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Official websites use. Share sensitive information only on official, secure websites. There is an urgent need for more widespread naloxone access considering the growing problem of opioid overdose deaths, accounting for more than , deaths worldwide annually. Rises in mortality are particularly sharp in North America, where the ongoing prescription opioid problem is now overlaid with a rapid growth in overdose deaths from heroin and illicit fentanyl. Using opioids alone is dangerous, and the mortality risk is clustered at certain times and contexts, including on prison release and discharge from hospital and residential care. The provision of take-home naloxone has required the introduction of new legislation and new naloxone products. Choosing the right naloxone dose in the fentanyl era is a matter of ongoing debate, but the safety margin of the approved nasal sprays is superior to improvised nasal kits. New legislation in different countries permits over-the-counter sales or other prescription-free methods of provision. However, access remains uneven with take-home naloxone still not provided in many countries and communities, and with ongoing barriers contributing to implementation inertia. Take-home naloxone is an important component of the response to the global overdose problem, but greater commitment to implementation will be essential, alongside improved affordable products, if a greater impact is to be achieved. With an increasing global problem of opioid use and dependence, the mortality rate from opioid overdose continues to rise, and there are more than , deaths globally per annum \[ 1 \]. Heroin is the most common drug involved in opioid overdose in much of the world, although prescription drugs and illicitly manufactured fentanyl IMF and analogues are increasingly implicated, particularly in North America. In the USA, 20, deaths from prescription opioids and 13, deaths from heroin were registered in alone \[ 2 \]. As such, these deaths are potentially preventable with timely detection and administration of naloxone, along with wider resuscitation measures, by non-medical members of the general public. Naloxone is a remarkable antidote that is opioid specific and actively displaces heroin and other opioids from the mu-opioid receptor MOR. It is a long-established medicine that is essential in the hospital emergency department and the ambulance medication kit. The concept of THN constitutes an example of technology transfer, in that it tells us to take the solution emergency naloxone kit from the hospital into the community where the emergency overdose occurs, with the aim to reduce any harm i. Researchers have found that both peers and family members are highly willing to act as first responders providing interim emergency care whilst awaiting the arrival of ambulance or other emergency medical care \[ 7 , 8 \]. Support for THN has increased greatly in recent years, including guidelines from the World Health Organization \[ 9 \] and endorsement from the United Nations \[ 10 \], as well as from various national governments. Nevertheless, intervention inertia around THN continues to exist, with countries, services and clinicians uncertain what they can, or cannot, provide. In the meantime, lives continue to be lost, including in situations where the overdose victim was still alive at the point of discovery and therefore death was likely preventable. To achieve a balanced reflection of the wider developments in the field of THN, we have deliberately brought together a team of co-authors with different areas of expertise who have led on the sections of this review. This paper draws on peer-reviewed and grey literature identified through a desk-based review of THN and naloxone formulations. Given the wide scope of this review, search terms included opioids, opiates, overdose, mortality, prevention, naloxone, intranasal IN and nasal. This general search strategy was then adapted by our co-authors to meet the specific focus of their respective section s. Key literature including grey literature cited within the retrieved material was also consulted, and as a general principle, more recent literature was preferred over older data — Data from published papers and reports were extracted and synthesised as narrative reviews. We also refer the interested reader to earlier reviews with a more limited focus, including THN programmes \[ 11 , 12 \] and naloxone delivery systems \[ 13 , 14 \]. Sections 2 and 3 discuss the prevalence of opioid mortality and situational risk factors for overdose. Section 4 describes the discovery of naloxone and history of its use in medical practice as background for Sect. This is followed by a discussion of the pharmacodynamics of naloxone and its efficacy and safety for the emergency management of opioid overdose in Sect. In Sects. To understand the levels and variations in opioid overdose deaths, it is important to understand one of the important drivers in high-income countries, namely, prescription opioid utilisation \[ 15 \]. Mean availability of opioids for pain management in — Source: \[ 15 \]. S-DDD defined daily doses for statistical purposes. The USA had a substantial increase in opioid prescribing for chronic non-cancer pain \[ 16 \], with opioid analgesic use in North America rising from about 2. In recent years, a number of policies have been introduced to reduce the problem of excessive opioid prescribing \[ 17 \]. Despite an overall reduction in per capita prescribing since , the oral morphine