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Published: 4 June 2021
Last updated: 12 February 2022

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1

Freye, Enno. Opioid Agonists, Antagonists and Mixed Narcotic Analgesics. Berlin, Heidelberg: Springer Berlin Heidelberg, 1987. http://dx.doi.org/10.1007/978-3-642-71854-0.

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2

Freye, Enno. Opioid agonists, antagonists and mixed narcotics analgesics: Theoretical background and considerations for practical use. Berlin: Springer, 1987.

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3

Opioid Agonists, Antagonists and Mixed Narcotic Analgesics. Springer Verlag, 1987.

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4

Krondahl, Eva. Transport & Metabolism of Opioid Tetrapeptide Agonists With a Focus on Oral & Respiratory Delivery. Uppsala Universitet, 2001.

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5

Otis, James A. D. Non-Opioid Pharmacotherapies for Chronic Pain (DRAFT). Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780190265366.003.0015.

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The objective of chapter 15 is to describe analgesic approaches to chronic pain, excluding opioids. As such, it emphasizes, first, the available pharmacotherapies; and then procedures. The pharmacotherapies divide into analgesics, such as non-steroidal anti-inflammatory drugs (NSAIDs); adjuvant analgesics, such as tricyclic antidepressants and anticonvulsants; oral anesthetic agents (cardiotropics); adrenergic agonists; topical agents such as capsaicin and local anesthetic solutions and ointments; and muscle relaxants such as cyclobenzaprine, tizanidine, and baclofen. Interventions include many best administered by anesthesiologists such as infusions of anesthetic agents; trigger point injections; local and regional blockade, spinal injections including corticosteroids; and electrical spinal cord stimulation. A text box is provided with additional resources.
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6

Opioid Agonists, Antagonists and Mixed Narcotic Analgesics: Theoretical Background and Considerations for Practical Use. Springer, 2012.

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7

Opioid Agonists, Antagonists and Mixed Narcotic Analgesics: Theoretical Background and Considerations for Practical Use. Springer, 1987.

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8

Gevirtz, Clifford M., Elizabeth Frost, and Alan D. Kaye. Ultrarapid Opiate Detoxification. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780190495756.003.0035.

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Extended opioid use results in physical dependence and neural adaptation. Opioid dependence treatment can be carried out with opioid receptor agonists, partial agonists, and antagonists. Conventional treatments have low success rates. Methadone and buprenorphine treatments involve substituting long-duration agonists for the opiate of abuse, essentially substituting one opiate for another. Rapid opiate detoxification is a 3-day process involving large amounts of an opiate antagonist. Both treatments have associated problems. Ultrarapid opiate detoxification (UROD) anesthetizes a patient and precipitates withdrawal while unconscious. It shortens withdrawal, avoiding much of the subjective withdrawal discomfort. Clonidine is critical to reduce catecholamine levels and mitigate central nervous system hyperarousal in acute withdrawal. A UROD advantage is that the withdrawal period is markedly shortened to 8 hours or less versus up to several months for conventional treatments. The patient is anesthetized during the acute withdrawal period and does not experience the unpleasant consequences of acute detoxification.
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9

Patel, Mayur B., and Pratik P. Pandharipande. Analgesics in critical illness. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199600830.003.0043.

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Analgesia is a critical component of intensive care unit (ICU) care. Accordingly, understanding the mechanism, physiological consequences, and assessment of pain is important when caring for the ICU patient. Non-pharmacological approaches should be attempted before supplementing analgesia with pharmacological agents. Pharmacologically-based therapies are divided into regional and systemic therapies. Regional analgesic therapies target specific areas of the body while limiting the systemic effects of intravenous analgesics, but at the risk of invasiveness, local anaesthetic toxicity, and infection of in-dwelling catheters. Systemic analgesic therapy is comprised of two main categories—non-opioids and opioids. Typically, non-opioid analgesics are used as adjunctive therapies and consist of agents such as non-steroidal anti-inflammatory drugs, gabapentinoids, ketamine, or α‎2 agonists. Opioid analgesia in the ICU is commonly infusion-based using fentanyl, hydromorphone, morphine, or recently, remifentanil.
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10

Sabbe, Marc. Toxicologic, Pharmacodynamic and Kinetic Studies Following Spinal Administration of U Opioid, B Gaba and A2 Adrenergic Agonists. Coronet Books Inc, 1997.

