Naloxone, which reverses the effects of opioids, was synthesized in 1960, though the hunt for opioid antagonists began a half-century earlier. The history of this quest reveals how cultural and medical attitudes toward opioids have been marked by a polarization of discourse that belies a keen ambivalence. From 1915 to 1960, researchers were stymied in seeking a “pure” antidote to opioids, discovering instead numerous opioid molecules of mixed or paradoxical properties. At the same time, the quest for a dominant (...) explanatory and therapeutic model for addiction was likewise unsettled. After naloxone’s discovery, new dichotomizing language arose in the “War on Drugs,” in increasingly divergent views between addiction medicine and palliative care, and in public debates about layperson naloxone access. Naloxone, one of the emblematic drugs of our time, highlights the ambivalence latent in public and biomedical discussions of opioids as agents of risk and relief. (shrink)

The number of police departments carrying Narcan keeps increasing at a fast pace throughout the U.S., as it is considered an effective measure to fight the opioid epidemic. However, there have been strong oppositions to the idea of the police Narcan use. Still, in 2018, the nation is debating about it. Though not clearly visible to the public, there are important ethical arguments against the police Narcan use which necessarily involve understanding of the ethical roles and responsibilities of police as (...) the law enforcement agency and apprehension of the moral status of a non-therapeutic opioid use. The authors of the paper investigate, primarily, the existing ethical controversies surrounding the police Narcan use while touching upon the issue of the decriminalizing drug policy in the U.S. The authors conclude that the police can carry and administer Narcan without self-contradiction and that the policymakers’ investigation on the drug decriminalization policy should begin with the understanding of the “common morality” of the American public, the ethical view shared and practiced by the greatest number of people. (shrink)

The practice of equipping police officers with naloxone has generated controversy within the profession. I adjudicate the disagreement in this article. I diagnose the dispute as rooted in a philosophical account of professional, role-based obligations. Parties to the debate appear to agree that what the police are permitted to do is determined in part by the essential goal of the police profession. Instead, I argue that we should make room for “experiments in working.” Finally, I argue that naloxone (...) use by police is an experiment in working that falls squarely within the tradition of order maintenance policing. (shrink)

North America is in the grips of an epidemic of opioid-related poisonings. Overdose education and naloxone distribution programmes emerged as an option for structurally vulnerable populations who could not or would not access mainstream emergency medical services in the event of an overdose. These task shifting programmes utilize lay persons to deliver opioid resuscitation in the context of longstanding stigmatization and marginalization from mainstream healthcare services. OEND programmes exist at the intersection of harm reduction and emergency services. One goal (...) of OEND programmes is to help redress the health-related inequities common among people who use drugs, which include minimizing the gap between people who use drugs and the formal healthcare system. However, if this goal is not achieved these inequities may be entrenched. In this article, we consider the ethical promises and perils associated with OEND as task shifting. We argue that public health practitioners must consider the ethical aspects of task shifting programmes that may inadvertently harm already structurally vulnerable populations. We believe that even if OEND programmes reduce opioid-related deaths, we nevertheless question if, by virtue of its existence, OEND programmes might also unintentionally disenfranchise structurally vulnerable populations from comprehensive healthcare services, including mainstream emergency care. (shrink)

