EMCDDA PAPERS Preventing fatal overdoses: a systematic … · EMCDDA PAPERS. I. Preventing fatal...

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Abstract: Drug overdose is one of the major causes of death among young people in Europe. Naloxone is an effective antidote that can reverse opioid (including synthetic opioid) intoxication. As overdoses quite often occur in the presence of peers or family members, programmes that enable bystanders to provide first aid and administer naloxone before an ambulance arrives can save lives.

We conducted a systematic review of the available studies on take-home naloxone to reverse opioid overdose and included 21 studies for analysis (with various study designs). There is evidence from one interrupted time-series study, involving 2 912 opioid users at risk of overdose in 19 communities followed up for seven years, that educational and training interventions

complemented by take-home naloxone decrease overdose-related mortality.

There is weaker, but consistent, evidence that similar interventions for opioid-dependent patients and their peers effectively improve knowledge while forming positive attitudes to the correct use of naloxone and the management of witnessed overdoses.

Keywords naloxone overdose opioids systematic review

Preventing fatal overdoses: a systematic review of the effectiveness of take-home naloxone

EMCDDA PAPERS

Contents: Abstract (p. 1) I Background (p. 2) I Methods (p. 4) I Results (p. 6) I Discussion (p. 11) I Conclusions (p. 11) I References (p. 13) I Annexes (p. 19) I Acknowledgements (p. 37)

Recommended citation: European Monitoring Centre for

Drugs and Drug Addiction (2015), Preventing fatal overdoses:

a systematic review of the effectiveness of take-home

naloxone, EMCDDA Papers, Publications Office of the

European Union, Luxembourg.

EMCDDA PAPERS I Preventing fatal overdoses: a systematic review of the effectiveness of take-home naloxone

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benzodiazepines), as well as use of a combination of

substances (polysubstance use) (Giraudon et al., 2013). In

addition, in a substantial number of deaths, evidence of

polydrug use (heroin in combination with other central

nervous system depressants such as alcohol or

benzodiazepines) was found. Among the new psychoactive

substances (NPSs) are synthetic opioids, which have emerged

as a key concern because of links to serious adverse events

such as fatal and non-fatal intoxications (EMCDDA, 2014a),

for example fentanyls causing fatal overdoses, particularly in

east and central European countries (EMCDDA, 2012).

Overdose risk is influenced by individual, situational and

organisational factors (Figure 1). Beyond the type of

substance used and the route of administration, the

circumstances of use also affect the probability of overdose.

Risk factors can include interrupted treatment provision

because of discontinuous treatment and care, completion of

the detoxification process or discharge from drug-free

treatment (Cornish et al., 2010). In fact, although the majority

of deaths occur in individuals with a history of opioid

addiction, most of these individuals commonly have a reduced

tolerance to opioids at the time of their death (Darke et al.,

2007). This implies an increased risk linked to relapse into use

after a period of abstinence, for example following release

from detention (Binswanger et al., 2013; Zlodre and Fazel,

2012). Furthermore, occasional users of NPSs can also

experience opioid overdose (EMCDDA, 2013b).

I Background

Drug use is one of the major causes of health problems and

mortality among young people in Europe, and it can account

for a considerable proportion of deaths among adults. The risk

of premature death among injecting drug users can be 15

times higher than in the general population of the same age

group (Mathers et al., 2013). Some studies show that one third

to one half of deaths among drug users may be caused by

overdose (Bargagli et al., 2006; Degenhardt et al., 2011;

EMCDDA, 2011, 2013a). Combined with acquired immune

deficiency syndrome (AIDS), overdose represents the primary

cause of death among people who inject drugs.

Drug overdose accounts for approximately 3.5 % of all deaths

in adult males under 40 years of age (Eurostat, 2012, cited in

EMCDDA, 2013a). In absolute numbers in 2012, for example,

there were 6 100 overdose deaths across Europe.

In particular, the use of heroin and other opioids contributes

disproportionately to drug-related deaths: overdose

represents a common event among opioid users (EMCDDA,

2011, 2013a). Injecting drug use in Europe is becoming less

prevalent (EMCDDA, 2013b) but mortality among injectors

remains high (Mathers et al., 2013), and injecting drug use is

associated with increased risk for fatal and non-fatal

overdoses compared with non-injected routes of

administration (Darke et al., 2007). Among the substances

associated with the risk of overdose are opioids (including

prescription and non-medical use) and non-opioids (e.g.

