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Medications for opioid use disorders: clinical and pharmacological considerations
The Journal of Clinical Investigation ( IF 15.9 ) Pub Date : 2019-11-25 , DOI: 10.1172/jci134708
Nora D. Volkow , Carlos Blanco

The opioid epidemic, now in its second decade, is one of the most challenging public health crises in the US. Providing an effective response is complicated by multiple underlying causes and consequences as well as a misunderstanding of addiction and the medications used to treat it (1). Indeed, medications for opioid use disorder (MOUDs) are the most effective interventions for treating opioid addiction, but are not prescribed to many who would benefit. Here, we describe the distinction between physical dependence and addiction along with its implication for treatment, and discuss the mechanisms of action of MOUDs.

Opioid withdrawal versus opioid dependence

Opioid use disorder (OUD) is defined as a pattern of maladaptive opioid use that leads to significant impairment or distress. Severity is classified on the basis of the number of symptoms (Table 1) present: mild (one or two), moderate (three or four), and severe (six or more) (2). In this description, opioid addiction corresponds to moderate and severe OUD.

Table 1

DSM-5 criteria for diagnostic criteria OUD

In diagnosing OUD, many confuse opioid physical dependence with OUD, yet this distinction is crucial for selecting treatment. Physical dependence develops rapidly and occurs in most people who are given repeated doses of opioid medications and manifests as the emergence of acute withdrawal symptoms following discontinuation of opioid drugs. When physical dependence is associated with tolerance, it can lead to a diagnosis of mild OUD (two of the criteria in Table 1). Note that physical dependence and tolerance will be present in many pain patients who are properly treated with opioid medications; hence, the distinction from mild OUD requires the clinician to assess whether significant impairment or distress is present. Physical dependence and the associated acute withdrawal symptoms are adaptations that recover rapidly (within days) and can be managed by slowly tapering the opioid drug without the need of maintenance on opioid medications (3). In contrast, opioid addiction develops in less than 10% of those exposed repeatedly to opioids and is the result of neuroplastic adaptations in brain circuits underlying reward and motivation, self-regulation and decision-making, and mood and stress reactivity that are long lasting, persisting years after drug discontinuation (4, 5). Opioid addiction significantly benefits from the use of medications for OUD.

Abrupt cessation of opioids after repeated use can produce an intense but rarely life-threatening withdrawal syndrome, which can be understood as an adaptation to maintaining homeostasis or allostatic process (3). Common symptoms of early withdrawal include mydriasis, piloerection, muscle twitching, lacrimation, rhinorrhea, diaphoresis, yawning, tremor, insomnia, restlessness, myalgia, arthralgia, diarrhea, and nausea or vomiting. As withdrawal progresses, tachycardia, tachypnea, hypertension or hypotension, and dehydration can appear. Note that this is distinct from the protracted withdrawal syndrome characterized by dysphoria, craving, and insomnia that reflects brain circuitry neuroadaptations associated with addiction. Symptoms of acute withdrawal (as well as protracted withdrawal) can be a powerful trigger for relapse for individuals with OUD (1), but can also lead to opioid seeking in pain patients in whom acute opioid withdrawal is not properly managed.

Multiple neuroadaptations underlie physical dependence (6), including desensitization and internalization of the μ-opioid receptor (MOR), impaired MOR signaling with intracellular effectors, intracellular upregulation of cAMP/PKA in opioid-sensitive neurons, adaptations in neuropeptide systems that interact with μ-opioid–sensitive neurons, and activation of glial signaling (7). Hyperactivity of the locus coeruleus (LC) underlies many of the symptoms of acute withdrawal, and α1 adrenergic agonists, such as lofexidine and clonidine, which reduce noradrenergic release, are useful for the management of acute opioid withdrawal.