equivalent amount prescribed in was still approximately three times as high as in \[ 18 \]. The unintended consequences of these supply-side interventions need to be considered. With access reduced and demand still high, individuals began to turn to the black market \[ 19 \]. The rise in opioid analgesic use in the USA has been associated with substantial increases in non-fatal and fatal overdose. Since , there has been a steady increase in the rate of opioid overdose deaths see Fig. From to , more than , people died from overdoses related to prescription opioids. In fact, the escalation in opioid overdose deaths has been a significant factor in reduced US life expectancy in and , particularly for white Americans \[ 20 \]. These significant increases in mortality were largely driven by opioids other than methadone, predominantly IMF see below and heroin \[ 21 \]. A population-based study reported that the prevalence of heroin use increased from 0. The increased availability of high-purity heroin combined with its low price compared with diverted prescription opioids have been major drivers of the upward trends in heroin use and overdose deaths \[ 21 \]. Nonmedical use of prescription opioids is considered a significant risk factor for heroin use \[ 17 \]. In recent years, deaths from illicit synthetic opioids have outstripped deaths due to heroin and prescribed opioids in the USA. Illicitly manufactured fentanyl and its analogues are significantly more potent than morphine: carfentanil, for example, is approximately 10, times more potent, gram for gram. Fentanyl is more likely to lead to overdose than other opioids and is thought to have reduced cross-tolerance to other opioids \[ 24 \]. A much smaller dose of fentanyl than heroin is required to achieve the same drug effect: thus errors at the level of the illicit manufacture and distribution, as well as errors at the level of the end user, result in frequent accidental errors of dosage whose implications are far more profound than errors where the dose alteration is less severe \[ 24 \]. The high potency of fentanyl makes it often both cheaper and easier to trade and access than heroin given its much smaller bulk \[ 19 , 25 \]. Illicitly manufactured fentanyl is also increasingly found as adulterant in non-opioid drugs e. It has been speculated whether massive overdoses are able to benefit from naloxone at all \[ 28 \]. Notably, muscle rigidity can be reversed by naloxone \[ 30 , 31 \]. Therefore, the same principles of response with THN initiatives apply to the prevention of deaths from fentanyl overdose, although early administration of naloxone is likely crucial. From to , annual prescriptions for opioids increased from to per individuals \[ 32 \], with opioid-related deaths doubling, from There are also recent indications of the use of IMF and analogues and associated overdoses \[ 33 \], localised to certain provinces, such as British Columbia and Alberta \[ 33 \]. Although pharmaceutical opioid use is increasing gradually in Western Europe, the prevalence is four times lower than in North America \[ 34 \]. In general, heroin remains the most prevalent illicit opioid in Europe. However, in some countries, such as Estonia and Finland, where the heroin market plummeted in the early s, heroin has been entirely displaced by fentanyl mostly illicit and buprenorphine, respectively \[ 35 \]. In , there were drug overdose deaths any substance; occurring most commonly in the UK, followed by Germany and Sweden in the European Union plus Turkey and Norway , a total that continues to rise \[ 36 \]. For example, in Estonia there was a spike in overdose deaths in that was mainly attributable to fentanyl. On the European boundary, there have also been reports of fentanyl use in parts of Russia owing to heroin shortages. Of the drug-related deaths reported in Russia in , were attributed to opioid use \[ 38 \]. Various factors are associated with increased risk of overdose death in people who use opioids PWUO. These include individual and behavioural risk factors, such as male sex, older age, intravenous IV use, co-administration of other sedative drugs e. It is also a serious problem that that those around the individual often do not understand that the victim is not sleeping, but in imminent danger from an overdose \[ 27 \]. Different types of opioid overdose victims die at different times after injection. In heroin overdose, the time course of opioid metabolites in post-mortem cases indicated that most victims stayed alive for more than 30 min, indicating a window for intervention within at least this time frame \[ 43 , 44 \]. In the case of immediate deaths from fentanyl or heroin, it is possible that these may not be secondary to respiratory depression, but rather the direct effect of primary cardiovascular collapse in susceptible undernourished and dehydrated individuals. Situational factors are important, with the prison release population identified as a particularly high-risk group. For prisoners with a previous history of heroin use by injection, one in will be dead within a fortnight of their release from prison, with most deaths being caused by opioid overdose \[ 46 — 48 \]. These deaths likely occur during post-release deliberate intoxication, where, following a period of abstinence and consequent loss of tolerance, a previously regular dose may now lead to fatal overdose. A similar clustering of deaths is seen after discharge from hospital or abstinence-based residential rehabilitation \[ 49 , 50 \], and the explanation is likely