Delta-9-tetrahydrocannabinol and Cannabidiol for Pain: Preclinical and Clinical Models.

Cocaine use disorder is a persistent public health problem for which no widely effective medications exist. Self-administration procedures, which have shown good predictive validity in estimating the abuse potential of drugs, have been used in rodent, nonhuman primate, and human laboratory studies to screen putative medications. This review assessed the effectiveness of the medications development process regarding pharmacotherapies for cocaine use disorder. The primary objective was to determine whether data from animal and human laboratory self-administration studies predicted the results of clinical trials. In addition, the concordance between laboratory studies in animals and humans was assessed. More than 100 blinded, randomized, fully placebo-controlled studies of putative medications for cocaine use disorder were identified. Of the 64 drugs tested in these trials, only 10 had been examined in both human and well-controlled animal laboratory studies. Within all three stages, few studies had been conducted for each drug and when multiple studies had been conducted conclusions were sometimes contradictory. Overall, however, there was good concordance between animal and human laboratory results when the former assessed chronic drug treatment. Although only seven of the ten reviewed drugs showed fully concordant results across all three types of studies reviewed, the analysis revealed several subject-related, procedural, and environmental factors that differ between the laboratory and clinical trial settings that help explain the disagreement for other drugs. The review closes with several recommendations to enhance translation and communication across stages of the medications development process that will ultimately speed the progress toward effective pharmacotherapeutic strategies for cocaine use disorder.

Mesenchymal stem cell therapy for acute respiratory distress syndrome: a light at the end of the tunnel?

Diffuse noxious inhibitory controls and conditioned pain modulation: a shared neurobiology within the descending pain inhibitory system?

This narrative review summarizes the evidence for the most commonly used intra-cardiac arrest adjunctive medications and routes of administration and discusses promising new therapies from preclinical animal models. Large trials on the administration of calcium as well as the combination of vasopressin and glucocorticoids during cardiac arrest have been published. Calcium administration during cardiopulmonary resuscitation does not improve outcomes and might cause harm. Vasopressin and glucocorticoid administration during cardiopulmonary resuscitation improve the chance of return of spontaneous circulation but has uncertain effects on survival. We identified a total of seven ongoing clinical trials investigating the potential role of bicarbonate, of vasopressin and glucocorticoids, and of intravenous versus intraosseous vascular access. Several medications such as levosimendan and inhaled nitric oxide show promise in preclinical studies, and clinical trials are either planned or actively recruiting. Large trials on intra-cardiac arrest administration of calcium and vasopressin with glucocorticoids have been performed. Several trials are ongoing that will provide valuable insights into the potential benefit of other intra-cardiac arrest medications such as bicarbonate as well as the potential benefit of intravenous or intraosseous vascular access.

What’s New in the Management of Pain in Children

Physiology and Treatment of Pain

A wide array of positron emission tomography (PET) ligands have been developed that provide information relevant to multiple aspects of addiction (1-3).Locations of targets are approximated on this diagram, which is color-coded by functional roles.On the presynaptic side (pink), targets include neurotransmitter precursors (orange, example [ 18 F]-fluorodopa, FDOPA), modulatory receptors (yellow, examples [ 11 C] GR103545, [ 11 C] LY27950509 and [ 18 F] LY2459989 for kappa opioid receptors, KOR; [ 18 F]FMPEP for cannabinoid 1 receptors, CB1), and neurotransmitter reuptake transporters (light green, examples [ 11 C] PE2I and [ 18 F] FE-PE2I for the dopamine transporter, DAT).On the postsynaptic side (purple), targets include neurotransmitter receptors (blue, examples [ 11 C] raclopride and [ 11 C]-(1)-PHNO for dopamine D 2 and D 3 receptors, D 2 R; [ 11 C] carfentanil for mu opioid receptors, MOR; [ 18 F] LY2459989 for both mu and kappa opioid receptors; 2-[ 18 F]fluoro-3-(2(S)-azetidinylmethoxy) pyridine for nicotinic acetylcholine receptors, nAChR).Some PET ligands target more generic functions.[ 18 F]-fluoro-deoxy-glucose (FDG) PET provides a measure of cerebral metabolic rate.

