介绍

阿片激动剂；菲衍生物。 ^{a b c}

酒石酸氢可酮的用途

在进行修订之前，应根据本专论开头的MedWatch通知中较新的可用信息来考虑本节中的内容。

疼痛

缓释氢可酮：缓解疼痛程度足够严重，需要长期，每日，全天候使用阿片类镇痛药，并且替代疗法（例如，非阿片类镇痛药或速释阿片类药物）不足或不容忍。 ^{122 133}未标记为按需使用（“ prn”）。 ^{122 133}

氢可酮/对乙酰氨基酚固定组合：中度至中度严重疼痛的症状缓解。 ^123个

氢可酮/布洛芬固定组合：短期（通常<10天）用于缓解急性疼痛；不适用于治疗与骨关节炎或类风湿关节炎等慢性疾病相关的疼痛。 ¹²⁴

氢可酮与NSAIA或对乙酰氨基酚的组合可能会产生不同的镇痛作用，因为其作用机理不同。 ^C

在对症治疗急性疼痛时，应为因重伤，严重医疗条件或外科手术而引起的疼痛保留鸦片止痛药，或预期缓解疼痛和恢复功能的非鸦片替代物无效或禁忌使用。 ^{431 432 433 435 435}由于长期服用鸦片制剂通常始于急性疼痛的治疗，因此在尽可能短的时间内使用最小的有效剂量。 ^{411 431 434 435}优化其他适当疗法的同时使用。 ^{432 434 435} （请参阅在剂量和给药方式下管理阿片类药物治疗急性疼痛）。

一般使用阿片类药物用于治疗慢性疼痛的管理（即，疼痛持续> 3个月或过去的正常组织的时间愈合^{410 411 412 413），}其不与活性癌症治疗，姑息治疗，或结束时的生活护理仅当相关联的其他适当的非药物和非鸦片药物策略无效，预计减轻疼痛和改善功能的预期收益将超过风险。 ^{411 412 413 414 422 429}

如果用于慢性疼痛，阿片类镇痛药应成为综合方法的一部分，该方法还应包括适当的非药物疗法（例如认知行为疗法，放松技术，生物反馈，功能恢复，运动疗法，某些介入程序）和其他适当的药物疗法（例如，非鸦片类镇痛药，镇痛辅助药，例如针对某些神经性疼痛病情选择的抗惊厥药和抗抑郁药。 ^{411 412 413 422 429}

现有证据不足以确定长期鸦片类药物治疗慢性疼痛是否能持续缓解疼痛或改善生活功能和生活质量^{411 423 431 432 436 436}还是优于其他药物或非药物治疗。 ⁴³²使用会带来严重的风险（例如，鸦片使用障碍，药物过量）。 ^{411 431 436} （请参阅剂量和给药方式管理阿片类药物治疗慢性非癌性疼痛。）

咳嗽

单独或与其他镇咳药或祛痰药合用可缓解非生产性咳嗽的症状。 ^b

未指示可用于<18岁患者的咳嗽治疗。 ⁷¹⁰ （请参阅“谨慎使用儿科”。）

氢可酮酒石酸氢盐的剂量和给药

一般

管理阿片类药物治疗急性疼痛

• 优化其他适当疗法的同时使用。 ^{432 434 435}

• 当需要鸦片镇痛时，应以最小的有效剂量和最短的持续时间使用常规（立即释放）鸦片，因为长期使用鸦片通常始于治疗急性疼痛。 ^{411 431 434 435}

• 当足以缓解疼痛时，可根据需要使用对乙酰氨基酚或NSAIA联合使用的低效阿片类镇痛药。 ⁴³²

• 对于与创伤或手术无关的急性疼痛，将处方量限制在预期的严重疼痛持续时间以至需要鸦片类镇痛（通常≤3天，很少> 7天）所需的量。 ^{411 433 434 435 435}如果疼痛持续的时间比预期的长，请不要开较大剂量的药。 ^{411 432}相反，如果严重的急性疼痛不重新评估病人不要汇款。 ^{411 431 435}

• 对于中度至重度的术后疼痛，作为一种多式联运方案的一部分，提供鸦片类镇痛药，该方案还包括对乙酰氨基酚和/或NSAIAs以及其他药物治疗（例如某些抗惊厥药，局部局部麻醉技术）和非药物治疗（视情况而定）。 ^{430 431 432}

• 在可以耐受口服治疗的术后患者中，口服常规阿片类镇痛药通常优于静脉注射。 ^{430 431}

• 术后即刻或大手术后，需要定期（全天候）给药。 ^{430 432}当需要重复肠胃外给药时，一般建议静脉注射患者自控镇痛（PCA）。 ^{430 431}

管理阿片类药物治疗慢性非癌性疼痛

• 尽管具体建议可能会有所不同，但临床指南建议中的共同要素包括降低风险的策略，较高的剂量阈值，谨慎的剂量滴定以及对与特定鸦片制剂和制剂，共存疾病以及伴随药物治疗相关的风险的考虑。 ^{410 411 414 415 423}

