Publications by authors named "Rebecca McDonald"

48 Publications

Rethinking 'carriage' of take-home naloxone.

Int J Drug Policy 2021 Apr 10;95:103253. Epub 2021 Apr 10.

National Addiction Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; South London and Maudsley NHS Foundation Trust, London, UK. Electronic address:

Take-home naloxone (THN) provision to people who use drugs, their family/friends, and non-medical personnel is considered a public health strategy to improve community-based naloxone access and reduce the time to antidote treatment for opioid overdose in order to prevent fatal outcome. THN programs typically report up to three performance indicators: the volume of THN kits distributed, the rate of requests for re-supply of THN kits (e.g., following naloxone use for overdose reversal), and - increasingly - THN "carriage". In this Research Methods piece, we discuss the current shortcomings in the latter measurement of THN carriage from a mixed-methods perspective and describe possible implications for public health related research and improved data analyses. We present an argument for the need to improve research methods in the case of THN "carriage" and propose a multidimensional measurement structure that takes into account: 1) the location of the THN kit relative to its owner, 2) the owner's immediate access to the kit in an emergency, 3) the type of THN device, and 4) the purpose of THN ownership (i.e., for use in self or known/unknown other/s).
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http://dx.doi.org/10.1016/j.drugpo.2021.103253DOI Listing
April 2021

Fatal Outcome in Acutely Poisoned Children With Hospitalization: A 10-Year Retrospective Study From Tehran, Iran.

Pediatr Emerg Care 2021 Apr 9. Epub 2021 Apr 9.

From the *Department of Pediatrics, Loghman Hakim Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran †King's College London, National Addiction Centre, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom ‡Kish Institute of Science and Technology §Social Determinants of Health Research Center ∥Department of Clinical Toxicology, Loghman Hakim Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: Acute poisoning is a significant and preventable cause of mortality among children internationally. The aims of this study were to assess the case fatality rate of children admitted to an inner-city hospital for acute poisoning and to compare the demographics and source of poisoning of fatal cases.

Methods: This was a retrospective review of patient data recorded in the Hospital Information System for Loghman Hakim Hospital, that is, the central referral hospital for poisoning in Tehran, Iran. We searched Hospital Information System for all admissions for poisoning in children (age, 0-12 years) over the 10-year period from March 2010 to March 2020, and all cases were included in the analysis. We determined the case fatality rate by dividing the number of fatal cases by the number of included cases.

Results: Of 8158 children admitted for poisoning, 28 cases (0.3%) died, among whom 19 (67.9%) were boys and 9 (32.1%) girls. The median age was 42 months, ranging from 2 to 144 months. Twenty-two cases (78.6%) were 0 to 5 years old. The most common cause of mortality in acute poisoning was methadone (n = 13, 46.4%), followed by raw opium (n = 5, 17.9%), aluminum phosphide, carbon monoxide, and wild mushrooms (n = 2 deaths each, 7.1%). Tramadol, colchicine, and petroleum accounted for 1 death each (3.6%).

Conclusions: Mortality from unintentional poisoning disproportionately affects children younger than 5 years. Opioids (ie, methadone, opium, tramadol) accounted for two thirds of deaths in our sample. Our findings highlight the importance of educating parents that any toxic materials (licit or illicit) must be stored out of reach for children.
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http://dx.doi.org/10.1097/PEC.0000000000002429DOI Listing
April 2021

Troponin, A Predictor of Mortality in Methadone Exposure: An Observational Prospective Study.

J Am Heart Assoc 2021 Apr 6;10(8):e018899. Epub 2021 Apr 6.

Social Determinants of Health Research CenterShahid Beheshti University of Medical Sciences Tehran Iran.

Background Methadone poisoning/overdose is a global public health problem. We aimed to determine whether methadone poisoning increased cardiac troponin and whether high-sensitivity cardiac troponin I (hs-cTnI) levels predicted the need for intensive care unit admission, intubation, and mortality. Methods and Results This observational, prospective single-center study was done at Loghman-Hakim Hospital (Tehran, Iran) from June 2018 until February 2019. Patients aged >14 years admitted with a diagnosis of methadone exposure were included. Patients were excluded if they had coexisting conditions associated with elevated hs-cTnI levels. An ECG and hs-cTnI levels were obtained on emergency department presentation. Patients were followed up on their need for intubation, intensive care unit admission, and in-hospital mortality. Of 245 included patients (186 [75.9%] men; median age, 33 years), most referred to loss of consciousness (210 cases, 89%). Nineteen (7.7%) patients had hs-cTnI levels of >0.1 ng/mL (positive), and 41 (16.7%) had borderline levels of 0.019 to 0.1 ng/mL. Twenty-three (9.3%) cases were admitted to the intensive care unit, 21 (8.5%) needed intubation, and 5 (2%) died during hospitalization. An hs-cTnI cutoff value of 0.019 ng/mL independently predicted mortality. For optimal concomitant sensitivity and specificity, receiver operating characteristic curve analysis was conducted and showed that hs-cTnI had an independent significant association with mortality, with a cutoff value of 0.0365 ng/mL (odds ratio, 38.1; 95% CI, 2.3-641.9; <0.001). Conclusions Methadone exposure/toxicity is a newly identified cause of elevated hs-cTnI. Values >0.019 ng/mL, and particularly >0.0365 ng/mL, of hs-cTnI predicted mortality in our sample. Future studies should measure troponin levels in methadone maintenance treatment clients to assess the risk of myocardial injury from long-term exposure.
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http://dx.doi.org/10.1161/JAHA.120.018899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174177PMC
April 2021

Complications and hospital stay after endoscopic retrieval of drug baggies in body stuffers: an observational prospective study.

