Community management
`of opioid overdose
`
`COMMUNITY MANAGEMENT OF OPIOID OVERDOSE
`
`substance
`use
`
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`IPR2019-00694
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`Community management
`of opioid overdose
`
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`IPR2019-00694
`Page 3
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`WHO Library Cataloguing-in-Publication Data
`
`Community management of opioid overdose.
`
`1.Opioid-Related Disorders – prevention and control. 2.Drug Overdose – prevention and control. 3.Naloxone – therapeutic use. 4.Community Health Services. 5.Guideline. I.World
`Health Organization.
`
`ISBN 978 92 4 154881 6
`
`(NLM classification: WM 284)
`
`© World Health Organization 2014
`
`All rights reserved. Publications of the World Health Organization are available on the WHO website (www.who.int) or can be purchased from WHO Press, World Health Organization,
`20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int).
`
`Requests for permission to reproduce or translate WHO publications –whether for sale or for non-commercial distribution– should be addressed to WHO Press through the WHO
`website (www.who.int/about/licensing/copyright_form/en/index.html).
`
`The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization
`concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps
`represent approximate border lines for which there may not yet be full agreement.
`
`The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to
`others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
`
`All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being
`distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World
`Health Organization be liable for damages arising from its use.
`
`
`Design and layout: L’IV Com Sàrl, Villars-sous-Yens, Switzerland.
`
`Printed by the WHO Document Production Services, Geneva, Switzerland.
`
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`CONTENT
`
`Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`iv
`
`Glossary of terms used in these guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
`
`Acronyms & abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viii
`
`Executive summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`ix
`
`Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
`Opioid overdose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
`Preventing opioid overdose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
`Who is at risk of an opioid overdose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
`Who is likely to witness an opioid overdose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
`Management of opioid overdose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
`Access to naloxone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
`Why these guidelines were developed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
`Existing relevant guidelines on related problems and disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
`Who should use these guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
`Objectives and scope of these guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
`Individuals and partners involved in development of the guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
`Management of conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
`How the guidelines were developed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
`Systematic evidence search amd retrieval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
`Evidence to recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
`Peer preview process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
`
`Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
`Key question 1 – Naloxone distribution (see Annex 2 for details) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
`Key questions 2 and 3 – Formulation and dose of naloxone (see Annex 3 for details) . . . . . . . . . . . . . 10
`Key question 4 – Cardiopulmonary resuscitation (see Annex 4 for details) . . . . . . . . . . . . . . . . . . . . . . 12
`Key question 5 – Post-resuscitation care (see Annex 5 for details) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
`
`Evidence gaps and research priorities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
`
`Plans for disseminating, adapting and implementing these recommendations . . . . . . . . . . . . . . . . . 18
`Evaluating the impact of these recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
`Review date . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
`
`Annex 1: Systematic review methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
`
`Annex 2: Key question 1 – Evidence profile and decision table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
`
`Annex 3: Key questions 2 and 3 – Evidence profiles and decision table . . . . . . . . . . . . . . . . . . . . . . . . . . 35
`
`Annex 4: Key question 4 – Evidence profile and decision table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
`
`Annex 5: Key question 5 – Evidence profile and decision table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
`
`Annex 6: Values-and-preferences survey and key-informant interviews . . . . . . . . . . . . . . . . . . . . . . . 59
`Online survey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
`In-depth interviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
`
`Annex 7: Composition of guideline groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
`
`Annex 8: Declarations of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
`
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`ACKNOWLEDGEMENTS
`
`These guidelines were produced by the Management of Substance Abuse unit of the WHO Department of
`Mental Health and Substance Abuse in collaboration with the WHO HIV Department. Vladimir Poznyak and
`Nicolas Clark coordinated the development of these guidelines under the direction of Shekhar Saxena and in
`collaboration with Rachel Baggaley and Annette Verster.
`
`Members of the project’s WHO Steering Group included: Annabel Badderley, Rachel Baggaley, Nicolas Clark,
`Selma Khamassi, Elizabeth Mathai, Maggie Peden, Vladimir Poznyak, and Annette Verster (see Annex 7 for
`affiliations).