The Acute Respiratory Distress Syndrome (ARDS) is a devastating clinical condition that is associated with a 30–40% risk of death, and significant long term morbidity for those who survive. Mesenchymal stromal cells (MSC) have emerged as a potential novel treatment as in pre-clinical models they have been shown to modulate inflammation (a major pathophysiological hallmark of ARDS) while enhancing bacterial clearance and reducing organ injury and death. A systematic search of MEDLINE, EMBASE, BIOSIS and Web of Science was performed to identify pre-clinical studies that examined the efficacy MSCs as compared to diseased controls for the treatment of Acute Lung Injury (ALI) (the pre-clinical correlate of human ARDS) on mortality, a clinically relevant outcome. We assessed study quality and pooled results using random effect meta-analysis. A total of 54 publications met our inclusion criteria of which 17 (21 experiments) reported mortality and were included in the meta-analysis. Treatment with MSCs, as compared to controls, significantly decreased the overall odds of death in animals with ALI (Odds Ratio 0.24, 95% Confidence Interval 0.18–0.34, I2 8%). Efficacy was maintained across different types of animal models and means of ALI induction; MSC origin, source, route of administration and preparation; and the clinical relevance of the model (timing of MSC administration, administration of fluids and or antibiotics). Reporting of standard MSC characterization for experiments that used human MSCs and risks of bias was generally poor, and although not statistically significant, a funnel plot analysis for overall mortality suggested the presence of publication bias. The results from our meta-analysis support that MSCs substantially reduce the odds of death in animal models of ALI but important reporting elements were sub optimal and limit the strength of our conclusions.

Therapeutic potential of minor cannabinoids in psychiatric disorders: A systematic review

Despite the large amount of human and experimental studies no effective (prophylactic) treatment exists for chemotherapy induced peripheral neuropathy (CIPN), a disabling side effect of many cancer treatments. One of the underlying reasons for this could be that often the preclinical animal models used are not the best representation of the clinical situation. We therefore present a systematic summary and comparison of all animal models currently described in literature for CIPN focusing on stimulus evoked pain-like behaviour and neurophysiological alterations in nerve function (650 included papers, and a comparison of 183 models), that resulted in a clear overview of the most effective and robust CIPN models using an administration route used in clinical practice. Using our three-step approach (step 1: efficacy; step; 2 robustness and step 3: mimicking the clinical situation) we show that all mice CIPN models treated with either paclitaxel or cisplatin using an administration route used in clinical practice seem suitable models. Three specific models using paclitaxel or cisplatin that stand out are 1) C57BL/6 female mice receiving paclitaxel and 2) CD1 male mice receiving paclitaxel and 3) C57BL/6 male mice receiving cisplatin. This overview may help scientists selecting suitable CIPN models for their research. We hypothesize that by using effective and robust animal models that mimic the clinical situation as much as possible, the translational value of preclinical study results with respect to the potential of identifying promising treatments for CIPN in the future, will prove. The methodology described in this paper, aimed at comparing animal models, is novel and can be used by scientist in other research fields as well.

Cannabis has been used for centuries for its medicinal properties. Given the dangerous and unpleasant side effects of existing analgesics, the chemical constituents of Cannabis have garnered significant interest for their antinociceptive, anti-inflammatory and neuroprotective effects. To date, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) remain the two most widely studied constituents of Cannabis in animals. These studies have led to formulations of THC and CBD for human use; however, chronic pain patients also use different strains of Cannabis (sativa, indica and ruderalis) to alleviate their pain. These strains contain major cannabinoids, such as THC and CBD, but they also contain a wide variety of cannabinoid and noncannabinoid constituents. Although the analgesic effects of Cannabis are attributed to major cannabinoids, evidence indicates other constituents such as minor cannabinoids, terpenes and flavonoids also produce antinociception against animal models of acute, inflammatory, neuropathic, muscle and orofacial pain. In some cases, these constituents produce antinociception that is equivalent or greater compared to that produced by traditional analgesics. Thus, a better understanding of the extent to which these constituents produce antinociception alone in animals is necessary. The purposes of this review are to (1) introduce the different minor cannabinoids, terpenes, and flavonoids found in Cannabis and (2) discuss evidence of their antinociceptive properties in animals.