FIGURE 1

Risk factors for overdose

Adapted from WHO (2014). HIV, human immunodeficiency virus

Access n Family members of people in possession of strong opioids

n Injected usen Use of high-dosage prescription opioidsn Use in combination with other sedating substances

n Reduced tolerance (following detoxification, release from incarceration,

cessation of treatment)n Opioid users with other significant medical conditions (HIV positive, liver

or lung disease, depression)

Dependence

Use


3 / 37

I Overdose prevention interventions

Several interventions are implemented with the direct aim of

preventing opioid overdose, whereas other interventions have

an indirect effect on reducing overdoses and overdose

mortality.

These interventions act at different stages and levels of risk

and they can address (i) the general population, such as

drug-use prevention interventions; (ii) drug users, for example

induction into treatment; (iii) active drug users, as is the case

with harm reduction strategies; and (iv) those experiencing an

ongoing overdose, in order to reduce lethality (Figure 2).

I Cause of death in opioid overdose and the role of naloxone

Opioid overdose is characterised by drowsiness or coma,

decreased respiratory rate, abnormally slow breathing,

pinpoint pupils and possibly apnoea (Boyer Edward, 2012).

Death from opioid overdose is caused primarily by respiratory

depression leading to cardiac arrest. Naloxone is an opioid

antagonist that can reverse the effects of opioids, including

respiratory depression, in the body within a few minutes. In

the absence of an agonist drug (such as an opioid) naloxone is

almost inert, but in individuals who are in acute respiratory

depression caused by an opioid overdose naloxone can

normalise respiration, level of consciousness, pupil size, bowel

activity and other signs and symptoms of overdose (Katzung,

1995). As naloxone, like naltrexone, has antagonistic effects, it

can precipitate opioid withdrawal syndrome in those under

the influence of opioid agonists.

It is standard practice for ambulance personnel to administer

naloxone to victims of acute opioid overdose, as well as

perform resuscitation techniques. When emergency

personnel intervene in sufficient time, opioid overdoses can be

effectively reversed. Nevertheless, it has been observed that

although bystanders are present during the majority of

overdoses they fail to call for ambulance services. The person

most likely to be present during an overdose is another drug

user, and a large proportion of heroin users have witnessed an

overdose (Darke et al., 2007; Frischer and Baldacchino, 2012).

Therefore, they are reluctant to call for medical help for fear of

possible legal consequences for themselves (Frischer and

Baldacchino, 2012).

On the other hand, it has been reported that laypeople present

during overdoses attempt a variety of methods to rescue the

FIGURE 2

Targets of overdose prevention

Prevention

Treatment

Harm reduction

Emergency interventions

Intervention Target population

n Increasing

awareness and

information

about overdose

risks

n Retention in

treatment as a

protective factor

n Needle and

syringe

programmesn Naloxone

programmes

n Naloxone

administration


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I Methods

We included randomised controlled trials (RCTs), controlled

clinical trials (CCTs), controlled cohort studies, interrupted

time-series analyses, cross-sectional surveys, case series and

population-based results of programme implementations. We

considered studies enrolling current or former opioid injectors,

their parents and their peers. All participants were included

regardless of age, gender and nationality. The experimental

intervention was take-home emergency naloxone

accompanied or not by explanatory leaflets, education and

training for opioid users, peers and families; the control

intervention was intervention as usual (e.g. information on the

risks of overdose) or no intervention.

The types of outcomes were as follows: (a) knowledge,

management and first aid in overdose cases; (b) attitudes

towards naloxone (acceptability and willingness to use); (c)

management of witnessed overdoses — use of naloxone and

adequacy of care given to the patient; (d) adverse events

following administration of naloxone to reverse overdose; and

(e) deaths due to overdose.

I Search strategy

The following electronic databases were searched (Figure 3):

Cochrane Drugs and Alcohol Group (CDAG) Specialized

Register; the Cochrane Central Register of Controlled Trials

(CENTRAL) Issue 6, 2013; PubMed (also known as MEDLINE,

1996 to June 2013); EMBASE (Elsevier, EMBASE.com, 1974

to June 2013); the Cumulative Index to Nursing and Allied

Health Literature (CINAHL, EBSCOhost, 1982 to June 2013);

and the Web of Science (1991 to June 2013). The detailed

search strategy for each database is reported in Annex 4.