similar. In addition, those in abstinence-based outpatient treatment are at increased risk if they then relapse \[ 51 \]. The importance of this clustering characteristic is that it should direct both policymakers and clinicians to points of transition in care and setting that would benefit from preventive measures and emergency interventions, including THN. We need to remember that treatment markedly reduces the risk of overdose death. A different type of clustering is seen with outbreaks of overdose deaths in communities, which occur with the presumed arrival and distribution of a particularly potent batch of heroin or contaminated supply e. Certainly, this accounts for some of the clusters of deaths, but it is unclear why this does not then lead to modification of drug-taking behaviour e. Jack Fishman and Dr. Mozes J. Naloxone hydrochloride is a white-to-slightly-off-white powder and is soluble in water, dilute acids and strong alkali. It is slightly soluble in alcohol and practically insoluble in ether and chloroform. Naloxone has a fat-water partition coefficient 20 times that of morphine and similar to meperidine. Its pKa 3 is 7. The chemical structure of naloxone is shown in Fig. Naloxone entered international clinical practice in the following years and was included as a specific antidote i. Owing to its unique effectiveness and safety profile, naloxone has become the treatment of choice for reversing opioid overdose in hospital emergency departments and ambulance services. The first serious consideration of THN occurred in a BMJ editorial \[ 57 \], which described how emergency naloxone kits could be pre-provided for emergency use to the following groups:. Subsequent studies identified the willingness of PWUO \[ 58 , 59 \] and family members \[ 8 \] to be trained in overdose management and naloxone administration. Early implementation of THN was made possible through user advocates working with physicians willing to prescribe naloxone despite medicolegal uncertainty or explicit barriers. The identification of legal pathways for THN provision from the mids onwards facilitated the introduction of first national and state-wide programmes in parts of Europe and USA. Because injectable naloxone was not developed for layperson use, non-injectable naloxone formulations have been considered to have several implementation advantages for THN programmes. First, injectable medications are intimidating for laypersons to use \[ 70 \] and present logistical barriers: they require product assembly e. Second, with use of naloxone by injection, there is the risk of needle-stick injury. Third, non-injectable naloxone could likely overcome regulatory obstacles e. Naloxone was originally developed and FDA approved as an injectable formulation for use by medical professionals see above. The IV route requires skilled personnel and takes time to establish. Intramuscular is now the widely preferred parenteral route because IV carries a greater risk of exposure to contaminated blood as well as risks of withdrawals and potential aggression. Intranasal is the simplest and fastest procedure, and it circumvents the contamination hazard. While IV provides by far the most rapid and reliable response when measured from the time of administration, IM comes as a good second, followed closely by IN see Table 1. However, when time from contact with the patient is the starting point in the emergency situation, IN \[ 72 \] and subcutaneous \[ 73 \] have been found to be as fast as IV. A potential shortcoming with the IN route is that effective uptake may be reduced by septal abnormalities, bleeding, nasal mucous, trauma and use of nasal vasoconstrictors \[ 74 \]. This followed their use by EMS as well as fire fighters and police officers. The safety of use of the improvised kits in medical practice is discussed in more detail in Sect. Specifically, given the existence of licensed injectable products, the question was raised \[ 79 \] whether it was acceptable for clinicians to supply unlicensed improvised nasal naloxone kits for take-home use, where no back-up of injectable naloxone would be available in the case of non-response unlike the ambulance or hospital setting. This stirred a challenging debate among international experts in the field \[ 80 , 81 \]. Nevertheless, the evident successful reversals of opioid overdoses with these improvised kits \[ 75 — 77 \] should raise questions about the dose necessary for layperson reversal which, in these instances, appears to have been achieved with much lower absorbed concentrations of naloxone. In response to rising overdose mortality rates, the US FDA, Centers for Disease Control and Prevention, National Institute on Drug Abuse, and Office of the Assistant Secretary for Health and Human Services sponsored a stakeholder meeting in to encourage the development of non-injectable naloxone products suitable for layperson use in community-based settings. Following the meeting, the National Institute on Drug Abuse announced that it would provide funding for the development of user-friendly naloxone devices i. IN rather than injection \[ 84 \]. The key regulatory criteria for any New Drug Application \[ 85 , 86 \] involved that naloxone would need to be absorbed into the bloodstream rapidly, given the emergency situation, and in a quantity sufficient to effect quick reversal of opioid-induced respiratory depression. The reference for any candidate non-injectable product would be injectable naloxone, administered by the licensed IM, IV and subcutaneous routes \[ 9 \]. Strang et