Approximately 7 million people are affected by acute myocardial infarction (MI) each year, and despite significant therapeutic and diagnostic advancements, MI remains a leading cause of mortality worldwide. Preclinical animal models have significantly advanced our understanding of MI and have enabled the development of therapeutic strategies to combat this debilitating disease. Notably, some drugs currently used to treat MI and heart failure (HF) in patients had initially been studied in preclinical animal models. Despite this, preclinical models are limited in their ability to fully reproduce the complexity of MI in humans. The preclinical model must be carefully selected to maximise the translational potential of experimental findings. This review describes current experimental models of MI and considers how they have been used to understand drug mechanisms of action and support translational medicine development. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc.

Peripheral arterial disease (PAD) usually results from atherosclerosis and associated thrombosis and limits blood supply to the lower limbs. Common presenting symptoms include intermittent claudication (IC), rest pain and tissue loss. When limb viability is threatened, known as critical limb ischaemia (CLI), surgical and endovascular interventions are frequently undertaken; however, these are not always successful and ultimately major amputation may be required. There is significant interest in developing new therapeutic approaches to manage PAD which can be applied to patients unlikely to benefit from interventional approaches. Many of the therapeutic agents successful in inducing angiogenesis and arteriogenesis in pre-clinical animal models of PAD have failed to have efficacy in human randomized control trials. One possible reason for this inability to translate findings to patients could be the typeof pre-clinical animal models used. In the present review, we describe currently available pre-clinical models of PAD and discuss the advantages and disadvantages of the available models. A detailed assessment of the currently available pre-clinical animal models shows major limitations such as variability in the surgical procedure used to induce limb ischaemia, variability in the strains of rodents used, lack of risk factors incorporated into the model and lack of standardized functional outcomes. The most commonly used outcome assessments in studies within pre-clinical models differ from those employed in clinical trials within PAD patients. Most current pre-clinical models are designed to produce acute ischaemia which leads to muscle necrosis and inflammation. Patients, however, most commonly present with chronic ischaemia suggesting that more representative models are needed to evaluate therapeutic modalities that can be potentially translated to clinical practice.