The following were also searched: (a) the reference lists of all

relevant papers to identify further studies; (b) some of the

main electronic sources of ongoing trials, including

metaRegister of Controlled Trials (mRCT) (www.controlled-

trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the

WHO International Clinical Trials Registry Platform (ICTRP)

(www.who.int/ictrp/search/en); (c) conference proceedings

likely to contain trials relevant to the review (College on

Problems of Drug Dependence — CPDD); and (d) national

focal points for drug research (e.g. National Institute of Drug

Abuse and National Drug and Alcohol Research Centre).

The search was not limited by language of publication.

Data collection and analysis

Two authors independently inspected the search hits by

reading titles and abstracts. The full text of each potentially

victim, including a number of ineffective techniques. These

include injection of other drugs (such as cocaine) or salt and

allowing the victim to ingest ice or bathe in cold water (Strang

et al., 2013). These and other potentially harmful practices

show the willingness of bystanders to help.

The distribution of naloxone to potential victims of heroin

overdose and to those who may happen to assist during an

opioid overdose — together with a brief educational

intervention that aims to instruct how to recognise an

overdose, assist the patient and administer naloxone — has

been proposed as an innovative approach to reduce overdose

fatalities (Clark, 2014). Specifically, programmes for the

distribution of naloxone aim to increase the availability of

naloxone in the community and, consequently, decrease

overdose fatalities.

Naloxone injection is a liquid formulation that can be

injected intravenously, intramuscularly or

subcutaneously. Prefilled auto-injection devices

containing a solution for injection into a muscle or under

the skin also exist, as well as devices to administer

naloxone intranasally (sprayed into the nose)

(MedlinePlus, accessed May 2014). Nevertheless,

intranasal administration is an off-label use

(WHO, 2014).

What naloxone formulations are available?

I Why is this review important?

Implementation of take-home naloxone has been

recommended in the UK by the Advisory Council on the

Misuse of Drugs (ACMD, 2012) since 2000, recognising the

potential contribution of this intervention to the reduction in

the number of overdose mortalities and the need for naloxone

to be more widely available. Naloxone administration is

available in seven European countries, namely Denmark,

Germany, Estonia, Spain, Italy, United Kingdom and Norway

(see Annex 1 and EMCDDA, 2014b). It is therefore important

to exchange existing knowledge on such an intervention to

enable potential implementers to take informed decisions.

I Objective

The objective of this overview is to assess the effect of

take-home emergency naloxone and educational intervention

on knowledge improvement, naloxone use, management of

overdoses witnessed and death as a result of overdose.


5 / 37

performed using the approach recommended by the Cochrane

handbook; the first step is to describe what is reported in the

study and the second is to judge the risk of bias in terms of low,

high or unclear risk (Higgins and Green, 2011).

For a detailed description of the criteria used in this overview

to assess each type of study design, see Annex 5.

relevant study located in the search was obtained and

independently assessed for inclusion. Doubts were resolved

through discussion between the authors. Data were extracted

from included studies using a structured data extraction form.

One author extracted data and a second investigator checked

it. Differences were resolved through discussion and

consensus. A risk-of-bias assessment for RCTs and CCTs was

FIGURE 3

Flow chart of study assessment and selection

1 542 records identified through database searching

(PubMED: 471; EMBASE: 641, CENTRAL: 46; CINAHL: 61;

WEB OF SCIENCE: 302; CDAG Register: 21)2 additional records identified

through other sources

1 045 records after duplicates removed

1 045 records screened 975 records excluded based

on title and abstract

46 full-text articles

excluded, with reasons

70 full-text articles

assessed for eligibility

21 studies included in

qualitative synthesis

– 2 ongoing studies


6 / 37

Study design and location

One study was a RCT, three were case-series and 17 were

pre-post studies.

Furthermore, two ongoing trials were identified and the

descriptions of the protocols are reported in the Conclusions

(pp. 11–12).

Of the included studies, 14 were carried out in the USA, five in

the UK, one in Canada and one in the UK and Germany.