al. Only the transmucosal routes IN, buccal and sublingual met the required characteristics. Transmucosal uptake bypasses first-pass hepatic elimination. Among these three routes, approved products only exist for IN administration see below. In the following section, we describe the pharmacokinetics of injectable naloxone as the reference for the development of non-injectable products. Naloxone is rapidly and extensively metabolised mainly by glucuronidation to the inactive compound naloxonglucuronide N3G thought to be primarily by the liver at that time \[ 89 \]. Ngai et al. Recent pharmacokinetic studies \[ 92 — 95 \] confirmed terminal elimination half-lives of 60— min after IV administration of 0. It should be noted that arterial and venous serum concentrations are similar \[ 95 \]. However, Yassen et al. This is two to three times higher than the maximal liver clearance; consequently, naloxone must be exposed to significant extrahepatic metabolism. For IM naloxone see Table 4 , the mean time to maximum concentration and mean dose-corrected maximum serum concentration C max varied from 8 to 24 min and 1. The latter is far lower than those of IV The nose is readily available and presents the advantage that laypeople are already familiar with the use of nasal sprays. People who use opioids generally preferred nasal spray over injectable naloxone \[ 71 \]. The mucosa of the nose is extensively perfused. Its endothelial lining is very open to the external environment. Moreover, its mucosa is constantly cleared by mucociliary transport, requiring that uptake takes place within about 15 min. However, the nose cannot accommodate spray volumes greater than 0. Kreiter et al also report, in their paper, that they had been informed by Adapt Pharma, the manufacturer, that the 2mg product had not been marketed and that there were no current plans to launch it. Nonetheless, this product secured a marketing authorisation in France in July The pharmacokinetics of the spray formulation have been published \[ 92 \]. As part of the development of these high-concentrate naloxone spray products and their application for regulatory approval , a number of recent studies have explored the pharmacokinetics of IN naloxone see Table 4. Nasal naloxone doses in these studies ranged from 0. Edwards et al. The high-concentrate IN formulations all have reasonably rapid uptake with a mean time to maximum concentration of 15—30 min, which is somewhat slower than the 8—24 min for the IM formulations Tables 3 , 4 ; see also Fig. The mean dose-corrected C max for IN varied from 1. A dose—serum concentration relationship was repeatedly reported. Dose-corrected AUCs were far lower 1. However, Skulberg et al. Whether this is a specific remifentanil or generic opioid effect remains unknown, but a potential higher bioavailability under an opioid may have implications for future regulatory studies of nasal administration. Schematic of the pharmacokinetics of intranasal IN 2 mg, intramuscular IM 0. PK pharmacokinetic. Most importantly, these high-concentrate sprays deliver therapeutic doses 0. It is also important to acknowledge that the C max for the 2- to 4-mg doses of IM e. This is relevant for the discussion below on the risk of withdrawal symptoms. Skulberg et al. First-responder dosing of 1. However, the combined 1. It was concluded that it was beneficial to administer IN for up to 2 min before an ambulance paramedic delivered a 0. Naloxone is essentially a pure competitive MOR antagonist. Its affinity compares well with the opioid agonists such as morphine, methadone and fentanyl, thus being capable of reversing their actions see Table 5 \[ \]. It is estimated that a dose of 0. In humans, it was found that 0. Naloxone did not, in contrast to the two others, induce respiratory depression in subjects not given an opioid. Therefore, it was recommended that naloxone should be the opioid antagonist of choice for clinical use \[ \]. The partial agonist buprenorphine is different see Table 6. It has a high affinity to MOR and dissociates slowly, in contrast to the much faster dissociation of naloxone \[ \]. Thus, naloxone reversal of the action of buprenorphine is slow and far larger doses are required \[ \]. Naloxone equilibrates rapidly with the site of action in the brain as shown by its blood-effect site equilibration half-life of 6. It is speculated whether an active transport system is involved in this uptake process \[ \]. In a very recent, positron emission tomography study of nasal naloxone in healthy volunteers, carfentanil was used for initial characterisation of MOR availability. The MOR occupancy was slightly delayed to serum concentrations, and half of peak occupancy was reached at 10 min. These experimental findings concord with the clinically observed rapid onset of action of naloxone. Berkowitz \[ 91 \] showed in the rat that brain concentrations of subcutaneous naloxone rose as rapidly as serum concentrations and stayed steadily above these during a parallel decline. For the agonist morphine, both uptake and egress from the brain lagged its serum concentrations all the time. Kaufman et al. Onset of action after about 0. A dose of about 0. Pupilometers were used by Gufford et al. Intramuscular naloxone 0. In a subsequent paper from the same group \[ 95 \], the duration of action of 1 mg of naloxone IV was min. Moreover, a minimum effective concentration of naloxone in steady state of 0. Middleton et al. No statistically significant differences were found between formulations. Experimental studies of the effects