Developed by the Task Force on Pain Management, Cancer Pain Section: F. Michael Ferrante, M.D., F.A.B.P.M. (Chair), Philadelphia, Pennsylvania; Marshall Bedder, M.D., F.R.C.P.(C.), Portland, Oregon; Robert A. Caplan, M.D., Seattle, Washington; Hui-Ming Chang, M.D., Houston, Texas; Richard T. Connis, Ph.D. (Methodologist), Woodinville, Washington; Patricia Harrison, M.D., Buffalo, New York; Robert N. Jamison, Ph.D, Boston, Massachusetts; Elliot J. Krane, M.D., Stanford, California; Srdjan Nedeljkovic, M.D., Boston, Massachusetts; Richard Patt, M.D., Houston, Texas; and Russell K. Portenoy, M.D., New York, New York.Submitted for publication November 28, 1995. Accepted for publication December 1, 1995. Supported by the American Society of Anesthesiologists, under the direction of James F. Arens, M.D., Chairman of the Ad-Hoc Committee on Practice Parameters. Approved by the House of Delegates, October 22, 1995. A list of the articles used to develop these guidelines is available by writing to the American Society of Anesthesiologists.Address reprint requests to the American Society of Anesthesiologists: 520 North Northwest Highway, Park Ridge, Illinois 60068-2573.Click on the links below to access all the ArticlePlus for this article.Please note that ArticlePlus files may launch a viewer application outside of your web browser.Key words: Pain: cancer. Practice guidelines: cancer pain management. Cancer: supportive care; symptom management.Practice guidelines are systematically developed recommendations that assist the practitioner and patient in making decisions about health care. These recommendations may be adopted, modified, or rejected according to clinical needs and constraints.Practice guidelines are not intended as standards or absolute requirements. The use of practice guidelines cannot guarantee any specific outcome. Practice guidelines are subject to revision from time to time as warranted by the evolution of medical knowledge, technology, and practice. The guidelines provide basic recommendations that are supported by analysis of the current literature and by a synthesis of expert opinion, open forum commentary, and clinical feasibility data (Appendix 1).A. Definition of Cancer Pain. For these guidelines, cancer pain is defined as pain that is attributable to cancer or its therapy. The Task Force has not given preference to literature based on any particular system of definition or classification of cancer pain.B. Purpose of Guidelines for Cancer Pain Management. The purpose of these guidelines is to: (1) optimize pain control; (2) minimize side effects, adverse outcomes, and costs; (3) enhance functional abilities and physical and psychological well-being; and (4) enhance the quality of life for cancer patients.C. Focus. These guidelines focus on the knowledge base, skills, and range of interventions that are the essential elements of effective management of pain and pain-related problems in patients with cancer. The guidelines recognize that the management of cancer pain occurs within the broader context of supportive care, which also encompasses other quality of life concerns (e.g., functional status, psychosocial well-being).The guidelines recognize that comprehensive pain management by anesthesiologists may not be feasible in every clinical setting. However, aspects of these guidelines may be useful when comprehensive pain management cannot be offered.The Task Force recognizes that therapies used to modify the underlying cause of pain may improve analgesia and outcome. Commonly used approaches include radiotherapy, surgery, and chemotherapy. The decision to implement primary therapy should be based on a comprehensive assessment of risks and benefits and are outside the scope of these guidelines.D. Application. The guidelines are intended for use by anesthesiologists and individuals who deliver care under the direct supervision of anesthesiologists. The guidelines apply to patients of all ages and with all types of cancer.The literature suggests that a comprehensive cancer pain evaluation is associated with improved analgesia. The Task Force and panel of consultants support the conduct of a comprehensive pain evaluation. In the opinion of the Task Force and consultants, effective cancer pain management requires a clear understanding of the etiology and pathophysiology of the pain.Recommendations:1. General Constructs. The Task Force identifies four fundamental features that should guide the comprehensive evaluation of the patient with cancer pain.a. The patient's general medical condition and the extent of disease must be assessed.b. A knowledge of common pain syndromes is a prerequisite for conducting a cancer pain evaluation. Common pain syndromes include but are not limited to bone metastases, abdominal (visceral) pain, neuropathic pain (e.g., peripheral neuropathies, acute herpes zoster and postherpetic neuralgia, plexopathies), and mucositis.c. A knowledge of oncologic emergencies (e.g., hypercalcemia, spinal cord compression, cardiac tamponade, superior vena cava syndrome) is also required to conduct a comprehensive cancer pain evaluation.d. A thorough knowledge of the modalities that can be employed