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11

Fomberstein, Kenneth, Michael Rubin, Dipan Patel, Ivona Truszkowska, and S. Gabriel Farkas. Perioperative Nonopioid Analgesics of Use in Pain Management for Spine Surgery. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780190626761.003.0003.

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This chapter examines the developing role of multimodal analgesia in reducing opioid requirements/dependency in the postoperative period while also facilitating the recovery process without the unwanted adverse side effects associated with opioid use. It reviews a number of medications used in a multimodal regimen including NMDA receptor antagonists, α‎2 agonists, dexamethasone, gabapentinoids, acetaminophen, NSAIDs, COX-2 selective inhibitors, caffeine, and lidocaine. This chapter also discusses the evidence and implications for the use of a specific medication and in which perioperative setting its use has been corroborated. This chapter includes relevant tables and is written for qualified specialist attendings, fellows, residents, and nurses as well as all practitioners involved in the treatment of pain following spine surgery.
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12

Farquhar-Smith, Paul. The additive analgesia of adrenaline in epidural blockade. Edited by Paul Farquhar-Smith, Pierre Beaulieu, and Sian Jagger. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198834359.003.0058.

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The landmark paper discussed in this chapter is ‘Adrenaline markedly improves thoracic epidural analgesia produced by a low-dose infusion of bupivacaine, fentanyl and adrenaline after major surgery’, published by Niemi and Breivik in 1998. The analgesic potential of neuraxial blockade has long been recognized. The extensive opioid receptor expression in areas germane to pain pathways gave credence to the effective clinical application of lower doses of neuraxial opioids compared with systemic administration. Preclinical data also proposed a potential spinal action of α‎2 agonists in achieving analgesia by a number of mechanisms, including a direct antinociceptive action and by reducing elution of other epidural drugs from the spinal effector site. Early clinical data failed to show a clear benefit from the addition of adrenaline to epidural infusions. Niemi and Breivik’s experiment addressed the methodological flaws of previous studies by using combinations of relatively sub-analgesic doses of each of the combined elements.
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13

Accardo, Jennifer. Restless Legs Syndrome and Periodic Limb Movement Disorder. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0172.

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Restless legs syndrome (RLS), also known as Willis Ekbom disease (WED), is a sensory disorder with a circadian component. An irresistible urge to move the legs disrupts sleep onset and maintenance. Periodic limb movements in sleep, semirhythmic in nature, often overlap with RLS, though periodic limb movement disorder can be diagnosed in the absence of RLS’s distinctive sensory symptoms. Disruptions in dopaminergic pathways, iron metabolism, and the opioid system have all been implicated in pathogenesis, and there is a strong genetic component. RLS is common, affecting 5% to 10% of adults. Its best-known treatments are dopamine agonists; however, other treatments are effective.
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14

Ling, Walter, and Matthew Torrington. Integrative Approach to Opiates, Opioids, and Opiate Use Disorder. Edited by Shahla J. Modir and George E. Muñoz. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780190275334.003.0008.

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This chapter defines terms such as “opiate” and “opioid” and explains their physiological functions as agonist, antagonist, and partial agonist. It notes the long history of medicinal opioid use for acute pain, as well as the curse of addiction with chronic use, highlighting the three opioid use epidemics in the United States: the morphine addiction of the Civil War era, the heroin addiction of the Vietnam War era, and the current epidemic of prescription opioid addiction. The chapter describes the commonly encountered natural, synthetic, and semi-synthetic opioids, noting their therapeutic use, potential for abuse, and their use in management of opioid use disorders. Of particular interest are the sections on detoxification and relapse prevention using methadone, buprenorphine, and naltrexone. The sections also explain the rationale for their use against the epidemiological background and recent exploration of genetic influences. The chapter also emphasizes the need for an integrated strategy in overcoming opioid addiction.
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15

Nutt, David J., and Liam J. Nestor. The opioid system and addiction. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198797746.003.0010.