of naloxone in opioid addicts are rare. Loimer et al. Durations of actions exceeded 90 min for all administrations. Overall, several factors affect the outcome of naloxone antagonism see Table 7. Most of these factors are unknown in an overdose situation, where it is not clear what drugs were consumed. Therefore, naloxone should always be titrated to restore adequate respiration and cognitive function. Naloxone can reverse serious effects of opioids such as respiratory depression and stupor. Naloxone does not cause physical or psychological dependence and has virtually no effect in a healthy non-dependent person. As noted above, naloxone also reverses skeletal muscle rigidity from fentanyl and its analogues \[ 30 , 31 \]. The most rewarding use of naloxone is in opioid overdose. Opioid overdose is characterised by stupor, impaired respiration and pin-point miotic pupils. Respiratory failure may lead to hypercapnia also called hypercarbia and hypoxemia, which may eventually be fatal. The best predictor of a successful response to naloxone in overdose is the miotic pupil \[ \]. Naloxone is a short-acting drug compared to the duration of action of many of the opioids \[ \]. In overdose, the duration of action of methadone, extended-release morphine, buprenorphine, extended-release oxycodone and fentanyl may exceed 12 hours. Thus, the effect of naloxone may wane before the respiratory depression by these opioids has ended \[ \]. In such cases, hospitalisation and repeat doses or continuous infusion of naloxone may be required \[ \]. In opioid-dependent subjects, administration of naloxone may produce acute onset of withdrawal symptoms such as agitation, nausea, vomiting, piloerection, diarrhea, lacrimation, yawning and rhinorrhea \[ \]. Tachycardia and hypertension are potentially serious circulatory effects, while violent behaviour and drug craving are far from trivial. Opioid withdrawal is not considered life threatening \[ \]. Buajordet et al. Only 0. The initial naloxone doses administered were 0. Recently, a comprehensive review paper recommended for the interested reader on naloxone dosing for opioid reversal was published \[ 28 \]. The initial doses of naloxone commonly recommended for overdose are 0. The duration of action of naloxone is 20—90 min depending on dose and the situation of the patient \[ \]. As reported above, a duration of action of about 90— min of 1 mg of naloxone was found in healthy volunteers and opioid-dependent individuals \[ 95 , \]. Doses should be titrated every 2—3 min according to response for a total dose of up to 10 mg. Care should be taken in the elderly, patients with preexisting cardiovascular disease and in those receiving potentially cardiotoxic drugs. The limited available data on naloxone use in pregnant women are not sufficient to inform a drug-associated risk. However, there are risks to the foetus of the opioid-dependent mother with the use of naloxone Evzio summary of product characteristics. Children aged 5 years and below require relatively higher doses such as 0. However, lower initial doses 0. The situation is different when it comes to THN. The advantage of THN is that naloxone can be administered at an earlier stage, prior to ambulance arrival, similar to layperson use of defibrillators in cardiac arrest. At present, the naloxone dose required in this situation is controversial see below. One of the 18 overdose victims died. Seventeen required naloxone boluses, and four needed a prolonged infusion 26—39 hours of naloxone. Examination of about 95, cases in the national EMS data has also documented an overall increase in the severity of US opioid overdoses \[ \]. In contrast, Bell et al. As for the intoxications resulting in immediate deaths, only anecdotal reports are available on the effect of nasal naloxone on fentanyl overdoses. Somerville et al. Clear evidence that a bystander was unimpaired, witnessed the drug consumption and was present during an overdose i. Moderate titrated doses of nasal naloxone appeared effective when given. A few open-label randomised clinical studies in the pre-hospital setting have evaluated IN vs. IM naloxone. Both Kerr et al. Primary outcomes in these studies were similar, with adequate respiration and Glasgow Coma Scale response at 8—10 min. In the study by Kelly et al. The safety of IN naloxone was not inferior to IM. After dosing, patients were transported to an emergency department. This indicates that nasal systemic doses equivalent to 0. As the basis for approval of naloxone nasal sprays, the FDA requires that any new formulation must prove that it obtains a serum concentration similar to, or higher than the 0. It should be noted that there is a discussion within the FDA whether the comparator dose should be increased \[ \]. The focus of the FDA is on the first 10—15 min after administration. This carries a significant risk for naloxone overdosing that may provoke withdrawal symptoms. Although opioid withdrawal is not considered fatal, it is not trivial. Experiencing withdrawal is feared among people who use opioids. Qualitative interviews in Scottish and US cohorts of PWUO identified negative views on naloxone administration in the emergency room and the harm caused, such as acute withdrawal, aggression, self-discharge and further drug seeking activity \[ , \]. These attitudes were missed by ordinary observational studies. Indeed, these behaviours and further drug seeking activity perhaps constitute behaviourally mediated toxicity \[ \]. The relatively high success rates reported by first responders