmacy is a common complicating condition in the elderly and in patients with psychiatric illness, cancer, cardiovascular disease, diabetes mellitus or other chronic illnesses. Polypharmacy, though often necessary for patients with multiple medical conditions, also multiplies the risk of drug interactions. Pharmacokinetic drug interactions can increase or reduce exposure to the opioid or concurrent medications, reducing efficacy and/or tolerability and increasing toxicity. Pharmacodynamic interactions can enhance the depressive effects of opioids, compromising safety. Patients with impaired renal or hepatic function may have difficulty clearing or metabolizing opioids and concurrent medications, leading to increased risk of adverse events. Patients with cardiovascular, cerebrovascular or respiratory disease (including smokers of >/=2 packs/day with no other diagnosis) may be more susceptible to respiratory depression, bradycardia and hypotension with any opioid, and a few specific opioids pose additional risks. Patients with cerebrovascular disease, dementia, brain injury or psychiatric illness are more susceptible to opioid effects on the CNS, which can include euphoria, cognitive impairment and sedation. Appropriate opioid selection may mitigate these effects. Even in older patients, addiction, abuse and misdirection of prescribed opioids are of concern. Higher risk exists for patients with psychiatric illness, history of substance abuse, and identifiable substance abuse risk factors. Screening for abuse potential and vigilant patient monitoring should be routine. Opioids differ in their ability to produce euphoria, based on opioid receptor agonism, but substance abusers may be more influenced by availability, familiarity and cost factors. Consequently, opioid selection has limited influence on abuse potential but can facilitate ease of monitoring. This review provides an overview of opioid use in medically complicated patients and recommendations on how to optimize analgesia while avoiding adverse events and drug interactions in the clinical setting. Articles cited in this review were identified via a search of EMBASE and PubMed. Articles selected for inclusion discussed characteristics of specific opioids and general physiological aspects of opioid therapy in important patient populations.

The aim of this study was to assess the influence of a regional analgesia technique on the incidence of postoperative cognitive dysfunction (POCD) after hip surgery, in elderly patients.

Patients, aged over 65 years, were assigned in two groups according to the anaesthesia technique: group NKT (general anaesthesia with target concentration infusion of propofol and remifentanil, with a 0.1 mg/kg-bolus of morphine at the end of surgery), group KT (preoperative iliaca compartment block with catheter and then general anaesthesia without bolus of morphine). Postoperative analgesia was similar in both groups: paracetamol, tramadol, and subcutaneous morphine if verbal pain scale equal or greater than 2 (0.1 mg/kg). POCD was defined as a decrease in Mini Mental Status (MMSE) equal or greater than 2 points and was monitored during 2 days. Consumption of opioids, pain scores and side effects were recorded.

Sixty-five patients were included: 34 in NKT group and 31 in KT group. MMSE scores were higher in the KT group at day 1 and day 2 (p=0.01 and 0.0004, respectively). POCD was less frequent in group KT at day 2 (6 % vs 41 % ; p=0.001) and pain scores were lower during the first 48 hours (p=0.03). Remifentanil consumption was lower in KT group (0.43+/-0.18 mg vs 0.61+/-0.25 mg, p=0.002). Total amount of morphine, including the bolus in NKT group, was significantly lower in KT group (7 [5-17] mg vs 0 [0-5] mg, p<10(-6)).

Postoperative analgesia by iliaca compartment block with catheter seems to provide a decrease in the incidence of POCD after hip surgery in elderly patients.

Prospective, observational study.

Clinicians understand that individual patients differ in their response to specific opioid analgesics and that patients may require trials of several opioids before finding an agent that provides effective analgesia with acceptable tolerability. Reasons for this variability include factors that are not clearly understood, such as allelic variants that dictate the complement of opioid receptors and subtle differences in the receptor-binding profiles of opioids. However, altered opioid metabolism may also influence response in terms of efficacy and tolerability, and several factors contributing to this metabolic variability have been identified. For example, the risk of drug interactions with an opioid is determined largely by which enzyme systems metabolize the opioid. The rate and pathways of opioid metabolism may also be influenced by genetic factors, race, and medical conditions (most notably liver or kidney disease). This review describes the basics of opioid metabolism as well as the factors influencing it and provides recommendations for addressing metabolic issues that may compromise effective pain management. Articles cited in this review were identified via a search of MEDLINE, EMBASE, and PubMed. Articles selected for inclusion discussed general physiologic aspects of opioid metabolism, metabolic characteristics of specific opioids, patient-specific factors influencing drug metabolism, drug interactions, and adverse events.