In contrast to withdrawal, which is a physiological response to the abrupt decline in MOR occupancy and signaling, addiction is predominantly a disorder of brain circuits that impairs motivation, self regulation, and hedonic tone. The brain mechanisms underlying addiction include the following (3): (a) reward circuitry, originating in the dopamine neurons in the ventral tegmental area and projecting to the nucleus accumbens, ventral prefrontal cortex, and amygdala; (b) emotional circuitry, including the hippocampus, extended amygdala, lateral habenula, dorsal raphe, and insula; and (c) executive control circuitry, which involves widely distributed and complex prefrontal cortex–subcortical circuitry (3). In addition, circuitry involved in interoception modulates awareness of drug-conditioned cues, stress, and negative emotional states (3). Disruption of these circuits underlies the compulsive pattern of drug taking despite its adverse consequences (8).

MOUDs

MOUDs are the standard of care for OUD (9). They are associated with reduced risk of relapse, overdose deaths, infections, and criminal behavior and are more cost-effective than no OUD treatment or treatment with no medication. There are three medications approved by the FDA for the treatment of OUD: methadone (full MOR agonist), buprenorphine (partial MOR agonist, κ-opioid receptor [KOR] antagonist, and nociceptor receptor agonist), and naltrexone (MOR and KOR antagonist). The MOR is both the therapeutic target for MOUDs and the target for heroin and other opioids when misused for their rewarding effects. For this reason, many have dismissed agonist medications (methadone and buprenorphine) as only substituting one drug for another; however, this view ignores fundamental differences between drugs of abuse and MOUDs. These distinctions include differences in pharmacokinetics, pharmacological effects at the MOR, and doses and routes of administration.

Pharmacokinetics and route of administration. The rate at which opioid drugs enter the brain and bind to the MOR modulates their rewarding effects such that drugs with fast uptake into the brain and that interact rapidly with the MOR, such as heroin and fentanyl, are the most rewarding. The route of administration also affects pharmacokinetics; intravenous or smoking administration results in faster brain delivery than taking orally. When used therapeutically, MOUDs are either given orally or in slow-release formulations, which slows the rate of brain entry and clearance. The relatively slow brain clearance of buprenorphine and, to a lesser extent, methadone leads to milder severity of withdrawal upon their discontinuation than when discontinuing heroin or fentanyl. In this respect, buprenorphine leads to a milder withdrawal than methadone. Additionally, the slower pharmacokinetics of MOUDs result in more stable levels of MOR occupancy than misuse of opioid drugs for their rewarding effects. Stable occupancy of MOR by MOUDs controls opioid craving and prevents the emergence of acute withdrawal symptoms.

Doses and frequency of administration also differ when opioid drugs are misused for their rewarding effects than when used therapeutically. Methadone is typically injected when it is misused. In the case of buprenorphine, its injection is limited by the combination with the antagonist opioid drug naloxone (Suboxone formulation), which has very poor bioavailability when given sublingually, but if injected, will trigger an acute withdrawal. Nonetheless, there are multiple reports of diversion and misuse of buprenorphine, though it appears that misuse of buprenorphine is mostly to alleviate opiate withdrawal or achieve abstinence from other opioids, particularly when access to this medication is restricted (10).

Though MOR is the target for the rewarding and analgesic effects of opioids, the KOR is implicated in the aversive negative emotional states associated with addictions. Preclinical data indicate an upregulation of KOR signaling in animal models of addiction that, when blocked, prevents relapse into drug taking (11). Hence, a priority in addiction treatment has been the development of κ antagonist medications. In this respect the KOR antagonist effects of buprenorphine and naltrexone are likely to contribute to their therapeutic effects. Additionally, buprenorphine also binds to the nociceptin receptor where its agonist effects could also contribute to its efficacy in OUD (12).

Which MOUD to use

Although there are no empirically based predictors for selecting a specific MOUD, expert consensus and qualitative studies suggest that the selection should be based on the patient’s response to prior treatment with MOUDs, their level of physical dependence, the presence of coexisting conditions, and the patient’s preference (9). Often, the selection is determined by what is available in a given treatment program. Increasingly, however, there is recognition that patients might respond better to a particular MOUD depending on their characteristics and that optimal medication may be different during treatment initiation than stabilization.

