阿片类药物所致呼吸抑制与基因多态性

阿片类药物目前在临床上应用广泛,中度至重度疼痛以及大多数术后疼痛的治疗多依赖于阿片类药物的使用。目前临床上常用的吗啡等阿片类镇痛药治疗指数范围窄,个体差异较大,而且常常伴随着严重的耐受性和成瘾性,甚至呼吸抑制(RD)等严重不良反应。研究阿片受体的基因多态性有助于从分子生物学的角度解释个体间对阿片类药物反应存在的差异。确定基因特异性有助于指导临床用药,降低其呼吸抑制等不良反应的发生率。     

阿片受体激动剂的镇痛作用及其靶点通路研究进展

疼痛是一种复杂的生理现象,目前主要运用药物进行镇痛.阿片类受体激动剂类镇痛药受到了越来越多的关注,阿片受体及其与药物的作用机制研究取得了较大发展,近年来逐渐被用于临床治疗疼痛,但由于没有研究可以对其镇痛以及成瘾的机制进行明确地阐释,因此阿片受体激动剂在临床上没有得到广泛应用.探讨阿片类受体的结构特点和作用机制,并在此基础上开发结构全新或新作用机制的镇痛药物,是推动阿片类受体激动剂在临床上用于镇痛治疗的前提.综述阿片类受体激动剂在镇痛方面的应用及其信号通路,可以为今后高选择性镇痛药的研发及临床治疗提供思路.     

阿片类药物治疗老年中重度癌痛致便秘128例的护理

癌痛是癌症中晚期患者的主要症状之一,以吗啡为代表的强阿片类镇痛药是临床上治疗中重度癌痛的主要药物。但强阿片类药物除了与中枢神经系统内阿片受体结合缓解疼痛外,还可与胃肠道内阿片受体结合引发以便秘（OIC）为主要症状的胃肠功能紊乱。这类便秘会持续存在于阿片镇痛治疗的全过程,不仅是癌症患者额外的痛苦,更是阿片类药物的使用瓶颈[1]。     

高乌头温敏凝胶外用辅助治疗局部癌性疼痛的临床研究

目的评价高乌头温敏凝胶联合阿片类镇痛药治疗局部癌性疼痛的有效性和安全性。方法将Kamofsky评分50⁸0分的癌症患者随机分为2组,其中治疗组采用高乌头温敏凝胶联合阿片类镇痛药(53例),对照组单用阿片类镇痛药(50例);采用数字评分量表(numerical rating scale,NRS)评分进行疼痛评估;记录2组阿片药物的消耗量以及不良反应的发生率。结果治疗组和对照组的NRS评分基线值无显著性差异(P>0.05),但对照组阿片类药物的消耗量及不良反应和爆发痛发生率显著多余治疗组(P<0.05)。结论高乌头温敏凝胶联合阿片类药物可以更好地治疗癌性疼痛,减少阿片药品的用量,降低由阿片药引起的不良反应,且简单易行,不失为辅助治疗局部癌性疼痛安全、有效、经济的治疗手段。     

盐酸曲马多胶囊致排尿困难

曲马多(Tramadol)是一种较新的阿片受体弱激动剂,属于非阿片类中枢镇痛药,具有镇痛作用较强、药效持续时间长、药物依赖性低等特点,临床上常用于缓解各种中、重度疼痛,包括术后疼痛的治疗.     

