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Pain is an unpleasant sensory and emotional experience, unique to each individual patient. In the dynamic processes of nociceptive stimulation, signal transmission, central decoding and interpretation there are many potential sites for pharmacological intervention, and there are many drugs which will produce analgesia. An analgesic 'ladder' has been proposed for rational pain relief in cancer and a similar concept should be used in all forms of acute and chronic pain. Continuing research and drug development undoubtedly extends our understanding, but consistent improvement in our clinical ability to relieve pain depends more on our willingness to consider the need of each patient individually, to tailor the drug, route and mode of administration to that patient's requirements, and then to monitor on the basis of the response of the patient to the treatment.

The major clinical uses for opioids are to control pain, suppress cough, and to treat diarrhea. These drugs, however, have the potential for abuse. It is postulated that the significant mood-altering effects of opioids combined with their pharmacology, in which tolerance and physical and psychological dependence occur, account for their abuse liability. A classification of the groups of patients that commonly present with complications of opioid use is reviewed briefly before discussing the clinical pharmacology of the opioids and their acute and toxic effects.

Administration of epidural opioids is a technique that is currently being used by many veterinary anesthesiologists and surgeons to provide postoperative analgesia. The duration of analgesia is prolonged and the degree of sedation is much less than that which occurs with parenterally administered opioids and the risks appears to be minimal.

Bioconcentration and toxicity estimation for a group of substituted phenols often categorized as "polar narcotics" can be confounded by pH-dependent ionization. Two methods of correction for ionization were applied to toxicity data obtained by U.S. EPA-Duluth for fathead minnows exposed to 30 different phenols in 37 bioassays. Toxicity QSARs with corrected data were substantially different from those obtained with raw toxicity data. When ionization-corrected toxicity data were used in the critical body residue (CBR) estimation process previously successful with neutral narcotic organics, several categories of CBR, apparently related to different modes of toxic action, resulted. Published data on lethal CBR for substituted phenols were in general agreement, although such information is limited. Elimination half-life rate constants, estimated from nonlinear curve fitting to time-toxicity information, were relatively constant for the Duluth bioassay data, averaging 0.3 days. Half-life information for small aquatic organisms, both from toxicity- and bioconcentration-based tests in the literature, was in a similar range. Much of the relatively high variability encountered experimental data for substituted phenols may in large part be due to differences in metabolic degradation between chemicals and species.

Experimental studies in animal models have contributed significantly to our understanding of the pharmacokinetics of drug disposition in the maternal-fetal unit. This chapter has considered some of the factors that are important in determining the extent of fetal exposure to drugs that are consumed by the mother during pregnancy. A knowledge of the maternal-fetal pharmacokinetics of the drugs of abuse will help provide a better understanding of the limitations of the current methods used in perinatal drug screening and in the interpretation of the results.

The permeability of human thoracic and lumbar dura mater to various compounds in clinical use was determined in vitro. Sections of dura mater, 3 to 4 cm in diameter, obtained at post-mortem were placed between the ports (area = 3 cm2) of two glass chambers (A and B) which fitted tightly together to form a two-chamber apparatus for measuring permeability through the dura. Each chamber contained 5 ml of artificial cerebrospinal fluid. A sample of test drug solution was introduced into one chamber (A) and 50 microliters aliquots were withdrawn from the other chamber (B) at predetermined intervals. Permeability was determined by calculating the rate of diffusion (slope) from the plot of mean drug concentration (chamber B) versus time. Dura mater permeability was shown to be a simple diffusion process and to be independent of lipid-solubility and molecular weight. Permeability appeared to increase with age and may have a linear relationship to the initial concentration.