Sci Rep 2021 Mar 8;11(1):5359. Epub 2021 Mar 8.

National Addiction Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, Addiction Sciences, London, UK.

Body stuffers routinely receive conservative treatment, i.e. administration of the laxative polyethylene glycol for the passage of ingested drug baggies and observation. Endoscopic baggie removal may offer a safe alternative that could result in shorter hospitalization. We aimed to compare complications, hospital stay, and final outcome in body stuffers assigned to endoscopy versus conservative treatment. This is an observational prospective study of body stuffers presenting to a clinical toxicology center in Tehran (Iran) in 2016-2019, irrespective of the drug ingested. Eligible patients had baggies in their upper gastrointestinal tract and presented without severe poisoning. Patients received either endoscopy or conservative treatment, and clinical outcomes were compared between the groups. A total of 69 patients were enrolled, with a median age of 29 years (range 18-64), among whom 1 was female (2%). Eighteen and 51 patients were endoscopically and conservatively managed, respectively. Drugs most commonly ingested were heroin in endoscopy patients (8/18 cases; 44%) and methamphetamine in the conservative group (28/51 cases; 55%). Endoscopy patients had a shorter hospital stay (median 1.5 vs. 2 days, P = 0.018). In the conservative group, one patient died, and the rate of complications was significantly higher, with more patients experiencing side effects (OR = 1.4, 95% CI = 1.2, 1.7) and requiring intubation (OR = 1.3, 95% CI = 1.1, 1.5). Endoscopic retrieval was associated with fewer complications and shorter hospitalization. Endoscopy may be a safe treatment for body stuffers without severe poisoning on presentation.
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http://dx.doi.org/10.1038/s41598-021-84898-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940431PMC
March 2021

The traffic light pilot study: assessing the level of evidence for interventions in obstetrics and gynaecology.

J Obstet Gynaecol 2021 Feb 18:1-4. Epub 2021 Feb 18.

Monash Women's, Monash Health, Clayton, Australia.

Evidence-based medicine tries to support clinicians through research, integrated with clinical skill and patient values. This pilot study aimed to assess appropriateness and level of evidence of current clinical practices, through evaluating availability and quality of guidelines.A prospective observational study in a large tertiary hospital network was performed, sampling diagnostic and therapeutic interventions in obstetrics and gynaecology. Interventions performed were justified against knowledge in the published literature, and guideline recommended practice. We collected 58 patient observations, 40(69%) in obstetrics, 18(31%) in gynaecology. There were local guidelines relevant in 52%, national in 22%, and international guidelines in 12%. In 50 interventions with available guidelines, 54% provided strong and clear recommendations for practice, and were supported by research-based knowledge. Similarly, 66% of encounters were thought to be in concordance with research-based knowledge.There was good concordance between interventions and guideline recommendations. However, half of guidelines reviewed had limited or no knowledge to justify their recommendations.IMPACT STATEMENT Evidence based medicine should aim to improve patient outcomes. However, available trials assessing effectiveness of established practices suggest that they convey little to no benefit to patients. There remains a paucity of evidence for established practices in obstetrics and gynaecology This pilot study assesses the usefulness of interventions in obstetrics and gynaecology and confirms the feasibility of collecting and coding our interventions and clinical practices with a traffic light system. These findings demonstrate the feasibility of our traffic lights grading system within obstetrics and gynaecology. It demonstrates this method is useful to assess what knowledge base is guiding clinical practice, how well practice concords with guidelines and literature, as well as the presence and significance of any gaps in knowledge. These early findings will be used in an expanded study and have implications on the way healthcare effectiveness is evaluated, as well as reducing healthcare expenditure in obstetrics and gynaecology.
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http://dx.doi.org/10.1080/01443615.2020.1845635DOI Listing
February 2021

Unintentional buprenorphine and methadone poisoning in children: a matched observational study.

Clin Toxicol (Phila) 2021 Jan 21:1-11. Epub 2021 Jan 21.

Social Determinants of Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Objective: To compare accidental pediatric poisoning from methadone vs. buprenorphine in terms of clinical indicators and in-hospital morbidity.

Methods: A matched observational study conducted on children aged ≤12 years admitted to our center between March 2018 and March 2019 with acute poisoning from methadone or buprenorphine. Data were extracted from the electronic patient files of the pediatric methadone poisoning cases, and buprenorphine poisoning cases were followed from ED, during the study period. Cases were compared regarding rates of bradypnea/apnea (primary outcome), the need for antidote therapy and intubation, duration of hospital stay, miosis, loss of consciousness, blood gas analyses, and mortality (secondary outcomes).

Results: A total of 90 methadone- and 30 buprenorphine-poisoned children were evaluated. Methadone cases had significantly higher rates of apnea (20/90 methadone vs. 0/30 buprenorphine; OR = 17.7, 95% CI 1.1, 302.8;  = 0.047), but there was no group difference in bradypnea (39/90 methadone vs. 10/30 buprenorphine; = ns). 28 (31%) methadone and 3 buprenorphine (10%) cases had been referred to as fully awake ( = 0.013). Methadone cases required higher median naloxone doses for initial bolus (0.4 vs. 0.02 mg;  = 0.014) and maintenance infusion (14.4 vs. 2.4 mg;  < 0.001). 20 apnea cases (all from the methadone group) had miotic pupils, and miotic pupils were seen in 44 (90%) cases with bradypnea (OR = 3.2, 95% CI 1.1, 9.3;  = 0.026). Intubation was needed in only 5 methadone cases (5.5%; = ns). All patients survived.