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The opioid system of the brain is the major target for opiate drugs such as morphine and heroin, and has been implicated in processes such as pain, stress and reward. Many of these effects take place at the mu opioid receptor (mOR), which is distributed throughout the brain. Significantly, genetic polymorphisms at the mOR may confer a greater dopamine response to the reinforcing effects of alcohol, and it has been suggested that addiction per se may be associated with alterations to the opioid system. There is evidence for the potential efficacy of mOR antagonists (e.g. naltrexone) in reducing drug and alcohol relapse, increasing treatment retention and attenuating the subjective effects of substances of abuse. Medications with partial agonist activity at the kappa opioid receptor (e.g. nalmefene) may also confer an additional clinical advantage by reducing binging following relapse.
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16

(Editor), Stanley D. Glick, and Isabelle M. Maisonneuve (Editor), eds. New Medications for Drug Abuse (Annals of the New York Academy of Sciences, V. 909). New York Academy of Sciences, 2000.

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17

Bannwarth, Bernard, and Francis Berenbaum. Systemic analgesics (including paracetamol and opioids). Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199668847.003.0029.

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Apart from non-steroidal anti-inflammatory drugs (NSAIDs), there are only two categories of systemic analgesics, namely paracetamol (acetaminophen) and opioids, that are currently available worldwide for clinical use. Paracetamol is poorly effective in relieving pain and improving function in patients with symptomatic osteoarthritis (OA). Furthermore, its safety profile is less favourable than classically thought. In fact, there is evidence paracetamol acts as a weak inhibitor of the cyclooxygenase enzymes. Given that paracetamol poses a lower risk of severe adverse events than NSAIDs while being better tolerated than opioids, it is usually considered as the first-line systemic analgesic for OA. Commonly prescribed opioids are primarily agonists of the mu receptors, thereby producing similar desirable (analgesia) and untoward effects. Meta-analyses of short-term clinical trials showed that, on average, the modest clinical benefits of opioids did not outweigh the side effects in patients with knee or hip OA. Accordingly, most current guidelines support the use of opioids for selected OA patients only (e.g. patients who have not had an adequate response to other treatment modalities and are not candidates for total joint arthroplasty). In view of the limited efficacy and/or potential harms of available analgesics, particular attention was paid to novel painkillers, especially nerve growth factor (NGF) antagonists. Although these agents provided clinically meaningful improvements in pain and physical function in patients with hip or knee OA, they lead to severe side effects, including rapidly destructive arthropathies and neuropathies. Thus, if approved for marketing, NGF antagonists would be reserved for selected and well-defined patients with OA.
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18

Feng, Alexander J., George C. Chang Chien, and Alan D. Kaye. NMDA Receptor Antagonists, Gabapentinoids, Alpha-2 Agonists, and Dexamethasone. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780190457006.003.0002.

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Surgical pain is a major obstacle in the recovery of patients. Effective pain management is of upmost importance to optimize a patient’s recovery, decrease medical complications, and increase patient satisfaction. Traditional pain management with opioids and nonsteroidal anti-inflammatory drugs have significant side effect profiles leading to medical complications or insufficient pain management from reluctance of use. Adjuvant analgesic can provide improved pain management with significantly less side effect profile. In addition, the clinician can, with synergistic effects of adjuvant medications, lower the total dosages used, thus lessening the likelihood of the side effects that occur when medications are used alone at a higher dosage. This chapter presents several adjuvant analgesics—NMDA receptor antagonists, gabapentinoids, alpha-2 agonists, and dexamethasone—and evidence for their use. Ultimately, through the use of traditional pain management options along with adjuvant analgesics, the effectiveness of acute pain management can be increased while adverse outcomes are reduced and functional recovery and quality of life improved.
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19

Agarwal, Deepti, Ifeyinwa C. Ifeanyi, and Mercy A. Udoji. Intrathecal Drug Delivery Systems. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780190271787.003.0030.