A growing body of literature has demonstrated that chronic pain is common for patients with end- stage renal disease (ESRD), is typically moderate or severe, and impacts virtually every aspect of health-related quality of life. Unfortunately, there is a lack of clinical and research focus in this area in nephrology and pain in ESRD is undertreated. This paper reviews the epidemiology of chronic pain in ESRD, discusses basic principles of pain assessment and management, and highlights some of the challenges in pain management in ESRD with the hope of guiding health professionals in the effective management of pain in patients with ESRD.

To determine the efficacy and safety of intravenous postoperative morphine titration in the elderly compared with younger patients.

In the post-anaesthesia care unit, patients complaining of pain received morphine until adequate pain relief. Intravenous morphine was titrated as 3 mg boluses in young (age 65 yr) and 2 mg in elderly patients (>65 yr) every 5 min.

We studied 350 young and 68 elderly patients. There were no significant differences between the two age groups for pain intensity at the onset of titration (numerical rating scale, 7.4 +/- 1.7 in young vs. 7.5 +/- 1.7 in elderly patients), area under the curve of numerical rating scale vs. morphine boluses (97.7 +/- 59.6 vs. 98.2 +/- 62), number of boluses required to obtain pain relief (3 +/- 1.3 vs. 3 +/- 1.3), percentage of titration failures (10% vs. 9%) and incidence of excessive sedation (18% vs. 21%). Renal clearance was significantly reduced in elderly compared with young patients (55 +/- 21 vs. 85 +/- 15 mL min(-1); P < 0.0001).

Using lower bolus doses, pain relief in the immediate postoperative period with morphine was as efficacious and safe in elderly patients as in younger patients. The decrease in renal clearance of morphine in the elderly justifies the reduction of intravenous morphine boluses for the treatment of postoperative pain.

Patients with chronic kidney disease (CKD) and ischemic heart disease (IHD) have strikingly high mortality rates. In the general population, there has been a reduction in the mortality and morbidity rates for IHD through the implementation of effective risk-factor-reduction programs and better interventions for patients with established IHD. No such trend has been observed in patients with end-stage kidney disease. This review article addresses the following topics: (i) epidemiology, pathogenesis, clinical CKD patients with IHD; (ii) diagnostic modalities for IHD and their limitation in CKD patients; (iii) medical treatment options and revascularization strategies for these high-risk patients; and (iv) optimal cardiovascular risk management. Generally, in CKD patients with IHD an aggressive approach to IHD is warranted, a low threshold for diagnostic testing should be employed, and awaiting a clinical trial targeting these patients they should be considered for all proven strategies to improve outcomes.

Drug dosing in paediatric nephrology requires multiple considerations and is therefore time-consuming and error-prone. This review combines dose adjustment guidelines for children with renal failure and information on the immature renal function of neonates and premature babies in order to help both paediatric nephrologists and neonatologists estimate drug doses for their patients.

A growing body of literature has shown that chronic pain is common for patients with end-stage renal disease (ESRD), is typically moderate or severe, and impacts virtually every aspect of health-related quality of life. Unfortunately, there is a lack of clinical and research focus in this area in nephrology, and pain in ESRD is undertreated. This article will review the epidemiology of chronic pain in ESRD, discuss basic principles of pain assessment and management, and highlight some of the challenges in pain management in ESRD with the hope of guiding health professionals in the effective management of pain in patients with ESRD.

Patients with CKD and CAD have traditionally been a difficult population to diagnose and treat in the setting of ACS. In addition to having poorer outcomes post-ACS, data are lacking regarding best treatments available. Aggressive interventional and medical treatments in this group with already poor outcomes are not necessarily contraindicated and should always be considered. The appalling outcome for CKD patients post-ACS is improved by many therapies shown to benefit in the non-CKD patients. Data suggest that troponins are useful markers in CKD patients, that major bleeding is not increased with the use of GP IIb-IIIa antagonists, that thrombolytics have been used successfully in CKD patients, and that PCI electively and as a primary treatment for ACS is successful and probably more beneficial to treatment.