in the treatment of painful crisis (i.e., pain emergency) is also necessary.2. Elements. The Task Force identifies six essential features of a comprehensive evaluation and treatment plan. These features are outlined below (Table 1Template 1).a. History: A complete history includes a general medical and oncologic history with a description of the extent of disease and prognosis. A pain history should include: (1) the quality of the pain (e.g., "burning", "aching"), (2) pain intensity (i.e., numeric, categorical, or visual analog scales), (3) spatial relationships of the pain (i.e., location, areas of radiation), (4) factors that palliate or provoke pain, (5) temporal characteristics of the pain (i.e., continuous, episodic), (6) duration of the pain, (7) course of the pain (e.g., stable, progressive, "crescendo"), and (8) associated features of the pain (e.g., numbness, weakness, vasomotor changes).b. Psychosocial evaluation: A psychosocial evaluation should include: (1) the presence of psychological symptoms (e.g., anxiety, depression), (2) indicators of psychiatric disorder (e.g., delirium, major depression), (3) investigation of the "meaning" of the pain to the patient and his or her significant others, (4) changes in mood state, (5) premorbid and current coping mechanisms, (6) family function, (7) the availability of psychosocial support systems, and (8) assessment of the patient's expectations and preconceptions regarding pain management (e.g., fear of addiction surrounding opioids, psychostimulants).c. Physical examination: A physical examination should include general medical and neurologic examinations and a specific examination of the site of pain and surrounding anatomic regions.d. Impression and differential diagnosis: The findings of the history and physical examination should be used to determine the probable etiology and pathophysiology of the pain.e. Diagnostic evaluations: Additional diagnostic tests may be required to ascertain or confirm the etiology of the pain and its relationships to underlying disease processes.f. Treatment plan: Once a definitive diagnosis has been made, a treatment plan should be formulated and discussed with the patient. The treatment plan should characterize the expected outcome, define contingencies, and outline a plan for reassessment.There is insufficient literature to evaluate the efficacy of the longitudinal monitoring of pain. The Task Force and consultants support the contention that the longitudinal monitoring of pain will result in improved pain management and reduced adverse effects from therapy (Table 1template 1).Recommendations: The Task Force identifies three fundamental concepts in the longitudinal monitoring of pain.1. Patient Self-report. Reports of pain made by the patient should be the primary source of pain assessment and should take precedence, whenever possible, over inferences and observations made by others. Continuous assessment over time (e.g., pain diaries) is appropriate for outpatients. For some age groups and populations (e.g., the cognitively or developmentally impaired), external observation may be preferable. Age-appropriate instruments should be used in children.2. Rating Scale. The longitudinal monitoring of pain intensity should be based on rating scales that are easy to use and interpret. Typical examples of rating scales include discrete numeric scales (e.g., 0-10), categorical scales (none, mild, moderate, severe, worst possible), and continuous visual analog scales of pain or pain relief (Table 2Template 2).3. Frequency of Pain Ratings. Self-report should be obtained at regular intervals. Increased frequency and evaluation of self-reports may be indicated: (1) at the onset of new pain, (2) when established pain exhibits changes in pattern and/or intensity, or (3) when a major therapeutic intervention is performed.The literature supports the concept that involvement of specialists from multiple disciplines results in effective analgesia and suggests that such involvement improves other health outcomes. The panel of consultants and Task Force members endorse the importance of collaboration between anesthesiologists and other health-care providers in the management of cancer pain.Recommendations: Anesthesiologists who engage in cancer pain management should avail themselves of interdisciplinary expertise in their clinical environments. It is important to note that the patient's primary physician must be a part of the coordination of pain management. The Task Force recognizes that full interdisciplinary coordination of cancer pain treatment is not feasible in every clinical setting.The guidelines conceptualize the pharmacologic management of cancer pain as a continuum from indirect drug delivery (i.e., systemic analgesia) to direct drug delivery (i.e., neuraxial drug administration and neuroablation; Table 3Template 3). Indirect drug delivery systems rely on blood-borne carriage of analgesic to receptors after (1) systemic absorption, (2) formation of a depot for sustained and continuous release, or (3) administration into the blood stream. Direct drug delivery systems involve administration of an agent to the neuraxis or in the vicinity of "target" neural tissue.Recommendations for the oral administration of analgesics are provided by the World Health Organization (WHO) analgesic ladder (Table 4Template 4). These American Society of Anesthesiologists guidelines provide evidence and recommendations for cancer pain management involving the oral and other routes of administration. The literature provides supportive evidence for specific elements of the paradigm (Table 5Template 5).a. Oral pharmacologic interventions: The literature suggests and consultant opinion supports the view that oral pharmacologic interventions applied according to the WHO analgesic ladder are associated with adequate analgesia. The literature indicates an increased risk of adverse sequelae with the use of oral opioids (Appendix 2).b. Rectal and transdermal analgesia: The literature suggests that rectal and transdermal modes of analgesia are effective alternatives to oral analgesics. The Task Force supports the use of these analgesic modalities, when appropriate, before employment of more invasive systemic therapies.c. Subcutaneous and intravenous drug delivery: The literature suggests that subcutaneous or intravenous administration of opioids is effective for patients requiring continuous infusions and does not increase the risk of adverse effects. Subcutaneous administration provides blood levels similar to intravenous infusion, and the comparative risks and benefits of the continuous parenteral techniques have not been evaluated.Recommendations:1. General Recommendations. Oral medications should be used as the first line approach in most patients when initiating analgesic therapy. Because it is not effective in all patients and may not be optimal therapy in painful crisis (i.e., the pain emergency), the indications, risks, and potential benefits of alternative interventions must be understood and assessed.Any proposed systemic regimen must be individualized for the patient, and inflexible reliance should not be placed on any "standard" mixture of medications and/or dosing regimens. For patients with moderate or severe pain, opioid therapy is recommended. Once an opioid and a route of administration are chosen, the dose should be increased until a favorable response occurs or when unmanageable or intolerable adverse effects ensue. There is no predetermined maximum dose of an opioid. Dose titration may be required periodically because of the natural history of the primary disease or the development of tolerance. When pain is continuous or occurs frequently, medication generally should be administered around-the-clock with additional "rescue" doses available for breakthrough pain. The practitioner should be aware of the potential adverse sequelae of opioids and their appropriate treatment.When considering changing opioids or routes of administration, dose adjustments should be made to correct for differences in potency. Apparent differences in potency among opioids are the result of physicochemical and pharmacokinetic differences rather than pharmacodynamic distinctions (Table 6template 6). When tolerance to a particular opioid develops, another opioid may be substituted at approximately 50-75% of the equianalgesic dose, because cross-tolerance is incomplete. The size of the reduction should be based on the severity of pain, the presence of adverse effects, and the medical status of the patient. Based on clinical observation, a switch to methadone should be done with a reduction of 75% of the equianalgesic dose.Adjuvant agents should be used as coanalgesics (e.g., corticosteroids, antidepressants) or to treat adverse drug effects. These agents may be added at any stage (Table 7Template 7).2. Specific Recommendations.a. Oral medications: Oral medications such as acetaminophen, acetylsalicylic acid or other nonsteroidal antiinflammatory drugs (NSAIDs) should be employed first for mild to moderate pain. (Note: the simultaneous use of more than one NSAID or the concomitant use of an NSAID with a glucocorticoid is not recommended because the risk of toxicity is increased, and additional analgesia is not achieved.) If pain is not relieved or increases or if moderate pain is present at presentation, an opioid conventionally used for moderate pain (e.g., codeine, dihydrocodeine, oxycodone (compounded with a coanalgesic), or hydrocodone) should be used, usually combined with a nonopioid analgesic. When increasing opioid dose, an increment of 25-50% is usually the minimum required to observe effect. If pain is not relieved, increases, or is severe at presentation, an opioid conventionally used for severe pain (e.g., morphine, hydromorphone, methadone, oxycodone (not compounded with a coanalgesic), fentanyl, or levorphanol) should be selected. (Note: Besides consideration of a change in opioid, an increase in pain intensity should prompt a reevaluation of the cause of pain.)When analgesia with acceptable adverse effects is no longer attained with the oral route of administration or when oral administration is no longer viable (inability to swallow and/or absorb medication), an alternate systemic route of administration should be chosen. (Note: The enteral route should be used in patients with