美沙酮个体化治疗的遗传药理学基础

美沙酮为阿片受体激动药,目前主要用于阿片类药物成瘾者的替代治疗,其次作为二线镇痛药用于吗啡等其他阿片类药物治疗无效或无法耐受的癌症疼痛或非肿瘤性慢性疼痛。美沙酮临床应用个体差异大。本文综述了美沙酮个体化治疗的遗传药理学基础。1美沙酮临床治疗的主要问题1·1个体差异大据报道,阿片类药物成瘾者替代治疗、癌症及慢性疼痛时美沙酮的维持剂量可在5-160 mg。     

合理应用麻醉性镇痛药

麻醉性镇痛药根据来源分为天然阿片类和合成阿片类两大类。麻醉性镇痛药以吗啡、芬太尼等为代表药物 ,近年来其它人工合成的可待因衍生物如氢吗啡酮、羟吗啡酮、羟可酮和舒芬太尼、阿芬太尼、雷米芬太尼、左吗喃、美沙酮也逐渐应用于临床。本文对麻醉性镇痛药的药理学、适应证、副作用、用法与用量作一综述 ,以便更加合理的应用 ,尽量减少成瘾性的发生。1　天然阿片类镇痛药物阿片类镇痛药物可分为两类 :阿片受体激动剂和阿片受体部分激动剂 (或激动 拮抗剂 )。阿片受体有 5类 :μ、к、б、δ、ε R ,以 μ、κ、δ 3种受体为主。μ受体调…     

μ/δ阿片受体相互调节作用及药物发现与设计策略

阿片类镇痛药镇痛活性好,广泛用于临床。阿片受体主要分为3种亚型,即μ、δ、κ阿片受体。目前临床上使用的阿片类镇痛药大多为μ受体激动剂,但易引起成瘾性、呼吸抑制等副作用。δ受体激动剂镇痛活性较弱,但δ受体激动剂和拮抗剂均能调节μ受体激动剂的镇痛作用,同时参与成瘾性等副作用形成。因此,设计具有μ/δ双重功效的药物是新一代低毒副作用镇痛药的发展方向。该文综述了具有μ/δ双重功效药物的研究现状,为设计低毒副作用镇痛药物提供新思路。     

多靶点肽类镇痛药物的研究进展

Mu阿片受体为吗啡和芬太尼等传统阿片类镇痛药物的主要作用靶点。传统的阿片类镇痛药物广泛用于中度和重度疼痛的临床治疗,但长期使用该类药物会引起镇痛耐受和成瘾等副作用,并伴随着眩晕、恶心、呕吐、便秘、瘙痒、呼吸抑制等不良反应,从而限制了其临床应用。近年来,多靶点分子的研究取得重要进展,可对此类药物的镇痛活性与副作用进行有效分离。同时靶向mu阿片受体和其他受体的多靶点分子能产生有效的镇痛活性,并能降低镇痛耐受、成瘾、呼吸抑制和便秘等阿片样副作用,其在高效、低副作用的镇痛新药研发中具有潜在的应用前景。综述多靶点肽类镇痛药物的设计及其药理学活性,为新型肽类镇痛新药的研发提供新的思路。

     

防滥用阿片类镇痛药研究进展及专利分析

阿片类镇痛药是治疗中至重度疼痛的有效药物,但其潜在的成瘾性也使之成为常见的被滥用药物.随着阿片类药物使用的增加,滥用所导致的社会问题在全球范围内不断凸显.美国在阿片类药物防滥用制剂开发方面处于世界领先水平,为减少阿片类药物滥用,率先鼓励开发防滥用阿片类镇痛药.目前已开发了多种防滥用技术,包括形成物理/化学屏障、添加激动...     

Individual differences in analgesic effects of narcotics]

Narcotic analgesics have been widely used for management of severe pain, especially for cancer pain. Most of these drugs are opioids, and they show their analgesic effects by acting through opioid receptors. Significant individual differences in opioid sensitivity can hamper effective pain treatments and increase side effects, which is associated with decreased quality of life. It is thought that genetic factors may affect individual differences in opioid sensitivity. Recent studies using various inbred and knockout mice have revealed that the mu-opioid receptor (MOP) plays a mandatory role in the analgesic properties of opioids. There is also increasing evidence that differences in the sequence of the MOP gene might significantly affect the amount of MOP gene mRNA expression and sensitivity to opioids. Furthermore, it can be thought that individual differences in opioid sensitivity are caused by genetic differences in not only MOP but other biomolecules, such as endogenous opioid peptides, molecules related with metabolic process and second messenger systems. Rapid advances in this research field are leading to a better understanding of relationships between gene polymorphisms and opioid sensitivities, which, in turn, will allow us to more accurately predict opioid sensitivity and opioid requirements in individual patients.     