Patients with chronic kidney disease (CKD) are at high risk for adverse drug reactions and drug-drug interactions. Drug dosing in these patients often proves to be a difficult task. Renal dysfunction-induced changes in human pathophysiology regularly results may alter medication pharmacodynamics and handling. Several pharmacokinetic parameters are adversely affected by CKD, secondary to a reduced oral absorption and glomerular filtration; altered tubular secretion; and reabsorption and changes in intestinal, hepatic, and renal metabolism. In general, drug dosing can be accomplished by multiple methods; however, the most common recommendations are often to reduce the dose or expand the dosing interval, or use both methods simultaneously. Some medications need to be avoided all together in CKD either because of lack of efficacy or increased risk of toxicity. Nevertheless, specific recommendations are available for dosing of certain medications and are an important resource, because most are based on clinical or pharmacokinetic trials.

The transplant recipient has traded a life-threatening illness for a chronically immunosuppressed state. Subsequent anesthetic management for non-transplant surgical procedures may be challenging. The anesthesia provider must be aware of the degree of post-transplant organ dysfunction and alter anesthesia techniques accordingly. This article reviews the anesthetic concerns for patients who have undergone a variety of organ transplants.

To describe principles of intravenous (i.v.) morphine titration. To analyse current knowledge based on the experimental and clinical studies. To describe clinical implications in the operating room, postanaesthesia care unit (PACU), prehospital care, emergency and intensive care units (ICU), and cancerology. To provide recommendations for clinical practice.

Search in the Medline database without limitation, using the following keywords: morphine titration.

All types of articles were selected including prospective randomised (or not randomised) studies in adults and children, practice guidelines, reviews, editorials and case reports.

Intravenous (i.v.) morphine titration is a pharmacological method which involves morphine boluses administration until pain relief, allowing a limitation in morphine side effects which are mainly dose dependent. I.v. morphine titration is widely used in prehospital care, emergency unit, PACU, ICU, and cancerology, in young and elderly patients. In the PACU, when the VAS (visual analogue scale) increases to more than 30 mm, i.v. morphine titration every five minutes with an unlimited number of 2 or 3 mg boluses provides an efficient analgesic regimen in adults. Titration is performed until pain relief (VAS < or =30), sedation that is the most frequent side effect during i.v. morphine titration (Ramsay score >1), severe side effects (like respiratory depression).

Because of important pharmacological variability in morphine need, iv morphine titration is a simple method which allows a rapid and efficient pain relief notably in the postoperative care.

The perioperative management of patients with chronic kidney disease (CKD) or dialysis-dependent end-stage renal disease (ESRD) is complicated by both the underlying renal dysfunction, with associated disturbances of fluid and electrolyte homeostasis and altered drug clearance, and the presence of associated co-morbid conditions, including diabetes mellitus, chronic hypertension and cardiovascular and cerebrovascular disease. The impact of CKD on fluid and electrolyte management, haematological and cardiovascular complications and drug management in the perioperative period are reviewed. Special issues related to the management of haemodialysis and peritoneal dialysis patients in the perioperative period are also reviewed.

There is growing evidence that dialysis patients have a high burden of symptoms, including pain. However, the prevalence, cause, severity, and management of pain in dialysis patients have not been described.

This prospective cohort study of 205 Canadian hemodialysis (HD) patients describes the prevalence, cause, severity, and management of pain in this population. A chart review for demographic and clinical data was conducted, and patients completed a questionnaire that incorporated the Brief Pain Inventory, followed by the McGill Pain Questionnaire.

One hundred three patients (50%) reported a problem with pain. Patients with pain had been on HD therapy longer (52.2 months) than those without pain (37.7 months). Causes of pain were diverse, and 18.4% of patients had more than a single cause of their pain. Musculoskeletal pain was most common (50.5%) and equal in severity to pain associated with peripheral neuropathy and peripheral vascular disease. Fifty-five percent of patients with pain rated their worst episode in the previous 24 hours as severe. Thirty-two percent of patients with pain were administered no analgesics, 29.1% were administered nonopioid analgesics, 26.2% were administered weak opioids, and 9.7% were administered strong opioids. The Pain Management Index describes the effectiveness of pain management and was negative in 74.8% of patients, indicating ineffective management.