percutaneous feeding tubes and inability to swallow, as long as absorption still occurs.) If dose-limiting toxicity precludes effective therapy, a trial of a different opioid, a reduction of adverse effects by optimization of adjuvants, neuraxial drug delivery, or neuroablative therapy should be considered.b. Rectal and transdermal: Use of an alternative route of administration, specifically rectal or transdermal, should be chosen before use of invasive therapies. Rectal administration usually is considered when oral therapy is temporarily unavailable (e.g., nausea and vomiting refractory to therapy), although long-term use is effective in some patients. Transdermal fentanyl should be used in patients with stable pain states who are (1) noncompliant with oral medication, (2) unable to swallow or absorb, or (3) may benefit from a trial of fentanyl.c. Subcutaneous and intravenous administration: The subcutaneous route of administration should be used in (1) patients unable to swallow or absorb opioids who may benefit from a continuous infusion of opioid and (2) similar patients with dynamic pain states requiring frequent "rescue" doses for breakthrough pain. Subcutaneous administration of opioids may be used in the home setting. The recommendations for intravenous administration are the same as for subcutaneous administration. Intravenous administration may be preferred when the patient has permanent venous access. (Note: Intramuscular injection is not recommended as either short- or long-term therapy for cancer pain management because of the attendant discomfort, variable blood concentrations, and fluctuating levels of analgesia.)Opioids and local anesthetics can be delivered directly to the vicinity of neural tissue, obviating the need for systemic absorption as a means to reach receptor sites. Other potential agents for neuraxial drug delivery are under development. Neuroablation refers to the chemical, thermal, or surgical destruction of neural tissue.Neuroablation is preceded by diagnostic neural blockade. Regional analgesic techniques are referred to in these guidelines as neural blockade (e.g., intercostal blocks, celiac plexus blocks) and are distinct from neurolytic blocks. Neural blockade is used alone for short-term pain management with specific indications (see below). The Task Force is supportive of the efficacy of neural blockade for prognostic purposes. (Note: Sufficient literature is not available to assess the effectiveness of neural blockade as either a prognostic procedure or a long-term analgesic modality for the treatment of cancer pain.)a. Neuraxial drug delivery: The literature is supportive of the efficacy of neuraxial analgesic delivery (i.e., epidural, subarachnoid, intraventricular). Epidural or subarachnoid drug administration may be performed by either percutaneous catheterization, reservoir, or implantation of a catheter and pump. Although the literature suggests that neuraxial techniques are not associated with an increased incidence of adverse effects, the Task Force and consultants suggest that adverse effects may be possible (e.g., catheter-site infections).b. Neuroablation: The literature suggests and consultants and Task Force members support the view that neuroablation by chemical and thermal neurolysis or surgery can provide long-term control of severe cancer pain without a substantial incidence of adverse effects. Examples of chemical neuroablative procedures include but are not limited to intercostal neurolysis, neurolytic celiac plexus block, neurolytic superior hypogastric plexus block, neurolytic ganglion impar (ganglion of Walther) block, craniofacial neurolytic techniques, and subarachnoid rhizolysis. Examples of thermal neuroablative techniques include radiofrequency ablation (heat) and cryoanalgesia (cold).Recommendations:1. General Recommendations. When adequate analgesia cannot be achieved or intolerable side effects occur with indirect methods of drug delivery, direct drug delivery systems should be considered. In certain specific circumstances, neuraxial drug delivery or neuroablative therapies should be considered at the initiation of therapy or early in the natural history of the pain (see below). Neuraxial drug delivery and neuroablative therapies should not be used: (1) in individuals who are unmotivated or noncompliant or do not possess the cognitive functioning necessary to understand the risks and benefits and (2) when an appropriate logistical system does not exist. Patients must have access to a logistical system that provides the resources and availability of personnel to respond to patient needs on an around-the-clock basis. The establishment of an office or network with professional support may be necessary. For long-term therapies, appropriate home care must be available and functionally integrated into the office, and Specific Recommendations.a. Neuraxial drug delivery: Neuraxial drug delivery should be used: (1) when severe pain cannot be with systemic drugs because of dose-limiting (2) when is need for local neuropathic (3) after or (4) patient preference indicates its The between or subarachnoid is in part by patient life When life is subarachnoid catheter