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Intrathecal drug delivery (ITDD), while initially intended for terminal oncology patients suffering from cancer pain, is currently widely used for chronic nonmalignant pain states. Before intrathecal drug delivery device (IDDD) implantation, patients with nonmalignant chronic pain must be screened for psychologic, behavioral, and medical etiologies for their pain, in addition to having a documented failure of maximal medical therapy and a successful intrathecal drug trial. Classes of drugs used for intrathecal therapy include opioids, local anesthetics, adrenergic agonists, and NMDA receptor agonists. Drugs currently approved by the FDA for ITDD are morphine, ziconotide, and baclofen. Complications of IDDD implantation are surgical (bleeding, infection, CSF leak, nerve injury), mechanical (due to catheter kink, shear, or disconnection), pharmacologic (overdose, incorrect pump settings, contaminated drugs), or medical (hypogonadotropic hypogonadism).
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20

Wakeman, Sarah E., and Josiah D. Rich. Pharmacotherapy for substance use disorders within correctional facilities. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199360574.003.0046.

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Drug addiction treatment is increasingly complex. Only 5% of prisons and 34% of jails offer any detoxification services, and only 1% of jails offer methadone for opioid withdrawal. Even fewer facilities offer medication assisted therapy (MAT) for alcohol or substance use disorders despite the tremendous evidence base supporting the use of medications to treat addiction. Untreated opioid dependence both within corrections and in the community is associated with HIV, Hepatitis C, crime, and death by overdose. Substantial evidence argues that these risks are reduced through long-term treatment with agonist medications such as methadone and buprenorphine. Only a minority of prisoners receive any addiction treatment while incarcerated. Those that do are usually offered behavioral interventions, which when used alone have extremely poor outcomes. Although there are limited studies on the outcomes of drug treatment during incarceration, there are nearly 50 years of evidence documenting the efficacy of methadone given in the community in reducing opioid use, drug-related health complications, overdose, death, criminal activity, and recidivism. Buprenorphine is similarly an effective, safe, and cost-effective long-term treatment for opioid dependence that reduces other opioid use and improves health and quality of life outcomes. There is a growing role for MAT in jails, and to a lesser degree in prisons for the treatment of alcohol and opiate dependence. This chapter presents the current state of evidence based practice in correctional MAT models.
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21

Wakeman, Sarah E., and Josiah D. Rich. Pharmacotherapy for substance use disorders within correctional facilities. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199360574.003.0046_update_001.

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Drug addiction treatment is increasingly complex. Only 5% of prisons and 34% of jails offer any detoxification services, and only 1% of jails offer methadone for opioid withdrawal. Even fewer facilities offer medication assisted therapy (MAT) for alcohol or substance use disorders despite the tremendous evidence base supporting the use of medications to treat addiction. Untreated opioid dependence both within corrections and in the community is associated with HIV, Hepatitis C, crime, and death by overdose. Substantial evidence argues that these risks are reduced through long-term treatment with agonist medications such as methadone and buprenorphine. Only a minority of prisoners receive any addiction treatment while incarcerated. Those that do are usually offered behavioral interventions, which when used alone have extremely poor outcomes. Although there are limited studies on the outcomes of drug treatment during incarceration, there are nearly 50 years of evidence documenting the efficacy of methadone given in the community in reducing opioid use, drug-related health complications, overdose, death, criminal activity, and recidivism. Buprenorphine is similarly an effective, safe, and cost-effective long-term treatment for opioid dependence that reduces other opioid use and improves health and quality of life outcomes. There is a growing role for MAT in jails, and to a lesser degree in prisons for the treatment of alcohol and opiate dependence. This chapter presents the current state of evidence based practice in correctional MAT models.
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22

Unger, Annemarie, Gabriele Fischer, and Loretta P. Finnegan. Drug Dependence During Pregnancy and the Postpartum Period. Edited by Amy Wenzel. Oxford University Press, 2014. http://dx.doi.org/10.1093/oxfordhb/9780199778072.013.27.