• 在开始治疗之前，请对患者进行彻底评估；评估滥用，滥用和成瘾的风险因素； ^{411 412 413 415 422 429 429}建立治疗目标（包括疼痛和功能的现实目标）；考虑如果收益不超过风险，将如何终止治疗。 ^{411 415}

• 将鸦片类药物用于慢性非癌性疼痛的初始治疗作为治疗性试验，只有在疼痛和功能方面临床上有意义的改善大于治疗风险时，该试验才会继续进行。 ^{411 412 413}

• 在治疗之前和治疗期间要定期与患者讨论已知的风险和现实利益以及管理治疗的患者和临床医生的责任。 ^{411 412 413 414 415}

• 一些专家建议以最低有效剂量开具的常规（立即释放）阿片类镇痛药开始对慢性非癌性疼痛进行阿片类药物治疗。 ^{411 415}根据患者的健康状况，以前的鸦片使用情况，达到治疗目标以及预计或观察到的危害，个性化选择鸦片制剂，初始剂量和剂量滴定。 ^{412 413}

• 评估以下的治疗或剂量增加^{411 413}发起并重新评估现有基础上1-4周内利弊（例如，至少每3个月^411）整个治疗。 ^{411 412 413}记录疼痛强度和功能水平，并评估治疗目标，不良反应的存在以及对处方疗法的依从性。 ^{412 413 422 423}预计并管理常见的不良反应（例如，便秘，恶心和呕吐，认知和精神运动障碍）。 ^{412 413 415}如果益处不超过危害，请优化其他疗法和锥度鸦片制剂以降低剂量或锥度并停用鸦片制剂。 ^{411 412 413 415}

• 当需要重复增加剂量时，请评估潜在原因并重新评估相对利益和风险。 ^{412 413}尽管证据有限，但一些专家指出，尽管剂量增加，但阿片类药物旋转仍可用于无法耐受的不良反应或获益不足的患者。 ^{412 413 415}

• 较高的剂量需要特别注意， ^{410 412 415}包括更频繁和深入的监测或转介给专家。 ^{411 412 413}大剂量阿片类药物对慢性疼痛的更大益处尚未在对照临床研究中证实；更高的剂量会增加风险（机动车事故，超剂量，鸦片使用障碍）。 ^{411 415 423 424 425 426}

• 美国疾病预防控制中心（CDC）指出，初级保健临床医生应在开出相当于每天50毫克硫酸吗啡的剂量（每天约50毫克酒石酸氢可酮重度碳酸氢盐）治疗慢性疼痛之前，仔细评估个人的益处和风险，并应避免使用等于或等于90毫克硫酸吗啡的剂量每天（每天约≥90 mg酒石酸氢可酮）或仔细决定是否开此类剂量。 ⁴¹¹其他专家建议在超过相当于每天80-120毫克硫酸吗啡的剂量之前咨询疼痛管理专家。 ^{423 431}一些州建立了鸦片剂量阈值（例如，可以规定的最大每日剂量，必须或建议与专家协商的剂量阈值） ^{411 420 421 423}或已制定了风险管理策略（例如，审查州处方）处方前使用药物监测计划[PDMP]数据）。 ^{411 419 423}

• 建议的风险管理策略包括书面治疗协议或计划（例如，“合同”），尿液药物测试，审查州PDMP数据以及风险评估和监控工具。 ^{410 411 412 413 414 415 422 423 429}

• 如果患者发生严重或反复的与药物有关的异常行为或滥用或转移药物，则逐渐减少阿片类药物治疗。 ^{412 413 415}为阿片剂使用障碍患者提供或安排治疗。 ^{411 412 413}

• 考虑为阿片类药物过量服用风险增加的患者提供纳洛酮（例如，有过量用药或物质使用障碍史的患者，每天接受≥50毫克硫酸吗啡[或同等学历]的患者，同时接受苯并二氮杂类的患者，患有可能导致疾病的医疗条件的患者）增加对鸦片效应的敏感性）。 ^{411 431}

行政

口头管理

口服。 ^{A B 109 122 123 124 133}

氢可酮缓释胶囊（Zohydro ER）

每12小时管理一次。 ¹²²

必须整个吞下。 ¹²²破碎，切割，压碎，咀嚼或溶解胶囊会导致氢可酮的不受控制的输送，并可能导致剂量过大和死亡。 ¹²²

患者在治疗过程中不得饮用酒精饮料或服用含酒精的处方药或非处方药；酒精的同时摄入可能导致药物的血浆浓度升高和潜在的致命过量。 ¹²²

氢可酮缓释片（Hysingla ER）

每24小时管理一次，不考虑进餐。 ¹³³

必须整个吞下。 ¹³³压碎，咀嚼或溶解片剂会导致氢可酮的无法控制的递送，并可能导致剂量过量和死亡。 ¹³³

一次用足够的水一次服用一次片剂，以确保每片片剂在入口腔后立即被完全吞咽。 ¹³³请勿在吞咽片剂之前弄湿药片（例如，通过浸泡或舔）。 ¹³³ （请参阅“小心使用扩展版片剂的胃肠道并发症”。）

