Opioid Pharmacology Research Articles

Acute Pain Management: A Practical Guide.

Virginia Mason Medical Center, Department of Anesthesiology, Seattle, Washington. anessl@vmmc.orgAcute Pain Management: A Practical Guide. By Pamela E. Macintyre, L. Brian Ready. Harcourt Health Sciences, 2001. Pages: 258. Cost: $36.00.“Location, location, location” is the common advice when shopping for housing and “audience, audience, audience” could be considered the corollary when shopping for a textbook. The authors of Acute Pain Management rightly state in their preface that their target audience is nurses, medical students, and junior residents. This audience will find the book useful and full of information, whereas senior residents, fellows, and pain medicine physicians may be disappointed.The introduction does a succinct job of discussing rationale for treatment of acute pain and measurements of pain, although a brief summary of evidence for beneficial effects of acute pain management on costs and outcomes would have been welcome. The chapters on pharmacology of opioids and local anesthetics do a nice job of summarizing analgesic effects, side effects, and treatment of side effects. Chapters on delivery of opioids, including patient controlled analgesia, are well written and provide very nice examples of order forms and protocols used by the authors’ institutions. The chapter on epidural analgesia is a bit weaker. Epidural opioids and continuous epidural infusions are well covered. However, the section on trouble shooting epidural analgesia fails to discuss common clinical management strategies such as changing ratios of local anesthetic to opioid to address component specific side effects (e.g. , decreasing amount of opioid to reduce risk of pruritus) or use of “multi-modal” analgesia to treat inadequate analgesia (e.g. , nonsteroidal anti-inflammatory drugs, PRN intravenous opioids). More recently investigated agents such as clonidine and epinephrine and more recent delivery techniques such as patient controlled epidural analgesia are barely mentioned, as are spinal opioids. Again, nice examples of continuous epidural infusion order forms from the authors’ institution are provided. The sections on other techniques and agents for acute pain management are quite superficial and do not begin to cover continuous peripheral nerve techniques, transcutaneous electrical stimulation, acupuncture, or nonsteroidal anti-inflammatory drugs. The section on the opioid-dependent patient will be very important for the designed audience but primarily covers systemic opioids. Epidural analgesia in this population is barely addressed. The section on acute neuropathic pain could probably be eliminated, as this area begins to crossover into chronic pain, and the space would be better devoted to the previously mentioned bare spots. Overall, this will be a helpful guide for the tar-get audience in addressing management of conventional delivery (systemic, continuous epidural infusion) of conventional agents (opioids and local anesthetics) for acute pain. This guide would also be useful for the pain medicine practitioner looking to start an acute pain service and needing to in-service staff and design order forms and protocols.FIGURE

Understanding the physiology and pharmacology of epidural and intrathecal opioids

Epidural and intrathecal opioid administration has become an important part of contemporary medical practice in a variety of clinical settings. It has been widely assumed that any opioid placed in the epidural or intrathecal spaces will produce highly selective spinally mediated analgesia that is superior to that produced by other analgesic techniques. Unfortunately, this is simply not true. In fact, multiple opioids are currently employed for spinal use despite the fact that clinical evidence has shown that spinal administration does not produce analgesia with a selective spinal mechanism or that the analgesia produced is not superior to that produced by intravenous administration. This chapter presents the basic science and clinical data available to assist clinicians in identifying which opioids are appropriate for spinal use and which are not.

Synergy between mu opioid ligands: evidence for functional interactions among mu opioid receptor subtypes.

Pharmacological differences among mu opioid drugs have been observed in in vitro and in vivo preclinical models, as well as clinically, implying that all mu opioids may not be working through the same mechanism of action. Here we demonstrate analgesic synergy between L-methadone and several mu opioid ligands. Of the compounds examined, L-methadone selectively synergizes with morphine, morphine-6beta-glucuronide, codeine, and the active metabolite of heroin, 6-acetylmorphine. Morphine synergizes only with L-methadone. In analgesic assays, D-methadone was inactive alone and did not enhance morphine analgesia when the two were given together, confirming that L-methadone was not acting through N-methyl-D-aspartate mechanisms. Both L-methadone and morphine displayed only additive effects when paired with oxymorphone, oxycodone, fentanyl, alfentanyl, or meperidine. Although it displays synergy in analgesic assays, the L-methadone/morphine combination does not exhibit synergy in the gastrointestinal transit assay. This analgesic synergy of L-methadone with selective mu opioid drugs and the differences in opioid-mediated actions suggest that these drugs may be acting via different mechanisms. These findings provide further evidence for the complexity of the pharmacology of mu opioids.