Conclusion: Compared to children poisoned with methadone, buprenorphine cases had higher rates of loss of consciousness on admission but subsequently experienced fewer complications during hospital treatment, which is likely due to the buprenorphine partial antagonist effect. Our findings suggest that methadone exposure is more toxic than buprenorphine in pediatric populations.
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http://dx.doi.org/10.1080/15563650.2020.1869755DOI Listing
January 2021

Exogenous Nitric Oxide Improves Antibiotic Susceptibility in Resistant Bacteria.

ACS Infect Dis 2021 01 8;7(1):23-33. Epub 2020 Dec 8.

Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.

Antibiotic resistance in bacteria is a major global threat and a leading cause for healthcare-related morbidity and mortality. Resistant biofilm infections are particularly difficult to treat owing to the protective biofilm matrix, which decreases both antibiotic efficacy and clearance by the host. Novel antimicrobial agents that are capable of eradicating resistant infections are greatly needed to combat the rise of antibiotic-resistant bacteria, particularly in patients with cystic fibrosis who are frequently colonized by multidrug-resistant species. Our research group has developed nitric oxide-releasing biopolymers as alternatives to conventional antibiotics. Here, we show that nitric oxide acts as a broad-spectrum antibacterial agent while also improving the efficacy of conventional antibiotics when delivered sequentially. Alone, nitric oxide kills a broad range of bacteria in planktonic and biofilm form without engendering resistance. In combination with conventional antibiotics, nitric oxide increases bacterial susceptibility to multiple classes of antibiotics and slows the development of antibiotic resistance. We anticipate that the use of nitric oxide in combination with antibiotics may improve the outcome of patients with refractory infections, particularly those that are multidrug-resistant.
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http://dx.doi.org/10.1021/acsinfecdis.0c00337DOI Listing
January 2021

A study of the effectiveness of naltrexone in preventing recurrence of methadone poisoning in opioid-naive children.

Drug Alcohol Depend 2021 02 24;219:108425. Epub 2020 Nov 24.

Social Determinants of Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Clinical Toxicology, Loghman Hakim Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Background: The prevalence of poisoning from methadone and prescription opioids is increasing in pediatric populations. Naloxone is the main antidote for treatment. Long-acting opioid toxicity may need close observation in the intensive care unit (ICU). In our previous study, naltrexone prevented re-narcotization in methadone-poisoned adults. Here, we aim to share our experience with the use of oral naltrexone for preventing recurrence of toxicity in opioid-naïve children.

Methods: In a single-center, retrospective case series, children (age ≤12 years) admitted to a poison center in Tehran (Iran) between March 2014-March 2016 were included if they presented with methadone poisoning and received naltrexone treatment in hospital. Naltrexone (1 mg/kg) was administrated orally after initial administration of 0.1 mg/kg naloxone intravenously. Children were monitored for level of consciousness, cyanosis, respiratory rate, VBG results, and O2 saturation for ≥48 h during their hospitalization.

Results: Eighty patients with methadone poisoning were enrolled, with median age of three years (range: 0.2-12.0). None involved polysubstance poisoning. Following naltrexone treatment, none experienced recurrent opioid toxicity during hospitalization, and hospital records indicated no readmission within 72-h post-discharge.

Conclusion: Oral naltrexone could be a potential substitute for continuous naloxone infusion in methadone-poisoned children and reduce the need for ICU care.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.108425DOI Listing
February 2021

Oral clonazepam versus lorazepam in the treatment of methamphetamine-poisoned children: a pilot clinical trial.

BMC Pediatr 2020 12 3;20(1):543. Epub 2020 Dec 3.

Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Objectives: To evaluate the efficacy of oral clonazepam versus oral lorazepam following initial parenteral benzodiazepine administration to control methamphetamine-induced agitation in children.

Methods: In a single-center clinical trial, intravenous diazepam (0.2 mg/Kg) was initially administered to all methamphetamine-poisoned pediatric patients to control their agitation, followed by a single dose of oral clonazepam (0.05 mg/Kg; n = 15) or oral lorazepam (0.05 mg/Kg; n = 15) to prevent relapse of toxicity.

Results: The median age [IQR] (range) was 15 [10, 36] (6-144) months. The source of poisoning was methamphetamine exposure from oral ingestion in 23 (76.7%) and passive inhalation in 7 (23.3%) patients. The most common symptoms/signs were agitation (29; 96.7%), mydriatic pupils (26; 86.7%), and tachycardia (20; 66.6%). Two in each group (13.3%) needed re-administration of intravenous diazepam due to persistent agitation. There was no report of benzodiazepine complications in either group.

Conclusions: Clonazepam and lorazepam treatment was equally effective at similar doses. However, considering the higher potency of clonazepam, it seems that lorazepam is the safer benzodiazepine for oral maintenance treatment of methamphetamine-induced agitation in children and can be used with minimal complications.

Trial Registration: IRCT20180610040036N2, April 18th, 2020. Retrospectively registered.
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http://dx.doi.org/10.1186/s12887-020-02441-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713025PMC
December 2020

Understanding the composite dimensions of the EQ-5D: An experimental approach.

Soc Sci Med 2020 11 27;265:113323. Epub 2020 Aug 27.

University of Sheffield, UK.