提供所需总日剂量的多片低剂量强度片剂可作为每日一次剂量服用。 ¹³³

含有氢可酮Polistirex和Chlorpheniramine Polistirex的缓释混悬液（例如Tussionex Pennkinetic）

测量悬浮液的剂量时，请使用校准的加药装置。 ^{109 112}使用家用茶匙可能会导致过量。 ^{109 112}

不要多于每12个小时一次；如果咳嗽得不到控制，请联系临床医生。 ¹¹²

不要用液体稀释或与其他药物混合；服用前请摇匀。 ¹⁰⁹

剂量

在进行修订之前，应根据本专论开头的MedWatch通知中较新的可用信息来考虑本节中的内容。

可作为酒石酸氢可酮和氢可酮polistirex获得；剂量以氢可酮酒石酸氢盐表示。 ^{a b c 109}

使用与患者治疗目标一致的最低有效剂量和最短治疗时间。 ^{411 413 431 432 435}

与其他中枢神经系统抑制剂同时使用时，请使用最低有效剂量和尽可能短的持续治疗时间。 ^{700 703} （请参阅相互作用下的特定药物。）

大人

咳嗽

酒石酸氢可酮

口服

根据需要，通常剂量为每4-6小时5 mg。 ^{113 114 115 116}其他药物在联合制剂中可能会限制氢可酮的每日剂量。 ^{114 115 116}

含有氢可酮Polistirex和Chlorpheniramine Polistirex的缓释混悬液（例如Tussionex Pennkinetic）

口服

每12小时5毫升（以酒石酸氢可酮表示为10毫克）。 ¹⁰⁹

疼痛（酒石酸氢可酮缓释胶囊[Zohydro ER]）

口服

适当的剂量选择和滴定对于降低呼吸抑制的风险至关重要。 ¹²² （请参见“谨慎操作下的呼吸抑制”。）应根据患者先前的止痛药使用情况以及成瘾，滥用和误用的危险因素来确定初始剂量。 ¹²²

仅在已确定对类似药效鸦片具有耐受性的患者中，使用> 40 mg单剂量，50 mg缓释胶囊，以及每日总剂量> 80 mg。 ¹²²

如果患者每天至少接受60 mg口服吗啡硫酸盐，每小时25 mcg透皮芬太尼，每天30 mg口服盐酸羟可待酮，每天8 mg口服盐酸氢吗啡酮，25 mg口服盐酸吗啡酮的治疗，则被认为是鸦片耐受的每天一次，或每天至少等阿片等镇痛剂量，持续至少1周。 ¹²²

初次使用阿片类药物或非耐受性患者使用氢可酮胶囊的缓释治疗开始

口服

最初，每12小时10毫克。 ¹²²不耐受阿片类药物的患者较高的初始剂量可能导致致命的呼吸抑制。 ¹²²

从其他慢性口服阿片类药物治疗转向缓释氢可酮胶囊的患者的初始剂量选择

口服

当开始使用缓释氢可酮胶囊进行治疗时，请停止使用其他全天候鸦片制剂。 ¹²²

仔细个性化剂量；鸦片耐受患者高估初始剂量可能导致致命的过量。 ¹²²

使用表1中的转换因子作为指导，为表中列出的口服阿片类药物治疗后转出的患者选择缓释氢可酮胶囊的初始剂量。 ¹²²表1中的剂量不是镇痛药，并且该表不能用于将患者从缓释氢可酮胶囊转移到另一种鸦片制剂，因为这会高估剂量并可能导致致命的过量。 ¹²²

对于接受单次阿片类镇痛药的患者，将阿片类药物的当前每日总剂量乘以转换因子，即可计算出缓释氢可酮胶囊的近似每日剂量；每12个小时将计算出的每日剂量减半用于给药。 ¹²²

对于接受大于1种阿片类镇痛药的患者，计算每种阿片类药物的缓释氢可酮的近似每日剂量，然后将这些总和相加以获得缓释氢可酮胶囊的近似每日总剂量；每12小时将计算出的每日总剂量减半。 ¹²²

对于接受含有固定比例的阿片类药物和非阿片类药物的镇痛药的患者，仅考虑转换过程中的阿片类成分。 ¹²²

如果计算出的剂量与可用的胶囊强度不符，请始终将剂量四舍五入到最接近的整个胶囊。 ¹²²

转移至延长释放的氢可酮后，监测鸦片停药情况以及是否有过度镇静作用或毒性。 ¹²²

从美沙酮转换后，需要特别密切的监测，因为美沙酮与其他鸦片制剂之间的转化率会根据先前的美沙酮暴露程度而变化很大，并且因为美沙酮的半衰期较长，并且易于在血浆中蓄积。 ¹²²