Pain Management—A Practical Guide for Clinicians

Recently I was asked to see a patient with a very difficult pain problem related to reflex sympathetic dystrophy (now known as complex regional pain syndrome). I reached for Pain Management: A Practical Guide for Physicians to find out what to do. The relevant chapter is detailed, evidence-based and well referenced. Although I cannot claim to have cured the patient of her pain as a consequence, the text (which is written by members of the American Academy of Pain Management) gave me all the up-to-date information that I needed. I have since delved into other sections of the book that are of particular interest to me. Our unit is one of several involved in a clinical trial of the use of cannabis for the control of cancer-related pain. I was therefore keen to read the chapter on the role of cannabis and cannabinoids in pain management. In his introduction, the author proposes to examine the use of cannabinoids ‘historically, scientifically and anecdotally in relation to a variety of pain syndromes’. He obviously believes strongly in the benefits of these compounds, but as yet there are few hard clinical data to support their use as analgesics. Most of the evidence is in the form of case studies or anecdotal reports—hence the strong emphasis on history and anecdote. The management of neuropathic pain is complex and is often frustrating to patient and physician alike. The chapter on neuropathic pain and its management is excellent. It gives an unbiased, evidence-based, well-referenced over-view of the current situation. It is obviously written by someone who has much clinical experience in the area and not by a laboratory-based academic reporting on what should happen on the basis of rat-tail flicks. The author stresses that it is important to have realistic expectations when treating patients with chronic nerve damage. Complete pain relief is unlikely. Improving function, providing a degree of comfort and treating associated problems are more appropriate goals. ‘The difficulty in treating this pain probably stems from our relatively poor understanding of the mechanisms and the limited efficacy of currently available analgesics’. Non-pharmacological methods may be as effective as pharmacological approaches. Patient support is paramount. There is relatively little on the use of NMDA antagonists in this chapter. This is appropriate. Despite animal studies suggesting similarities between opioid intolerance and neuropathic pain, there is little to support their use clinically and considerable concern about side-effects. Within the chapter on drug misuse and detoxification there is an interesting section on iatrogenic dependence. As more and more opioids are becoming licensed for use in benign pain, the author points to an unfortunate paradox. Whereas patients with chronic non-malignant pain are increasingly being prescribed opioids and other dependence-producing medications, pain in the terminally ill is still commonly under-treated. A frequent cry by authors in this book is for more emphasis and teaching on proper pain management techniques as opposed to treatment of all pain as acute pain. This chapter lacks a section on how to treat pain in drug abusers, a difficult and not uncommon dilemma, especially in oncology. The multitude of nerve blocks that have been used in the management of common pain syndromes are all very well described. I would have welcomed more diagrams to support the text; also, there is no discussion as to the efficacy of each technique in relation to standard analgesia. This book has a very wide scope, embracing such techniques as Koryo hand therapy, Tai Chi Chuan, magnetic stimulation and Qigong. The emphasis throughout is on pain management rather than drug treatment, which is laudable. There are lengthy discussions on how to set up and support a pain clinic and the necessity for multiprofessional input. As one of the authors points out, ‘the best pharmacotherapeutic approach to pain management is no drug therapy at all’. This might explain why the section on drug management is so short. With the recent explosion of new and alternative opioids onto the market, a somewhat deeper discussion of opioid pharmacology might have been warranted. In summary, Weiner's text is state-of-the-art on all aspects of pain and its multidisciplinary management. It rises to the fact that pain (especially chronic benign pain) is ‘the most common medical complaint of civilised man’. Unusually for a tome this large, it makes for quite a good read. It even tells you how to fix a headache.

Determinants of the behavioral effects of opioids and their antagonists: contributions of the Laboratory of Psychobiology.