Tramadol as an analgesic for mild to moderate cancer pain

In most cancer patients, pain is successfully treated with pharmacological measures such as opioid analgesics alone or opioid analgesics combined with adjuvant analgesics (co-analgesics). Opioids for mild-to-moderate pain (formerly called weak opioids) are usually recommended in the treatment of cancer pain of moderate intensity. There is a debate whether the second step of the WHO analgesic ladder, which, in Poland, is composed of opioids such as tramadol, codeine, dihydrocodeine (DHC), is still needed for cancer pain treatment. One of the most interesting and useful drugs in this group is tramadol. Its unique mechanism of action, analgesic efficacy and profile of adverse effects are responsible for its successful use in patients with different types of acute and chronic pain, including neuropathic pain. The aim of this article is to summarize the data regarding pharmacodynamics, pharmacokinetics, possible drug interactions, adverse effects, dosing guidelines, equipotency with other opioid analgesics and clinical studies comparing efficacy, adverse reactions and safety of tramadol to other opioids in cancer pain treatment.     

Imidazoline I2 receptors: target for new analgesics?

Pain remains a major clinical challenge because there are no effective analgesics for some pain conditions and the mainstay analgesics for severe pain, opioids, have serious unwanted effects. There is a dire need for novel analgesics in the clinic. Imidazoline receptors are a family of three receptors (I(1), I(2) and I(3)) that all can recognize compounds with an imidazoline structure. Accumulating evidence suggests that I(2) receptors are involved in pain modulation. Ligands acting at I(2) receptors are effective for tonic inflammatory and neuropathic pain but are much less effective for acute phasic pain. When studied in combination, I(2) receptor ligands enhance the analgesic effects of opioids in both acute phasic and chronic tonic pain. During chronic use, patients can develop tolerance to and dependence on opioids. Imidazoline I(2) receptor ligands can attenuate the development of tolerance to opioid analgesia and inhibit drug withdrawal or antagonist precipitation induced abstinence syndrome in animals. Taken together, drugs acting on I(2) receptors may be useful as a monotherapy or combined with opioids as an adjuvant for treating pain. Future studies should focus on understanding the relative efficacy of I(2) receptor ligands and developing new compounds to fill the gap in intrinsic efficacy continuum of I(2) receptors.     

Pharmacological management of cancer pain in the elderly

Existing studies indicate a high prevalence rate and poor management of cancer pain in the elderly. Pain is often considered an expected concomitant of aging, and older patients are considered more sensitive to opioids. Despite the well known pharmacokinetic changes in the elderly, the complex network of factors involved in the opioid response make the evaluation of a single element, such as age, more difficult.Notwithstanding such difficulties, appropriate analgesic treatment is able to control cancer pain in the elderly in most cases. Skills necessary to optimise pain control in older cancer patients include the ability to objectively assess functional age (not necessarily related to chronological age since the rate of decline is variable), understand the impact of coexisting conditions, carefully manage the numbers and types of drugs taken at the same time and adequately communicate with patients and relatives.The most common treatment of cancer pain consists of the use of regularly given oral analgesics. The elderly are at increased risk of developing toxicity from NSAIDs, and the overall safety of these drugs in frail elderly patients should be considered. When older patients have clear contraindications to NSAIDs, manifest signs of toxicity from these agents, or find that pain is no longer controlled with this class of drugs, opioids should be started. A variety of opioids are available, and they differ widely with respect to analgesic potency and adverse effects among the elderly.Although the aged population requires lower doses of opioids, only careful titration based on individual response can ensure the appropriate response to clinical demand. Elderly patients are potentially more likely to be affected by opioid toxicity because of the physiological changes associated with aging. Nevertheless, appropriate dosage and administration may limit these risks. Cancer patients with pain who do not respond to increasing doses of opioids because they develop adverse effects before achieving acceptable analgesia may be switched to alternative opioids. Despite the favourable effects reported with opioid switching, monitoring is crucial, particularly in the elderly or patients who are switched from high doses of opioids. Adjuvant analgesics, including antidepressants, antiepileptics, corticosteroids and bisphosphonates may help in the treatment of certain types of chronic pain.With an appropriate and careful approach, it should be possible to reduce or eliminate unrelieved cancer pain in most elderly patients and, consequently, to enhance their quality of life. Older patients with cancer should be continuously assessed for cancer pain, both before and after analgesic treatment.     