The present study examines the physiological alterations in prolactin (PRL) messenger ribonucleic acid (mRNA) and serum PRL levels during the rat estrous cycle and the effed of naloxone, an endogenous opioid peptide receptor antagonist, on PRL gene expression during the rat estrous cycle. Adult female rats exhibiting at least two consecutive 4-day estrous cycles were used in this study. A single injection of naloxone (2mg/kg b.w.) or saline was given sc 30 mm prior to decapitation. Animals were sacrificed (...) at 10:00 h of each stage of the estrous cycle, and at 2-h intervals from 10:00 h to 20:00 h during the proestrus. PRL mRNA and serum PRL levels were determined by an RNA-blot hybridization with the rat PRL cDNA probe and by a PRL radioimmunoassay, respectively. PRL mRNA and serum PRL levels were not dramatically altered in the morning of each stage of diestrus I, II, and proestrus, and naloxone failed to modify the two parameters. During estrus naloxone clearly suppressed serum PRL levels, but it was unable to modify PRL mRNA levels. A more detailed examination of the proestrus stage revealed that PRL mRNA and serum PRL levels fluctuated as a function of time: PRL mRNA levels reached a maximum level at 12:00 h and gradually decreased until 18:00 h. PRL mRNA levels then rose at 20:00 h. No difference in PRL mRNA levels between the control and naloxone-treated groups was observed. Changes in serum PRL level during proestrus were conversely related to changes in PRL mRNA: serum PRL levels were low from 10:00 h to 14:00 h, then increased and reached a maximum level at 16:00-18:00 h. Following then, serum PRL levels were decreased. Naloxone was effective in suppressing the characteristic afternoon surge of PRL from 16:00 h to 20:00 h. These data clearly showed that alterations in PRL mRNA levels were conversely correlated with changes in serum PRL levels on proestrus, indicating differential regulation of PRL gene expression and secretion. (shrink)

Although activated spinal cord glia contribute importantly to neuropathic pain, how nerve injury activates glia remains controversial. It has recently been proposed, on the basis of genetic approaches, that toll-like receptor 4 may be a key receptor for initiating microglial activation following L5 spinal nerve injury. The present studies extend this idea pharmacologically by showing that TLR4 is key for maintaining neuropathic pain following sciatic nerve chronic constriction injury. Established neuropathic pain was reversed by intrathecally delivered TLR4 receptor antagonists derived (...) from lipopolysaccharide. Additionally, -naltrexone, -naloxone, and -naloxone, which we show here to be TLR4 antagonists in vitro on both stably transfected HEK293-TLR4 and microglial cell lines, suppressed neuropathic pain with complete reversal upon chronic infusion. Immunohistochemical analyses of spinal cords following chronic infusion revealed suppression of CCI-induced microglial activation by -naloxone and -naloxone, paralleling reversal of neuropathic pain. Together, these CCI data support the conclusion that neuron-to-glia signaling through TLR4 is important not only for initiating neuropathic pain, as suggested previously, but also for maintaining established neuropathic pain. Furthermore, these studies suggest that the novel TLR4 antagonists -naloxone and -naloxone can each fully reverse established neuropathic pain upon multi-day administration. This finding with -naloxone is of potential clinical relevance. This is because -naloxone is an antagonist that is inactive at the -opioid selective receptors on neurons that produce analgesia. Thus, these data suggest that -opioid antagonists such as -naloxone may be useful clinically to suppress glial activation, yet -opioid agonists suppress pain. (shrink)

The rising cost of the opioid antagonist and overdose reversal agent naloxone is an urgent public health problem. The recent and dramatic price increase of Evzio, a naloxone auto-injector produced by Kaléo, shows how pharmaceutical manufacturers entering the naloxone marketplace rely on market exclusivity guaranteed by the patent system to charge prices at what the market can bear, which can restrict access to life-saving medication. We argue that 28 U.S.C. § 1498, a section of the federal code (...) that allows the government to use patent-protected products for its own purposes in exchange for reasonable compensation, could be used to procure generic naloxone auto-injectors, or at least bring Kaléo to the negotiating table. Precedent exists for the use of § 1498 to procure pharmaceuticals, and it could give meaning to the federal government's recent declaration of a public health emergency around the opioid epidemic, discourage new market entrants from charging exorbitant prices, and yield important public health benefits. (shrink)