The behavioral pharmacology of opioids has been influenced significantly by the research and writings of Drs. Peter B. Dews, Roger T. Kelleher, and William H. Morse, their colleagues, and their students. Their conceptual and methodological approach to the topic is reviewed briefly, and three areas of research are described to provide an empirical perspective. The objective of determining the general effects of opioids on behavior is described; the effects of opioids on schedule-controlled behavior and punished behavior are described and compared to non-opioids. The differential effects of opioid antagonists on responding reinforced by different stimuli are also presented. The conceptual and methodological approach taken by the group, as well as their discoveries in the behavioral pharmacology of opioids, will continue to exert a positive influence on the field.

Clinical pharmacology of opioids for pain.

The pharmacological effects of the opioid analgesics are derived from their complex interactions with three opioid receptor types (mu, delta, and kappa; morphine is an agonist at the mu opioid receptor). These receptors are found in the periphery, at presynaptic and postsynaptic sites in the spinal cord dorsal horn, and in the brain stem, thalamus, and cortex, in what constitutes the ascending pain transmission system, as well as structures that comprise a descending inhibitory system that modulates pain at the level of the spinal cord. The cellular effects of opioids include a decrease in presynaptic transmitter release, hyperpolarization of postsynaptic elements, and disinhibition. The endogenous opioid peptides are part of an endogenous pain modulatory system. A number of opioids are available for clinical use, including morphine, hydromorphone, levorphanol, oxymorphone, methadone, meperidine, oxycodone, and fentanyl, and their advantages and disadvantages for the management of pain are discussed. An understanding of the pharmacokinetic properties, as well as issues related to opioid rotation, tolerance, dependence, and addiction are essential aspects of the clinical pharmacology of opioids for pain.

Commentary: the role of anaesthesia in interventional radiology.

‘‘When you’ve got a hammer everything lookslike a nail’’… Interventional radiology came ofage with the medical profession’s desire to devel-op minimally invasive therapies. One of the greatappeals of interventional radiology was that mostprocedures were carried out under local anaes-thesia, occasionally supplemented by iv sedation.This was embraced by all, as it allowed proce-dures to be undertaken on a day-case or shortstay basis thus reducing the nurse and wardburden, it negated the need for the presence of ananaesthetist and Operating Department Assistant(ODA), and it did not use valuable theatre time.However, is this all-pervading minimalistic culturein the best interest of either the patient or theradiologist?Historically, neuroradiologists have maintainedclose links with anaesthetists through their needfor total patient compliance in carrying outboth diagnostic and therapeutic neuroradiologicalprocedures. General anaesthesia ensures patientimmobility and allows controlled apnoea, permit-ting optimal image acquisition and treatmentdelivery. More importantly, experience has shownthat should a complication occur during a pro-cedure, such as aneurysm rupture, it is impossibleto control the situation by coil delivery anddetachment unless the patient remains absolutelyimmobile. These gold standards of anaesthesia arebecoming increasingly necessary in general inter-ventional work. It is no longer appropriate for theoperator/anaesthetist role to be borne by the inter-ventional radiologist alone. Reports for training ofnon-anaesthetic staff in the provision of sedation,monitoring and recovery of patients have beenpublished [1]. The advice includes the need to bewell versed in the pharmacology of opioids, benzo-diazepines and their respective reversal agents;that staff need to be trained in the recovery andmonitoring of patients and need 5 yearly up-dates in resuscitation techniques such as advancecardiac life support. In spite of these reports,recent media reports have again highlighted theincrease in mortality rates in hospital patientsundergoing procedures using sedation techniqueswhen they are carried out by non-anaestheticpersonnel.Assessment of patients prior to sedation is atbest cursory, usually taking the form of a sim-plified patient checklist. Most radiological unitsdo not routinely use the categories describedby the American Society of Anaesthesiologists.Although sedation techniques are safe and with-out mishap in the majority of individuals, thereare certain patient groups in whom cautionshould be exercised, for example extremes ofage [2], morbid obesity or wasting, active bleedingand concurrent systemic illness (cerebrovascular,cardiovascular, respiratory, liver or renal disease,infection and blood dyscrasias). Radiologicalinvestigation of children is a case in point. MRIis becoming increasingly used in the paediatricpopulation as it produces excellent cross-sectionalimages without a radiation burden. MRI requiresthe patient to be completely immobile for a rela-tively long period of time in a rather noisy andenclosed space. To achieve this, dedicated pae-diatric centres have established nurse-led sedationservices, with a high published success rate andno adverse respiratory events [3], a practice fromwhich many lessons can be learnt.It is in high risk groups that more and more‘‘minimally invasive’’ interventional techniquesare being undertaken. As a result, we are makingourselves more vulnerable to the possibility ofsuboptimal practice in the use of sedation becauseof an increase in the unpredictable and unreliableresponse in these patients to the administeredagents. Frequently, analgesia in the form ofopioids is given as an adjunct to iv sedation, soadding to the difficulties in management of thepatient’s airway and respiratory depression.Together, these agents are synergistic in theirunwanted side effects such as decreasing patientcooperation and increasing irritability. Conver-sely, the increasing complexity of interventionalprocedures necessitates greater control over thedegree of patient compliance if treatments are

