Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone).
Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone).
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DOI：
10.1111/j.1533-2500.2008.00204.x
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发表时间：
2008-07-01
期刊：
影响因子：
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通讯作者：
Sacerdote, Paola
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作者：
Pergolizzi, Joseph;Boger, Rainer H;Sacerdote, Paola
共识总结：1。阿片类药物在癌症疼痛中的使用：选择用于老年人疼痛治疗的镇痛药的标准包括但不限于总体疗效、总体副作用、起效、药物相互作用、滥用潜力和实际问题，如药物的成本和可获得性，以及疼痛的严重程度和类型（伤害性、急性/慢性等）。在任何给定的时间，决策过程中的选择顺序都可以改变。这一共识是基于循证文献（不包括扩展数据，不包括慢性缓释阿片类药物）。开处方有各种各样的驱动因素，包括化合物的可获得性和成本，这有时可能是主要的驱动因素。丁丙诺啡的透皮配方在大多数欧洲国家都有，特别是那些阿片类药物使用率高的国家，但法国除外；然而，丁丙诺啡舌下制剂在欧洲的供应有限，因为它仅在包括德国和比利时在内的少数国家销售。阿片类贴片目前在美国是实验性的，舌下配方有配药限制，因此其使用受到限制。很明显，人口金字塔是向上的。在全球范围内，未来将会有一个需要照顾的老年人口。老年人口对生活有期望，因为退休人员不再是减少生活方式活动的人。六七十岁的“婴儿潮一代”是“婴儿潮一代”；他们想要一种功能性的积极的生活方式。他们愿意在治疗选择方面做出权衡，并理解他们可能会经历疼痛，前提是这可以提高生活质量和功能。因此，在治疗老年人疼痛时，需要仔细考虑合并症——包括癌症和非癌症疼痛、骨关节炎、类风湿关节炎和带状疱疹后神经痛——以及患者的功能状态。世界卫生组织第三步阿片类药物是治疗癌症患者疼痛的主要药物，几十年来，吗啡一直是最常用的药物。一般来说，存在高水平的证据数据（Ib或IIb），尽管许多研究只包括少数患者。基于这些研究，所有阿片类药物被认为对癌症疼痛管理有效（尽管部分癌症疼痛不是或只是部分阿片类药物敏感），但没有针对老年癌症患者的精心设计的特异性研究。在可用于透皮制剂的两种阿片类药物中——芬太尼和丁丙诺啡——芬太尼是研究最多的，但根据已发表的数据，这两种药物似乎都是有效的，毒性低，耐受性好，特别是在低剂量下。2. 阿片类药物在非癌性疼痛中的应用：越来越多的证据表明，阿片类药物对非癌性疼痛有效（治疗数据大多为Ib或IIb级），但需要单独剂量滴定并考虑各自的耐受性。同样，没有针对老年人的具体研究，但可以得出结论，阿片类药物对非癌症性疼痛有疗效，这种疼痛通常是由老年人的典型疾病引起的。当不清楚哪种药物和哪种方案在维持镇痛效果方面更优越时，应根据安全性和耐受性考虑选择适当的药物。循证医学已被纳入最佳临床实践指南，应作为患者护理决策过程的基础；然而，在实践中，当我们对病人进行个性化护理时，医学艺术才得以实现。这在循证医学和轶事经验之间取得了平衡。在临床实践中应用指南时，事实性建议和专家意见都有价值。3. 阿片类药物在神经性疼痛中的应用：阿片类药物在神经性疼痛中的作用在过去一直存在争议，但现在越来越被接受；然而，与伤害性疼痛相比，神经性疼痛通常需要更高的阿片类药物剂量。大多数治疗数据为II级或III级，表明早期合并阿片类药物可能有益。丁丙诺啡在改善神经性疼痛症状方面表现出明显的益处，这被认为是其特定药理学特征的结果。4. 阿片类药物在肝肾功能受损老年患者中的应用：排泄器官功能损害在老年人中很常见，尤其是在肾功能方面。对于除丁丙诺啡以外的所有阿片类药物，活性药物和代谢物的半衰期在老年人和肾功能不全患者中增加。因此，除丁丙诺啡外，建议减少剂量，延长用药间隔时间，并监测肌酐清除率。因此，丁丙诺啡似乎是老年人阿片类药物治疗的首选。5. 阿片类药物和呼吸抑制：对于有潜在肺部疾病或同时接受与低通气相关的中枢神经系统（CNS）药物的阿片类药物治疗的患者，呼吸抑制是一个重大威胁。并不是所有的阿片类药物对呼吸抑制的作用都是一样的：丁丙诺啡是唯一一种在不使用其他中枢神经系统抑制剂时显示出呼吸抑制上限的阿片类药物。在治疗有呼吸问题风险的患者时，应考虑阿片类药物在呼吸作用方面的不同特征，因此必须保持谨慎的给药。6. 阿片类药物和免疫抑制：年龄与免疫系统的逐渐衰退有关：免疫衰老，这与传染病、自身免疫性疾病和癌症的发病率和死亡率增加以及免疫治疗（如疫苗接种）的疗效下降有关。阿片类药物对老年人免疫抑制作用的临床相关性尚不完全清楚，疼痛本身也可能引起免疫抑制。在没有明显不良事件的情况下可以实现足够的镇痛，应该在老年人中使用具有最小免疫抑制特性的阿片类药物。大多数阿片类药物的免疫抑制作用描述不佳，这是评估阿片类药物谱真正作用的问题之一，但有一些迹象表明，高剂量阿片类药物与免疫抑制作用增加相关。考虑到临床前和临床工作中所有非常有限的可用证据，丁丙诺啡可以推荐，而吗啡和芬太尼则不能。7. 阿片类药物的安全性和耐受性概况：阿片类药物的不良事件概况差异很大。由于老年人不良事件的后果可能很严重，因此应使用具有良好耐受性的药物（特别是关于中枢神经系统和胃肠道的影响），并且在过量使用时尽可能安全，特别是关于对呼吸的影响。缓慢剂量滴定有助于减少恶心和呕吐等典型初始不良事件的发生率。缓释制剂，包括透皮制剂，增加患者的依从性。
SUMMARY OF CONSENSUS: 1. The use of opioids in cancer pain: The criteria for selecting analgesics for pain treatment in the elderly include, but are not limited to, overall efficacy, overall side-effect profile, onset of action, drug interactions, abuse potential, and practical issues, such as cost and availability of the drug, as well as the severity and type of pain (nociceptive, acute/chronic, etc.). At any given time, the order of choice in the decision-making process can change. This consensus is based on evidence-based literature (extended data are not included and chronic, extended-release opioids are not covered). There are various driving factors relating to prescribing medication, including availability of the compound and cost, which may, at