Objective: To determine the pharmacokinetics and pharmacodynamics of the neuromuscular blocking agent atracurium besylate in patients with fulminant hepatic failure (FHF)., Design: Open study of patients receiving atracurium infusions to facilitate mechanical ventilation., Setting: Intensive care unit in a tertiary referral university teaching hospital., Patients: Ten encephalopathic patients with FHF requiring mechanical ventilation while awaiting orthotopic liver transplantation. Three patients died before transplantation could be performed, three died after transplantation, and four survived following successful transplantation., Methods: Plasma, urine and dialysate fluid were analysed for atracurium and its metabolites using HPLC. Neuromuscular blockade was measured using transcutaneous ulnar nerve stimulation and an accelerometer. Electroencephalography and liver function tests were performed daily., Results: Patients received atracurium infusions for a period ranging from 38 to 217 h. Six patients required continuous arteriovenous haemodiafiltration (CAVHD) to replace renal function. Atracurium mean steady state clearance was 8.6 ml/min/kg, and train-of-four recovery ratio to 75% took 63 min (range 32-108). Laudanosine clearance was markedly reduced in the non-survivors; the half-life was 38.5 hrs compared with 5.3 h in the 4 patients who underwent successful transplantation. Laudanosine accumulation could be observed in all patients before transplantation, but kinetics returned to normal after successful transplantation. The highest laudanosine level recorded was 6,860 ng/ml. There was no evidence of adverse central neurological effects attributable to laudanosine. CAVHD did not contribute significantly to clearance of atracurium or its metabolites., Conclusions: Atracurium kinetics and dynamics are near-normal even in patients with fulminant hepatic failure and renal failure; laudanosine accumulation will occur, but this is not associated with measurable central neurological effects. Implantation of a functioning liver graft results in clearance of laudanosine, which seems to be independent of renal function. Atracurium is an appropriate choice for producing neuromuscular blockade for periods of several days in patients with fulminant hepatic failure and renal impairment.

To examine the relationship between the electroencephalograph (EEG) and plasma opioid concentration, one would like to collapse the high-dimensional EEG signal into a univariate quantity. Such a simplification of the EEG is desirable because a univariate quantity can be modeled using standard nonlinear regression techniques, and because most of the information in the EEG is redundant or unrelated to drug concentration. In previous studies of the EEG response to opioids, the manner in which a univariate component was extracted from the EEG was ad hoc. In this paper, this extraction was performed optimally using a new statistical technique, semilinear canonical correlation. Data from 15 patients who received an intravenous infusion of the semisynthetic opioid alfentanil were analyzed. The components of the EEG that were nearly maximally correlated with plasma drug concentration were found, based on a standard pharmacokinetic-pharmacodynamic model. Two new EEG components were produced from the powers in the frequency spectrum of the EEG: a weighted sum of the logarithms of the powers, and a weighted sum of the powers expressed as percentages of the total power. These components both had a median R2 of 0.84, compared to median R2s ranging from 0.37 to 0.83 for five commonly used ad hoc EEG components. The new components also had less variability in R2 between subjects.

The objectives of the study were to compare the efficacy and safety of a continuous infusion (CIV) of morphine and intermittent parenteral opioids (IPO) in children with sickle cell vaso-occlusive crises (VOCs); to determine whether 50% oxygen administration through a face mask can reduce the duration of severe pain in patients receiving CIV morphine; and to measure morphine concentration at steady state for pharmacokinetic and pharmacodynamic analysis in patients receiving CIV morphine. The study was designed as a prospective, controlled, "before-and-after" evaluation of two different analgesic regimens. For patients receiving CIV morphine, there was a randomized, double-blind, placebo-controlled study of O2 vs. air. The patients were 66 children with sickle cell disease, 3-18 years old, requiring opioid therapy for severe VOC (32 patients in phase A, 34 in phase B). The analgesic regimens were as follows: phase A: meperidine, morphine, or codeine IM or IV bolus every 3 or 4 hours; phase B: morphine sulfate, loading dose 0.15 mg followed by CIV 0.04 mg/kg/hr. The infusion rate was adjusted every 8 hours according to pain and/or symptoms of opioid toxicity. Pain assessment was by behavioral observation (BPS). In terms of results, the mean opioid dose (morphine equivalent) was similar in both groups (0.032 +/- 0.020 mg/kg/hr in phase A and 0.035 +/- 0.011 in phase B). However, the duration of severe pain was significantly shorter in phase B (0.9 +/- 1.0 days) than in phase A (2.0 +/- 1.8 days). No severe opioid toxicity was observed in either group. Oxygen did not shorten the duration of severe pain compared to the placebo group (0.94 +/- 1.08 and 0.95 +/- 1.19 days, respectively) nor did it prevent the appearance of new pain sites. Pharmacokinetic analysis was performed in 24 patients of phase B. Total body clearance (TBC) of morphine was greater in children before puberty than after (40.4 +/- 10 vs. 28 +/- 11 mL/kg/min; p < 0.05). In conclusion, in children with severe VOCs, continuous infusion of morphine provides better analgesia than intermittent opioid therapy. Fifty percent oxygen inhalation had no effect on the duration of pain.