Methadone has been available for more than 50 years and has the largest evidence of efficacy (13). Methadone would be indicated in patients with severe tolerance in whom buprenorphine treatment might trigger withdrawal symptoms. In general, there is overall better retention with methadone than buprenorphine and higher methadone doses up to 100 mg/day are associated with better outcomes than lower doses (14). As a full agonist, methadone has no ceiling effect, which increases risk for overdoses when used at doses above the patient’s tolerance or when combined with other central nervous depressants such as alcohol, benzodiazepines, heroin, or other synthetic opioids. Methadone is administered daily in an oral formulation. In the US methadone must be administered in licensed outpatient treatment programs (OTPs), which constitutes an important barrier to treatment to many patients, though it might improve outcomes in individuals who benefit from daily behavioral intervention given in OTPs (1). There is interest in exploring expanded access to methadone, such as office-based or via pharmacies (15), and developing extended release formulations of methadone to improve adherence, minimize diversion, and facilitate use in healthcare or justice settings.

Buprenorphine has been available to treat OUD for almost two decades (13). Buprenorphine is prescribed in medical offices by clinicians who require a waiver to do so. There are currently 102,570 waivered clinicians in the US, though many are not treating OUD patients (16). Buprenorphine requires daily or every other day dosing, and typical doses range between 8 to 24 mg, with a recommended target dose of 16 mg. Optimal responses to buprenorphine have been obtained in OUD patients with depressive symptoms, which might reflect in part the mood-enhancing effect of KOR antagonists. As a partial MOR agonist, buprenorphine can precipitate acute withdrawal in individuals with OUD who use high doses of heroin or fentanyl or have been maintained on high doses of methadone. In those instances, it might be best to initiate treatment with methadone and, after slowly tapering the dose, continue with buprenorphine. Buprenorphine is less likely to induce respiratory depression than methadone, but it can still be lethal when combined with other central nervous depressant substances (17). Extended-release (XR) formulations of buprenorphine were recently developed that include an FDA-approved six-month implant, a one-week formulation that is being reviewed by the FDA, and one-month formulations of buprenorphine, one of which was already approved by FDA (1). Limited data are available regarding the acceptability and efficacy of these new formulations in OUD.

Naltrexone is a MOR antagonist, but the utility of the immediate release formulation for OUD treatment has been limited by poor adherence. The development of a monthly XR–extended release naltrexone (XR-NTX) formulation significantly improved treatment retention and outcomes (18). Naltrexone is an antagonist drug that triggers acute withdrawal if OUD patients are not detoxified prior to induction. Current recommendations are for patients to be abstinent for one week prior to XR-NTX induction, which constitutes a barrier to induct some patients into treatment. Some protocols have been developed for faster supervised medical withdrawal (formerly known as detoxification), but further research is needed before adoption in routine clinical practice. The KOR antagonist effects could contribute to the mood improvements reported in OUD patients treated with naltrexone.

Presence of cooccurring disorders may be another consideration in MOUD selection. For example, naltrexone is also effective for alcohol dependence so comorbid OUD with alcoholism might benefit uniquely from this medication, whereas the KOR antagonist properties of buprenorphine may offer unique benefits for OUD patients with comorbid depression. For pregnant women, methadone or buprenorphine is recommended, due to insufficient data on safety of naltrexone.

Conclusion

MOUDs are among the most effective interventions for preventing overdose mortality and improving outcomes in patients with OUD. However, stigmatization and lack of understanding of addiction and the medications used to treat OUD have interfered with their implementation. The increased recognition that MOUDs are crucial for controlling the current opioid crisis highlights the importance of engaging healthcare in the screening and treatment of OUD.

The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of any of the sponsoring organizations or agencies or the US government.

Footnotes

Conflict of interest: The authors have declared that no conflict of interest exists.

Copyright: © 2020, American Society for Clinical Investigation.