The EQ-5D(-5L) includes two composite dimensions: "Pain or Discomfort" (P/D) and "Anxiety or Depression" (A/D), which involves an inherent ambiguity. Little is known about how these composite dimensions are interpreted across contexts where (i) individuals self-report their own health; and (ii) individuals value stylised health states. We detail the nature of the ambiguity and present experimental evidence from two large online surveys (n = 1007 and n = 1415). In one survey, individuals reported both their current health and their health at the time they felt the worst because of their health. In the other, they valued stylised EQ-5D states using Discrete Choice Experiments with duration as an attribute. In both surveys, participants were randomised into treatments in which the presentation of one of the composite dimensions was altered, or a control. Our results suggest (1) In self-report, use of the composite dimensions differs across the dimensions, with P/D used mainly to report Pain, but A/D used mainly to mean the more severe component of Anxiety and Depression. (2) In valuation, Pain was perceived to be worse than Discomfort at the same level, and Depression was perceived to be worse than Anxiety at the same level. (3) In valuation, the composite dimension P/D was interpreted to mean Pain, whilst the composite dimension A/D was interpreted to lie between Anxiety and Depression. We conclude that care must be taken when interpreting responses to existing health (or wellbeing) descriptive systems that rely on composite dimensions, and that caution should be applied when designing new ones.
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http://dx.doi.org/10.1016/j.socscimed.2020.113323DOI Listing
November 2020

Double trouble: methanol outbreak in the wake of the COVID-19 pandemic in Iran-a cross-sectional assessment.

Crit Care 2020 07 9;24(1):402. Epub 2020 Jul 9.

The Norwegian CBRNE Centre of Medicine, Department of Acute Medicine, Oslo University Hospital, Oslo, Norway.

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http://dx.doi.org/10.1186/s13054-020-03140-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344025PMC
July 2020

Loss of Cxcr5 alters neuroblast proliferation and migration in the aged brain.

Stem Cells 2020 09 29;38(9):1175-1187. Epub 2020 May 29.

Faculty of Medicine, Department of Clinical Sciences and Neurology, Stem Cells, Aging and Neurodegeneration Group, Lund University, Lund, Sweden.

Neurogenesis, the production of new neurons from neural stem cells, dramatically decreases during aging concomitantly with increased inflammation both systemically and in the brain. However, the precise role of inflammation and whether local or systemic factors drive the neurogenic decline during aging is poorly understood. Here, we identify CXCR5/5/CXCL13 signaling as a novel regulator of neurogenesis in the aged brain. The chemokine Cxcl13 was found to be upregulated in the brain during aging. Loss of its receptor, Cxcr5, led to increased proliferation and decreased numbers of neuroblasts in the aged subventricular zone (SVZ), together with accumulation of neuroblasts in the rostral migratory stream and olfactory bulb (OB), without increasing the amount of new mature neurons in the OB. The effect on proliferation and migration was specific to neuroblasts and likely mediated through increased levels of systemic IL-6 and local Cxcl12 expression in the SVZ. Our study raises the possibility of a new mechanism by which interplay between systemic and local alterations in inflammation regulates neurogenesis during aging.
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http://dx.doi.org/10.1002/stem.3207DOI Listing
September 2020

The efficiency-equity trade-off, self-interest, and moral principles in health and safety valuation.

Soc Sci Med 2019 10 9;238:112477. Epub 2019 Aug 9.

Department of Economics, University of Birmingham, Edgbaston, B15 2SB, UK. Electronic address:

Policy makers try to take account of public preferences when making trade-offs between policy options. Yet most estimates of the value of health and safety reflect only individuals' self-interested preferences, neglecting their preferences over the distribution of public resources. We conduct an experiment in which participants choose between policy options that differ in their efficiency (expected number of fatalities or cases of ill health they would prevent) and their equity (defined in terms of the balance of risk reductions for different sections of the population). The policy options were framed as interventions to improve a hypothetical city's water supply that would reduce the risk of death or ill health for people in different areas of the city to varying degrees. In order to examine whether self-interest would affect the trade-offs, we asked half of the sample about scenarios where they would personally benefit from some options. Our results suggest that efficiency is the most important single factor determining preferences between policy options, but decisions were influenced almost as much by equity as by efficiency. The effect of self-interest was smaller than that of the general concern for efficiency. We also elicited participants' stated moral principles regarding trade-offs between equity, efficiency and self-interest, and found that their expressed principles were well-aligned with their choices. Our findings contribute to the growing evidence that distributional concerns matter when evaluating health interventions.
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http://dx.doi.org/10.1016/j.socscimed.2019.112477DOI Listing
October 2019

Take-Home Naloxone for the Emergency Interim Management of Opioid Overdose: The Public Health Application of an Emergency Medicine.

Drugs 2019 Sep;79(13):1395-1418

Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway.

Naloxone is a well-established essential medicine for the treatment of life-threatening heroin/opioid overdose in emergency medicine. Over two decades, the concept of 'take-home naloxone' has evolved, comprising pre-provision of an emergency supply to laypersons likely to witness an opioid overdose (e.g. peers and family members of people who use opioids as well as non-medical personnel), with the recommendation to administer the naloxone to the overdose victim as interim care while awaiting an ambulance. There is an urgent need for more widespread naloxone access considering the growing problem of opioid overdose deaths, accounting for more than 100,000 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. These include pre-filled syringes and auto-injectors and, crucially, new concentrated nasal sprays (four formulations recently approved in different countries) with speed of onset comparable to intramuscular naloxone and relative bioavailability of approximately 40-50%. 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.
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http://dx.doi.org/10.1007/s40265-019-01154-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728289PMC
September 2019

Should we worry that take-home naloxone availability may increase opioid use?

Addiction 2019 10 12;114(10):1723-1725. Epub 2019 Jun 12.

National Addiction Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

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http://dx.doi.org/10.1111/add.14637DOI Listing
October 2019

Patient views of opioid pharmacotherapy biodelivery systems: Qualitative study to assist treatment decision making.

Exp Clin Psychopharmacol 2018 Dec 23;26(6):570-581. Epub 2018 Jul 23.

National Addiction Centre.