should be considered because may The presence of subarachnoid of an neuraxial drug delivery efficacy and appropriate dose range should be by trial injection or use of a delivery Patients should have access to "rescue" doses for breakthrough pain. doses may be given by any route of administration as appropriate by the administration of opioids may be considered in patients with and cancer and (Note: Neural blockade should be used before neuraxial drug delivery because of (1) the presence of pain to neural blockade (e.g., pain, pain, pain of acute herpes or (2) patient when Neuroablation: techniques should be (1) when systemic therapies have to provide adequate pain control or when adverse side effects from systemic therapies are (2) after of neuraxial drug (3) early in the natural history of the cancer pain in the presence of (e.g., (e.g., cancer of the or neuropathic (e.g., pain that is to be to neuroablation with limited or (4) patient preference indicates use of neuroablative techniques, if for the specific indications, chemical, radiofrequency and surgical neuroablation should be until life is the potential for pain. the other consideration of life is with cryoanalgesia because of the potential for associated with the The procedure must be because the is over of chemical, thermal, or surgical neurolysis, opioid administration should not be to of should be and opioids should be to which may occur in the of pain blockade should be used to determine the possible efficacy of However, with under neural blockade does not the of a Neural blockade should be performed at the time of potential neuroablation and should not be performed as a If analgesia is not achieved with neural blockade or significant adverse sequelae neuroablation should be neuroablation should be performed with the of techniques when feasible or with direct of the intended neural in the of open surgical literature supports the efficacy of interventions to symptoms to primary disease and its In the literature suggests that specific interventions used to treat the adverse effects of pain therapy are drug effects directly from cancer pain therapies include but are not limited to nausea and and (Note: is in the cancer patient opioid therapy (Appendix literature does not suggest that management of symptoms or adverse effects has an on Task Force and consultants are supportive of the of symptoms and adverse drug effects as part of the comprehensive management of cancer pain.Recommendations:1. General Recommendations. effects should be and and appropriate should be should not be from cancer patients for fear of physical or Specific Recommendations.a. patients with an increased risk for should (Appendix or therapy should involve the use of (e.g., or or and/or (e.g., or A may be used with the patients should be by (1) factors such as drugs and (2) the dose of an opioid by 25-50% if analgesia is (3) the for opioids by the of a nonopioid analgesic or (4) to another opioid, (5) the use of or (6) considering more invasive modalities if is refractory to and nausea is and therapy is not nausea and vomiting should be with such as or In some or can be patients may benefit from the use of alternative treatment for (i.e., or a (i.e., Treatment of factors to nausea (e.g., should be considered when The treatment of cognitive should the management of The of may be necessary for states by can be administered to in the of but should not be administered to is not usually a clinical and should be given to patients regarding its However, if function, or increases pain, or should be A reduction in opioid dose or a switch to a different opioid should be considered in the of refractory or severe is a with opioid administration, and consideration should be given to an trial of if it is also with opioid administration and should be by administration of a direct such as The of should be administered to analgesia and (Appendix Because of the of a continuous infusion may be literature suggests that psychosocial interventions are effective in analgesia and the quality of life for cancer pain patients. The Task Force and panel of consultants similar Psychosocial interventions for the management of cancer pain include pain and management. is given to the effects of and for the of the patient. of the psychosocial of cancer pain includes the use of interventions (e.g., and and A psychosocial assessment should be as an part of the comprehensive pain evaluation. of the psychosocial assessment should be considered when a pain treatment plan. Pain and should be considered to enhance medication if The should recognize that pharmacologic and neurolytic techniques may not be effective in pain and that and therapy are important The should with and other health when psychosocial interventions are The should recognize that psychosocial to cancer not to cancer may to appropriate health literature suggests that home parenteral therapy is effective for analgesia without risk of adverse effects. The panel of consultants and Task Force members support the importance of home parenteral therapy in increasing analgesia and patient quality of parenteral therapy provides an

Cancer Pain: From Molecules to Suffering.