`
`The members of the project’s Guideline Development Group (GDG) were: Robert Balster (Chair), Barbara
`Broers, Jane Buxton, Paul Dietze, Kirsten Horsburgh, Raka Jain, Nadeem Ullah Khan, Walter Kloeck, Emran M
`Razaghi, Hendry Robert Sawe, John Strang, and Oanh Thi Hai Khuat (see Annex 7 for affiliations).
`
`Observers at the Guideline Development Group meeting in Geneva in February 2014, who provided comments
`and technical information, were: Anja Busse (United Nations Office on Drugs and Crime), David Sugerman
`(Centres for Disease Control, USA), Regis Bedry (European Association of Poisons Centres and Clinical
`Toxicologists), Marica Ferri (European Monitoring Centre for Drugs and Drug Addiction), Mauro Guarinieri (the
`Global Fund to Fight AIDS, Tuberculosis and Malaria), Sharon Stancliff (Harm Reduction Association, USA),
`Marc Augsburger (The International Association of Forensic Toxicologists), Ruth Birgin (International Network
`of People who Use Drugs), Hannu Alho (International Society of Addiction Medicine), Simon Lenton (National
`Drug Research Institute, Australia), Steven Gust (National Institute on Drug Abuse, USA), Daniel Wolfe (Open
`Society Foundations), H. Westley Clark (Substance Abuse and Mental Health Services Administration, USA).
`
`WHO would like to acknowledge the contributions made by the following individuals to the development of
`these guidelines:
`
`Consultants: Margaret Harris advised on WHO guideline methodology, including use of GRADE, at the guideline
`development meeting and assisted with preparation of the final guideline document. Mary Henderson conducted
`the in-depth survey on the values and preferences of key informants. Cadi Irvine, an HIV consultant, assisted
`with the preparation of background material. Caitlin Kennedy advised on initial methodology and assisted in the
`development of the systematic review protocol. Nandi Siegfried assisted with study selection (as a reviewer)
`and preparation of GRADE evidence profiles. Nick Walsh developed the background documentation for the
`GDG meeting and the systematic review protocol. He also conducted the systematic reviews, presented the
`findings to the GDG, wrote the first draft of the guidance and assisted with preparation of the final guideline
`document. Anna Williams and Rebecca McDonald assisted with the preparation of background documentation.
`
`WHO staff: Tomas Allen (WHO library) assisted with the development and conduct of the literature search.
`
`WHO interns: Agata Boldys (Management of Substance Abuse unit) assisted with the organization of the
`meeting and the preparation of background documents. Sally Cruse (Management of Substance Abuse unit)
`assisted with the external and peer-review process and the preparation of the guideline document. Pramudie
`Gunaratne (HIV Department) assisted with the values-and-preferences survey.
`
`Funding: WHO gratefully acknowledges the financial support of the Government of Norway and the U.S.
`President’s Emergency Plan for AIDS Relief (PEPFAR) for the production of these guidelines.
`
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`GLOSSARY OF TERMS USED IN THESE GUIDELINES
`
`abstinence
`Refraining from alcohol or drug use. The term “abstinence” should not be confused with the term “abstinence
`syndrome”, which refers to a withdrawal syndrome.
`
`agonist
`A substance that acts at a neuronal receptor to produce effects similar to those of a reference drug; for example,
`heroin is a morphine-like agonist at opioid receptors.
`
`antagonist
`A substance that counteracts the effects of another agent. Pharmacologically, an antagonist interacts with
`a receptor to inhibit the action of agents (agonists) that produce specific physiological or behavioural effects
`mediated by that receptor.
`
`delirium
`An acute organic cerebral syndrome characterized by concurrent disturbances of consciousness, attention,
`perception, orientation, thinking, memory, psychomotor behaviour, emotion, and the sleep-wake cycle. Duration
`is variable from a few hours to a few weeks and the degree of severity ranges from mild to very severe. An
`alcohol-induced withdrawal syndrome with delirium is known as delirium tremens.