Reference information: J Clin Invest. 2020;130(1):10–13. https://doi.org/10.1172/JCI134708.

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中文翻译:

阿片类药物使用障碍的药物:临床和药理学考虑

阿片类药物流行病已进入第二个十年,是美国最具挑战性的公共卫生危机之一。由于多种潜在的原因和后果,以及对成瘾和用于治疗成瘾的药物的误解,提供有效的响应变得很复杂(1)。的确,阿片类药物使用障碍(MOUDs)药物是治疗阿片类药物成瘾的最有效干预措施,但并未向许多受益者开出处方。在这里,我们描述了身体依赖和成瘾之间的区别及其对治疗的含义,并讨论了MOUD的作用机制。

阿片类药物戒断与阿片类药物依赖

阿片类药物使用障碍(OUD)定义为导致严重损害或困扰的适应不良的阿片类药物使用模式。严重程度根据出现的症状数量(表1)进行分类:轻度(一或两种),中度(三或四种)和重度(六种或更多)(2)。在本说明书中,阿片类药物成瘾对应于中度和重度OUD。

表格1

用于诊断标准OUD的DSM-5标准

在诊断OUD时,许多人将阿片类药物的物理依赖性与OUD相混淆,但是这种区别对于选择治疗方法至关重要。身体依赖性迅速发展,并在大多数反复服用阿片类药物的人中发生,并表现为在停用阿片类药物后出现急性戒断症状。当身体依赖性与耐受性相关时,可以导致轻度OUD的诊断(表1中的两个标准)。请注意,许多接受阿片类药物治疗的疼痛患者会出现身体依赖性和耐受性。因此,与轻度OUD的区别要求临床医生评估是否存在重大损害或困扰。3)。相比之下,在反复接触阿片类药物的人中,阿片类药物成瘾的发生率不到10%,这是长期奖励,动机,自我调节和决策以及情绪和压力反应性基础的大脑回路神经塑性适应的结果,停药后持续多年(45)。阿片类药物成瘾明显受益于OUD药物的使用。

重复使用阿片类药物突然停止会产生强烈但很少危及生命的戒断综合征,这可以理解为对维持体内稳态或同种异体过程的适应(3)。早期戒断的常见症状包括瞳孔散大,竖毛,肌肉抽搐,流泪,鼻漏,发汗,打哈欠,震颤,失眠,不安,肌痛,关节痛,腹泻,恶心或呕吐。随着戒断的进展,可能出现心动过速,呼吸急促,高血压或低血压以及脱水。请注意,这与旷日持久的戒断综合症不同,后者以烦躁不安,渴望和失眠为特征,反映出与成瘾相关的大脑电路神经适应。急性戒断症状(以及长期戒断)可能是OUD患者复发的有力触发因素(1),但如果疼痛的急性阿片类药物停药处理不当,也会导致寻找阿片类药物。

多种神经适应是身体依赖性的基础(6),包括μ阿片受体(MOR)的脱敏和内在化,细胞内效应子的MOR信号减弱,阿片敏感神经元中cAMP / PKA的细胞内上调,与μ相互作用的神经肽系统的适应性阿片类药物敏感的神经元和神经胶质信号的激活(7)。蓝斑(LC)的肺热underlies许多急性戒断的症状,以及α 1肾上腺素能激动剂,如洛非西定和可乐定,这减少去甲肾上腺素的释放,是用于急性阿片样物质戒断的管理是有用的。

与戒断相反,戒断是对MOR占用和信号突然下降的生理反应,成瘾主要是一种大脑回路疾病,会损害动力,自我调节和享乐主义。成瘾的大脑机制包括以下(3):(a)奖励电路,起源于腹侧被盖区的多巴胺神经元,并突出到伏隔核,腹侧前额叶皮层和杏仁核;(b)情绪回路,包括海马,伸展的杏仁核,外侧哈贝努拉,背ra和孤立岛;(c)执行控制电路,其中涉及分布广泛且复杂的前额叶皮层-皮层下电路(3)。此外,参与感知的电路会调节对药物条件暗示,压力和负面情绪状态的认知(3)。尽管有不良后果,但这些回路的中断是强制性吸毒方式的基础(8)。