Upon their first experience with milk, fetal rats express a stretch response that is similar to the postnatal behavior exhibited by infant rats at the nipple. Fetuses also possess a functional opioid system that is activated by prenatal milk exposure. The opioid receptor antagonist naloxone and the specific kappa antagonist nor-binaltorphimine blocked the stretch response and prevented the increase in rearlimb activity that is typically induced by milk. The mu antagonist beta-funaltrexamine blocked the stretch while permitting the expression of rearlimb activity. The kappa agonist U50,488 promoted rearlimb activity in the absence of milk, whereas the mu agonist [D-Ala2,NMe-Phe4,Gly5-ol]-enkephalin (DAMGO) exerted little influence on fetal behavior. Fetuses pretreated with U50,488 stretched to nonmilk stimuli (saline or lemon), but fetuses pretreated with DAMGO did not. Opioid activation is part of a chain of events that culminates in the fetal stretch response and may be important in promoting milk ingestion during the newborn's first suckling episode.

To determine the feasibility of primary care-based ambulatory opiate detoxification (AOD) and an optimal regimen, the authors conducted a pilot study of AOD in a medical clinic comparing two regimens: clonidine and clonidine plus naltrexone. Sixty-two opiate addicts who had been referred for AOD had the following features: mean age was 34 years, 75% were male, 74% used cocaine, and 64% shared needles. Initially, 40 patients selected clonidine, 22 clonidine/naltrexone. The groups (clonidine and clonidine/naltrexone) were similar in baseline features, including: craving scores (44/100 vs. 42/100) and withdrawal scores (20/72 vs. 17/72). Overall, 61% (38/62) of initial AODs were successful, including 43% (17/40) of those using clonidine and 95% (21/22) of those using clonidine/naltrexone (p less than 0.0001). Of 45 patients who ultimately completed AOD, 78% (35/45) remained in treatment for at least one month.

Electroencephalogram (EEG) effect parameters may be useful in pharmacokinetic-pharmacodynamic modelling studies of drug effects on the central nervous system (CNS). Effect parameters derived from a quantitative analysis of the EEG appear to be perfectly suited to characterise the relationships between pharmacokinetics and pharmacodynamics of benzodiazepines and intravenous anaesthetics. EEG parameters represent many of the characteristics of ideal pharmacodynamic measures, being continuous, objective, sensitive and reproducible. These features provide the opportunity to derive concentration-effect relationships for these drugs in individuals, which yield important quantitative information on the potency and intrinsic efficacy of these drugs. The EEG techniques presented can be used to study the influences of factors such as age, disease, chronic drug use and drug interactions on the concentration-effect relationships of psychotropic drugs. An important issue is the choice of the EEG parameter to characterise the CNS effects of the compounds. More attention must be paid to evaluating the relevance of EEG parameters to the pharmacological effects of the drugs. Knowledge of the relationship between EEG effect parameters and clinical effects of drugs under different physiological and pathophysiological conditions is crucial to determining the value of EEG parameters in drug effect monitoring. Pharmacodynamic parameters derived from the concentration-EEG effect relationship may be correlated to pharmacodynamic parameters obtained from other in vitro and in vivo effect measurements. These comparisons revealed that changes in the amplitudes in the beta frequency band of EEG signals is a relevant measure of pharmacological effect intensity of benzodiazepines, which reflects their affinity and intrinsic efficacy at the central gamma-aminobutyric acid (GABA) benzodiazepine receptor complex. The exact EEG correlates of the anxiolytic, anticonvulsant, sedative and hypnotic actions of benzodiazepines have not yet clearly been elucidated. For intravenous anaesthetics, close correlations between the potency determined with EEG measurements and clinical measures of anaesthetic depth have been established, suggesting that, in principle, EEG parameters can adequately reflect depth of anaesthesia. However, more study is required to further substantiate these findings.

Electrotransport involves the transport of ionized drugs across the skin under the influence of an electric current. This method of delivery has been used for many years to deliver drugs locally to the skin or the mouth, but now it is being studied as a means of delivering drugs for their systemic effects. Opioid analgesics may be administered via this route.

Recent reviews conclude that there is some evidence that drug abusers' self-reports are reliable and valid. However, there are wide variations among studies depending upon the samples and procedures used to obtain the data. The current study was conducted to extend the findings in this area. An examination of the intake interviews and same day urinalyses on 150 patients enrolling for outpatient opioid detoxification or maintenance revealed a fairly high agreement between drug use self-reports and urinalyses. A second study (N = 70) looking at the validity of self-reported drug use at intake and at 4 weeks follow-up revealed some noticeable changes in validity measures, suggesting that contingencies on positive urine results influence self reported drug use of addicts.