The effects of heroin on prolactin levels in male rhesus monkeys: use of cumulative-dosing procedures.

There is considerable evidence that mu opioid receptors are involved in the regulation of anterior pituitary function. For example, in nonhuman primates and humans, mu agonists generally increase prolactin (PRL) levels. In contrast, mu antagonists decrease or have no effect on PRL levels. The goal of this study was to assess the potential utility of cumulative-dosing procedures to evaluate the endocrine effects of mu opioid receptor ligands. The effects of single and multiple, cumulative doses of the mu agonist heroin and the mu-selective antagonist quadazocine on PRL levels were investigated in four male rhesus monkeys. Cumulative dose-response curves were determined by infusing increasing drug doses at 60 min intervals over 290 min. Blood samples for PRL analysis were collected at 25 and 50 min after each cumulative infusion. Samples were collected at similar time points following single drug dose administration. Heroin (0.01-0.32 mg/kg, IV) administration dose-dependently increased PRL levels. Maximum levels of heroin-induced PRL levels were equivalent after single and cumulative doses. Quadazocine alone (0.032-1.0 mg/kg, IM) did not alter PRL levels significantly. However, quadazocine (0.1 mg/kg, IM) antagonized heroin-stimulated increases in PRL levels and produced a significant rightward shift in the heroin dose-effect curve. These data suggest that a cumulative-dosing procedure similar to that used in behavioral pharmacology may be useful to study the endocrine pharmacology of mu opioids in rhesus monkeys.

Trends in the pharmacology of opioids: implications for the pharmacotherapy of pain

Some 25 years ago, it was popular to write a figurative equation for drug treatment:Patient+drug→effect. Clearly, this was too simplistic for the reliable pharmacotherapy of pain. The ‘patient’ with pain is a complex individual and the ‘drug’ is not the same in effect to every patient, regardless of being an opioid analgesic. Besides, the ‘effect’ needs specification: it really means an acceptable balance between therapeutic and side-effect—to that patient. These days, neural plasticity and neuromodulation associated with nociception are well-known. Psychological involvement in the physical domain of nociception is similarly well-known. Given these complexities, it is surprising that the pharmacological control of pain through the application of relatively simple analgesics can be so effective. Opioid analgesics have been administered by every possible route. Because the degree of invasion of the patient differs between routes, the balance between simplicity, aesthetic appeal, and efficacy of the various routes needs to be considered. The effectiveness of opioid analgesics depends in large measure on the application of the right agent, in the right dose, by the right route, at the right time for that patient. To assist in this task, researchers have produced patient-controlled analgesia and ‘pharmacologically engineered’ analgetic molecules to achieve receptor selectivity and pharmacokinetic predictability. Also, much relevant data concerning the time courses of analgetic drug (±metabolite) concentrations in the body and in the ways in which these properties are modified by different normal and pathophysiological variations have been gathered, and the philosophy of ‘opioid rotation’ has arisen to maintain therapeutic benefits when tolerance or metabolite-induced side-effects prevail. This essay discusses some of the trends in opioid pharmacotherapy over the past 25 years.

Recent advances in opioid pharmacology

Despite their many and sometimes life-threatening side-effects, opioids in general and morphine in particular are valuable and potent painkillers. This article describes recent developments in sex-related differences in opioid (morphine) pharmacodynamics, morphine metabolites, the nociceptin/orphanin FQ receptor system, acute opioid tolerance and opioid-induced side-effects, such as opioid-induced respiratory depression and itch, and P-glycoprotein modulation of opioid effect.