Pain is a significant problem in more than 50% of HD patients and is not being effectively managed. The development of effective pain management strategies, underpinned by appropriate training and education, is necessary to improve the quality of life for dialysis patients.

The aim of this review of the literature was to evaluate the effectiveness of anesthetics in protecting the heart against myocardial ischemia-reperfusion injury.

Articles were obtained from the Medline database (1980-, search terms included heart, myocardium, coronary, ischemia, reperfusion injury, infarction, stunning, halothane, enflurane, desflurane, isoflurane, sevoflurane, opioid, morphine, fentanyl, alfentanil sufentanil, pentazocine, buprenorphine, barbiturate, thiopental, ketamine, propofol, preconditioning, neutrophil adhesion, free radical, antioxidant and calcium).

Protection by volatile anesthetics, morphine and propofol is relatively well investigated. It is generally agreed that these agents reduce the myocardial damage caused by ischemia and reperfusion. Other anesthetics which are often used in clinical practice, such as fentanyl, ketamine, barbiturates and benzodiazepines have been much less studied, and their potential as cardioprotectors is currently unknown. There are some proposed mechanisms for protection by anesthetic agents: ischemic preconditioning-like effect, interference in the neutrophil/platelet-endothelium interaction, blockade of Ca2+ overload to the cytosolic space and antioxidant-like effect. Different anesthetics appear to have different mechanisms by which protection is exerted. Clinical applicability of anesthetic agent-induced protection has yet to be explored.

There is increasing evidence of anesthetic agent-induced protection. At present, isoflurane, sevoflurane and morphine appear to be most promising as preconditioning-inducing agents. After the onset of ischemia, propofol could be selected to reduce ischemia-reperfusion injury. Future clinical application depends on the full elucidation of the underlying mechanisms and on clinical outcome trials.

To compare postoperative morphine use, analgesic efficacy, and side effect profiles in patients following orthotopic liver transplantation (OLTx) and liver resection (LR).

Retrospective study.

Liver transplant and liver resection surgery at a university hospital.

25 ASA physical status I, II, III, and IV patients undergoing OLTx or liver resection.

Morphine use was significantly decreased in the OLTx patients at 6,12, 24, 48, and 72 hours following commencement of patient-controlled analgesia. After commencement of patient-controlled analgesia, pain scores were significantly reduced in the OLTx group compared with those in the liver resection group at 6 and 12 hours.

Orthotopic liver transplant patients experienced less pain and used less morphine postoperatively than did liver resection patients.

The appropriateness of the default uncertainty factor for human variability in kinetics has been investigated for glucuronidation using an extensive database of substrates metabolised primarily by this pathway. Inter-individual variability was quantified for 15 compounds from published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and other subgroups using parameters relating to chronic exposure (metabolic and total clearances, area under the plasma concentration time-curve (AUC)) and acute exposure (C(max)). Low inter-individual variability (about 30-35%) was found for all parameters (clearance corrected or not corrected for body weight, metabolic clearance, oral AUC and C(max)) after either iv or oral administration to healthy adults. The overall variability of 31% for glucuronidation in healthy adults supported the validity of the default kinetic uncertainty factor of 3.16 for this group, because it would cover more than 99% of individuals. Comparisons between potentially sensitive subgroups and healthy adults using differences in means and variability indicated that neonates showed the greatest impairment of glucuronidation, and that the 3.16 kinetic default factor applied to the mean data for adults would be inadequate for this subpopulation. The in vivo data have been used to derive pathway-related default factors for compounds eliminated largely via glucuronidation.

We investigated the effects of morphine on postoperative pain in patients undergoing intraocular surgery using a new indwelling catheter. Although morphine produced central analgesic effects, there was no evidence for the involvement of peripheral opioid receptors in the modulation of ocular pain.

To study the pharmacokinetic parameters of morphine and lidocaine after a single intravenous (i.v.) bolus in severe trauma patients.

Clinical case study.

Department of Anesthesiology and Intensive Care of a university hospital.

Nine patients, ages 24 to 91 years (mean 54.4 yrs), admitted to the hospital with severe trauma (Injury Severity Score > 20) were included in the study.

After initial evaluation and stabilization, a single i.v. dose of morphine 0.025 mg/kg and lidocaine 1.5 mg/kg was given separately, and blood samples were drawn for each drug serum concentration.