Recent developments in both applied dermal physiology and in pharmaceutical technology are paving the way towards the introduction of novel routes of drug administration which will have both a direct and an indirect effect on critical care practice. Among these approaches, transdermal and transmucosal applications appear particularly promising because of the accessibility, noninvasiveness, compliance, safety, and efficacy associated with the techniques. Fentanyl, as the prototypical opioid for transdermal and transmucosal applications, and midazolam (a benzodiazepine) will ultimately be replaced with newer synthetic compounds specifically formulated for these routes of administration.

The process of nociception, the anatomy of the epidural space, and the placement of the epidural catheter are reviewed, and the pharmacology and pharmacokinetics, analgesic efficacy, and potential adverse effects of epidurally administered narcotics and local anesthetics are discussed, as well as patient monitoring standards and solution preparation guidelines for these agents. The epidural space is located between the dura mater (the outer-most membrane surrounding the spinal cord) and the vertebral canal. The site of catheter placement is determined by the dermatomes corresponding to the site of desired analgesia. The primary factors that differentiate epidural narcotics are related to their pharmacokinetic profiles. Morphine, which is hydrophilic, has a slower onset of action and a longer duration of analgesia than lipophilic compounds such as fentanyl; morphine also results in less segmentalization (the degree to which analgesia is limited to discrete dermatomal segments corresponding to the level of the epidural narcotic injection) than is seen with lipophilic compounds. Studies have shown that epidural narcotics provide superior pain relief compared with systemic narcotics. Common adverse effects associated with therapeutic doses of intraspinal narcotics include itching, nausea and vomiting, urinary retention, and sedation; respiratory depression is uncommon after epidural administration of narcotics. The most bothersome adverse effect encountered with analgesic doses of local anesthetics is paresthesia. Solutions for epidural administration must be sterile and preservative free. Epidural administration of narcotics and local anesthetics seems to provide better pain relief than conventional methods but may be associated with more bothersome adverse effects.

The anatomy and physiology of the epidural space and the mechanism of action, sites of action, and pharmacokinetics of analgesics administered by continuous epidural infusion are reviewed, and the efficacy, adverse effects, and postoperative indications for use of analgesics administered by this route are discussed. Narcotics selectively block pain conduction by occupying specific opiate receptors in the spinal cord. Local anesthetics provide analgesia by axonal membrane blockade; they also can produce nonselective sympathetic and somatic (sensory and motor) blockade in addition to analgesia. A narcotic-local anesthetic mixture should provide an additive analgesic effect, without an increase in the incidence of adverse effects. Comparative efficacy studies have shown that continuous epidural infusions of narcotics, local anesthetics, and narcotic-local anesthetic combinations, when used appropriately, may produce better analgesia than conventional bolus methods of pain relief. Continuous epidural infusions also offer a safety advantage over intermittent epidural injections because peak and trough levels of the analgesic agent are avoided. Adverse effects of epidurally administered narcotics include respiratory depression, pruritus, urinary retention, nausea and vomiting, and sedation. Adverse effects of epidurally administered local anesthetics include urinary retention, hypotension, numbness, motor weakness, tachyphylaxis, and, rarely, systemic toxicity. The cost of epidurally administered drugs is substantially higher than that for i.m. or i.v. narcotic analgesia, but this cost may be offset by other benefits such as a shorter hospital stay. Current studies suggest superior analgesia for the majority of surgical procedures with continuous epidural analgesia infusions compared with more traditional methods of providing analgesia.