times, be the main driving factor. The transdermal formulation of buprenorphine is available in most European countries, particularly those with high opioid usage, with the exception of France; however, the availability of the sublingual formulation of buprenorphine in Europe is limited, as it is marketed in only a few countries, including Germany and Belgium. The opioid patch is experimental at present in U.S.A. and the sublingual formulation has dispensing restrictions, therefore, its use is limited. It is evident that the population pyramid is upturned. Globally, there is going to be an older population that needs to be cared for in the future. This older population has expectations in life, in that a retiree is no longer an individual who decreases their lifestyle activities. The "baby-boomers" in their 60s and 70s are "baby zoomers"; they want to have a functional active lifestyle. They are willing to make trade-offs regarding treatment choices and understand that they may experience pain, providing that can have increased quality of life and functionality. Therefore, comorbidities--including cancer and noncancer pain, osteoarthritis, rheumatoid arthritis, and postherpetic neuralgia--and patient functional status need to be taken carefully into account when addressing pain in the elderly. World Health Organization step III opioids are the mainstay of pain treatment for cancer patients and morphine has been the most commonly used for decades. In general, high level evidence data (Ib or IIb) exist, although many studies have included only few patients. Based on these studies, all opioids are considered effective in cancer pain management (although parts of cancer pain are not or only partially opioid sensitive), but no well-designed specific studies in the elderly cancer patient are available. Of the 2 opioids that are available in transdermal formulation--fentanyl and buprenorphine--fentanyl is the most investigated, but based on the published data both seem to be effective, with low toxicity and good tolerability profiles, especially at low doses. 2. The use of opioids in noncancer-related pain: Evidence is growing that opioids are efficacious in noncancer pain (treatment data mostly level Ib or IIb), but need individual dose titration and consideration of the respective tolerability profiles. Again no specific studies in the elderly have been performed, but it can be concluded that opioids have shown efficacy in noncancer pain, which is often due to diseases typical for an elderly population. When it is not clear which drugs and which regimes are superior in terms of maintaining analgesic efficacy, the appropriate drug should be chosen based on safety and tolerability considerations. Evidence-based medicine, which has been incorporated into best clinical practice guidelines, should serve as a foundation for the decision-making processes in patient care; however, in practice, the art of medicine is realized when we individualize care to the patient. This strikes a balance between the evidence-based medicine and anecdotal experience. Factual recommendations and expert opinion both have a value when applying guidelines in clinical practice. 