Update on Opioid and Analgesic Pharmacology

One of the most remarkable advances in the past decade has been in unraveling the molecular processes in opioid pharmacology. There have also been substantial advances in our understanding of the mechanisms involved in the processing of nociceptive information. It has become obvious that this is a very complex process, involving multiple neuropeptides, neurotransmitters, and their respective receptors. These advances have led to exciting new developments in the management of acute and chronic pain. These advances will be surveyed in this review.

Opioid Sensitivity of Chronic Noncancer Pain.

Virginia Mason Clinic Seattle, Washington.anedgm@vmmc.orgOpioid Sensitivity of Chronic Noncancer Pain. Edited by E. Kalso, H. J. McQuay, Z. Wiesenfeld-Hallin.Seattle, International Association for the Study of Pain, 1999. Pages: 397. Price: $68.00 (International Association for the Study of Pain member price: $44.20).“Opioids do not work for chronic pain.”“Opioids do not work for neuropathic pain.”“People with chronic noncancer pain who are prescribed opioids will become addicted.” How often have you heard one or more of these shibboleths? How often have you said one or more of them? You may need to read this book.No? Do you know how and where opioids work? Exactly? Do you know where receptors for opioids are produced or how inflammation or rhizotomy affects that process? Do you understand the molecular basis for the weak effect of most opioids on most allodynia?Most anesthesiologists need to read this book. It is one book in the series published by the International Association for the Study of Pain entitled “Progress in Pain Management and Research” and is a compilation of 24 of the papers presented at the first international research symposium of the International Association for the Study of Pain in late 1998. Therein lie the reasons for some of the problems and some of the highlights of the book. The papers presented are primarily a mix of literature reviews and reports of personal clinical and basic research. The result is a solid overview of the current science of opioids and their uses in animal and human pain models.The book is divided into four sections, dealing with opioid receptors, the pharmacology of opioids, the “sensitivity” of opioids in various pain states, and chronic pain states and the effectiveness of opioids in each.Overall, this book provides an excellent review of the current state of opioid and pain transmission science in general and the specific research that pertains to the use of these medications in chronic pain. In some places, it reads as well as a mystery novel in the description of the researchers’ efforts to ferret out specific answers to questions regarding receptor or opioid characteristics.There are some flaws. Some of these accounts are bogged down in unnecessary detail, and in-text references sometimes fill up so much of the sentence structure that the meaning is lost. Also, as might be expected in a book of 24 independently (and simultaneously) written articles on such a specialized subject, there is a fair amount of overlapping information. This is not all bad because some of the concepts are bound to be new to some of the readers and bear reiteration. However, the editors could have made better use of this situation by referencing related portions of the text to each other specifically by page number (rather than using the frustrating term “elsewhere”). The book could have been made more useful to a wider readership had the editors included a glossary of terms and concepts with references to the several portions of the book that dealt with each. Tables and graphs are spare and clear in meaning for the most part, although sometimes (chapter 6) they are too remote from their discussion in the text. However, there are certain chapters (1, 5, 6, 8, 18, 19, 22, and 24) that should be required reading for any physician who prescribes opioids—and for all anesthesiologists.In summary, all pain and opioid researchers and all physicians who treat patients with chronic pain should own and read most of this book. It should also be read by those anesthesiologists who wish to review the pharmacology and pharmacokinetics of opioids and their receptors. Those who are interested in the near future of the science of the physiology of pain and its relief will find many fascinating, new ideas here. Finally, those who wish to refute cogently the supporters of the use of codeine and meperidine and who wish to explain to their surgical colleagues why meperidine is of no advantage in the presence of biliary disease will enjoy wielding this tome in the operating room. That should be almost all anesthesiologists.