The technology for delivering opioid pharmacotherapy (OPT) is expanding. It is important to know what OPT patients think of these developments and to find ways of enabling patients and clinicians to make informed decisions about which biodelivery system to choose. We explored the views of current and former OPT patients with a history of heroin use to identify factors influencing their preferences regarding routes of OPT administration. Data were generated via seven focus groups conducted in London, United Kingdom. Participants ( = 44) considered standard biodelivery systems (liquid/linctus, tablet, injectables), emergent systems (implants, depot injections), and a hypothetical system (nasal sprays). Groups were audio-recorded, transcribed verbatim, coded using qualitative software, and analyzed inductively via iterative categorization. Participants were cautious of, but willing to consider, new ways of receiving OPT and they welcomed having more choice. Their preferences and decision-making processes were influenced by nine interconnected factors: (a) personal dislike of particular biodelivery systems, (b) desired feelings following OPT administration, (c) perceived effectiveness of OPT biodelivery systems, (d) concerns about side effects, (e) ability to control the OPT, (f) impact on daily lives, (g) concerns about OPT-related stigma, (h) need for psychosocial support, and (i) personal treatment goals. This complexity may make it difficult for patients and clinicians to evaluate the pros and cons of the expanding array of OPT biodelivery systems and to arrive at clear conclusions. We therefore use the findings to construct a checklist that may facilitate discussions with patients when decisions about OPT need to be made. (PsycINFO Database Record (c) 2018 APA, all rights reserved).
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http://dx.doi.org/10.1037/pha0000217DOI Listing
December 2018

Evidence for neurogenesis in the medial cortex of the leopard gecko, Eublepharis macularius.

Sci Rep 2018 06 25;8(1):9648. Epub 2018 Jun 25.

Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada.

Although lizards are often described as having robust neurogenic abilities, only a handful of the more than 6300 species have been explored. Here, we provide the first evidence of homeostatic neurogenesis in the leopard gecko (Eublepharis macularius). We focused our study on the medial cortex, homologue of the mammalian hippocampal formation. Using immunostaining, we identified proliferating pools of neural stem/progenitor cells within the sulcus septomedialis, the pseudostratified ventricular zone adjacent to the medial cortex. Consistent with their identification as radial glia, these cells expressed SOX2, glial fibrillary acidic protein, and Vimentin, and demonstrated a radial morphology. Using a 5-bromo-2'-deoxyuridine cell tracking strategy, we determined that neuroblast migration from the ventricular zone to the medial cortex takes ~30-days, and that newly generated neuronal cells survived for at least 140-days. We also found that cell proliferation within the medial cortex was not significantly altered following rupture of the tail spinal cord (as a result of the naturally evolved process of caudal autotomy). We conclude that the sulcus septomedialis of the leopard gecko demonstrates all the hallmarks of a neurogenic niche.
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http://dx.doi.org/10.1038/s41598-018-27880-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018638PMC
June 2018

Implants and depot injections for treating opioid dependence: Qualitative study of people who use or have used heroin.

Drug Alcohol Depend 2018 08 25;189:1-7. Epub 2018 May 25.

King's College London, National Addiction Centre, Institute of Psychiatry, Psychology & Neuroscience, 4 Windsor Walk, London, SE5 8BB, United Kingdom; South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Monks Orchard Road, Beckenham, Kent, BR3 3BX, United Kingdom.

Background: Long-acting opioid pharmacotherapy (OPT) is presumed to offer benefits over more conventional OPT formulations. This paper analyzes the views and experiences of people who use or have used heroin in order to explore two novel systems for delivering long-acting OPT: implants and depot injections. New materialism theorizing is used to interpret and frame the findings.

Methods: Qualitative data were generated via seven focus groups conducted during 2017 in London, UK. Participants (n = 44; 28 men and 16 women; ages 33-66 years) had all received OPT. Focus group discussions covered real and potential OPT delivery systems. All participant data relating to implants and depot injections were coded using MAXQDA software and analysed inductively via Iterative Categorisation.

Findings: Participants discussed implants and depot injections in terms of interacting physical, psychological and social factors: dose stability; OPT administration; stopping treatment; co-presence of an antagonist; breaking rituals and habits; reduced choice and control; feeling normal; information needs; getting on with everyday life; and social interaction. Participants identified both benefits and concerns, and variable needs and preferences, with respect to each delivery system.

Conclusions: Implants and depot injections are not 'fixed' medications that can be administered to people to achieve pre-determined treatment aims. Rather, they are complex 'assemblages' with uncertain outcomes. Furthermore, they are themselves part of wider interactive 'assemblages'. Drug developers and treatment providers need to understand this complexity in order to target long-acting OPT at people most likely to benefit from it, and to reduce any unintended negative consequences.
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http://dx.doi.org/10.1016/j.drugalcdep.2018.03.057DOI Listing
August 2018

Improving recruitment to pharmacological trials for illicit opioid use: findings from a qualitative focus group study.

Addiction 2018 06 21;113(6):1066-1076. Epub 2018 Feb 21.

National Addiction Centre, King's College London, London, UK.

Aim: To explore potential study participants' views on willingness to join clinical trials of pharmacological interventions for illicit opioid use to inform and improve future recruitment strategies.

Design: Qualitative focus group study [six groups: oral methadone (two groups); buprenorphine tablets (two groups); injectable opioid agonist treatment (one group); and former opioid agonist treatment (one group)].

Settings: Drug and alcohol services and a peer support recovery service (London, UK).

Participants: Forty people with experience of opioid agonist treatment for heroin dependence (26 males, 14 females; aged 33-66 years).

Measurements: Data collection was facilitated by a topic guide that explored willingness to enrol in clinical pharmacological trials. Groups were audio-recorded and transcribed. Transcribed data were analysed inductively via Iterative Categorization.

Findings: Participants' willingness to join pharmacological trials of medications for opioid dependence was affected by factors relating to study burden, study drug, study design, study population and study relationships. Participants worried that the trial drug might be worse than, or interfere with, their current treatment. They also misunderstood aspects of trial design despite the researchers' explanations.