Participants

In all the included studies participants were opioid users and

their parents or carers. In one study (Walley et al., 2013a)

participants were patients enrolled on methadone

maintenance programmes. The sample size varied greatly,

ranging from 19 to 53 032 subjects enrolled and assessed.

Excluded articles

Forty-six full text articles were excluded (see ‘Excluded

studies (articles)’ in References). The reasons for exclusion

were as follows: study design not in the inclusion criteria

(narrative review, editorial, letter, case report) (n = 18); types

of intervention not in the inclusion criteria (take-home

naloxone not provided) (n = 17); outcome of interest not

provided (n = 7); poster or abstract of already included study

(n = 4).

I Results

I Included studies

Twenty-two publications, covering 21 studies, were included

in the present overview (two publications referred to the same

study whereas one publication reported the results of two

programmes). For more details see Annex 1.

The main objective of epidemiological research is to find

explanations for the manifestation of diseases in the

population. Bias is a false result influenced by uncontrolled

factors. A typical example of bias is an unwanted selection

of the population studied so that the sample does not

adequately represent the target population. Bias has been

defined as ‘incorrect assessment of the association

between an exposure and an effect in the target population’

(Delgado-Rodríguez, 2004, p. 635). The quality of studies is

highly linked to the reduction of possible bias. There are

many known types of bias, including selection bias, the risk

of selecting the sample for uncontrolled characteristics

(Delgado-Rodríguez, 2004); indication bias, which emerges

from RCTs when patients, instead of being assigned to

treatment randomly, are assigned on the basis of some

characteristic, for example a higher susceptibility to a

disease; detection bias, when some patients have a higher

chance of being diagnosed because they are tested more

often owing to a concurrent condition (e.g. those with

diabetes who are tested daily have more chance of testing

positive for hyperglycaemia than those who are not tested);

assessment bias, when the professionals assessing the

results of an intervention are influenced by their knowledge

of the interventions provided (a typical example is a nurse

who measures body temperature more often or more

accurately in patients given placebo than in those given the

active substance); and performance bias, when patients are

given different interventions not on the basis of random

allocation but because of some other characteristic or

situation. In addition, publication bias is a distortion in the

availability of studies. It has been observed that studies

with positive results have more probability of being

published and, in general, are published faster and in higher

impact journals (Dubben and Beck-Bornholdt, 2005).

Why are some studies defined as ‘blinded’?

Blinding refers to all the strategies that are put in place to

prevent knowledge of the intervention influencing behaviour

(of patients, clinicians, carers or outcome assessors), which

could lead to biased results. In a RCT, patients are usually

blinded to the intervention so that they cannot over- or

under-report some symptoms. The same strategy applies to

the assessors. The term ‘double blinded’ describes a

situation in which neither the patient nor the assessor of

the outcome (e.g. the professional asking questions) is

aware of the treatment provided to the specific patient.

What is ‘bias’?


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Interventions

In all the included studies (Table 1) the intervention consisted of

(i) education and information on the identification of overdose

risk factors, the usual signs of opiate overdose, appropriate

methods for dealing with an overdose, the use of naloxone,

methods for administering naloxone, period of time over which

naloxone is effective and recommended injection sites; (ii)

practical training; and (iii) provision of one or two doses of

naloxone as prefilled syringes. In three studies the device for

administering intranasal naloxone was provided to participants.

I Outcome measures

The outcome measures were as follows:

Knowledge of risk factors of overdose, signs of opiate

overdose, correct use of naloxone, management of witnessed

overdose: training provision is aimed at enabling laypeople to

proactively manage an overdose occurrence. For this reason,

some of the studies primarily measure how effective the

training interventions were in communicating the basic

information required in such an occurrence. These outcomes

were covered by eight studies (Bennett and Holloway, 2012;

Gaston et al., 2009; McAuley et al., 2010; Seal et al., 2005;

Strang et al., 2008; Tobin et al., 2009; Wagner et al., 2010;

Williams et al., 2014).

Attitudes: willingness to use naloxone, confidence in and

acceptability of naloxone. Acquisition of knowledge may not

be associated with preparedness to put it into practice,

especially under emotional circumstances. These outcomes

were covered by seven studies (Bennett and Holloway, 2012;

Galea et al., 2006; McAuley et al., 2010; Strang et al., 2008;

Tobin et al., 2009; Wagner et al., 2010; Williams et al., 2014).