Opioids and their proper use as analgesics in the management of head and neck cancer patients

Opioid analgesics play an important part in the interdisciplinary management of head and neck cancer patients. Acute pain during the initial treatment period and chronic pain after treatment may be undertreated by head and neck surgeons because of unwarranted fear of the opioid side effects and toxicities. Properly used, opioid analgesics are among the safest and most effective medications in the armamentarium of the head and neck surgeon. Knowledge of opioid pharmacology can help surgeons treat pain aggressively in patients while managing side effects and toxicities. This understanding can also address the unique problems in pain management presented in head and neck cancer patients attributable to the involvement by the disease of the aerodigestive tract, which interferes with the oral route of administration of opioid analgesics. Significant difficulties in the use of opioid analgesics arise when the patient is a substance abuser. This article discusses the basic principles of opioid pharmacology, discusses opioid use in head and neck cancer patients, and provides guidelines on the use of opioids in the substance abuser. (Am J Otolaryngol 2000;21:244-254. Copyright © 2000 by W.B. Saunders Company)

Experimental arthritis in the rat does not alter the analgesic potency of intrathecal or intraarticular morphine.

To explore further the role of inflammatory processing on peripheral opioid pharmacology, we examined whether the potency of intraarticular (i.a.) or intrathecal (i.t) morphine in tests of thermal and mechanical nociception changed during the induction of experimental arthritis in the rat. Thermal nociception by i.t. morphine (3, 10, and 50 micrograms) or i.a. morphine (100, 1000, and 3000 micrograms) was assessed by means of a modified Hargreaves box ever) 28 h. Mechanical antinociception was determined for the largest applied doses of morphine using von Frey hairs. Morphine produced dose-dependent thermal antinociception after i.t. or i.a. administration: a 50% increase in maximum antinociceptive thermal response (50% effective dose) was produced by i.t. doses of 9.7 micrograms at the start and 9.1 micrograms at the end of this 28-h observational interval, whereas after i.a. administration, 50% effective dose values were 553 micrograms at the start and 660 micrograms at the end. The largest applied dose of either i.t. or i.a. morphine produced mechanical antinociception. On Day 1, the antinociceptive effect for mechanical nociception (expressed as the area under the curve of the percentage of maximal possible effect values at 0.5, 1, 2, and 4 h) was 68% for i.t. morphine 50 micrograms and 53% for i.a. morphine 3000 micrograms. Neither result differed from the corresponding area under the curve values on Day 2. Naloxone administered either i.t. or i.a. abolished the antinociceptive action of morphine given at the same site. We conclude that, although morphine has a peripheral analgesic site of action in a rat arthritis model, its potency for both i.a. and i.t. routes of administration does not change during the onset of arthritis. In this animal study, we showed that the administration of morphine modulates thermal and mechanical antinociception at central and peripheral sites in inflammatory pain.

Opioid Equianalgesic Calculations

Among the knowledge required by healthcare professionals to manage pain is an understanding of the differences between opioid agents and formulations. As the list of new opioid formulations continues to grow, it is increasingly important that clinicians understand the basic pharmacology of these analgesics and how to calculate equianalgesic doses. Administering an equianalgesic dose increases the likelihood that the transition to another opioid or route will be tolerated without loss of pain control or excessive side effects. Although calculation of equianalgesic doses requires relatively simple mathematical skills, few clinicians are prepared to compute them. The purpose of this article is to provide a basic review of the pharmacology of opioids, explain how to calculate an equianalgesic dose, and briefly describe some of the current controversies of the relative potencies of opioids listed in equianalgesic tables.

Analgesics and Pain

There has been a substantial increase in the use of analgesics for pain management in the last 10 years. Traditionally, veterinarians have not been trained in the identification of or monitoring of patients that are in pain, even though an evaluation of pain is inherent in assessing improvement in many medical and surgical diseases. Until recently, the physiology and pharmacology of opioids, NSAIDs, local anesthetics, and alpha 2 agonists were taught, but the therapeutic role of these drugs was generally believed to be related to restraint, anesthesia, or control of inflammation rather than to pain management.

Testing a multimedia module in cancer pain management.

The technologies for providing better pain management for cancer patients are widely available, but barriers still exist that prevent their optimal use. One of the most important barriers is a knowledge deficit among primary care physicians in adequate pain assessment, in opioid pharmacology, and in the importance of an interdisciplinary approach to the management of pain. The authors prepared a CD-ROM multimedia cancer pain management module to overcome the physician knowledge barrier. Tests of the module with primary care physician and primary care resident volunteers indicate that the cancer pain management multimedia module meets its educational objectives.