Risk-benefit assessment of opioids in chronic noncancer pain.

Opioids have been accepted as appropriate treatment for acute and cancer pain, but their role in the management of chronic nonmalignant pain is the subject of much debate, mainly due to concerns about waning efficacy, the potential for neuropsychological impairment and the development of drug addiction. Controlled clinical trials demonstrated that opioids may be effective in both nociceptive and neuropathic noncancer pain, although the former responded more consistently than the latter. Gastrointestinal and CNS adverse effects were frequent in most studies. Observational studies have generated contradictory findings regarding efficacy and safety as well as the risk of drug addiction in patients with chronic noncancer pain receiving long term opioid therapy. However, they suggest that opioids may be effective in individual cases, whichever the pathophysiological mechanism of pain. Taken together, the available data indicate that the outcomes associated with opioid therapy vary markedly across patients experiencing chronic nonmalignant pain. The main consensus is that a subset of these patients may gain substantial benefit from opioid analgesics without requiring rapidly escalating doses or developing intolerable adverse effects or drug addiction. Prescribing guidelines have been developed to assist practitioners in selecting the appropriate patients and ensuring an acceptable risk : benefit ratio of opioid therapy. Finally, it must be emphasised that chronic pain is a complex entity wherein analgesics, including opioids, are only part of the treatment.     

Opioid switching and rotation in primary care: implementation and clinical utility

ABSTRACT

Background: Opioid therapy is the standard treatment for moderate-to-severe cancer pain and is becoming a more frequent treatment for moderate-to-severe chronic noncancer pain. Response to opioids varies significantly between patients and even within the individual patient at different stages of treatment. Finding an opioid at a dose that provides adequate long-term analgesia with minimal adverse effects can be difficult. Opioid switching and opioid rotation, at different stages of therapy, represent two clinical strategies used to optimize opioid response for patients with moderate-to-severe pain.

Objectives: Review the theoretical and clinical evidence supporting the concepts of opioid switching and rotation, outline the conditions under which these practices should be considered, and briefly suggest practical steps for their implementation

Scope: Clinical literature, clinical practice and guideline databases, and professional society websites were searched for articles or reports describing opioid switching or opioid rotation in chronic pain therapy; variability in patient response to opioid therapy; physiologic, pharmacologic, and genetic factors that affect clinical response to opioids; and practical approaches to maximizing analgesia and minimizing adverse effects in opioid therapy. It is outside the scope of this review to evaluate the pharmacoeconomic aspects that affect changes in opioid therapy.

Findings: The variability in de novo clinical response to opioids likely represents the interaction of the varying properties of the individual opioids with the variability in individual patient biology. This interaction forms the rationale for opioid switching and explains its clinical utility. As with opioid switching, success with opioid rotation is related to the myriad of factors determining an individual patient's response to a specific opioid. However, the benefits of opioid rotation also derive from a partial reversal of tolerance at the μ-opioid receptor and the response of different μ-opioid receptor subtypes to the different opioids.     