TABLE 1

Interventions and comparisons

Intervention Comparison References

Naloxone hydrochloride (2 mg/2 ml prefilled syringe) for taking away and 1-hour training session

The control group was asked only to read a short booklet on overdose risk factors, opioid overdose signs, actions to take in an overdose and basic information about naloxone

Williams et al. (2014)

Educational and training programme with the provision of take-home naloxone

No comparison Gaston et al. (2009), Seal et al. (2005), Strang et al. (2008)

Implementation of education and naloxone distribution programmes realised at city or regional level

N/A (but one study compared different levels of intensity of intervention)

Bennett and Holloway (2012), Bennett et al. (2011), Dettmer et al. (2001), Enteen et al. (2010), Galea et al. (2006), Gaston et al. (2009), Heller and Stancliff (2007), Leece et al. (2013), McAuley et al. (2010), Maxwell et al. (2006), Piper et al. (2008), Tobin et al. (2009), Wagner et al. (2010), Walley et al. (2013a), Walley et al. (2013b), Wheeler et al. (2012), Yokell et al. (2011)

Implementation of education and intranasal naloxone distribution programmes realised at city or regional level

N/A Doe-Simkins et al. (2009)

N/A, not applicable.

Several study designs are available in the epidemiologist’s

toolbox to assess the effectiveness of interventions. The

choice of study design is influenced by many factors,

including the type of research question, the resources

available, the setting and how common a health condition

is. The studies included in the present review are:

randomised controlled studies — typically used to assess

the effectiveness of interventions, this study design

randomly allocates patients to one intervention or a control;

clinical controlled studies — studies in which patients

are assigned to one intervention or a control, but not

randomly;

case-series studies — studies in which a consecutive

series of patient cases described;

time-series studies — studies in which the end points

(e.g. the mortality in a town) are measured at different

points in time;

pre–post studies — studies in which the end points are

measured before and after the study interventions.

Study design

Overdose management: including calling for an ambulance,

putting the patient in the recovery position and performing

cardiopulmonary resuscitation. Twelve studies assessed

whether or not the target population followed the instructions

given during the training sessions (Bennett et al., 2011;


8 / 37

The interrupted time-series (ITS) analysis (Walley et al.,

2013b) was judged to be at low risk of bias for all the items

assessed (clearly defined point in time when the intervention

occurred; at least three data points before, and three after, the

intervention; protection against secular changes; protection

against detection bias; blinded assessment of primary

outcomes) and at unclear risk of bias for the completeness of

data sets (Annex 2).

Even if a validated checklist was not available to assess the

risk of bias of the other study designs, we noted that the

generalisability of the results is limited. All but one study

(Bennett and Holloway, 2012) had no control groups. Bennett

and Holloway (2012) had a control group of 50 participants

compared with 521 individuals exposed to the intervention.

Four studies (Galea et al., 2006; Gaston et al., 2009; McAuley

et al., 2010; Seal et al., 2005) included a very small number of

patients (n = 25, n = 70, n = 19 and n = 24, respectively) and

the method for the sample selection was not reported. In five

studies there were many patients lost at follow-up: 20 % in

Galea et al. (2006), 35 % in Gaston et al. (2009), 23 % in

Strang et al. (2008), 66 % in Tobin et al. (2009) and 29 % in

Wagner et al. (2010). In Piper et al. (2008) detailed information

on the management of overdose was reported for 61 % of the

overdoses for which naloxone was administered. In five

studies (Bennett et al., 2011; Bennett and Holloway, 2012;

Dettmer et al., 2001; Enteen et al., 2010; Yokell et al., 2011) the

results about naloxone use and management of overdose

were reported only for those participants who voluntarily

reported back and/or returned for a refill of naloxone, who

constituted a small percentage of the overall sample: 33 % in

Bennett et al. (2011), 5.3 % in Bennett and Holloway (2012),

41 % in Dettmer et al. (2001), 24 % in Enteen et al. (2010) and

8.3 % in Yokell et al. (2011). In Leece et al. (2013), Maxwell et

al. (2006) and Wheeler et al. (2012) there was no information

about the method used for collecting data on the

management of overdose. All the outcomes were self-

reported.