Conclusions: Recruitment of participants for clinical trials of pharmacological interventions for illicit opioid use could be improved if researchers became better at explaining clinical trials to potential participants, dispelling misconceptions about trials and increasing trust in the research process and research establishment. A checklist of issues to consider when designing pharmacological trials for illicit opioid use is proposed.
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http://dx.doi.org/10.1111/add.14163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5969063PMC
June 2018

Toxicity: exploring and expanding the concept.

Addiction 2018 04 4;113(4):592-594. Epub 2017 Dec 4.

National Addiction Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

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http://dx.doi.org/10.1111/add.14080DOI Listing
April 2018

Pharmacokinetics of concentrated naloxone nasal spray for opioid overdose reversal: Phase I healthy volunteer study.

Addiction 2018 03 16;113(3):484-493. Epub 2017 Nov 16.

National Addiction Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Background And Aims: Take-home naloxone can prevent death from heroin/opioid overdose, but pre-provision is difficult because naloxone is usually given by injection. Non-injectable alternatives, including naloxone nasal sprays, are currently being developed. To be effective, the intranasal (i.n.) spray dose must be adequate but not excessive, and early absorption must be comparable to intramuscular (i.m.) injection. We report on the pharmacokinetics (PK) of a specially produced concentrated novel nasal spray. The specific aims were to: (1) estimate PK profiles of i.n. naloxone, (2) compare early systemic exposure with i.n. versus i.m. naloxone and (3) estimate i.n. bioavailability.

Design: Open-label, randomized, five-way cross-over PK study.

Setting: Clinical trials facility (Croydon, UK).

Participants: Thirty-eight healthy volunteers (age 20-54 years; 11 female).

Intervention And Comparator: Three doses of i.n. (1 mg/0.1 ml, 2 mg/0.1 ml, 4 mg/0.2 ml) versus 0.4 mg i.m. (reference) and 0.4 mg intravenous (i.v.) naloxone.

Measurements: Regular blood samples were taken, with high-frequency sampling during the first 15 minutes to capture early systemic exposure. PK parameters were determined from plasma naloxone concentrations. Exploratory analyses involved simulation of repeat administration.

Findings: Mean peak concentration (C ) values for 1 mg (1.51 ng/ml), 2 mg (2.87 ng/ml) and 4 mg (6.02 ng/ml) i.n. exceeded 0.4 mg i.m. (1.27 ng/ml) naloxone. All three i.n. doses rapidly achieved plasma levels > 50% of peak concentrations (T50%) by 10 minutes, peaking at 15-30 minutes (T ). For comparison, the i.m. reference reached T at 10 minutes. Mean bioavailability was 47-51% for i.n. relative to i.m. naloxone. Simulation of repeat dosing (2 × 2 mg i.n. versus 5 × 0.4 mg i.m. doses) at 3-minute intervals showed that comparable plasma naloxone concentrations would be anticipated.

Conclusions: Concentrated 2 mg intranasal naloxone is well-absorbed and provides early exposure comparable to 0.4 mg intramuscular naloxone, following the 0.4 mg intramuscular curve closely in the first 10 minutes post-dosing and maintaining blood levels above twice the intramuscular reference for the next 2 hours.
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http://dx.doi.org/10.1111/add.14033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836974PMC
March 2018

Tail regeneration and other phenomena of wound healing and tissue restoration in lizards.

J Exp Biol 2017 08;220(Pt 16):2858-2869

Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada N1G 2W1

Wound healing is a fundamental evolutionary adaptation with two possible outcomes: scar formation or reparative regeneration. Scars participate in re-forming the barrier with the external environment and restoring homeostasis to injured tissues, but are well understood to represent dysfunctional replacements. In contrast, reparative regeneration is a tissue-specific program that near-perfectly replicates that which was lost or damaged. Although regeneration is best known from salamanders (including newts and axolotls) and zebrafish, it is unexpectedly widespread among vertebrates. For example, mice and humans can replace their digit tips, while many lizards can spontaneously regenerate almost their entire tail. Whereas the phenomenon of lizard tail regeneration has long been recognized, many details of this process remain poorly understood. All of this is beginning to change. This Review provides a comparative perspective on mechanisms of wound healing and regeneration, with a focus on lizards as an emerging model. Not only are lizards able to regrow cartilage and the spinal cord following tail loss, some species can also regenerate tissues after full-thickness skin wounds to the body, transections of the optic nerve and even lesions to parts of the brain. Current investigations are advancing our understanding of the biological requirements for successful tissue and organ repair, with obvious implications for biomedical sciences and regenerative medicine.
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http://dx.doi.org/10.1242/jeb.126862DOI Listing
August 2017

Twenty years of take-home naloxone for the prevention of overdose deaths from heroin and other opioids-Conception and maturation.

Drug Alcohol Depend 2017 09 25;178:176-187. Epub 2017 May 25.

National Addiction Centre, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, Addictions Sciences Building, 4 Windsor Walk, Denmark Hill, London, SE5 8BB, United Kingdom. Electronic address:

Background: Opioid overdose is a major cause of mortality, but injury and fatal outcomes can be prevented by timely administration of the opioid antagonist naloxone. Pre-provision of naloxone to opioid users and family members (take-home naloxone, THN) was first proposed in 1996, and WHO Guidelines were issued in 2014. While widespread in some countries, THN is minimally available or absent elsewhere. This review traces the development of THN over twenty years, from speculative harm reduction proposal to public health strategy.

Method: Medline and PsycINFO were searched for peer-reviewed literature (1990-2016) using Boolean queries: 1) "naloxone OR Narcan"; 2) "(opioid OR opiate) AND overdose AND prevention". Grey literature and specialist websites were also searched. Data were extracted and synthesized as narrative review, with key events presented as chronological timeline.