从经皮芬太尼转为缓释氢可酮胶囊的患者的初始剂量选择

口服

去除透皮芬太尼系统后等待18个小时，开始使用缓释氢可酮胶囊进行治疗；对于每25 mcg /小时的透皮芬太尼，每12小时使用大约10 mg的初始保守剂量。 ¹²²

密切监控；这种剂量转换的经验是有限的。 ¹²²

剂量调整以达到足够的镇痛作用

口服

逐渐调整剂量，每3-7天以每12小时10 mg的增量递增，以提供足够的镇痛作用并最大程度地减少副作用。 ¹²²

中止治疗

口服

每2-4天逐渐减少剂量，以免突然停药。 ¹²²密切监视可能表示需要减慢渐缩速度的退缩表现。 ¹²²

表2中的递减时间表用于3期临床试验；在该试验中未使用每日两次的> 100 mg剂量。 ¹²²

疼痛（酒石酸氢可酮缓释片[Hysingla ER]）

口服

适当的剂量选择和滴定对于降低呼吸抑制的风险至关重要。 ¹³³ （请参阅“预防性呼吸抑制”。）应根据患者先前的止痛药使用情况以及成瘾，滥用和误用的危险因素来确定初始剂量。 ¹³³

仅在耐受鸦片的患者中每天使用≥80mg的剂量。 ¹³³

如果患者每天至少接受60 mg口服吗啡硫酸盐，每小时25 mcg透皮芬太尼，每天30 mg口服盐酸羟可待酮，每天8 mg口服盐酸氢吗啡酮，25 mg口服盐酸吗啡酮的治疗，则被认为是鸦片耐受的每天一次，或每天至少等阿片等镇痛剂量，持续至少1周。 ¹³³

初次使用阿片类药物或非耐受性患者的氢可酮片缓释治疗的开始

口服

最初，每24小时20毫克。 ¹³³不耐受阿片类药物的患者较高的初始剂量可能导致致命的呼吸抑制。 ¹³³

从其他口服含氢可酮制剂转换为患者的初始剂量选择

口服

每天一次相同的每日总剂量。 ¹³³

从其他慢性口服阿片类药物疗法改为缓释氢可酮片的患者的初始剂量选择

口服

当开始使用缓释氢可酮片剂治疗时，请中止所有其他24小时使用的鸦片制剂。 ¹³³

仔细个性化剂量；鸦片耐受患者高估初始剂量可能导致致命的过量。 ¹³³

使用表3中的转换因子作为指导，为表中列出的口服阿片类药物治疗转出的患者选择缓释氢可酮片剂的初始剂量。 ¹³³表3中的剂量不是镇痛药，并且该表不能用于将患者从缓释氢可酮片剂转移到另一种鸦片制剂，因为这会高估剂量并可能导致致命的过量。 ¹³³

对于接受单次阿片类镇痛药的患者，将阿片类药物的当前每日总剂量乘以转换因子，即可得出口服氢可酮的近似每日剂量。 ¹³³将计算出的剂量减少25％，以说明不同阿片类药物相对药效的患者间差异。 ¹³³

对于接受阿片类镇痛药> 1的患者，计算每种阿片类药物口服氢可酮的近似每日剂量，然后将这些总和相加即可得出口服氢可酮的近似每日总剂量。 ¹³³将计算出的剂量减少25％，以说明不同阿片类药物相对药效的患者间差异。 ¹³³

对于接受含有固定比例的阿片类药物和非阿片类药物的镇痛药的患者，仅考虑转换过程中的阿片类成分。 ¹³³

如果计算出的剂量不符合可用的片剂强度，请始终将剂量向下舍入到最接近的整个片剂。 ¹³³

如果计算的剂量小于20毫克，则每天使用20毫克的初始剂量。 ¹³³

转移至延长释放的氢可酮后，监测鸦片停药情况以及是否有过度镇静作用或毒性。 ¹³³

从美沙酮转换后，需要特别密切的监测，因为美沙酮与其他鸦片制剂之间的转化率会根据先前的美沙酮暴露程度而变化很大，并且因为美沙酮的半衰期较长，并且易于在血浆中蓄积。 ¹³³

从经皮芬太尼转为缓释氢可酮片的患者的初始剂量选择

口服

去除芬太尼透皮系统后等待18个小时，以开始使用缓释氢可酮片剂的治疗；对于每25 mcg /小时的透皮芬太尼，每24小时使用大约20 mg的初始保守剂量。 ¹³³

密切监视；这种剂量转换的经验是有限的。 ¹³³

从经皮丁丙诺啡转为缓释氢可酮片的患者的初始剂量选择

口服

最初，以前接受透皮丁丙诺啡≤20 mg /小时的患者每24小时服用20 mg。 ¹³³

密切监视；这种剂量转换的经验是有限的。 ¹³³

剂量调整以达到足够的镇痛作用

口服

逐渐调整剂量，每3-5天每24小时以10-20 mg的增量递增，以提供足够的镇痛作用并最大程度地减少副作用。 ¹³³

中止治疗

口服

每2-4天逐渐减少剂量，以免突然停药。 ¹³³

锥度中的每个新剂量应≥先前剂量的50％；将剂量降低至每天20 mg，持续2-4天，然后停止治疗。 ¹³³

疼痛（立即释放固定组合）

口服

根据需要每4-6小时5-10 mg（与对乙酰氨基酚固定结合使用）。 ^123个

视需要每4-6小时服用2.5-10 mg（与布洛芬固定组合），一般少于10天。 ^124个132制造商状态总的每日剂量不应超过5片（每片从2.5-10毫克重酒石酸氢可酮和200毫克的布洛芬的提供）。 ^{124 132}