States are rapidly modifying law and policy to increase access to the opioid antidote naloxone, and the provision of naloxone rescue kits for use in the event of overdose is becoming increasingly common. As of late 2014 the majority of states had passed laws increasing naloxone access, and nearly as many have modified emergency responder scope of practice protocols to permit Emergency Medical Technicians and law enforcement officers to administer the medication. While the text of these laws (...) is generally similar, their implementation varies among states.This article outlines experiences and lessons learned from two diverse states, Massachusetts and North Carolina. In Massachusetts naloxone access initiatives were well underway before formal legislative action occurred, while in North Carolina the passage of a naloxone access law served as a catalyst for the creation of new programs and facilitated the scale-up of existing ones. In both states legislative action was necessary to permit the prescription and dispensing of naloxone to the friends and family members of people who use opioids, a key legal change. (shrink)

This paper seeks to understand the treatment effect of Prescription Drug Monitoring Programs on opioid prescription rates. Using county-level panel data on all opioid prescriptions in the U.S. between 2006 and 2015, we investigate whether state interventions like PDMPs have heterogeneous treatment effects at the sub-state level, based on regional and temporal variations in policy design, extent of urbanization, race, and income. Our models comprehensively control for a set of county and time fixed effects, countyspecific and time-varying demographic controls, potentially (...) endogenous time-series trends in prescription rates, and other state-level opioid interventions such as Naloxone Access and Good Samaritan laws, Medicaid expansion, and the provision of Methadone Assistance Treatment. We find that PDMPs are only effective in reducing prescription rates if they obligate doctors to check for patients' history prior to filling out a prescription, but the frequency at which a state requires its PDMP to be updated is irrelevant to its effectiveness. Moreover, the significant treatment effects of PDMPs are almost exclusively driven by urban and predominantly white counties, with the relatively more affluent regions showing greater responsiveness than their less affluent counterparts. (shrink)

Physicians generally recommend that patients resuscitated with naloxone after opioid overdose stay in the emergency department for a period of observation in order to prevent harm from delayed sequelae of opioid toxicity. Patients frequently refuse this period of observation despiteenefit to risk. Healthcare providers are thus confronted with the challenge of how best to protect the patient’s interests while also respecting autonomy, including assessing whether the patient is making an autonomous choice to refuse care. Previous studies have shown that (...) physicians have widely divergent approaches to navigating these conflicts. This paper reviews what is known about the effects of opioid use disorder on decision-making, and argues that some subset of these refusals are non-autonomous choices, even when patients appear to have decision making capacity. This conclusion has several implications for how physicians assess and respond to patients refusing medical recommendations after naloxone resuscitation. (shrink)

Identifying the role of opioids in the mediation of learned sexual behaviors has been complicated by the use of differing methodologies in the investigations. In this review addressing multiple species, techniques, and pharmaceutical manipulations, several features of opioid mediation become apparent. Opioids are differentially involved in conditioned and unconditioned sexual behaviors. The timing of the delivery of a sexual reinforcer during conditioning trials, especially those using male subjects, acutely influences the role that opioids have in learning. Opioids may be particularly (...) important in the maintenance of conditioned sexual behaviors during periods of non-reinforcement. This appears to be true both for probe trials and procedures designed explicitly to extinguish a sexual conditioned response. These features of opioid mediation of learning do not appear to be restricted to sexual conditioning paradigms. This suggests that, as for other aspects of sexual learning that despite distinctive features conform to underlying behavioral principles, the mediation of conditioned sexual behavior by opioids relies on processes common across reinforcement systems. Keywords: opiate; conditioning; extinction; persistence; naloxone; learning (Published: 15 March 2012) Citation: Socioaffective Neuroscience & Psychology 2012, 2 : 14874 - DOI: 10.3402/snp.v2i0.14874. (shrink)

Numerous mediators are involved in both the control and the transmission of nociceptive messages, and several lines of research have been developed in the management of pain. Complete enkephalin- degrading enzyme inhibitors, which produce naloxone-reversible analgesia in all tests where morphine has been found to be active, remains the most promising way. CCK compounds, especially the CCKB antagonists also may be interesting drugs. Indeed, they are able to strongly potentiate the antinociceptive effects of the opioids. [dickenson, wiesenfeld-hallin et al.].