Results: Results are presented in 5-year intervals, starting with the original proposal and THN pilots from 1996 to 2001. Lack of familiarity with THN challenged early distribution schemes (2001-2006), leading to further testing, evaluation, and assessment of challenges and perceived medicolegal barriers. From 2006-2011, response to social and legal concerns led to the expansion of THN programs; followed by high-impact research and efforts to widen THN availability from 2011 to 2016.

Conclusions: Framed as a public health tool for harm reduction, THN has overcome social, clinical, and legal barriers in many jurisdictions. Nonetheless, the rising death toll of opioid overdose illustrates that current THN coverage is insufficient, and greater public investment in overdose prevention will be required if THN is to achieve its full potential impact.
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http://dx.doi.org/10.1016/j.drugalcdep.2017.05.001DOI Listing
September 2017

International patent applications for non-injectable naloxone for opioid overdose reversal: Exploratory search and retrieve analysis of the PatentScope database.

Drug Alcohol Rev 2018 02 8;37(2):205-215. Epub 2017 Jun 8.

National Addiction Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Issues: Non-injectable naloxone formulations are being developed for opioid overdose reversal, but only limited data have been published in the peer-reviewed domain. Through examination of a hitherto-unsearched database, we expand public knowledge of non-injectable formulations, tracing their development and novelty, with the aim to describe and compare their pharmacokinetic properties.

Approach: (i) The PatentScope database of the World Intellectual Property Organization was searched for relevant English-language patent applications; (ii) Pharmacokinetic data were extracted, collated and analysed; (iii) PubMed was searched using Boolean search query '(nasal OR intranasal OR nose OR buccal OR sublingual) AND naloxone AND pharmacokinetics'.

Key Findings: Five hundred and twenty-two PatentScope and 56 PubMed records were identified: three published international patent applications and five peer-reviewed papers were eligible. Pharmacokinetic data were available for intranasal, sublingual, and reference routes. Highly concentrated formulations (10-40 mg mL ) had been developed and tested. Sublingual bioavailability was very low (1%; relative to intravenous). Non-concentrated intranasal spray (1 mg mL ; 1 mL per nostril) had low bioavailability (11%). Concentrated intranasal formulations (≥10 mg mL ) had bioavailability of 21-42% (relative to intravenous) and 26-57% (relative to intramuscular), with peak concentrations (dose-adjusted C  = 0.8-1.7 ng mL ) reached in 19-30 min (t ).

Implications: Exploratory analysis identified intranasal bioavailability as associated positively with dose and negatively with volume.

Conclusion: We find consistent direction of development of intranasal sprays to high-concentration, low-volume formulations with bioavailability in the 20-60% range. These have potential to deliver a therapeutic dose in 0.1 mL volume. [McDonald R, Danielsson Glende Ø, Dale O, Strang J. International patent applications for non-injectable naloxone for opioid overdose reversal: Exploratory search and retrieve analysis of the PatentScope database. Drug Alcohol Rev 2017;00:000-000].
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http://dx.doi.org/10.1111/dar.12571DOI Listing
February 2018

A mapping review of take-home naloxone for people released from correctional settings.

Int J Drug Policy 2017 08 30;46:7-16. Epub 2017 May 30.

National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW, Australia; Center for Prisoner Health and Human Rights, Brown University, Providence, RI, USA. Electronic address:

Background: People released from correctional settings are at an elevated risk of opioid overdose death in the weeks immediately following release. However, it is not well understood how this population, as a particularly high-risk group, is included in, and benefits from take-home naloxone (THN) programs. The objective of this review is to map research into THN for people released from correctional settings in order to identify further research needs.

Method: We searched electronic databases, grey literature, and conference abstracts for reports on THN for people in or released from correctional settings. Studies were categorised into themes defined by the study's aims and focus. Results from each study were summarised by theme.

Results: We identified 19 studies reporting on THN programs for people released from correctional settings. Studies have examined attitudes towards naloxone among people in custody or recently released from custody (theme 1), and among non-prisoner stakeholders such as prison staff (theme 2). Evaluations and interventional studies (theme 3) have examined process indicators and approaches to naloxone training, including for contacts of prisoners, but there are challenges in assessing health outcomes of THN in the correctional context. Case reports suggest that training in correctional settings translates to action post-release (theme 4).

Conclusion: The feasibility of THN in the context of release from a correctional setting has been established, but there is a need for rigorous research into health outcomes and program implementation. This is an emerging field of study and ongoing assessment of the state of the literature and research needs is recommended.
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http://dx.doi.org/10.1016/j.drugpo.2017.05.015DOI Listing
August 2017

Pharmacokinetics of concentrated naloxone nasal spray over first 30 minutes post-dosing: analysis of suitability for opioid overdose reversal.

Addiction 2017 Sep 28;112(9):1647-1652. Epub 2017 May 28.

National Addiction Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Background And Aims: Lack of non-injectable naloxone formulations has impeded widespread take-home provision for the prevention of heroin/opioid overdose deaths. For non-injectable formulations that are finally being investigated, rapid onset of action and sufficient bioavailability will be vital. We present analysis of data from a study of concentrated naloxone nasal spray formulations. Our aims are: to assess (1) pharmacokinetic properties and (2) suitability for overdose reversal in terms of naloxone absorption within 30 minutes post-dosing.

Design And Interventions/comparator: Open-label, randomized, four-way cross-over Latin-square pharmacokinetic study of naloxone administration by three routes: intranasal at two doses (8 mg/0.4 ml, 16 mg/0.4 ml) versus sublingual (16 mg/ml) versus intravenous reference (1 mg/ml).

Setting: Clinical Pharmacology Unit at The Ohio State University (Columbus, OH, USA).