The role of spinal cholecystokinin in chronic pain states

It is well established that cholecystokinin (CCK) reduces the antinociceptive effect of opioids. The level of CCK and CCK receptors, as well as CKK release, exhibits considerable plasticity after nerve injury and inflammation, conditions known to be associated with chronic pain. Such altered CCK release coupled in some situation with changes in CCK receptor levels may underlie the clinical phenomenon of varying opioid sensitivity in different clinical pain conditions. In particular, neuropathic pain after injury to the peripheral and central nervous system does not respond well to opioids, which is likely to be caused by increased activity in the endogenous CCK system. CCK receptor antagonists may thus be useful as analgesics in combination with opioids to treat neuropathic pain.     

CYP2D6 in the metabolism of opioids for mild to moderate pain

In most cancer patients, pain is successfully treated with pharmacological measures using opioid analgesics for moderate to severe pain (strong opioids) alone or in combination with adjuvant analgesics (coanalgesics). Opioids for mild to moderate pain (weak opioids) are usually recommended in the treatment of cancer pain of mild to moderate intensity. There is a debate whether the second step of the WHO analgesic ladder comprising weak opioids such as tramadol, codeine and dihydrocodeine is still needed for the treatment of cancer and chronic pain since low doses of strong opioids show similar efficacy. However, many patients with mild, moderate and in some cases strong pain intensity are still successfully treated with weak opioids. All these drugs are metabolized through CYP2D6, an important enzyme for approximately 25% of all drugs administered in clinical practice. The aim of this review is to summarize data on the impact of CYP2D6 polymorphism on pharmacokinetics, pharmacodynamics and adverse effects of weak opioids.     

Mechanistic and functional differentiation of tapentadol and tramadol

INTRODUCTION: Many opioid analgesics share common structural elements; however, minor differences in structure can result in major differences in pharmacological activity, pharmacokinetic profile, and clinical efficacy and tolerability. Areas covered: This review compares and contrasts the chemistry, pharmacodynamics, pharmacokinetics, and CNS 'functional activity' of tapentadol and tramadol, responsible for their individual clinical utilities. EXPERT OPINION: The distinct properties of tapentadol and tramadol generate different CNS functional activities, making each drug the prototype of different classes of opioid/nonopioid analgesics. Tramadol's analgesia derives from relatively weak μ-opioid receptor (MOR) agonism, plus norepinephrine and serotonin reuptake inhibition, provided collectively by the enantiomers of the parent drug and a metabolite that is a stronger MOR agonist, but has lower CNS penetration. Tapentadol's MOR agonist activity is several-fold greater than tramadol's, with prominent norepinephrine reuptake inhibition and minimal serotonin effect. Accordingly, tramadol is well-suited for pain conditions for which a strong opioid component is not needed-and it has the benefit of a low abuse potential; whereas tapentadol, a schedule-II controlled substance, is well-suited for pain conditions requiring a strong opioid component-and it has the benefit of greater gastrointestinal tolerability compared to classical strong opioids. Both drugs offer distinct and complementary clinical options.     

Development and use of methylnaltrexone,a peripherally acting opioid antagonist,to treat side effects related to opioid use

Opioid medications are used extensively as potent analgesics for treating moderate to severe pain. Although opioids offer reliable pain relief, their use is associated with a number of adverse effects, especially constipation. Conventional measures for ameliorating opioid‐induced adverse effects are often insufficient. Thus, reducing the severity of these adverse effects is of utmost importance for patients who require the benefits of opioid analgesics. Since opioids mediate pain‐relieving and adverse effects through the same classes of receptors, i.e., mu, delta, and kappa, it has been challenging to dissociate beneficial effects from detrimental ones. Methylnaltrexone is the first peripherally acting opioid receptor antagonist to receive FDA approval. This compound offers the therapeutic potential to block or reverse the undesired side effects of opioids that are mediated by receptors located in the periphery (e.g., in the gastrointestinal tract), without affecting analgesia or precipitating opioid withdrawal symptoms, which are mediated predominantly by receptors in the central nervous system. This review provides a history of the development of methylnaltrexone, discusses studies that relate to opioid bowel dysfunction, and explores other uses of this compound. Drug Dev Res, 2009. © 2009 Wiley‐Liss, Inc.