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The chaotic lives of women who are drug dependent and their frequent lack of consistent prenatal care put them at risk for many medical problems during pregnancy. Illicit drug use during pregnancy also places women at increased risk for obstetrical complications. The complexity of medical problems in the pregnant drug abuser is complicated by the attendant psychosocial problems and psychiatric comorbidities seen in this population. Psychiatric diagnoses, treatment, and patient compliance are often hindered when the main focus of attention is on drug-related problems. The stigma associated with maternal drug use and difficult life circumstances are additional burdens to successful treatment entry and adherence for women. The basis for stabilizing most opioid-dependent pregnant women is agonist maintenance therapy in the context of comprehensive services, and the treatment of psychiatric comorbidities is a key component in optimizing pregnancy and child outcomes.
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23

Finnerup, Nanna Brix, and Troels Staehelin Jensen. Management issues in neuropathic pain. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199656097.003.0133.

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Neuropathic pain is a common complication to cancer, cancer treatment, HIV, and other conditions that may affect the somatosensory nervous system. Neuropathic pain may be present in up to 40% of cancer patients and may persist independently of the cancer and affect the quality of life in disease-free cancer survivors. Particular surgical treatment and chemotherapy may cause chronic persistent neuropathic pain in cancer survivors. The diagnosis of neuropathic pain can be challenging and requires documentation of a nervous system lesion and pain in areas of sensory changes. The pharmacological treatment may include tricyclic antidepressants, selective serotonin noradrenaline reuptake inhibitors (duloxetine or venlafaxine), calcium channel α2↓ agonists (gabapentin or pregabalin), and opioids. Topical lidocaine and capsaicin, NMDA antagonists, carbamazepine, oxcarbazepine, and cannabinoids may be indicated. Due to limited efficacy or intolerable side effects at maximal doses, combination therapy is often required and careful monitoring of effect and adverse reactions is important.
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24

Azbel, Lyuba, and Frederick L. Altice. Drug Use, HIV, and the High-Risk Environment of Prisons. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199374847.003.0007.

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Prisons often concentrate people with or at risk for HIV within them and, due to the high-risk environment within prison, further amplify disease. Suboptimal access to evidence-based HIV prevention and treatment within prisons, including opioid agonist therapies with methadone or buprenorphine, antiretroviral therapy, and needle/syringe programs, results in worsening of disease during incarceration. Effective transitional programs that address continuity of prevention and treatment of HIV and substance use disorders, along with other co-morbid conditions, are crucial to reduce the harms from incarceration. Such programs not only must provide access to these services within prison but also must ensure that the services are continued after release. This chapter reviews how prisons contribute to negative health consequences related to HIV and addiction, provides examples of settings where policies and services greatly influence the high-risk prison setting, and offers a number of strategies to improve HIV detection, treatment, and prevention.
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25

Shapiro, Benjamin. Ibogaine: History, Pharmacology, Spirituality, & Clinical Data. Edited by Shahla J. Modir and George E. Muñoz. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780190275334.003.0027.

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Ibogaine is an indole alkaloid derived from the African shrub Tabernathe iboga with broad anti-addictive, anti-depressant, and central nervous system stimulating effects. It is categorized as an oneriogen (or atypical hallucinogen) and has been used in West African tribal rituals for centuries. It was identified by French explorers in the early 1900s, came to the United States in the 1960s, and became marginalized in the mid-1990s after adverse outcomes halted federally funded human trials. Since then legal ibogaine treatment clinics have been established in countries without use restrictions. Ibogaine is a σ‎1 and σ‎2 receptor and μ‎ and κ‎ opioid receptor agonist and a α‎3β‎4 nicotinic and NMDA receptor antagonist. Decades of trials have demonstrated ibogaine’s potential. Human trials of ibogaine consistently demonstrate rapid remission of acute withdrawal symptoms but differ in their findings with regard to abstinence and toxicity. While ibogaine is not a “magic bullet,” considerable abstinence may result after multiple treatments, however QT prolongation can produce lethal ventricular tachyarrhythmias.18 MC is in pre-clinical investigation.
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