`
`dependence
`A cluster of physiological, behavioural and cognitive phenomena in which the use of a substance or a class of
`substances takes on a much higher priority for a given individual than other behaviours that once had greater
`value. A central descriptive characteristic of the dependence syndrome is the desire (often strong, sometimes
`overpowering) to take psychoactive drugs (which may or may not have been medically prescribed), alcohol or
`tobacco.
`
`depressant
`Any agent that suppresses, inhibits, or decreases some aspects of central nervous system (CNS) activity. The
`main classes of CNS depressants are the sedatives/hypnotics (alcohol, barbiturates, benzodiazepines), opioids,
`and neuroleptics. Anticonvulsants are sometimes included in the depressant group because of their inhibitory
`action on abnormal neural activity. Disorders related to depressant use are classified as psychoactive-substance
`use disorders in ICD-10 in categories F10 (for alcohol), F11 (for opioids), and F13 (for sedatives or hypnotics).
`See also: opioid; sedative/hypnotic.
`
`detoxification
`Also referred to as managed withdrawal or supported withdrawal, detoxification describes supported cessation
`of a psychoactive substance.
`
`illicit drug
`A psychoactive substance, the production, sale, or use of which is prohibited. Strictly speaking, it is not the
`drug that is illicit, but its production, sale, or use in particular circumstances in a given jurisdiction. “Illicit drug
`market”, a more exact term, refers to the production, distribution and sale of any drug outside legally-sanctioned
`channels.
`
`intoxication
`A condition that follows the administration or consumption of a psychoactive substance causing disturbances in
`the level of consciousness, cognition, perception, judgement, affect or behaviour, or other psychophysiological
`functions and responses.
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`multiple drug use
`The use of more than one drug or type of drug by an individual, at the same time or sequentially, usually with
`the intention of enhancing, potentiating or counteracting the effects of another drug. The term is also used
`more loosely to include the unconnected use of two or more drugs by the same person.
`
`naloxone
`An opioid-receptor blocker that antagonizes the actions of opioid drugs. It reverses the features of opiate
`intoxication and is prescribed for the treatment of overdose with this group of drugs. See also: antagonist.
`
`opiate
`One of a group of alkaloids derived from the opium poppy (Papaver somniferum) with the ability to induce
`analgesia, euphoria and, in higher doses, stupor, coma and respiratory depression. The term opiate excludes
`synthetic opioids. See also: opioid.
`
`opioid
`A generic term applied to alkaloids from the opium poppy (Papaver somniferum), their synthetic analogues and
`compounds synthesized in the body, which interact with the same specific receptors in the brain, have the
`capacity to relieve pain and produce a sense of well-being (euphoria). The opium alkaloids and their synthetic
`analogues also cause stupor, coma and respiratory depression in high doses.
`
`opioid maintenance treatment
`Also referred to as opioid agonist maintenance treatment or opioid substitution treatment. Examples of opioid
`maintenance therapies are methadone and buprenorphine maintenance treatment. Maintenance treatment
`can last from several months to more than 20 years, and is often accompanied by other treatment (such as
`psychosocial treatment).
`
`overdose
`The use of any drug in such an amount that acute adverse physical or mental effects are produced. Deliberate
`overdose is a common means of suicide and attempted suicide. In absolute numbers, overdoses of licit drugs
`are usually more common than those of illicit drugs. Overdose may produce transient or lasting effects, or death.
`The lethal dose of a particular drug varies with the individual and with circumstances. See also: intoxication;
`poisoning.
`
`poisoning, alcohol or drug
`A state of major disturbance of consciousness level, vital functions and behaviour following the administration
`in excessive dosage (deliberately or accidentally) of a psychoactive substance. In the field of toxicology, the
`term poisoning is used more broadly to denote a state resulting from the administration of excessive amounts
`of any pharmacological agent, psychoactive or not. See also: overdose; intoxication.
`
`polydrug use/abuse
`See multiple drug use.
`
`psychosocial intervention
`Any non-pharmacological intervention carried out in a therapeutic context at an individual, family or group level.
`Psychosocial interventions range from structured, professionally-administered psychological interventions
`(such as cognitive behaviour therapy or insight-oriented psychotherapy) to non-professional psychological and
`social interventions (such as self-help groups and non-pharmacological interventions from traditional healers,
`accommodation, financial support, legal support, employment assistance, information and outreach).