I Effect of the interventions

Overall, the available studies considered in the present

overview showed that naloxone provision among drug users

and their peers may be an effective strategy to reduce fatal

overdoses (Table 2). The outcomes measured included the

improvement of knowledge on how to manage an overdose

and the willingness to put into practice the acquired

knowledge, along with the process and the outcomes of

overdose management. The studies also measured the

percentage of naloxone administration in the event of

overdose and the requests to refill naloxone, and the fatal

cases in spite of naloxone administration.

Bennett and Holloway, 2012; Dettmer et al., 2001; Doe-

Simkins et al., 2009; Enteen et al., 2010; Galea et al., 2006;

Gaston et al., 2009; McAuley et al., 2010; Piper et al., 2008;

Seal et al., 2005; Tobin et al., 2009; Wagner et al., 2010).

Naloxone administration: all but three studies (Heller and

Stancliff, 2007; Maxwell et al., 2006; Wheeler et al., 2012)

reported the number of times when naloxone was given to

patients, but only 13 studies reported the number of

overdoses witnessed, allowing calculation of the percentage

of overdoses in which naloxone was given. Two studies (Leece

et al., 2013; Tobin et al., 2009) did not report the number of

overdoses witnessed, but only the number of participants who

used naloxone, without specifying if they did so on one or

more occasions.

Request for naloxone refill, naloxone lost or stolen: a proxy

outcome for actual use and/or interest in using the naloxone

at occurrence. These outcomes were covered by nine studies

(Bennett et al., 2011; Doe-Simkins et al., 2009; Enteen et al.,

2010; Galea et al., 2006; Gaston et al., 2009; Piper et al., 2008;

Tobin et al., 2009; Wagner et al., 2010; Walley et al., 2013a and b).

Death due to overdose: 11 studies (Bennett et al., 2011;

Bennett and Holloway, 2012; Dettmer et al. 2001; Doe-

Simkins et al., 2009; Enteen et al., 2010; Galea et al., 2006;

McAuley et al., 2010; Piper et al., 2008; Seal et al., 2005;

Strang et al., 2008; Wagner et al., 2010) assessed this

outcome among subjects with overdoses witnessed by study

participants; one study (Walley et al., 2013b) reported

overdose deaths in communities covered by the intervention

compared with communities not covered by the intervention.

Three studies (Heller and Stancliff, 2007; Maxwell et al., 2006;

Wheeler et al., 2012) reported only the total number of

overdoses reversed.

I Methodological quality

The assessment of methodological quality using standardised

criteria was possible for only two studies: the RCT (Williams et

al., 2014) and the interrupted time-series study (Walley et al.,

2013b). Three studies were uncontrolled case series and all

the other studies used a pre–post (or only post) evaluation

design without a control group for which standardised and

validated checklists for quality assessment were not available.

The RCT was judged to be at low risk of selection bias but at

high risk of performance and detection bias. This is because it

was an open-label study with subjective outcome measures

based on self-reported data. It was also judged to be at risk of

attrition bias because the analysis was done on a per-protocol

basis with a high rate of patients lost at follow-up and

unbalanced between the arms of the study (Annex 2).


9 / 37

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hre

e sh

ow

ed

a s

ign

ifica

nt

imp

rove

me

nt,

on

e re

po

rte

d o

nly

th

e p

ost

-in

terv

en

tio

n r

esu

lts

and

th

ree

did

no

t sh

ow

im

pro

vem

en

t

7+

Be

nn

ett a

nd

Ho

llow

ay (

20

12

), G

ale

a et

al.

(20

06

), M

cAu

ley

et a

l. (2

01

0),

Str

ang

et a

l. (2

00

8),

Tob

in e

t al.

(20

09

), W

agn

er

et a

l. (2

01

0),

Will

iam

s et

al.