模数

MOUD是OUD的护理标准(9)。它们与降低复发风险,过量死亡,感染和犯罪行为相关,并且比不使用OUD治疗或不使用药物治疗更具成本效益。FDA批准了三种用于治疗OUD的药物:美沙酮(完全MOR激动剂),丁丙诺啡(部分MOR激动剂,κ阿片受体[KOR]拮抗剂和伤害感受器受体激动剂)和纳曲酮(MOR和KOR拮抗剂) 。MOR被滥用时,既是MOUD的治疗目标,也是滥用海洛因和其他阿片类药物的有益目标。因此,许多人将激动剂(美沙酮和丁丙诺啡)视为仅将一种药物替代了另一种药物。但是,这种观点忽略了滥用毒品和违禁药物之间的根本区别。这些区别包括药代动力学方面的差异,

药代动力学和给药途径。阿片类药物进入大脑并与MOR结合的速率调节了其有益作用,使海洛因和芬太尼等具有快速吸收到大脑中并与MOR相互作用迅速的药物具有最大的收益。给药途径也会影响药代动力学。与口服相比,静脉内或吸烟可以更快地使大脑分娩。当用于治疗时,可以口服或以缓释制剂形式给予MOUD,这会减慢大脑进入和清除的速度。与停药海洛因或芬太尼相比,停药后丁丙诺啡和美沙酮在大脑中的清除速度相对较慢,导致美沙酮戒断的严重程度较轻。在这方面,丁丙诺啡比美沙酮可导致较轻的戒断。另外,相较于滥用阿片类药物的有益作用,MOUDs较慢的药代动力学可以使MOR的占用水平更加稳定。MOUDs对MOR的稳定占用可控制阿片类药物的渴望并防止出现急性戒断症状。

当滥用阿片类药物的有益作用时,其剂量和给药频率也与治疗性使用时不同。美沙酮通常在滥用时注射。就丁丙诺啡而言,其注射受限于与拮抗剂阿片类药物纳洛酮(Suboxone制剂)的组合,后者在舌下给药时的生物利用度非常差,但如果注射,将触发急性停药。尽管如此,有许多关于丁丙诺啡转移和滥用的报道,尽管滥用丁丙诺啡似乎主要是为了减轻鸦片戒断或戒除其他阿片类药物,特别是在限制使用这种药物的情况下(10)。

尽管MOR是阿片类药物的奖励和镇痛作用的靶标,但KOR却与成瘾相关的厌恶性负面情绪状态有关。临床前数据表明,成瘾动物模型中的KOR信号上调,如果被阻止,则会阻止其再次吸毒(11)。因此,成瘾治疗的重点是开发κ拮抗剂药物。在这方面,丁丙诺啡和纳曲酮的KOR拮抗剂作用可能有助于其治疗作用。此外,丁丙诺啡还与Nociceptin受体结合,其激动剂作用也可能有助于其在OUD中的功效(12)。

使用哪个MOUD

尽管没有基于经验的预测因素来选择特定的MOUD,但专家共识和定性研究表明,选择应基于患者对MOUD先前治疗的反应,其对身体的依赖程度,是否存在共存疾病以及患者的状况偏好(9)。通常,选择取决于给定治疗程序中的可用内容。但是,越来越多的人认识到,患者可能会根据自己的特征对特定的MOUD做出更好的反应,并且在治疗开始期间最佳药物可能会比稳定药物有所不同。