`
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`rebound toxicity
`The re-emergence of respiratory depression and other features of opioid overdose following the temporary
`reversal of opioid overdose symptoms with an opioid antagonist such as naloxone.
`
`relapse
`A return to drinking or other drug use after a period of abstinence, often accompanied by reinstatement of
`dependence symptoms. Some distinguish between relapse and lapse (“slip”), with the latter denoting an
`isolated occasion of alcohol or drug use.
`
`sedative/hypnotics
`Central nervous system depressants that relieve anxiety and induce calmness and sleep. Several such drugs
`also induce amnesia and muscle relaxation and/or have anticonvulsant properties. Major classes of sedatives/
`hypnotics include alcohol, the benzodiazepines and the barbiturates.
`
`substance use disorders
`This concept includes both the dependence syndrome and the harmful use of psychoactive substances such
`as alcohol, cannabis, amphetamine-type stimulants (ATS), cocaine, opioids and benzodiazepines.
`
`tolerance
`A decrease in response to a drug dose that occurs with continued use. Increased doses of alcohol or other drugs
`are required to achieve the effects originally produced by lower doses. Both physiological and psychosocial
`factors may contribute to the development of tolerance, which may be physical, behavioural or psychological.
`
`withdrawal syndrome
`Also known as abstinence syndrome, withdrawal reaction, or withdrawal state. A group of symptoms of variable
`clustering and degree of severity that occur on cessation or reduction of the use of a psychoactive substance
`that has been taken repeatedly, usually for a prolonged period or in high doses (ICD-10 code F1x.3). The onset
`and course of a withdrawal syndrome are time limited and relate to the type of substance and dose being
`taken immediately before cessation or reduction of use. Typically, the features of a withdrawal syndrome are
`the opposite of acute intoxication.
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`Community management of opioid overdose
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`ACRONYMS & ABBREVIATIONS
`
`ABC
`airway, breathing, and circulation
`aRR
`adjusted relative risk
`AIDS
`acquired immunodeficiency syndrome
`AMA
`against medical advice
`ART
`anti-retroviral treatment
`BBV
`blood borne virus
`BLS
`basic life support
`CI
`confidence interval
`CND
`Commission on Narcotic Drugs
`COCPR
`chest compression only cardiopulmonary resuscitation
`CNS
`central nervous system
`CPR
`cardiopulmonary resuscitation
`CPS
`controlled prospective study
`ECOSOC United Nations Economic and Social Council
`EMS
`emergency medical services
`GCS
`Glascow Coma Scale
`GDG
`guideline development group
`GRADE
`Grading of Recommendations Assessment, Development and Evaluation
`HCV
`hepatitis C virus
`HIV
`human immunodeficiency virus
`ICD-10
`International Classification of Diseases, 10th edition
`IM
`intramuscular
`IN
`IQR
`inter-quartile range
`IV
`intravenous
`OD
`overdose
`OR
`odds ratio
`PICO
`population, intervention, comparison, outcome
`PWID
`people who inject drugs
`PWUD
`people who use drugs
`RevMAN Review Manager
`RR
`relative risk or risk ratio
`RCT
`randomized controlled trial
`SC
`subcutaneous
`SMD
`standardized mean difference
`TB
`tuberculosis
`UNODC
`United Nations Office on Drugs and Crime
`WHO
`World Health Organization
`OR
`odds ratio
`
`intranasal
`
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`EXECUTIVE SUMMARY
`
`Opioids are potent respiratory depressants, and overdose is a leading cause of death among people who use
`them. Worldwide, an estimated 69 000 people die from opioid overdose each year. The number of opioid
`overdoses has risen in recent years, in part due to the increased use of opioids in the management of chronic
`pain. In 2010, an estimated 16 651 people died from an overdose of prescription opioids in the United States
`of America alone.
`
`Opioid overdose is treatable with naloxone, an opioid antagonist which rapidly reverses the effects of opioids.