3. The use of opioids in neuropathic pain: The role of opioids in neuropathic pain has been under debate in the past but is nowadays more and more accepted; however, higher opioid doses are often needed for neuropathic pain than for nociceptive pain. Most of the treatment data are level II or III, and suggest that incorporation of opioids earlier on might be beneficial. Buprenorphine shows a distinct benefit in improving neuropathic pain symptoms, which is considered a result of its specific pharmacological profile. 4. The use of opioids in elderly patients with impaired hepatic and renal function: Functional impairment of excretory organs is common in the elderly, especially with respect to renal function. For all opioids except buprenorphine, half-life of the active drug and metabolites is increased in the elderly and in patients with renal dysfunction. It is, therefore, recommended that--except for buprenorphine--doses be reduced, a longer time interval be used between doses, and creatinine clearance be monitored. Thus, buprenorphine appears to be the top-line choice for opioid treatment in the elderly. 5. Opioids and respiratory depression: Respiratory depression is a significant threat for opioid-treated patients with underlying pulmonary condition or receiving concomitant central nervous system (CNS) drugs associated with hypoventilation. Not all opioids show equal effects on respiratory depression: buprenorphine is the only opioid demonstrating a ceiling for respiratory depression when used without other CNS depressants. The different features of opioids regarding respiratory effects should be considered when treating patients at risk for respiratory problems, therefore careful dosing must be maintained. 6. Opioids and immunosuppression: Age is related to a gradual decline in the immune system: immunosenescence, which is associated with increased morbidity and mortality from infectious diseases, autoimmune diseases, and cancer, and decreased efficacy of immunotherapy, such as vaccination. The clinical relevance of the immunosuppressant effects of opioids in the elderly is not fully understood, and pain itself may also cause immunosuppression. Providing adequate analgesia can be achieved without significant adverse events, opioids with minimal immunosuppressive characteristics should be used in the elderly. The immunosuppressive effects of most opioids are poorly described and this is one of the problems in assessing true effect of the opioid spectrum, but there is some indication that higher doses of opioids correlate with increased immunosuppressant effects. Taking into consideration all the very limited available evidence from preclinical and clinical work, buprenorphine can be recommended, while morphine and fentanyl cannot. 7. Safety and tolerability profile of opioids: The adverse event profile varies greatly between opioids. As the consequences of adverse events in the elderly can be serious, agents should be used that have a good tolerability profile (especially regarding CNS and gastrointestinal effects) and that are as safe as possible in overdose especially regarding effects on respiration. Slow dose titration helps to reduce the incidence of typical initial adverse events such as nausea and vomiting. Sustained release preparations, including transdermal formulations, increase patient compliance.