(20

14)

Man

age

me

nt o

f ove

rdo

seA

mb

ula

nce

cal

l: m

ed

ian

30

% o

f ove

rdo

se

wit

ne

sse

d —

se

lf-re

po

rte

d (r

ang

e 1

0–

85

%);

me

dia

n o

f 54

.5 %

of o

verd

ose

wit

ne

sse

d —

a

ctiv

e fo

llow

-up

(ran

ge

19

–1

00

%)

Re

cove

ry p

osi

tio

n: 4

0 %

of o

verd

ose

s (t

hre

e st

ud

ies

self-

rep

ort

ed

)C

PR

: 61

% o

f ove

rdo

ses

(six

stu

die

s, s

elf-

rep

ort

ed

)N

alo

xon

e re

fill:

me

dia

n o

f 59

.5 %

(ran

ge

23

–8

0 %

) o

f ove

rdo

se w

itn

ess

ed

– a

ctiv

e fo

llow

-up

in f

ou

r st

ud

ies

12

+B

en

net

t et a

l. (2

011

), B

en

net

t an

d

Ho

llow

ay (

20

12

), D

ettm

er

et a

l. (2

00

1),

Do

e-S

imki

ns

et a

l., (

20

09

), E

nte

en

et a

l.,

(20

10

), G

ale

a et

al.

(20

06

), G

asto

n e

t al.

(20

09

), M

cAu

ley

et a

l. (2

01

0),

Pip

er

et a

l. (2

00

8),

Se

al e

t al.

(20

05

), To

bin

et a

l. (2

00

9),

Wag

ne

r et

al.

(20

10

)

Nal

oxo

ne

ad

min

istr

atio

nP

erc

en

tag

e o

f ove

rdo

ses

wit

ne

sse

d in

wh

ich

n

alo

xon

e w

as a

dm

inis

tere

d (

by

the

targ

et

po

pu

lati

on)

In t

he

RC

T n

alo

xon

e w

as g

ive

n in

28

% o

f o

verd

ose

s w

itn

ess

ed

. In

th

e tw

o s

tud

ies

bas

ed

on

se

lf-re

po

rt, n

alo

xon

e w

as

ad

min

iste

red

in 7

6 %

an

d 5

0 %

of o

verd

ose

s w

itn

ess

ed

. In

se

ven

stu

die

s b

ase

d o

n a

ctiv

e fo

llow

-up

by

stu

dy

rese

arch

ers

nal

oxo

ne

was

u

sed

in a

me

dia

n o

f 67

% (r

ang

e 0

–1

00

%)

of

ove

rdo

ses

wit

ne

sse

dO

ne

stu

dy

rep

ort

ed

th

e p

erc

en

tag

e o

f p

arti

cip

ants

wh

o a

dm

inis

tere

d n

alo

xon

e (4

4 %

) an

d o

ne

stu

dy

rep

ort

ed

17

nal

oxo

ne

ad

min

istr

atio

ns

du

rin

g th

e fir

st 8

mo

nth

s, a

ll w

ith

su

cce

ssfu

l ou

tco

me

s

11+

+D

ettm

er

et a

l. (2

00

1),

Do

e-S

imki

ns

et a

l. (2

00

9),

Gal

ea

et a

l. (2

00

6),

Gas

ton

et a

l. (2

00

9),

Lee

ce e

t al.

(20

13

), M

cAu

ley

et a

l. (2

01

0),

Se

al e

t al.

(20

05

), S

tran

g et

al.

(20

08

), W

agn

er

et a

l. (2

01

0),

Will

iam

s et

al

. (2

014

), Yo

kell

et a

l. (2

011

)


10 / 37

Pop

ula

tion

Ou

tcom

eIn

terv

enti

onE

ffec

tsN

um

ber

of

stu

die

sQ

uic

k g

uid

eR

efer

ence

s

Co

mm

un

itie

sR

ed

uci

ng

de

ath

du

e to

o

verd

ose

On

e IT

S s

ho

we

d t

hat

th

e ri

sk f

or

op

ioid

-re

late

d

ove

rdo

se f

atal

itie

s w

as s

ign

ifica

ntl

y lo

we

r b

oth

in

co

mm

un

itie

s w

ith

hig

h p

rog

ram

me

imp

lem

en

tati

on

an

d in

co

mm

un

itie

s w

ith

low

p

rog

ram

me

imp

lem

en

tati

on

wh

en

co

mp

are

d

wit

h c

om

mu

nit

ies

wit

ho

ut p

rog

ram

me

imp

lem

en

tati

on

(h

igh

vs.

no

ne:

ad

just

ed

RR

0

.54

, 95

% C

I 0.3

9–

0.7

6; l

ow

vs.