`Death does not usually occur immediately, and in the majority of cases, overdoses are witnessed by a family
`member, peer or someone whose work brings them into contact with people who use opioids. Increased access
`to naloxone for people likely to witness an overdose could significantly reduce the high numbers of opioid
`overdose deaths. In recent years, a number of programmes around the world have shown that it is feasible
`to provide naloxone to people likely to witness an opioid overdose, in combination with training on the use of
`naloxone and the resuscitation of people experiencing opioid overdose, prompting calls for the widespread
`adoption of this approach. In 2012, the United Nations Economic and Social Council (ECOSOC) called upon
`the World Health Organization (WHO), in collaboration with the United Nations Office on Drugs and Crime
`(UNODC) to provide advice and guidance, based on scientific evidence, on preventing mortality from drug
`overdose, in particular opioid overdose.
`
`While community management of opioid overdose with naloxone is expected to reduce the proportion of
`witnessed opioid overdoses which result in death, it does not address the underlying causes of opioid overdose.
`To further reduce the number of deaths due to opioid overdose other measures should be considered, such as:
` o monitoring opioid prescribing practices;
` o curbing innapropriate opioid prescribing;
` o curbing inappropriate over-the-counter sales of opioids;
` o increasing the rate of treatment of opioid dependence, including for those dependent on prescription
`opioids.
`
`Objectives of the guidelines
`These guidelines aim to reduce the number of deaths from opioid overdose by providing evidence-based
`recommendations on the availability of naloxone for people likely to witness an opioid overdose along with
`advice on the resuscitation and post-resuscitation care of opioid overdose in the community. Specifically, these
`guidelines seek to:
` o increase the availability of naloxone to people likely to witness an opioid overdose in the pre-hospital setting;
` o increase the preparedness of people likely to witness an opioid overdose to respond safely and effectively
`by carrying naloxone and being trained in the management of opioid overdose;
` o increase the rate of effective resuscitation and post-resuscitation care by persons witnessing an opioid
`overdose.
`
`The guidelines aim to meet these objectives by:
` o informing health policy-makers of the benefits of increased availability and use of naloxone and effective
`resuscitation in the pre-hospital setting;
` o informing programme managers of the benefits of developing programmes to equip people likely to witness
`an opioid overdose with naloxone and to train them in managing an opioid overdose;
` o informing medical practitioners of the benefits of prescribing naloxone to people at risk of opioid overdose
`and providing advice on the management of opioid overdose.
`
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`How these guidelines were developed
`Development of these guidelines began in October 2013 with the identification of the key issues for which
`advice was needed. The WHO steering group and Guideline Development Group (GDG) were established
`and appropriate clinical questions were formulated. These were then set in the PICO format (population,
`intervention, comparator, outcome) and systematic reviews were conducted for each PICO question. The
`quality of the evidence was then assessed according to GRADE criteria. A narrative evidence synthesis was
`also provided. A GDG meeting was held in Geneva (19-20 February 2014). Evidence of values and preferences,
`cost-effectiveness, feasibility and resource use was presented along with the evidence of benefits and harms
`and the GDG formulated recommendations taking all these domains into consideration.
`
`The strength of the recommendation was set as either:
`‘strong’: meaning that the GDG was confident that the evidence of effect, combined with
`certainty about the values, preferences, benefits and feasibility, made this a recommendation
`that should be applied in most circumstances and settings;
`
`or
`
`‘conditional’: meaning that there was less certainty about the evidence of effect and values,
`preferences, benefits and feasibility of this recommendation. Thus there may be circumstances
`or settings in which the recommendation does not apply.
`
`TABLE 1. SUMMARY OF THE RECOMMENDATIONS
`
`No.
`
`
`
`2
`
`3
`
`4
`
`Recommendation
`People likely to witness an opioid overdose should have access
`to naloxone and be instructed in its administration to enable them
`to use it for the emergency management of suspected opioid
`overdose.
`Naloxone is effective when delivered by intravenous,
`intramuscular, subcutaneous and intranasal routes of
`administration. Persons using naloxone should select a route of
`administration based on the formulation available, their skills in
`administration, the setting and local context.
`In suspected opioid overdose, first responders should focus on
`airway management, assisting ventilation and administering
`naloxone.