根据疼痛的严重程度以及患者的反应和耐受性调整剂量。 ^{123 124一}

含非鸦片剂的止痛药固定组合：非鸦片剂成分可能会限制鸦片剂成分的剂量。 ^{117 119 120 121非}鸦片剂止痛药与氢可酮的固定比例不同，也可用于许多其他处方药和非处方药。确保不会重复治疗，并且非鸦片剂量不会超过建议的最大剂量。 ^{117 118 119 121}

限度

大人

咳嗽

酒石酸氢可酮

口服

每天最多30毫克。 ¹¹³但是，组合制剂中的其他药物可能会进一步限制氢可酮的每日剂量。 ^{114 115 116}

含有氢可酮Polistirex和Chlorpheniramine Polistirex的缓释混悬液（例如Tussionex Pennkinetic）

口服

每天最大10毫升（以酒石酸氢可酮表示为20毫克）。 ¹⁰⁹

疼痛

口服

对于与创伤或手术无关的急性疼痛，将处方量限制在预期的严重疼痛持续时间以至需要鸦片类镇痛（通常≤3天，很少> 7天）所需的量。 ^{411 433 434 435}

美国疾病预防控制中心（CDC）建议初级保健临床医生在开出相当于每天50毫克硫酸吗啡（每天约50毫克酒石酸氢可待酮）的慢性疼痛处方，并避免每天等于90毫克硫酸吗啡的剂量时，谨慎地重新评估个人益处和风险。每天约90毫克以上的酒石酸氢可待酮）或仔细证明其决定开此类剂量的决定是合理的。 ⁴¹¹其他专家建议在超过相当于每天80-120毫克硫酸吗啡的剂量之前咨询疼痛管理专家。 ^{423 431}

一些州设定了处方限制（例如，可以规定的最大每日剂量，要求或建议与专家会诊的剂量阈值）。 ^{411 420 421 423}

特殊人群

肝功能不全

轻度或中度肝功能损害：无需调整初始剂量。 ^{122 133}

Severe hepatic impairment (extended-release capsules [Zohydro ER]): Initially, 10 mg every 12 hours. ¹²²

Severe hepatic impairment (extended-release tablets [Hysingla ER]): Reduce initial dosage by 50%. ¹³³

Monitor closely for adverse effects. ^{122 133}

肾功能不全

Manufacturer of extended-release capsules recommends use of low initial dosage in patients with renal impairment. ¹²²

Manufacturer of extended-release tablets states that no initial dosage adjustment required in mild renal impairment; reduce initial dosage by 50% in patients with moderate or severe renal impairment, including end-stage renal disease. ¹³³

Monitor closely for adverse effects. ^{122 133}

老年患者

Use low initial dosage in older patients. ^{a b 109 122 123 133} Monitor closely for adverse effects. ^{122 133}

Cautions for Hydrocodone Bitartrate

禁忌症

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• Known hypersensitivity to hydrocodone or any ingredient in the formulation. ^{b 109 122 123 124 133}

• Possible cross-sensitivity to hydrocodone if hypersensitive to other opiates. ^{123 124}

• Extended-release hydrocodone: Substantial respiratory depression, acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment, known or suspected paralytic ileus and GI obstruction. ^{122 133}

• Hydrocodone antitussives: Children <6 years of age. ^{109 113 136 137 138}

警告/注意事项

警告事项

呼吸抑制

Possible dose-related respiratory depression. ^{b c e 109 112 123 124 133}

Even therapeutic doses of hydrocodone may decrease respiratory drive to the point of apnea in patients with COPD, cor pulmonale, substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression. ^{122 133} Monitor closely, particularly when initiating therapy or titrating dosage. ^{122 133} Use nonopiate analgesics if possible. ^{122 133}

Geriatric, cachectic, and debilitated patients are at increased risk of life-threatening respiratory depression. ^{122 133} Close monitoring of therapy with extended-release hydrocodone is required, particularly following initiation of therapy, during dosage titration, and during concomitant therapy with other respiratory depressants. ^{122 133}

Carbon dioxide retention from opiate-induced respiratory depression can exacerbate the drug's sedative effects. ^{122 133}

Serious, life-threatening, or fatal respiratory depression reported with use of opiates, even when used as recommended; can occur at any time during therapy, but risk is greatest during initiation of therapy and following dosage increases. ^{122 133 136} Monitor for respiratory depression, especially during the first 24–72 hours of therapy and following any dosage increase. ^{122 133 136}

Only clinicians who are knowledgeable in the use of potent opiates for the management of chronic pain should prescribe extended-release hydrocodone. ^{122 133}

Appropriate dosage selection and titration of hydrocodone are essential to reduce the risk of respiratory depression; overestimation of the dosage when transferring patients from another opiate analgesic can result in fatal overdosage with the first dose. ^{122 133}

Accidental ingestion of even 1 dose of hydrocodone, especially by a child, can result in respiratory depression and a fatal overdose. ^{122 133 136}

Potential for increased viscosity of bronchial secretions and suppression of cough reflex, with subsequent respiratory insufficiency, in patients with asthma or pulmonary emphysema who indiscriminately use antitussives. ^b

Patients should seek immediate medical assistance if they experience respiratory depression. ^{109 112} (See Advice to Patients.)

