Fentanyl, a synthetic opioid with analgesic and anesthetic properties, is currently associated with one of the deadliest addiction crises in the US. Misuse of fentanyl (and fentanyl analogues) has been estimated to be responsible for 48,000 (out of a total of 83,335) overdose deaths in the 12 months ending in June 2020¹, a rate that has increased more than 29 fold since 2012, when the annual fatalities from fentanyl and its analogues were 1,615.

The cases of overdoses and deaths in the US are linked to illegally manufactured fentanyl, which rapidly penetrated the US illicit market since 2013. Though not as pervasively as in the US, increases in overdose deaths due to illicit fentanyl and its analogues have also occurred in Canada, in several European countries (including Estonia, Germany, Finland and the UK) and in Australia².

Fentanyl is relatively easy to synthesize and manufacture, and less difficult to traffic than heroin, since it requires much smaller volumes to transport across borders. It is, therefore, hugely profitable to drug dealers (50‐100 times more than heroin), which can be expected to result in an expansion of the illicit fentanyl market across the globe.

The majority of opioid‐related overdose deaths in the US are the result of fentanyl being ingested as a substitute for heroin or with drugs such as cocaine and methamphetamine that had been adulterated (cut) with the opioid, frequently without users being aware of this. Fentanyl, when used by itself or in combination with other drugs, can be taken orally, injected, snorted or smoked. Most heroin users do not report actively seeking fentanyl, and some are afraid of it but might have no choice because of the higher costs of uncontaminated heroin or its unavailability.

When fentanyl is used to adulterate other drugs (heroin, prescription opioids, psychostimulants), it increases their lethality. In the case of psychostimulants, this occurs not only due to the synergistic effects on the cardiopulmonary system, but also because stimulant users, who have no tolerance to opioids, are at very high risk of overdosing when ingesting fentanyl.

The unique pharmacological effects of fentanyl have contributed to its widespread misuse and are also the ones that make it a valuable therapeutic for anesthesia and for severe pain management. Fentanyl binds to mu‐opioid receptors (MOR), which mediate the analgesic and the rewarding effects of opioid drugs, such as morphine and heroin, as well as their respiratory depressing actions³. However, fentanyl is much more potent at activating MOR‐associated signaling than morphine (80‐100 fold) or heroin (30‐50 fold), and its higher lipophilicity leads to higher and faster brain uptake than for those other drugs. These properties underlie fentanyl’s high potency as an analgesic and its rapid actions, which are beneficial for the treatment of breakthrough pain or other severe pain conditions. However, they are also responsible for its powerful rewarding effects, which can rapidly result in physical dependence and in addiction, and for its severe and abrupt inhibition of respiration, which increases the risk for overdose.

The treatment of fentanyl addiction (fentanyl opioid use disorder or fOUD) is the same as for other opioid use disorders (OUD). It is based on the use of medications such as methadone (full MOR agonist), buprenorphine (partial MOR agonist) and naltrexone (MOR antagonist)⁴. These medications are the gold standard for OUD treatment, and multiple studies have shown that they prevent overdoses and relapse in patients exposed to fentanyl.

However, clinical cases and anecdotal reports indicate that it is much more challenging to treat patients with fOUD than with other OUD. There are greater difficulties in initiating buprenorphine treatment, resulting from buprenorphine‐precipitated withdrawal⁵ and lower rates of abstinence and retention after six months of buprenorphine treatment⁶. The slow clearance of fentanyl as a result of its accumulation in fatty tissues may require slower detoxification prior to buprenorphine or naltrexone induction, and the higher rates of tolerance and physical dependence associated with repeated fentanyl use might necessitate higher doses of methadone or buprenorphine than for other OUDs. Treatment of withdrawal symptoms during fentanyl detoxification might be aided, as for other opioids, by the use of the alpha‐adrenergic drugs lofexidine and clonidine⁷. Overall, much more clinical research is needed to investigate how to optimally treat fOUD.

Like other opioids, fentanyl can result in overdoses due to its respiratory depressant effects. Signs of overdose include slow irregular breathing, slowing of circulation, sedation, acute respiratory distress, seizures, and coma. With repeated opioid exposure, individuals develop tolerance to the respiratory depressant effects of opioids (tolerance also develops for analgesia and reward), allowing them to tolerate much higher doses than naïve individuals⁸. Because tolerance to opioids decreases with interruption of use, whether during voluntary detoxification or incarceration, the relapse to opioid use after treatment discontinuation or after release from jail/prison is particularly dangerous.