Those researching HIV prevention measures for people who inject drugs face a dilemma. Regions where baseline HIV prevalence and onward transmission via injecting is sufficiently high to power HIV prevention trials are also those where repressive laws, policies and practices raise concerns about the ethics of research subject protection. Dawson et al, outlining criteria to address ethical challenges in HIV prevention research among PWID, recommend that all trial participants be offered sterile injecting equipment and urge additional strategies to limit research (...) and background risks.1 In light of ethical questions opened by recent clinical trials involving PWID, including several the authors cite favourably, these cautions are timely. Dawson et al urge weighing of costs and benefits of PWID participation in research trials as an essential part of the ethical calculus. Overdose is a particular risk in any trial that uses abstinence from opioids as a precondition for participation or as an outcome of interest, and a risk that institutional review boards and researchers frequently ignore. Given the increased likelihood of fatal overdose for those who return to injection following a period of abstinence, provision to all trial participants of naloxone—the overdose antidote …. (shrink)

Dr. Brown, a hospitalist, admits Mark, a patient transferred from a local jail for management of cellulitis. The patient, who was taken into custody two days prior to hospital admission, has a history of intravenous heroin use. Mark explains that he had been prescribed buprenorphine-naloxone maintenance therapy for opioid use disorder for several years prior to being arrested and had not used other opioids during that time. As a policy, the jail where Mark is detained does not prescribe opioid (...) agonists, and his maintenance therapy was stopped upon his arrival there. Dr. Brown discovers that Mark is diaphoretic and appears distressed. Mark's symptoms suggest to Dr. Brown that, in addition to having cellulitis, Mark is actively withdrawing from opioids. Mark tells Dr. Brown that he has felt “horrible” since his buprenorphine-naloxone therapy was stopped and that he now has intense cravings for opioids. He asks Dr. Brown to help alleviate the withdrawal symptoms. Dr. Brown, who is accustomed to treating opioid withdrawal with opioid replacement therapy, wonders if she should initiate ORT for Mark while he is in the hospital. (shrink)

Buprenorphine is a form of opioid agonist treatment that has been demonstrated to be an effective medication for opioid addiction. It is available in different formulations and marketed under various trade names, including commonly as a buprenorphine/naloxone combination. This paper provides an overview of existing literature on the supply of buprenorphine treatment, the ability of people to access treatment with buprenorphine, and the quality of treatment received. We argue that better data for each of these aspects of treatment could (...) inform policy to expand effective treatment with buprenorphine, and we suggest steps to obtain and act on such data. (shrink)

States have implemented a variety of legal and policy approaches to address the overdose epidemic. Some approaches, like increasing access to naloxone and connecting overdose survivors with evidence-based treatment, have a strong public health foundation and a compelling evidence base. Others, like increasing reliance on punitive criminal justice approaches, have neither. This article examines law and policy changes that are likely to be effective in reducing overdose-related harm as well as those that are likely to increase it.

Harm reduction initiatives such as the distribution of naloxone have been crucial in saving lives during the opioid crisis in North America. Despite these efforts, today’s drug supply contaminated...

Marshall et al. (2024) persuasively argue that some patients with opiate use disorder (OUD), who refuse observation after naloxone resuscitation in the emergency department (ED), “may be making non...

Drug overdose has recently surpassed motor vehicle accidents to become the leading cause of unintentional injury death in the United States. The epidemic is largely driven by opioids such as oxycodone, hydrocodone, and methadone, which kill more Americans than heroin and cocaine combined. The demographics of overdose have changed over the past few decades as well: according to the latest data, the average overdose victim is now a non-Hispanic white man aged 45-54.These deaths — over 16,000 per year — are (...) almost entirely preventable. Opioid overdose kills by slowly depressing respiration, a process that can take several hours. It can be quickly and effectively reversed by the timely administration of naloxone, an opioid antagonist that works by displacing opioids from the brain receptors to which they attach, reversing their depressant effect. Naloxone, also known as Narcan, has many benefits and minimal risks. Although it is a prescription drug, it is not a controlled substance and has no abuse potential. (shrink)