using one or two sub-therapeutic doses of naloxone systemic equivalents of about 0. Moreover, in their review of new naloxone products, regulatory bodies did not consider that characteristics of the nose may differ in the target population compared to healthy volunteers or the unexpected observation by Skulberg et al. However, we know that all the approved nasal sprays deliver far higher systemic doses than doses supplied by the unapproved dilute nasal sprays. This should secure a very broad safety margin. This complies well with the observational studies that demonstrated unexpected high success rates, also in fentanyl overdoses. Therefore, the new purpose-developed concentrated naloxone nasal sprays which are being approved dose range 1. Nevertheless, the suitability of the different products will likely depend on the patterns of opioid use in a community, with higher strength formulations potentially needed for the reversal of overdoses from potent synthetic opioids e. Last, ventilator support given as rescue breathing is the cornerstone of opioid-induced respiratory failure. As stated above, there are basically no safety data on the approved products. Pharmacovigilance may answer some of the important questions related to the new products. There is an urgent need for high-quality randomised comparisons of IM vs. IN naloxone administration in overdose. Moreover, observational studies independent of industry examining the efficacy of the new potent nasal naloxone sprays in overdose are warranted. Any consideration of significantly higher initial doses than those that worked in the past should be based not on anecdotes but on hard facts. Twenty years after the BMJ editorial in which the notion of THN was first mooted \[ 57 \], it remained unclear whether THN programmes would reduce the rate of opioid overdose deaths. The absence of published data from randomised controlled trials meant that uncertainty regarding the potential public health benefit of THN programmes persisted, leading to implementation delays and lack of political support in many jurisdictions. A small meta-analysis \[ \] had found a significantly increased odds of recovery from overdose for naloxone administration by bystanders compared with no naloxone administration odds ratio 8. To address this evaluation gap, a systematic review \[ \] was carried out to assess the effectiveness of THN, in terms of impact of opioid overdose mortality. Because of a lack of randomised controlled trials and a wide range in the methodological quality of the research studies, a meta-analysis was dismissed in favour of an analysis using the Bradford Hill \[ \] criteria: \[ 1 \] Strength of the Association, \[ 2 \] Consistency, \[ 3 \] Specificity, \[ 4 \] Temporality, \[ 5 \] Biological Gradient, \[ 6 \] Plausibility, \[ 7 \] Coherence, \[ 8 \] Experiment and \[ 9 \] Analogy. Based on their analysis, the authors \[ \] concluded that THN programmes lead to improved survival rates among programme participants and to reduced overdose mortality rates in the community. A later publication, which also based its analysis on the Bradford Hill criteria, reached a close-to-identical conclusion \[ \]. Successful implementation of THN would result in widespread acceptability and availability of the intervention, such that it is accessed by relevant target populations and embedded in usual practice in drug treatment and mainstream health services. A number of papers have explored legal \[ \] and workforce \[ , \] barriers. These have been country and region specific. To date, there has not been a consolidated analysis of barriers to effective THN implementation. The first reason is that there is not a singular model of THN. The second reason is that a comprehensive analysis of implementation barriers requires a conceptual framework. For the purposes of the analysis here, we refer to two broad types of models of THN implementation. Peer-led PL models were initially developed by and for PWUO, to provide training and supply naloxone directly to people who are likely to witness overdoses \[ , — \]. In contrast, mainstream healthcare practitioner MHCP models harness medical services doctors and pharmacies to supply naloxone to patients and carers. Despite some overlap, they are very different approaches, involve different types of negotiation, and bring different advantages and disadvantages. They also vary in their suitability for different countries or states at different points in time. Here, we use Greenhalgh et al. Based on the framework, achieving scaled-up implementation of THN involves considerations regarding the features of the innovation such as efficacy, product, compatibility ; the outer context including socio-political climate, legal regime and policies, incentives and mandates ; the system antecedents and readiness for change such as organisational structures ; the role of individual adopters such as match with needs, motivation ; communication and influence such as social networks, champions ; and the implementation process itself formalised decision making, logistics and costs. This framework is not a prescription for successful diffusion of innovation, but an aid to considering the multiple aspects, behaviours, and determinants and their interactions. Several determinants of successful implementation reside in the innovation itself, including the nature of the naloxone product. The injectable naloxone products present some barriers, with concerns including those relating to needle-stick injuries \[ 76 \]. The newer IN formulations represent