`After successful resuscitation following the administration
`of naloxone, the level of consciousness and breathing of the
`affected person should be closely observed until full recovery has
`been achieved.
`
`Strength of
`recommendation
`Strong
`
`Quality of
`evidence
`Very low
`
`Conditional
`
`Very low
`
`Strong
`
`Very low
`
`Strong
`
`Very low
`
`x
`
`Opiant Exhibit 2096
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 12
`
`

`

`INTRODUCTION
`
`Opioids are potent respiratory depressants, and overdose is a leading cause of death among people who use
`them. Worldwide, an estimated 69 000 people die from opioid overdose each year (1). Among people who
`inject drugs, opioid overdose is the second most common cause of mortality after HIV/AIDS (2). A recent rise
`in opioid-overdose deaths in a number of countries is associated with an increase in the prescribing of opioids
`for chronic pain (3–5). In 2010, an estimated 16 651 people died from an overdose of prescription opioids in the
`United States of America alone (6).
`
`Opioid overdose
`Opioids depress the respiratory drive and overdose is characterised by apnoea, myosis and stupor. A severely
`reduced respiration rate results in hypoxaemia, leading to cerebral hypoxia and impaired consciousness.
`Cardiac arrest is a late complication of opioid overdose and secondary to respiratory arrest and hypoventilation.
`Prolonged cerebral hypoxia is the mechanism for brain injury and death in opioid overdose, resulting from
`apnoea or cardiac dysrhythmias and cardiac arrest.
`
`Opioids act at μ, κ and δ-opioid receptors, which are widely distributed throughout the body. Endogenous
`opioids act tonically on brain-stem-located opioid receptors to modulate respiration in response to hypoxia and
`hypercapnea (7). These centres are in turn modulated by connections to other structures in the central nervous
`system (CNS) including the motor cortex, the cerebellum and limbic centres. Administered opioids depress all
`components of the respiratory drive (the rate and depth of breathing). An effect most pronounced in individuals
`with chronic cardio-pulmonary and renal disease, whose respiratory responses are diminished. In addition to
`reducing respiratory drive, opioids reduce upper-airway tone and chest-wall rigidity.
`
`Preventing opioid overdose
`While community management of opioid overdose with naloxone is expected to reduce the proportion of
`witnessed opioid overdoses which result in death, it does not address the underlying causes of opioid overdose.
`To further reduce the number of deaths due to opioid overdose other measures should be considered (8), such
`as:
` o monitoring opioid prescribing practices;
` o curbing innapropriate opioid prescribing;
` o curbing inappropriate over-the-counter sales of opioids;
` o increasing the rate of treatment of opioid dependence, including for those dependent on prescription
`opioids.
`
`Who is at risk of an opioid overdose
`People dependent on opioids are the group most likely to experience an overdose. The incidence of fatal opioid
`overdose among opioid-dependent individuals is estimated at 0.65 per 100 person years (8). Non-fatal opioid
`overdoses are several times more common than fatal ones (9).
`
`A number of risk factors lead to increased likelihood of a fatal opioid overdose. Injecting opioid users are at
`elevated risk, particularly when first using injection as a route of administration (10–12).
`
`A reduction in tolerance, seen when opioid use is restarted after a period of abstinence, markedly increases
`the risk of an opioid overdose (13, 14). This commonly occurs during the first few weeks after release from
`incarceration (15–17), after discharge from inpatient or residential detoxification, or cessation of drug dependence
`treatment (including treatment with the opioid antagonist naltrexone) (18–21).
`
`1
`
`Community management of opioid overdose
`
`Opiant Exhibit 2096
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 13
`
`

`

`People who inject drugs and have HIV infection have an increased risk of overdose but it is unclear if the
`mechanism is direct or relates to a combination of biological, risk-behavioural and structural factors (26). Liver
`disease may also impair hepatic opioid metabolism (27) and therefore contribute to lowering overdose thresholds
`among individuals with chronic viral hepatitis, particularly long-standing hepatitis C viral infection (28).
`
`Although people taking prescribed opioids are at lower risk of overdose than people using unprescribed opi