Consider offering naloxone when opiate agonists are prescribed for patients at increased risk of opiate overdosage (eg, those with history of overdose or substance use disorder, those receiving ≥50 mg of morphine sulfate [or equivalent] daily, those receiving benzodiazepines concomitantly, those with medical conditions that could increase sensitivity to opiates). ^{411 431}

上瘾，滥用和滥用

Addiction can occur with appropriately prescribed or illicitly obtained opiates, and at recommended dosages or with misuse or abuse. ^{122 133}

Assess each patient's risk for addiction, abuse, and misuse prior to prescribing; monitor all patients for development of these behaviors or conditions. ^{122 133} Personal or family history of substance abuse (drug or alcohol addiction or abuse) or mental illness (eg, major depression) increases risk. ^{122 133}

The potential for addiction, abuse, and misuse should not prevent opiate prescribing for appropriate pain management, ^{122 133} but does necessitate intensive counseling about risks and proper use and intensive monitoring for these behaviors and conditions. ¹²²

Modified-release (eg, extended-release) opiates are associated with a greater risk of overdose and death because of the larger amount of drug contained in each dosage unit. ^{122 133}

Abuse or misuse of extended-release hydrocodone formulations by crushing or chewing the capsules or tablets, snorting the contents, or injecting the dissolved contents will result in uncontrolled delivery of hydrocodone and can result in a fatal overdose. ^{122 133}

Because of the challenges associated with providing access to an adequate array of options for management of chronic pain while simultaneously preventing prescription opiate abuse and misuse, FDA's decision to approve hydrocodone bitartrate extended-release capsules (Zohydro ER) was controversial, as the formulation lacks tamper-resistant features that might deter abuse and, like other extended-release opiates, some strengths contain substantial amounts of the drug (up to 50 mg ¹²² ). ^{126 127 128 129 130}

Physical and chemical properties of Hysingla ER extended-release tablets (containing up to 120 mg of the drug) are intended to hinder manipulation for IV or intranasal abuse and misuse; some extended-release characteristics are retained if the tablet is physically compromised. ¹³³ However, potential for IV, intranasal, and oral abuse still exists. ¹³³

Potential for abuse of hydrocodone-containing combinations is similar to that of schedule II (C-II) oxycodone-containing combinations. ^{290 291} Because of increasing concerns about misuse, abuse, and diversion, hydrocodone-containing fixed-combination analgesic and antitussive preparations previously subject to control as C-III drugs were rescheduled as C-II drugs effective October 6, 2014. ^{290 291} (See Preparations.)

Interactions with Drugs that Affect CYP3A4

Concomitant use of CYP3A4 inhibitors may increase plasma hydrocodone concentrations, increasing or prolonging opiate effects. ^{122 133}

Concomitant use of CYP3A4 inducers may result in decreased plasma hydrocodone concentrations, lack of efficacy, or manifestations of withdrawal. ^{122 133} (See Drugs Affecting Hepatic Microsomal Enzymes under Interactions.)

Concomitant Use with Benzodiazepines or Other CNS Depressants

Concomitant use of opiates, including hydrocodone, and benzodiazepines or other CNS depressants (eg, anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiate agonists, alcohol) may result in profound sedation, respiratory depression, coma, and death. ^{416 417 418 700 701 702 703 704} Substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use. ^{416 417 418 435 700 701}

Avoid concomitant use of CNS depressants with hydrocodone antitussives; ^{700 704} reserve concomitant use with hydrocodone-containing analgesics for patients in whom alternative treatment options are inadequate. ^{700 703} （请参阅相互作用下的特定药物。）

其他警告/注意事项

Shares the toxic potentials of the opiate agonists; observe the usual precautions of opiate agonist therapy.^一种

中枢神经系统抑郁症

可能会影响需要精神警觉和身体协调的活动的进行。 ^{b c e 109 122 123 124 133}

Concurrent use with other CNS depressants may result in profound sedation, respiratory depression, coma, or death. ^{122 133 700 703 704} (See Specific Drugs under Interactions.)