Pharmacologic advances in anesthesia over the last decade have focused on drug safety, shorter durations of action, reversibility, and ease of administration. This is reflective of major changes in the focus of patient care from inpatient to outpatient settings as well as from available risk management data that support the investigation of these new drugs. The pharmacologic advances discussed included those drugs in current practice as well as experimental drugs yet to be released for general clinical use. Inhaled agents, such as isoflurane and perhaps the experimental agent, desflurane, will maintain or achieve their popularity because of the relative ease of administration and wide margins of safety. Propofol, the most recent intravenous anesthetic available for clinical use, has already gained wide acceptance because of its dual function as an induction and maintenance agent and its appropriateness for use in the ambulatory surgical population. The role of midazolam in anesthesia practice has increased to such an extent that it has largely supplanted the use of diazepam (Valium). The introduction of the antagonist, flumazenil, will undoubtedly enhance the safety and efficacy of midazolam as well as broaden its applicability of use across various patient populations. Several of the newer synthetic narcotics, such as alfentanil and sufentanil, have replaced other narcotics formerly used in anesthesia practice, such as meperidine and morphine, primarily because of their short action and lack of significant side effects. The use of muscle relaxants as a critical component of anesthetic management has led to the development of a number of new drugs in this classification. Pharmacologic management of patients under anesthesia will at some future date likely include the administration of alpha 2 agonists. Administration of these drugs can reduce anesthetic requirements of traditional agents by as much as 50%. As research continues, new drugs will be incorporated into the practice of anesthesia, ones that will promote rapid uptake, low toxicity, intense analgesia, easy reversibility, shorter durations, and fewer side effects. One measure of success relative to pharmacologic development in anesthesia is the recent and dramatic decreases in patient morbidity and mortality figures over the last decade. This attests to the rapid growth and development of not only improved patient monitoring systems but also newly improved "agents of sleep."

Rectal administration of drugs has become a standard procedure in clinical anesthesia, most notably for anorectal induction in children. Limitations of this method include low bioavailability, a wide scatter of pharmacokinetic and pharmacological results, and poor predictability of the clinical effect in any particular patient. Historically, the rectal route has been used for the administration of smoke ("fumigation") for resuscitation and various other purposes. An ether boiler for rectal application was developed by Pirogoff as early as 1847. The pharmacokinetics of rectally administered drugs are determined by the anatomical properties of the rectum and, owing to interindividual variance, this adds to the inconsistency of absorption. Aspects that can be better controlled include the drug preparation and the vehicle, with hydrophilic solutions resulting in improved absorption. Larger volumes such as are associated with lower concentrations increase the bioavailability by enlarging the mucosal surface in contact with the drug. In contrast to the hypothetical assumption that hepatic circulation may be circumvented--thus avoiding first-pass metabolism--by direct venous drainage from the rectum into the systemic circulation via the vena cava, it has been shown that hepatic clearance is the main factor affecting bioavailability. This may be due to blood flow through anastomoses interconnecting the superior, medium and inferior rectal venous systems. Resorption from the rectum is also determined by physicochemical properties of drugs. According to the pH-partition hypothesis, only the non-ionized moiety of a compound will be available for transmucosal diffusion. The degree of ionization is a function of the local (or microclimate) milieu pH and pKa of the drug; the former is close to neutral in adults but alkaline in most children. Adsorption of feces, intraluminal degradation by microorganisms, metabolism within the mucosal cell, and lymphatic drainage do not significantly affect the fate of rectally administered drugs. In clinical practice, the rectal administration of methohexital and midazolam is an established method of premedication or induction of anesthesia in children; so far, midazolam appears to be associated with fewer complications. Ketamine has been shown to be as effective and as quick-acting as methohexital, but at least in one study its use as sole induction agent was associated with respiratory distress in some cases. However, painful diagnostic or therapeutic procedures in children may be indications for the rectal administration of ketamine. Early trials with rectally administered etomidate have been abandoned since its implication in suppression of cortisol synthesis. Narcotic analgesics in a hydrogel vehicle are effective in adult pain management.(ABSTRACT TRUNCATED AT 400 WORDS)

We review current knowledge on the rectal, buccal, and sublingual routes of narcotic administration as potential alternatives to oral, intramuscular, intravenous, and subcutaneous administrations of narcotics for the management of cancer pain. Most of the experience reported in the literature is based on the use of rectal, sublingual, and buccal narcotics for the management of acute pain syndromes. Preliminary evidence suggests that both morphine sulfate and chlorhydrate can be administered rectally because there is acceptable absorption with this route even if considerable interpersonal variation exists. There are no controlled trials on the long-term use of rectal morphine for cancer pain. There are very few reports on the clinical effects of sublingual and buccal morphine, and pharmacokinetic data are often debatable. There is evidence to justify further research into all three routes of narcotic administration. At the moment rectal use is justified in clinical trials in cancer patients, but there are not enough data on the pharmacokinetics of different narcotics when administered by the buccal or sublingual routes.