a significant advance in the product formulation and address previous concerns about IN bioavailability \[ 11 , 92 , \]. With recent reports of synthetic fentanyl not being responsive to usual doses of naloxone \[ \], we should also not be complacent about efficacy issues please consult the THN safety discussion, Sect. The prescription status of THN is a significant feature impacting on implementation. Prescription products almost always require medical scripting and pharmacy dispensing and a trained, resourced and supported workforce see below. Availability via OTC \[ \] and standing orders \[ \] address some barriers but not without other barriers arising such as workforce, the potential cost to patients in some countries and access \[ , \]. Currently, there are also major issues with stock and supply in many countries including the USA, UK and Australia \[ , \]. Implementation success is also subject to the compatibility of the intervention with the groups delivering it. In theory, THN is highly compatible with the values, norms, and needs of peers and carers saving friends and loved ones , as well as healthcare professionals reduced mortality. There was no consensus on defining the line between a good high and an overdose \[ \]. For MHCP, there are concerns that providing such a life-saving intervention may encourage less safety in drug use \[ — \]. Heavey et al. Nevertheless, the intensity of debate from this paper reveals that there is more work to do in ensuring that THN is seen as compatible with health caring roles, as well as managing the perceived risks associated with THN. The second domain of implementation in Greenhalgh et al. The extent to which these legal regimes are directly associated with increased uptake has yet to be empirically demonstrated \[ \]. Nonetheless, a conducive legal environment is a prerequisite for widespread implementation. A key barrier within the outer context domain is the broad stigma and marginalisation of people who use opioids. The general community largely has negative attitudes towards PWUO \[ , \], and this is compounded by internalised stigma \[ \]. The outer context in the Greenhalgh et al. These are the formalised policies and procedures that regulate and support THN programmes. While international documents reference the importance of THN \[ 9 , \], beyond these, there appear to be few formal organisational incentives, directives and mandates in place currently. Mandatory co-prescribing of naloxone with opioid prescriptions has been proposed to address prescription opioid overdoses, and pilot studies have tested this in clinical practice, finding it feasible and associated with reduced opioid-related adverse events \[ \]. In Greenhalgh et al. A receptive context for change, with leadership and vision by the medical profession and by drug user organisations is a pre-requisite for success. Drug user organisations are often under-resourced, and specific funding to provide PL programmes is required. For the MHCP model, the systems and structures for prescribing and dispensing naloxone are certainly well developed. However, barriers remain with respect to adoption by the workforce see Sect. One barrier for potential adopters is stigma, including negative perceptions of PWUO by healthcare providers \[ \], as well as the stigma of being identified as a person who may use drugs \[ \]. Stigma reduction programmes targeted at the potential adopters as well as the general community, see Sect. The cost effectiveness of universal supply models is unknown. There are also significant barriers in relation to knowledge and skills including the need for education and training of potential healthcare providers to enable adoption of THN in the MHCP model \[ , \]. While PWUO often have considerable knowledge of overdose signs and symptoms, knowledge gaps exist amongst different populations with opioid-overdose risk \[ , , \]. The process of implementation presents two key barriers here for THN: the workflow logistics and cost. Healthcare professionals have limited time, and THN needs to be incorporated into their workflow, including how to get the THN kit to the patient and the timing of this \[ \]. There is an opportunity cost for time-pressured healthcare professionals, where training patients on naloxone use may leave less time for other needs. For general medical practitioners and pharmacists, this can be compounded by the systems that pay for their time. For PL models, significant resources are required to deliver training programmes, which peer organisations may not have. A further substantial implementation barrier is cost, which relates to the medication itself and who is expected to pay. Thus, while new supply routes such as OTC and formulations IN reduce some barriers, they simultaneously present other barriers in these cases, the cost. At present, THN largely remains an isolated initiative led by individual champions, harm reduction advocates or health professionals experienced in drug dependence. For it to become a mainstay of usual care, much wider dissemination and diffusion of the technology need to take place. Here, the system variables discussed earlier become most important: widespread stigma against PWUO, the lack of systematic endorsement across all settings and the absence of wide access such as OTC that can be provided at low cost. Across the analysis conducted here using one conceptual implementation framework, it becomes clear that THN implementation has barriers related to the intervention itself notably the product and its prescription