肾上腺功能不全

Adrenal insufficiency reported in patients receiving opiate agonists or opiate partial agonists. ⁴⁰⁰ Manifestations are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension. ⁴⁰⁰

If adrenal insufficiency is suspected, perform appropriate laboratory testing promptly and provide physiologic (replacement) dosages of corticosteroids; taper and discontinue the opiate agonist or partial agonist to allow recovery of adrenal function. ⁴⁰⁰ If the opiate agonist or partial agonist can be discontinued, perform follow-up assessment of adrenal function to determine if corticosteroid replacement therapy can be discontinued. ⁴⁰⁰ In some patients, switching to a different opiate improved symptoms. ⁴⁰⁰

Increased Intracranial Pressure or Head Trauma

Respiratory depressant effects and ability of opiates to increase CSF pressure may be markedly exaggerated in patients with head injury, other intracranial lesions, or preexisting elevation in intracranial pressure. ^{b c e 109 122 123 124 133}

Hydrocodone produces effects (eg, pupillary changes, altered consciousness) that may obscure clinical course and neurologic signs of further increase in CSF pressure in patients with head injuries. ^{b c e 109 122 123 124 133}

Closely monitor patients with increased intracranial pressure or impaired consciousness. ^{122 133} Avoid use of extended-release hydrocodone in patients with impaired consciousness or coma. ^{122 133}

低血压

Possible severe hypotension in individuals whose ability to maintain their BP is compromised by depleted blood volume or concomitant drugs that compromise vascular tone (eg, phenothiazines, general anesthetics). ^{122 133} (See Specific Drugs under Interactions.)

May cause severe hypotension, including orthostatic hypotension and syncope, in ambulatory patients. ^{122 133}

Avoid use of extended-release hydrocodone in patients with circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and BP. ^{122 133}

Seizure Disorders

May aggravate preexisting seizure disorder. ¹²² Monitor for worsened seizure control. ¹²²

May induce seizures in some clinical settings. ¹²²

GI Complications with Extended-release Tablets

Some patients report difficulty in swallowing the extended-release tablets. ¹³³ The tablets form a gelatinous mass when wet. ¹³³ (See Hydrocodone Extended-release Tablets [Hysingla ER] under Dosage and Administration.)

Choking, dysphagia, and esophageal obstruction (at least 1 case requiring medical intervention to remove the tablet) reported. ¹³³ Increased risk in patients with underlying GI disorders (eg, esophageal or colon cancer) associated with narrow GI lumen. ¹³³

Consider using an alternative analgesic in patients who have difficulty swallowing and in those at risk for underlying GI disorders associated with narrow GI lumen. ¹³³

急性腹部疾病

May obscure diagnosis or clinical course of patients with acute abdominal conditions. ^{e 109 122 123 124 133}

Obstructive Bowel Disease

May diminish propulsive peristaltic waves in GI tract and decrease bowel motility. ^{122 133} Use may result in obstructive bowel disease, especially in patients with underlying intestinal motility disorder. ¹⁰⁹

Monitor postoperative patients for decreased bowel motility. ^{122 133}

Extended-release hydrocodone is contraindicated in patients with known or suspected GI obstruction, including paralytic ileus. ^{122 133}

Postoperative Patients

Suppression of cough reflex following thoracotomy or laparotomy may lead to postoperative retention of secretions; cautious use recommended. ^{b 109}

Biliary Disease

Monitor patients with biliary disease, including acute pancreatitis; may cause spasm of the sphincter of Oddi and decrease biliary and pancreatic secretions. ^{122 133}

Debilitated and Special Risk Patients

Use with caution in debilitated patients and in those with hypothyroidism, Addison's disease, prostatic hypertrophy, urethral stricture, or pulmonary disease. ^{b c e 109 123 124}

Tolerance and Dependence

Possible tolerance and physical dependence following prolonged administration. ^{b c e 109 122 123 124 133} When discontinuing therapy, gradually taper dosage to avoid symptoms of withdrawal. ^{122 133}

QT Interval Prolongation

Prolongation of corrected QT (QT _c ) interval observed in healthy individuals receiving 160 mg daily (as extended-release tablets). ¹³³

Consider this observation when making decisions regarding monitoring (eg, periodic monitoring of ECGs and electrolyte concentrations) of patients with CHF, bradyarrhythmias, or electrolyte abnormalities and those receiving drugs that prolong the QT _c interval. ¹³³

Manufacturer recommends avoiding use of extended-release tablets in patients with congenital long QT syndrome. ¹³³

If QT _c interval prolongation occurs, consider reducing dosage by 33–50% or using an alternative analgesic. ¹³³

Hypogonadism

Hypogonadism or androgen deficiency reported in patients receiving long-term opiate agonist or opiate partial agonist therapy; ^{400 401 402 403 404} causality not established. ⁴⁰⁰ Manifestations may include decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility. ⁴⁰⁰ Perform appropriate laboratory testing in patients with manifestations of hypogonadism. ⁴⁰⁰

Fixed-Combination Preparations

When used in fixed combination with other drugs, consider the cautions, precautions, and contraindications associated with the other drug(s). ^{a 123 124}

特定人群

怀孕

Category C. ^{e 109 122 123 124 133}

Analysis of data from the National Birth Defects Prevention Study (large population-based, case-control study) suggests therapeutic use of opiates in pregnant women during organogenesis is associated with a low absolute risk of birth defects, including heart defects, spina bifida, and gastroschisis. ^{134 135}