Even for those who have developed tolerance to opioids, the very high potency of fentanyl, the impossibility of precisely dosing and the frequency with which drugs are mixed in the black market contribute to the high overdose risk associated with its misuse. As for other opioids, the treatment of fentanyl overdoses requires the timely delivery of naloxone (MOR antagonist) either via parenteral or intranasal administration³. Naloxone, which also has a very high affinity for MOR, displaces fentanyl from the receptor, thereby restoring breathing (as well as precipitating an acute opioid withdrawal).

Clinical cases and case reports have indicated that overdoses from fentanyl frequently require multiple naloxone administrations, due to the shorter duration of the action of naloxone (t_1/2: 1.3‐2.4 hours) than that of fentanyl (t_1/2: 7 to 8 hours), prolonged further by the slow clearance rates of fentanyl in frequent users. Additionally, when fentanyl is injected rapidly, it can result in chest wall rigidity, which interferes further with breathing and exacerbates the risk of death; these effects are not MOR‐mediated and might reflect noradrenergic and cholinergic mechanisms⁹.

All this generates the need for further development of fentanyl overdose treatments, including higher‐dose naloxone formulations, autoinjectors that automatically release naloxone with an impending overdose, longer‐acting opioid antagonists (i.e., nalmefene), treatments against chest wall rigidity, and medications to stimulate respiration and oxygenation to help overdoses from the combination of opioids with alcohol, benzodiazepines or stimulants.

Modeling studies have revealed that the epidemic of opioid overdose deaths, including those from fentanyl, can be reversed by multi‐pronged approaches that expand access to medications to treat opioid use disorders and increase retention in medication treatment, and by widely expanding access to naloxone for overdose reversals. It will also require strengthening the education of health care professionals in pain management, in safe use of opioids, and in how to screen and treat substance use disorders (including OUD).

Allocation of resources to implement these interventions is necessary, and timely surveillance systems that can serve as early warning signals for the presence of fentanyl or other opioids in a community would also be beneficial. In parallel, prevention interventions are needed to protect against opioid misuse initiation, recognizing that socioeconomic factors have contributed to the opioid crisis and that addressing them is necessary for preventing OUD and other substance use disorders in the long term.

芬太尼是一种具有镇痛和麻醉特性的合成阿片类药物，目前与美国最致命的成瘾危机之一有关。芬太尼（和芬太尼的类似物）的误用已经估计为48000个（总数83335的）过量死亡的12个月在2020年6月结束负责¹，自2012年起倍已经超过29增大的速率，当芬太尼及其类似物的年度死亡人数为1,615。

在美国，过量和死亡的案例与非法生产的芬太尼有关，自2013年以来，芬太尼迅速渗透到美国的非法市场。尽管不像美国那样普遍，但非法芬太尼及其类似物引起的过量死亡也增加了。加拿大，几个欧洲国家（包括爱沙尼亚，德国，芬兰和英国）和澳大利亚²。

与海洛因相比，芬太尼相对易于合成和制造，并且运输难度较小，因为芬太尼跨界运输所需的体积要小得多。因此，这对毒贩来说是巨大的利润（是海洛因的50到100倍），这有望导致全球非法芬太尼市场的扩大。

在美国，大多数与阿片类药物过量有关的死亡是由于芬太尼被用作海洛因的替代品或因掺入了阿片类药物（被割伤）的可卡因和甲基苯丙胺等药物而引起的，而用户往往不知道这一点。芬太尼单独使用或与其他药物联合使用时，可以口服，注射，吸鼻或吸烟。大多数海洛因使用者并未报告主动寻求芬太尼，有些人对此表示恐惧，但由于未受污染的海洛因的成本较高或无法获得，因此可能别无选择。

当芬太尼用于掺假其他药物（海洛因，处方阿片类药物，精神兴奋剂）时，会增加其杀伤力。就精神兴奋剂而言，这不仅是由于对心肺系统的协同作用，而且还因为对阿片类药物没有耐受性的兴奋剂使用者在摄入芬太尼时有超剂量的高风险。

芬太尼的独特药理作用助长了它的广泛滥用，也是使其成为麻醉和严重疼痛治疗的有价值的治疗剂。芬太尼与阿片受体（MOR）结合，后者介导吗啡和海洛因等阿片类药物的镇痛和奖励作用，以及它们的呼吸抑制作用³。但是，相比于吗啡（80-100倍）或海洛因（30-50倍），芬太尼在激活MOR相关信号方面的作用要强得多，并且其更高的亲脂性导致其对大脑的吸收更高和更快。这些特性奠定了芬太尼作为止痛药的高功效及其快速作用，这对于治疗突破性疼痛或其他严重疼痛状况非常有利。但是，它们还负责其强大的奖励作用，这种作用会迅速导致身体上的依赖性和成瘾性，并对其呼吸产生严重而突然的抑制作用，这会增加用药过量的风险。