Morphine pharmacokinetics was studied in eight patients, lidocaine pharmacokinetics in seven patients, and both drugs were studied in six patients. Morphine clearance 2.5 to 10 ml/kg/min (6 +/- 2.6, mean +/- SD) and volume of distribution 0.28 to 3.30 L/kg (1.4 +/- 1.0) were found to be lower than values described previously for healthy volunteers (33.5 +/- 9 ml/kg/min and 5.16 +/- 1.40 L/kg, respectively), and are similar to those described in trauma patients (5 +/- 2.9 ml/kg/min and 0.9 +/- 0.2 L/kg, respectively). In contrast, lidocaine clearance 4.5 to 9.4 ml/kg/min (6.7 +/- 1.7) and volume of distribution 0.39 to 1.20 L/kg (0.72 +/- 0.28) were similar to the value described in healthy volunteers (10 ml/kg/min and 1.32 L/kg, respectively).

Changes in pharmacokinetics of drugs eliminated by the liver may occur in patients with severe trauma. The preserved lidocaine clearance indicates an almost normal hepatic blood flow and suggests that other mechanisms may be involved in the lower morphine clearance. The findings may have applications for the treatment of severe trauma patients and suggest that drug monitoring might be needed in some instances so as to avoid toxicity.

In a systematic review of 57 studies with information on 1232 patients we examined the effect of age, renal impairment, route of administration, and method of analysis on the ratios of morphine-3-glucuronide:morphine (M3G:M) and morphine-6-glucuronide:morphine (M6G:M) and the relative concentrations of M3G and M6G. Across all studies the range of the ratios of metabolites to morphine was wide (0.001-504 for M3G:M, and 0-97 for M6G:M). Neonates produced morphine glucuronides at a lower rate than older children or adults. Metabolite ratios were higher in renal impairment. Routes of administration which avoided first pass metabolism (intravenous, transdermal, rectal, intramuscular, epidural and intrathecal) resulted in lower metabolite production than oral, buccal or sublingual. Metabolite production was similar for single and multiple dosing. There was no evidence of differences between methods of assay. There was a high correlation between the two glucuronide metabolites in spite of the different situations studied, supporting a single glucuronidating enzyme. Morphine was present in CSF at a fourfold higher concentration than the glucuronide metabolites.

Patients with renal insufficiency commonly require the administration of an opioid analgesic to provide adequate pain relief. The handling of morphine, pethidine (meperidine) and dextropropoxyphene in patients with renal insufficiency is complicated by the potential accumulation of metabolites. While morphine itself remains largely unaffected by renal failure, accumulation, as denoted by an increase in both mean peak concentrations and the area under the concentration-time curve, of both the active metabolite (morphine-6-glucuronide) and the principal metabolite (morphine-3-glucuronide, thought to possess opiate antagonist properties) have been reported. The increased elimination half-lives of the toxic metabolites norpethidine and norpropoxyphene in patients with poor renal function administered pethidine and dextropropoxyphene, respectively, makes their routine use ill advised. Case reports of prolonged narcosis associated with the use of both codeine and dihydrocodeine in patients with renal insufficiency call for care to be used when prescribing these agents under such conditions. Although the pharmacokinetics of buprenorphine, alfentanil, sufentanil and remifentanil change little in patients with renal failure, the continuous administration of fentanyl can lead to prolonged sedation.

1. Until recently, when drugs were used in critically ill patients they were expected to behave in the same way as in less seriously ill patients. Now the unpredictability of even the most reliable drugs has been recognized. With this there is an awareness of the adverse effects drugs may have on organs other than the ones the drug was intended to act on. In patients with multiorgan dysfunction, poly-pharmacy is usually needed. The drugs may not only interfere with the action of each other at the receptor and enzyme level, but may also change protein binding and elimination. All these effects may be unimportant in less seriously ill patients, but may affect outcome in the critically ill. A high degree of awareness and suspicion of unknown drug-induced adverse reaction is needed by clinicians and pharmacologists alike.