Prolonged maternal use of opiates during pregnancy can result in neonatal opiate withdrawal syndrome; in contrast to adults, withdrawal syndrome in neonates may be life-threatening and requires management according to protocols developed by neonatology experts. ^{122 133} Syndrome presents with irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. ^{122 133} Onset, duration, and severity vary depending on the specific opiate used, duration of use, timing and amount of last maternal use, and rate of drug elimination by the neonate. ^{122 133}

Use of opiates during late pregnancy can result in neonatal respiratory depression. ¹³⁴

Extended-release opiates not recommended immediately before or during labor; shorter-acting analgesics or other analgesic techniques may be more appropriate. ^{122 133}

哺乳期

Low concentrations of hydrocodone and metabolite (hydromorphone) reported in breast milk of women receiving hydrocodone for postpartum pain. ¹²² Discontinue nursing or the drug. ^{109 122 123 124 133}

Monitor infants exposed to hydrocodone through breast milk for excessive sedation, respiratory depression, GI effects, and altered feeding patterns. ^{122 133 134} Symptoms of withdrawal can occur in opiate-dependent infants when maternal administration of opiates is discontinued or breast-feeding is stopped. ^{122 133}

儿科用

Safety and efficacy as an analgesic not established in pediatric patients. ^{122 123 124 133}

Pediatric patients may be at increased risk of esophageal obstruction, dysphagia, and choking (because of their smaller GI lumen) if they ingest the extended-release tablets, which form a gelatinous mass when exposed to fluids. ¹³³

Do not use antitussive agents containing opiates, including hydrocodone, in pediatric patients <18 years of age; FDA states that risks of respiratory depression, misuse, abuse, addiction, overdosage, and death outweigh the potential benefit. ⁷¹⁰

Hydrocodone antitussives contraindicated in children <6 years of age. ^{109 112 113 136 137 138}

老人用

≥65岁患者的经验不足，无法确定老年患者与年轻人的反应是否不同。 ^{109 122 123}

May cause confusion and oversedation in geriatric patients. ^{122 123 133} Increased risk of life-threatening respiratory depression in geriatric, cachectic, or debilitated patients. ^{122 124 133}

Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, use with caution and select dosage at the lower end of the dosage range. ^{109 122 123 124 133}

Monitor closely for adverse effects, especially during initiation of therapy and dosage titration and when used concomitantly with other respiratory depressants. ^{122 133}

肝功能不全

Exposure to the drug and the risk of adverse effects may be increased. ^{122 133} Monitor closely. ^{122 133} (See Hepatic Impairment under Dosage and Administration and see Absorption: Special Populations, under Pharmacokinetics.)

肾功能不全

Exposure to the drug and the risk of adverse effects may be increased. ^{122 133} Monitor closely. ^{122 133} (See Renal Impairment under Dosage and Administration and see Absorption: Special Populations, under Pharmacokinetics.)

常见不良反应

Lightheadedness, dizziness, sedation, nausea, vomiting, constipation. ^{b 109 123 124} Adverse effects occur infrequently with usual oral antitussive dosages. ^b

With extended-release capsules for chronic pain: Constipation, nausea, somnolence, fatigue, headache, dizziness, dry mouth, vomiting, pruritus, abdominal pain, peripheral edema, upper respiratory tract infection, muscle spasms, urinary tract infection, back pain, tremor. ¹²²

With extended-release tablets for chronic pain: Nausea, constipation, vomiting, dizziness, headache, somnolence, fatigue, pruritus, tinnitus, insomnia, decreased appetite, influenza. ¹³³

Interactions for Hydrocodone Bitartrate

Metabolized by CYP3A4 and to a lesser extent by CYP2D6. ^{122 124} Also may be metabolized to a small extent by CYP2B6 and CYP2C19. ¹³³

影响肝微粒体酶的药物

CYP3A4 inhibitors: Possible decreased clearance and increased plasma concentrations of hydrocodone; may result in increased or prolonged opiate effects, including increased risk of fatal respiratory depression. ^{122 133} If concomitant use is necessary, monitor for respiratory depression and sedation at frequent intervals; consider dosage adjustments until stable drug effects are achieved. ^{122 133}

CYP3A4 inducers: Possible increased clearance and decreased plasma concentrations of hydrocodone; may result in lack of efficacy or withdrawal manifestations. ^{122 133} If concomitant use is necessary, monitor for opiate withdrawal; consider dosage adjustments until stable drug effects are achieved. ^{122 133} If CYP3A4 inducer is discontinued, plasma hydrocodone concentrations may increase, possibly increasing or prolonging therapeutic and adverse effects of the drug and increasing risk of fatal overdosage. ^{122 133}

Drugs Associated with Serotonin Syndrome

Risk of serotonin syndrome when used with other serotonergic drugs. ⁴⁰⁰ May occur at usual dosages. ⁴⁰⁰ Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases. ⁴⁰⁰ (See Advice to Patients.)

If concomitant use of other serotonergic drugs is warranted, monitor patients for serotonin syndrome, particularly during initiation of therapy and dosage increases. ⁴⁰⁰

If serotonin syndrome is suspected, discontinue hydrocodone, other opiate therapy, and/or any concurrently administered serotonergic agents. ⁴⁰⁰

特殊药物