The oxidative metabolism of many drugs is under genetic control. The enzyme responsible for this reaction for this group of drugs is cytochrome P-450IID6. Humans can be classified either as extensive metabolisers or, if lacking this enzyme, poor metabolisers. The incidence of poor metabolisers in caucasian subjects is 7-10%. The hepatic O-demethylation of codeine to morphine, quantitatively a minor metabolic process, represents this type of genetic polymorphism and has been studied in human pharmacokinetic studies, human urinary recovery studies, and in human and rat liver microsome experiments. Based on the current understanding that the analgesic effect of codeine is mediated primarily through morphine, one might anticipate that poor metabolisers would not obtain pain relief from codeine. The clinical significance of this polymorphism to the antidiarrhoeal and antitussive properties of codeine is not known. Others opioids (dihydrocodeine, hydrocodone, oxycodone, and thebaine) are structurally similar to codeine and their metabolism (O-demethylation at the 3 position) might also be under genetic control. Pharmacogenetics may play an important role in explaining the wide variability of the clinical response to many opioid drugs.

We have studied the kinetics of the conservative behavior of systems which are subject to the dual action of an external effector or a negative feedback. Conditions have been found under which the dual-action mechanism produces conservative behavior. Negative feedback alone was shown not to produce the conservative behavior of an enzyme-receptor system.

The comparative analgesic and sedative (narcosis potentiating) efficacy of mu and kappa opioids was studied as a function of time in rats and mice. The mu agonists, morphine and fentanyl, produced antinociceptive actions against both heat and chemical noxious agents, but the half-lives of their ED50s were longer in the writhing than in the hot plate test. The kappa agonist drugs, bremazocine, ethylketocyclazocine and pentazocine, proved to be inactive against heat nociception, and produced a potent, long-lasting analgesia in the acetic acid writhing test, similar to mu agonists. The combination of two mu agonists resulted in a synergistic interaction and a remarkable prolongation of antinociceptive action. When the kappa-drug bremazocine was coadministered with morphine, there was a significant prolongation of the duration of analgesic action, without any influence on the potency. The interactions of mu and kappa opioids with agonists and antagonists at dopamine receptors were also studied in narcosis. The time course of the naloxone-morphine antagonism in analgesiometric assays revealed similarities, when apparent pA2 values were estimated at the peak of agonist and antagonist activity, but it was different in the writhing test when the pA2 was determined 84 minutes after morphine administration (EDt1/2, half-life belonging to the ED50) while naloxone was given at its peak effect.

We report a method for controlling and adjusting plasma opioid concentration to preselected target values in individual human subjects in order to study analgesic and other effects of opioids at steady state. The method employs a computer-controlled infusion pump and an algorithm that utilizes individual subject pharmacokinetic parameters predetermined with tailoring bolus opioid doses. We used this approach to produce 3-step increases in plasma concentrations of alfentanil, fentanyl and morphine in each of 15 subjects. We maintained each plasma concentration plateau for 70 min, measured plasma opioid concentrations achieved during the infusions and analyzed the results for bias and precision of the individually tailored infusions. Our results show that pharmacokinetically tailored opioid infusions produce stable plasma opioid concentrations within 10 min for alfentanil and morphine; with each drug overall prediction error was 20% or less. Fentanyl was somewhat more difficult to control by this method than were the other 2 opioids. We conclude that individual tailoring of opioid infusions minimizes the impact of individual pharmacokinetic differences on achieving preselected plasma opioid concentrations and provides an accurate means of controlling steady-state drug concentrations for studies of concentration-effect relationships and comparisons of side-effect intensities produced by equianalgesic plasma opioid concentrations.

We used computer-controlled individually tailored infusions to study relationships between plasma drug concentration and opioid effects, and to evaluate the therapeutic margins of alfentanil, fentanyl and morphine in human subjects. In order to compare the 3 drugs, we infused each opioid to 3 different steady-state target plasma concentrations during separate 8 h test periods so that concentration-effect curves could be defined for each opioid and subject. Dental electrical stimulation produced a consistent degree of baseline experimental pain, and we measured the influence of increasing plasma opioid concentrations on pain intensity and the magnitude of pain-related evoked potentials. We also quantified ventilatory function and subjective side-effects during baseline (no drug), at the 3 target plasma concentrations with each drug. Finally, we measured actual plasma opioid concentrations during each phase of the infusion period. This procedure allowed us to calculate for each opioid the plasma concentration required to produce a 50% decrease in reported pain intensity and evoked potential amplitude (IC50). Subsequent calculation of side-effect magnitudes at the analgesic IC50s permitted direct comparisons of therapeutic margins between alfentanil, fentanyl and morphine. We found a robust relationship between plasma drug concentration and analgesic, ventilatory, and subjective-effect magnitudes for each opioid in this study. We conclude that the magnitudes of individual side-effects associated with equianalgesic, steady-state plasma concentrations of these 3 mu receptor-selective opioids do not differ across drugs.