芬太尼成瘾（芬太尼阿片类药物使用障碍或fOUD）的治疗与其他阿片类药物使用障碍（OUD）的治疗相同。它基于药物的使用，例如美沙酮（完全MOR激动剂），丁丙诺啡（部分MOR激动剂）和纳曲酮（MOR拮抗剂）⁴。这些药物是OUD治疗的金标准，多项研究表明，它们可防止暴露于芬太尼的患者服用过量和复发。

但是，临床病例和轶事报告表明，治疗fOUD的患者比其他OUD的治疗更具挑战性。丁丙诺啡治疗⁶个月后，由于丁丙诺啡沉淀的戒断⁵和较低的戒断率和滞留率6，启动丁丙诺啡治疗存在更大的困难。。由于其在脂肪组织中的积累而导致的芬太尼清除缓慢可能需要在丁丙诺啡或纳曲酮诱导之前进行较慢的排毒，并且与重复使用芬太尼相关的较高的耐受性和身体依赖性可能需要比其他药物更高剂量的美沙酮或丁丙诺啡OUD。与其他阿片类药物一样，芬太尼解毒期间戒断症状的治疗可能会通过使用α-肾上腺素药物洛非定和可乐定来辅助治疗⁷。总体而言，需要更多的临床研究来研究如何最佳地治疗fOUD。

像其他阿片类药物一样，芬太尼由于其呼吸抑制作用会导致服用过量。服用过量的迹象包括呼吸缓慢，循环不畅，镇静，急性呼吸窘迫，癫痫发作和昏迷。随着反复的阿片类药物暴露，个体对阿片类药物的呼吸抑制作用产生耐受性（对镇痛和奖励的耐受性也逐渐增强），使他们能够耐受的剂量要比幼稚的个体要高得多⁸。由于对阿片类药物的耐受性会随着使用中断而降低，无论是在自愿排毒还是在监禁期间，中止治疗后或从监狱/监狱释放后再次使用阿片类药物特别危险。

即使对于那些对阿片类药物具有耐受性的人来说，芬太尼的药效非常高，不可能精确地给药，而且黑市上药物混用的频率也会导致滥用其滥用的高药量风险。至于其他阿片类药物，芬太尼过量的治疗需要通过肠胃外或鼻内给药及时递送纳洛酮（MOR拮抗剂）³。纳洛酮对MOR的亲和力也很高，它可以从受体中置换出芬太尼，从而恢复呼吸（并促进急性阿片类药物戒断）。

临床病例和病例报告表明，由于芬太尼的服药持续时间（t _1/2：1.3-2.4小时）比芬太尼（t _1/2：7至1.5吨）短，因此芬太尼的过量服用经常需要多次纳洛酮给药。8小时），因频繁使用芬太尼的清除率较低而进一步延长了时间。此外，快速注射芬太尼会导致胸壁僵硬，进一步干扰呼吸并加剧死亡风险；这些影响不是MOR介导的，可能反映了去甲肾上腺素能和胆碱能的机制⁹。

所有这些都导致需要进一步开发芬太尼药物过量的治疗方法，包括高剂量纳洛酮制剂，使用即将到来的药物过量自动释放纳洛酮的自动注射器，作用时间更长的阿片类拮抗剂（即纳美芬），针对胸壁僵硬的治疗方法以及刺激呼吸和氧合作用，以帮助阿片类药物与酒精，苯二氮卓类药物或兴奋剂合用过量。

建模研究表明，阿片类药物过量死亡（包括芬太尼死亡）的流行可以通过多管齐下的方法来扭转，这些方法可以扩大对阿片类药物使用障碍的药物获取并增加药物治疗的保留率，并可以广泛地扩大纳洛酮的使用范围。药物过量逆转。它还将需要加强医疗保健专业人员的疼痛管理，安全使用阿片类药物以及如何筛查和治疗药物滥用（包括OUD）的教育。

分配资源来实施这些干预措施是必要的，及时的监视系统可以作为社区中存在芬太尼或其他阿片类药物的预警信号也将是有益的。同时，需要采取预防干预措施来防止阿片类药物滥用的发生，同时认识到社会经济因素已促成阿片类药物危机，并且从长远来看，解决这些问题对于预防OUD和其他物质使用失调是必不可少的。