美沙酮已有50多年的历史了,具有最大的疗效证据(13)。美沙酮适用于丁丙诺啡治疗可能引起戒断症状的严重耐受性患者。通常,与丁丙诺啡相比,美沙酮的总体滞留性更好,而高达100毫克/天的更高美沙酮剂量比低剂量美沙酮具有更好的疗效(14)。作为一种完全的激动剂,美沙酮没有上限作用,当以超出患者耐受范围的剂量使用或与其他中枢神经抑制药(例如酒精,苯二氮卓类,海洛因或其他合成阿片类药物)组合使用时,美沙酮会增加服用过量的风险。美沙酮每日口服。在美国,必须在获得许可的门诊治疗计划(OTP)中使用美沙酮,这对许多患者构成了重要的治疗障碍,尽管美沙酮可能会改善受益于接受OTP日常行为干预的患者的结局(1)。有兴趣探索扩大获取美沙酮的途径,例如通过办公室或通过药店(15),并开发美沙酮的缓释制剂,以改善依从性,最大程度地减少转移并促进在医疗保健或司法环境中的使用。

丁丙诺啡可用于治疗OUD近二十年了(13)。临床医生要求在医疗办公室开处方丁丙诺啡,但需要豁免。目前,美国有102,570名被豁免的临床医生,尽管许多人并未治疗OUD患者(16)。丁丙诺啡需要每天或隔天服用一次,典型剂量为8至24毫克,建议的目标剂量为16毫克。在患有抑郁症状的OUD患者中获得了对丁丙诺啡的最佳反应,这可能部分反映了KOR拮抗剂的情绪增强作用。作为部分MOR激动剂,丁丙诺啡可以促使使用高剂量海洛因或芬太尼或已维持高剂量美沙酮维持治疗的OUD患者急性戒断。在这些情况下,最好开始用美沙酮治疗,并在逐渐减量剂量后继续使用丁丙诺啡。丁丙诺啡比美沙酮更不可能诱发呼吸抑制,但与其他中枢神经抑制物质合用时,丁丙诺啡仍具有致命性(17)。丁丙诺啡的缓释(XR)制剂最近得到了开发,其中包括FDA批准的六个月植入物,FDA正在审查的一星期制剂以及丁丙诺啡的一个月制剂(其中一种已获批准)通过FDA(1)。关于这些新配方在OUD中的可接受性和功效的可用数据有限。

纳曲酮是一种MOR拮抗剂,但是速释制剂在OUD治疗中的应用受到依从性差的限制。每月XR延长释放纳曲酮(XR-NTX)制剂的开发显着改善了治疗的保留率和疗效​​(18)。纳曲酮是一种拮抗药物,如果在诱导前未对OUD患者进行解毒,它会触发急性停药。当前的建议是在XR-NTX诱导前禁忌患者一周,这是诱使某些患者接受治疗的障碍。已经开发出一些方案,以用于在有监督的情况下更快地撤药(以前称为排毒),但是在常规临床实践中采用之前需要进一步的研究。在纳曲酮治疗的OUD患者中,KOR拮抗剂的作用可能有助于改善情绪。

Presence of cooccurring disorders may be another consideration in MOUD selection. For example, naltrexone is also effective for alcohol dependence so comorbid OUD with alcoholism might benefit uniquely from this medication, whereas the KOR antagonist properties of buprenorphine may offer unique benefits for OUD patients with comorbid depression. For pregnant women, methadone or buprenorphine is recommended, due to insufficient data on safety of naltrexone.

Conclusion

MOUD是预防OUD过量死亡和改善预后的最有效干预措施之一。但是,污名化和对成瘾的缺乏理解以及用于治疗OUD的药物已经干扰了其实施。人们越来越认识到MOUD对控制当前的阿片类药物危机至关重要,这凸显了使医疗保健参与OUD筛查和治疗的重要性。

本报告中表达的观点和观点仅代表作者,不应解释为代表任何赞助组织或机构或美国政府的观点。

脚注

利益冲突:作者已经声明不存在利益冲突。

版权所有: ©2020,美国临床研究学会。

参考信息:J Clin Invest。2020; 130(1):10-13。https://doi.org/10.1172/JCI134708。

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更新日期:2020-01-04
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