Participants: Twelve healthy volunteers (age 20-41; seven female).

Measurements: From blood plasma naloxone concentrations, (1) standard pharmacokinetic parameters, including maximum plasma concentration (C ) and mean absolute bioavailability (F%, relative to intravenous injection), were determined; as well as (2) partial area under the curve (AUC) values, t (time to maximum plasma concentration) and t (time to 50% of maximum plasma concentration) as measures of early absorption.

Findings: (1) Bioavailability was F% = 25-28% for intranasal naloxone. Sublingual had low bioavailability (F% = 2%) and was not considered further. Mean C values for 8 mg (12.83 ng/ml) and 16 mg (18.25 ng/ml) intranasal exceeded 1 mg intravenous (9.64 ng/ml) naloxone. (2) Following intranasal administration, t was reached within 8 minutes and t within 20 minutes. Mean naloxone absorption from dosing to 30 minutes (AUC ) was greater following 8 mg (4.17 h × ng/ml) and 16 mg (5.91 h × ng/ml) intranasal than following 1 mg intravenous (1.70 h × ng/ml) administration.

Conclusions: Concentrated naloxone nasal spray has a promising pharmacokinetic profile, with substantial bioavailability. Its early absorption time-course suggests that concentrated nasal naloxone is suitable for emergency administration in the community, where rapid restoration of respiratory function is essential for opioid overdose reversal.
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http://dx.doi.org/10.1111/add.13849DOI Listing
September 2017

Optimal Interval between Ultrasound Scans for the Detection of Complications in Monochorionic Twins.

Fetal Diagn Ther 2017 25;41(3):197-201. Epub 2016 Aug 25.

Monash Women's Service, Monash Medical Centre, Clayton, Vic., Australia.

Introduction: Monochorionic-diamniotic (MCDA) twin pregnancies are high risk, due to twin-to-twin transfusion syndrome (TTTS), twin anaemia polycythaemia sequence (TAPS) and intrauterine growth restriction (IUGR). There is limited evidence to guide ultrasound surveillance protocols. Using a retrospective cohort, we aimed to provide insight into the optimal interval of ultrasound surveillance.

Methods: Retrospective cohort of women with MCDA pregnancies who received antenatal care at Monash Medical Centre (January 2011-October 2014). We reviewed all ultrasounds from ≥15 weeks' gestation and collected perinatal outcomes.

Results: A total of 162 women with MCDA pregnancies attended our care. Six women were excluded due to late referral. Of the remaining 156, 55% were uncomplicated. TTTS, TAPS, IUGR and fetal demise in utero occurred in 9%, 1%, 31% and 2%, respectively. Median interval between the last ultrasound and TTTS diagnosis was 3.1 weeks (IQR 0.8-5.8). There was a trend towards a longer interval for cases with advanced TTTS compared to early TTTS. Interval between ultrasound scans was longer in cases with unexplained fetal demise in utero and advanced TTTS than early TTTS [3.4 weeks (IQR 2.0-6.9) vs. 0.9 weeks (IQR 0.4-3.7); p < 0.05].

Discussion: Our observations support current recommendations for fortnightly ultrasound surveillance in MCDA pregnancies from 16 weeks' gestation and suggest that longer intervals may be associated with poorer outcomes.
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http://dx.doi.org/10.1159/000448094DOI Listing
February 2018

Commentary on Darke & Duflou (2016): Heroin-related deaths-identifying a window for intervention.

Addiction 2016 09;111(9):1614-5

National Addiction Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

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http://dx.doi.org/10.1111/add.13467DOI Listing
September 2016

Letters to Addiction from Coffin et al. and Doe-Simpkins et al. re: 'For Debate' on clinical use of improvised nasal naloxone sprays: authors' response.

Addiction 2016 10 13;111(10):1881-3. Epub 2016 Jul 13.

National Addiction Centre, King's College, London, UK.

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http://dx.doi.org/10.1111/add.13468DOI Listing
October 2016

Are take-home naloxone programmes effective? Systematic review utilizing application of the Bradford Hill criteria.

Addiction 2016 07 30;111(7):1177-87. Epub 2016 Mar 30.

National Addiction Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Background And Aims: Fatal outcome of opioid overdose, once detected, is preventable through timely administration of the antidote naloxone. Take-home naloxone provision directly to opioid users for emergency use has been implemented recently in more than 15 countries worldwide, albeit mainly as pilot schemes and without formal evaluation. This systematic review assesses the effectiveness of take-home naloxone, with two specific aims: (1) to study the impact of take-home naloxone distribution on overdose-related mortality; and (2) to assess the safety of take-home naloxone in terms of adverse events.

Methods: PubMed, MEDLINE and PsychINFO were searched for English-language peer-reviewed publications (randomized or observational trials) using the Boolean search query: (opioid OR opiate) AND overdose AND prevention. Evidence was evaluated using the nine Bradford Hill criteria for causation, devised to assess a potential causal relationship between public health interventions and clinical outcomes when only observational data are available.

Results: A total of 1397 records (1164 after removal of duplicates) were retrieved, with 22 observational studies meeting eligibility criteria. Due to variability in size and quality of the included studies, meta-analysis was dismissed in favour of narrative synthesis. From eligible studies, we found take-home naloxone met all nine Bradford Hill criteria. The additional five World Health Organization criteria were all either met partially (two) or fully (three). Even with take-home naloxone administration, fatal outcome was reported in one in 123 overdose cases (0.8%; 95% confidence interval = 0.4, 1.2).

Conclusions: Take-home naloxone programmes are found to reduce overdose mortality among programme participants and in the community and have a low rate of adverse events.
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http://dx.doi.org/10.1111/add.13326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5071734PMC
July 2016