Opioids: From receptors to clinical application

Opioid analgesia is produced by activation of the endogenous opioid system, which physiologically modulates nociceptive transmission.Two main strategies are used: decrease the inactivation of transmitters (enkephalinase inhibitors) and activation of the opioid receptors by opioid analgesics. Cloning the receptors (ώ opioid receptor, d opioid receptor, k opioid receptor) has confirmed their anatomic distribution and further defined their biochemical and pharmacologic properties. Peripheral opioid receptors may have therapeutic relevance in specific disease states and induce local opioid analgesia without central side effects. Clinically used opioid analgesics are classified according to receptor interaction, and ώ-agonists are most effective.They have no ceiling effect for antinociception, but side effects prevent the use of the doses required for complete analgesia. Most recent developments in opioid pharmacology include new targets (enzymes) and changes in the pharmacokinetic profile of conventional ώ-opioids. Further research in the molecular mechanisms of opioids may result in the introduction of more effective and less harmful compounds.

Knowledge and Attitudes of Health-Care Providers Toward Cancer Pain Management: A Comparison of Physicians, Nurses, and Pharmacists in the State of New Hampshire

The knowledge and attitudes toward cancer pain management of physicians, nurses, and pharmacists in the state of New Hampshire were examined through the use of a statewide survey. Many of the providers who completed the survey, and thus indicated that they treated patients with cancer pain on a regular basis, were not pain or oncology specialists. Most of these providers were quite well informed about the fundamentals of cancer pain management. Approximately 90% of providers in all three groups were not concerned about addiction among cancer patients. Yet, there was a small percentage of providers who responded in less than optimal ways to items dealing with opioid pharmacology, pain assessment, and the importance of pain relief. Comparison of responses among provider groups indicated that nurses were the most knowledgeable and pharmacists the least knowledgeable about pain assessment. Physicians were the most knowledgeable regarding opioid pharmacology but seemed the least committed to providing optimal pain relief. Further analysis identified a small group of physicians that included a disproportionately high percentage of family practitioners and surgeons who consistently responded in less than optimal ways to items dealing with the importance of pain relief. The results of this study indicate a continuing need for broad-based educational programs in cancer pain management and for new initiatives focused on practitioners who see relatively few cancer patients and may have difficulty accessing traditional educational programs.

Effect of continuous spinal remifentanil infusion on behaviour and spinal glutamate release evoked by subcutaneous formalin in the rat

Injection of formalin into the hind paw of the rat evokes a biphasic nociceptive behavioural response, which is considered to be an animal model of postoperative pain in humans. The initial response (phase 1) is caused by activation of peripheral nociceptors and is followed by a second phase attributed to ongoing activity in primary afferents and increased sensitivity of dorsal horn neurones. The latter effect is thought to result from glutamate-mediated N-methyl-D-aspartate receptor activation. In studies to date it has been difficult to discriminate mechanisms underlying phase 1 and phase 2 events because of the long-lasting half-times of intrathecally administered opioids. To further understanding of the opioid pharmacology of the two different phases of the formalin test, we have studied behavioural activity and spinal glutamate release after intrathecal administration of remifentanil, a new short-lasting mu opioid. Intrathecal remifentanil 3 micrograms microliter-1 min-1 delivered during phase 1 inhibited behavioural response during phase 1 (100%), but did not abolish subsequent phase 2 behavioural activity completely (67 (12) %). Intrathecal remifentanil administered separately in phase 1 and phase 2 revealed a similar ED50 (0.2 microgram microliter-1 min-1) for inhibition of the behavioural responses. In vivo, spinal microdialysis showed incomplete reduction in glutamate concentrations in response to intrathecal remifentanil administration; this in turn inhibited phase 1 behavioural responses. Therefore we contend that supramaximal doses of intrathecal remifentanil sufficient to inhibit phase 1 activity still permitted sufficient glutamate release to allow spinal facilitation. Incomplete suppression of spinal excitatory neurotransmitter release by intrathecal opioids is consistent with spinal wind-up that is triggered during phase 1 and results in phase 2 afferent drive. This might reflect one of the mechanisms underlying post-operative pain.