This review presents the pharmacology of spinal opioid receptor systems which are primarily involved in pain processing. The major areas upon which we will focus are: the structure and cellular functioning of the opioid receptor systems; the physiologic effects induced by spinally administered opioids, particularly in pain modulation; and pharmacokinetic and dynamic considerations, with special attention to the problem of opioid tolerance development.

In summary, there are now available very potent narcotics, with small side effect liability. Critical care physicians should be experts in administration of intravenous narcotics and should understand the concepts behind different methods of administration. Much more patient satisfaction and safety can be obtained if as much attention is paid to how a drug is administered as to its pharmacologic actions. Intravenous administration allows rapid and almost complete control of desired effect. Intravenous access is universally available in the ICU population, and we should take every advantage of it.

Narcotics are explored in this section. Receptor theory is presented. Narcotics are broken into their specific groups (agonist, agonist-antagonist, and pure antagonist) and compared. Narcotic effects, desirable and undesirable, are related to organ systems and common problems found in ICU patients. Pharmacokinetics of classic methods of narcotic delivery are discussed and compared to newer technologies of delivery. Finally, a strategy for decision making in pain control, tying together all the concepts previously discussed, is given.

The rectal route for the administration of opioid analgesics is often forgotten by physicians seeking alternatives to the oral route. This article reviews the physiology of rectal drug absorption and such data as exists on the different opioids that have been administered by this route. Conventional fatty-based suppositories have a place in the management of chronic pain but the variability in dissolution and drug absorption limit their usefulness. Recently, sustained release vehicles have become available that offer the prospect of the attainment of steady analgesic drug concentrations with once or twice daily dosing. Early studies with the morphine hydrogel suppository suggest that it may be capable of fulfilling this prospect. Their inherent safety, as dose-dumping is impossible, will make them suitable for use in the home.

Nurses often are responsible for administering narcotic analgesics to patients with pain due to cancer or the treatment of cancer. Because of frequent use of these agents, and their various and dramatic effects throughout the body, it is important to understand their pharmacological properties and appropriate therapeutic use. This article reviews the actions and side effects, appropriate selection and use of narcotic analgesics and provides guidelines for administration.

Urine samples of 31 probands who had come in conflict with the Dangerous Drugs act and therefore had to take part in urinalysis tests where analysed during a period of 34 months. The purpose of this study was to find out whether urinalysis testing can reduce drug abuse. The urine samples were tested on morphine/codeine, cannabis and barbiturates. 28 out of 31 persons were to be tested on morphine, 13 on cannabis and 26 on barbiturates. 32% of the persons tested on morphine showed no positive results during the whole period of investigation. 3% had continuous relapses (greater than 30% positive results) during this time. A significant (x2 = 28.98) decrease of positive samples at the end of the investigation period was found. The tests on barbiturates showed no significant (x2 = 0) influence of the urinalysis on the frequency of positive results. Tests on cannabis showed a slightly significant (x2 = 4.26) increase of positive results at the end of the investigation period. Most of the test persons showed an obvious improvement of their social and family conditions during this period.

Opiate dependence is not represented by a single neuronal substrate but probably reflects actions at multiple functional sites in the central nervous system. Classical measures of opiate dependence such as escape reactions and wet dog shakes may be elicited by neural substrates in the medial thalamus and periaqueductal gray. Our work and others suggests that the region in the nucleus accumbens and its afferent and efferent connections may be an important substrate to reinforcing properties of opiates. The nucleus accumbens is also an important substrate for the reinforcing properties of stimulant drugs. These data suggest that opiate dependence may represent functional changes not only in neural substrates responsible for physical dependence, but also in brain sites responsible for the reinforcing actions of opiates. It should be noted that there was inability in the early days when the endorphins first came to the forefront, to show correlations between changes in opiate binding and endorphin levels associated with dependence. This may be due to a failure to identify functionally significant substrates that may be implicated from what one would call the top-down approach. Perhaps the "neurohumor" that Dr. Cochin was thinking about is an opioid peptide located in brain regions high in opiate receptors and functionally sensitive to opiate antagonists. New work isolating particular loci for opiate actions may point to potential sites and neurochemical substrates for opiate dependence.