status , the outer context stigma and a lack of formalised policies and procedures , the adopters in particular attitudes, knowledge and skills of adopters , and in the practicalities of implementation, especially the cost and the logistics. These determine the extent of THN diffusion such that it becomes a part of regular practice. New naloxone products auto-injector and nasal spray have been developed in the last few years that have good bioavailability, can provide therapeutic doses in a single step, and hence are suitable for use by lay responders and other non-medical personnel. When comparing the different naloxone devices, including ampoules and vials as the most basic, there is a clear trade-off between usability and cost. New concentrated nasal sprays, if costs are kept low, might be particularly suitable for much wider public pre-provision. The affordability of new naloxone products will likely define their real-world availability and accessibility for the target population. As discussed above see Sect. By analogy, in the prevention of sexually transmitted infections, cost is a barrier to condom use \[ \], and free-of-charge condom distribution to target high-risk populations is recommended \[ , \]. A dual implementation model is likely optimal for naloxone access: potential OTC sales should best be considered as operating alongside free-of-charge THN programmes. The question of the cost of non-injectable naloxone vs. Local non-governmental organisations typically hand out two take-home ampoules per client, i. Given the cost disparity between the nasal spray and local ampoule supply, the purchase of naloxone nasal spray is likely not sustainable for low- and middle-income countries at present. Surprisingly little attention has been paid to study these new naloxone products with participants from the relevant target population of individuals with substance use disorders, hence uncertainty remains. Will damage to nasal membranes from long-term drug use alter the speed and effectiveness of absorption? Are the findings from healthy volunteers generalisable to overdose victims with potentially very low body weight, near-universal chronic smoker status or varying degrees of hepatic impairment? Is nasal bioavailability of naloxone higher under opioid influence? Can dose titration be taught effectively? What is a safe starting dose, the dose that together with a similar follow-up dose within 3 min that reverse most respiratory failures without provoking too much withdrawals? Such studies may be challenging to devise and conduct, but they would ordinarily be considered necessary steps with the development of new interventions with other clinical populations. There is also a need for stronger study designs to guide further improvements in THN provision. Take-home naloxone has established itself as a major new strand of our response to opioid overdose deaths. This has required new policies and practices, alongside new naloxone formulations and products. These have been developed successfully, and continue to be refined for new challenges, new countries and contexts, and for new opioid drug problems. More research is, of course, needed—with stronger research designs as well as the need for new products and new methods of provision; but this new research must be conducted alongside the introduction of the best products and practices that already exist. John Strang et al. None of these are directly relevant to the current article. These bodies had no involvement in or knowledge of the current article. Suzanne Nielsen has been a named investigator on untied educational grants from Indivior and Seqirus and has delivered training on opioid dependence for Indivior for which honoraria were paid to her institution. Suzanne Nielsen has participated in an advisory board meeting by Mundipharma relating to naloxone for which she declined a sitting fee. She has received no funding or untied educational grants from any pharmaceutical company in the last 15 years. The lower the p K a value, the stronger the acid. See footnote to Table 3 for explanation of dose of Nyxoid. As a library, NLM provides access to scientific literature. Find articles by John Strang. Find articles by Rebecca McDonald. Find articles by Gabrielle Campbell. Find articles by Louisa Degenhardt. Find articles by Suzanne Nielsen. Find articles by Alison Ritter. Find articles by Ola Dale. Contributed equally. Issue date Take-home naloxone is an effective public health intervention to prevent deaths and organ damage from opioid overdose. They are increasingly available in clinical practice in a growing number of countries Ongoing implementation challenges include naloxone cost as well as politico-social e. Australia, Canada, Italy, the UK. Open in a new tab. Kreiter et al also report, in their paper, that they had been informed by Adapt Pharma, the manufacturer, that the 2mg product had not been marketed and that there were no current plans to launch it b All formulations in this table are reported as naloxone hydrochloride, with the 1. Opioid receptor affinities modified from \[ \]. Long Fentanyl Rapid Medium? Medium Buprenorphine? Slow Long. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. They are increasingly available in clinical practice in a growing number of countries. Ongoing implementation challenges include naloxone cost as well as politico-social e. Tylleskar et al. McDonald et al. Gufford et al. Krieter et al. France: July temp. Skulberg et al \[ 98 \] opioid.

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