The advantages of continuous haemofiltration and haemodialysis over intermittent haemodialysis for the treatment of acute renal failure are well recognised. In intensive care patients, 4 different continuous procedures, arteriovenous and venovenous haemofiltration (CAVH and CVVH) or haemodialysis (CAVHD and CVVHD), are employed. These effective detoxification treatments require knowledge of their influence on drug disposition. Data on kinetics of drugs during continuous treatment are scarce and limited almost exclusively to the oldest and least effective procedure (CAVH). Selected dialysis membranes may adsorb drugs, as in the case of aminoglycosides. In addition, elimination of substances with large molecular weights may vary depending on the pore size of the membrane, as in the case of vancomycin. Thus, even if drug dosages can be based on pharmacokinetic studies, selection of a dialysis membrane not studied may cause unpredictable drug concentrations. With these limitations in mind and considering the available literature on pharmacokinetics in patients with renal failure, general guidelines for drug dosage during continuous renal replacement therapy can be given. In haemofiltration, drug protein binding is the major factor determining sieving, i.e. the appearance of the drug in the ultrafiltrate. In haemodialysis, diffusion is added to ultrafiltration, and therefore the saturation of the combined dialysate and ultrafiltrate will decrease further with increasing dialysate flow rate. In continuous haemofiltration or haemodialysis the extracorporeal clearance can be calculated by multiplying the saturation value (estimated or, better, measured) with the ultrafiltrate and dialysate flow rate. Dividing the extracorporeal clearance by the total clearance (including the nonrenal clearance) gives the fraction of the dose removed due to extracorporeal elimination. Whether dosage recommendations available for anuric patients have to be modified or not can be decided on the basis of this value. In case of high nonrenal clearance, the degree of saturation is without clinical significance. Based on these considerations guidelines have been constructed for the effect of extracorporeal elimination on more than 120 different drugs commonly used in intensive care patients.

1. The metabolism of morphine was studied in 12 children and nine premature neonates on a continuous infusion of morphine (10-360 micrograms kg-1 h-1). 2. The mean plasma clearance of morphine was significantly higher in children than neonates (25.7 and 4.7 ml min-1 kg-1, respectively) (P less than 0.01). 3. All the neonates and children had detectable concentrations of morphine-3-glucuronide (M3G) in plasma. All the children and five neonates had detectable concentrations of morphine-6-glucuronide (M6G) in plasma or urine. 4. The M3G/morphine ratios in plasma and urine, and M6G/morphine ratios in urine were significantly higher in children than neonates (P less than 0.01), suggesting that morphine glucuronidation capacity is enhanced after the neonatal period. 5. There was no difference in the M3G/M6G ratio in children and neonates, indicating a parallel development of both glucuronidation pathways.

The disposition of alfentanil has been investigated in 10 anaesthetized patients with chronic renal failure undergoing kidney transplantation and compared with eight age matched anaesthetized patients with normal renal function. Plasma samples were collected to 660 min following intravenous administration of alfentanil 3-5 mg (50 micrograms kg-1). Drug concentrations were measured by RIA; and alfentanil binding to plasma proteins by equilibrium dialysis against 0.1 M phosphate buffer, pH 7.4. Alfentanil binding to plasma proteins was 87.6% (s.d. 2.0) in the patients with chronic renal failure, and 89.7% (1.2) in patients with normal renal function (P = 0.025). There was no correlation between alfentanil binding and plasma albumin, total plasma proteins, plasma urea or plasma creatinine concentrations. In both groups, the drug concentration-time profile decayed in a curvilinear manner; in the chronic renal failure patients, restoration of function did not influence the decay profile. Elimination half life, mean residence time and apparent volume of distribution at steady state were not different in the two groups of patients (mean values: 142.4 and 120.2 min; 128.5 and 136.0 min; and 40.5 and 27.6 L, respectively in chronic renal failure patients and patients with normal renal function). Total drug clearance and Vd area were significantly increased in the chronic renal failure patients: 341.9 vs 211.8 mL min-1; and 69.3 and 35.5 L. There were no differences in intrinsic clearance or apparent volume of distribution at steady state for unbound drug between the two patient groups.

In a prospective study of 10 patients who underwent liver transplantation and 10 patients who underwent cholecystectomy, we analyzed the postoperative analgesic requirements and the resultant plasma morphine concentrations. Analgesia was more intense, with less medication, and the plasma morphine concentration was significantly lower in the liver transplant group than in the cholecystectomy group. This finding is most likely attributable to endogenous factors rather than to altered morphine pharmacokinetics.