The crude membrane fraction from the brain of the frog Rana ridibunda was shown to contain 0.7-0.8 pmol/mg protein for a site with high (KD = 0.1 nM) and about 3.2 pmol/mg protein for a site with lower (KD = 10-15 nM) affinity for the opiate agonist [3H]etorphine and for the opiate antagonist [3H]diprenorphine. In addition to its very high affinity for the two tritiated oripavine derivatives, the high affinity site displayed (i) a considerably reduced ability to bind the agonist but not the antagonist in the presence of Na+ ions and (ii) pronounced stereospecificity. These properties are all typical of an opioid receptor site. The lower affinity site, which was about four times as abundant as the other exhibited none of the aforementioned characteristics and is therefore probably not opioid in nature. Detailed testing of the potency of various unlabelled opioid ligands to inhibit the binding of [3H]etorphine at the high affinity site showed that the latter consists of a mixture of several types of opioid sites, including a major type with an apparent binding profile clearly different from those of mammalian brain mu, delta- and kappa-opioid sites. In particular, this major type of site, which accounted for about 70% of the opioid binding in frog brain membranes, bound mu ([D-Ala2,MePhe4,Glyol5]enkephalin), delta ([D-Thr2,Leu5]enkephalyl-Thr) and kappa (U50,488) selective ligands with much lower affinity than did mu-, delta- and kappa-opioid receptor sites, respectively.

Opioids are the mainstay of therapy for acute pain for both medical and surgical conditions. An understanding of their actions and a basic knowledge of pharmacokinetics and pharmaceutical preparation will enable a doctor to optimise the treatment of acute pain. If the basic principles are taken into account there is no reason now to allow patients to be distressed by inadequate analgesia.

Cardiopulmonary bypass is accompanied by profound changes in the organism that may alter the pharmacokinetics of drugs. Drug distribution can be altered, for example, by changes in blood flow and by haemodilution, with a decrease in protein binding; a decrease in the elimination of some drugs can be caused by impairment of renal or hepatic clearance, due, for example, to lowered perfusion and hypothermia. The subject was reviewed in the Journal in 1982, and the emphasis of the present review is on new data related to specific drugs. The following substances are dealt with: benzodiazepines, cephalosporins, digitalis glycosides, general anaesthetics, glyceryl trinitrate (nitroglycerin), lignocaine (lidocaine), muscle relaxants, nitroprusside, opiates, papaverine and propranolol. For many of these substances an abrupt decrease has been observed in serum concentration upon initiation of bypass, which is explained by haemodilution and an increase in distribution due to decreased protein binding. For nitrates and some opiates, adsorption to the bypass apparatus was shown to be important. The gradual increase in serum concentrations seen during cardiopulmonary bypass with some drugs after the initial fall is usually explained by redistribution of the drug and/or decrease in its elimination. The same phenomena are thought to explain why in the post-bypass period a concentration increase occurs, or at least a slower decrease than expected. However, drug elimination has been directly measured in only a few studies. The short duration of the bypass procedure and the continuous changes during the process hamper a rigorous pharmacokinetic evaluation. Studies allowing more precise understanding of the mechanisms underlying the observed concentration changes are needed, but are difficult to design. Similarly, more data are awaited on the pharmacodynamic and clinical consequences of the concentration changes.

A procedure is described for the extraction and determination of morphine (M), hydromorphone (HM), codeine (C) and metoclopramide (MCP) present in human plasma. The drugs are separated by reversed-phase liquid chromatography and detected amperometrically at a glassy carbon electrode. The method provides high sensitivity and selectivity and has been used successfully in bioavailability studies.

A capillary column gas chromatographic method is described for the simultaneous determination of morphine, codeine, heroin, 3- and 6-monoacetylmorphine, nalorphine, naloxone, ethylmorphine, and naltrexone. The drugs were extracted from 2 ml plasma, urine, or other biological samples, including tissue under alkaline conditions in chloroform-isopropanol-n-heptane (50:17:33, v/v), with levallorphan as an internal standard. The drugs were extracted into acid and then reextracted into chloroform after the acid had been alkalinized. After derivatization with trifluoroacetic anhydride, an aliquot was injected into a 25m capillary column equipped with a nitrogen phosphorus detector. The lower limits of detectability, extraction recovery, and the within-run and day-to-day precision of results were determined for each drug. Our results indicate that the procedure is suitable for use in overdose screening and therapeutic drug monitoring.