no

ne:

a

dju

ste

d R

R 0

.73

, 95

% C

I 0.5

7–0

.91

)O

ne

stu

dy

rep

ort

ed

th

at 8

3 %

of o

verd

ose

s th

at o

ccu

rre

d d

uri

ng

the

stu

dy

we

re r

eve

rse

d

bu

t no

info

rmat

ion

was

ava

ilab

le f

or

the

rem

ain

ing

17 %

. In

fo

ur

stu

die

s in

form

atio

n o

n

surv

ival

sta

tus

colle

cte

d f

rom

vo

lun

tary

p

arti

cip

ants

re

po

rtin

g fa

tal o

verd

ose

s (d

esp

ite

nal

oxo

ne

ad

min

istr

atio

n) r

ang

ed

fro

m 0

% t

o

4%

; th

e m

ed

ian

pe

rce

nta

ge

of d

eat

h w

as

0.8

%In

six

oth

er

stu

die

s w

ith

act

ive

follo

w-u

p f

atal

o

verd

ose

s (d

esp

ite

nal

oxo

ne

pro

visi

on)

ran

ge

d

fro

m 0

% t

o 3

3 %

Thre

e st

ud

ies

rep

ort

ed

th

e to

tal n

um

be

r o

f o

verd

ose

s re

vers

ed

(no

info

rmat

ion

is g

ive

n

abo

ut t

he

nu

mb

er

of o

verd

ose

s fo

r w

hic

h

nal

oxo

ne

was

ad

min

iste

red

)

13

++

Be

nn

ett e

t al.

(20

11),

Be

nn

ett a

nd

H

ollo

way

(2

01

2),

Det

tme

r et

al.

(20

01

–

Be

rlin

an

d J

ers

ey)

, Do

e-S

imki

ns

et a

l. (2

00

9),

En

tee

n e

t al.

(20

10

), G

ale

a et

al.

(20

06

), M

cAu

ley

et a

l. (2

01

0),

Pip

er

et a

l. (2

00

8),

Se

al e

t al.

(20

05

), S

tran

g et

al.

(20

08

), W

agn

er

et a

l. (2

01

0),

Wal

ley

et a

l. (2

01

3)

++

= t

he

stu

die

s in

clu

din

g th

e o

utc

om

e g

ave

co

nsi

ste

ntl

y fa

vou

rab

le r

esu

lts;

+ =

th

e st

ud

ies

me

asu

rin

g th

e o

utc

om

es

gav

e va

rie

d r

esu

lts.

CI,

con

fid

en

ce in

terv

al; C

PR

, car

dio

pu

lmo

nar

y re

susc

ita

tio

n; I

TS

, in

terr

up

ted

tim

e se

rie

s; R

CT,

ran

do

mis

ed

co

ntr

olle

d t

rial

; RR

, re

lati

ve r

isk.


11 / 37

studies on this topic have been missed is small, but the

possibility of some unpublished studies not being retrieved

cannot be ruled out.

I Conclusions

There is evidence that educational and training interventions

with provision of take-home naloxone decrease overdose-

related mortality.

There is weaker, but consistent, evidence that educational and

training interventions with naloxone provision for opioid-

dependent patients and their peers is effective in improving

knowledge about and creating positive attitudes to the correct

use of naloxone and management of witnessed overdoses.

There is sparse evidence that people return for naloxone refill.

Take-home naloxone provision is an emergency life-saving

intervention. As with other types of public health programmes

relying on layperson interventions in critical situations, it is

difficult to assess their effectiveness with properly designed

experimental studies. By analogy with the provision of public

access defibrillators (PADs) for out-of-hospital cardiac arrest,

for example, the factors contributing to survival rates are many

and difficult to control in an experimental study design.

Nevertheless, although the evidence in support of PADs is

scarce, the available systematic reviews of the literature

suggest the implementation of such an intervention (Clare,

2006; Smith et al., 2007) for the actual or potential reduction

of fatal cases.

Prospective controlled cohort studies of good methodological

quality comparing communities where the intervention is

implemented with communities where it is not implemented

or implemented at a lower intensity may contribute to the

supporting evidence. Those studies should be based on

current multiple-source data collections (including emergency

and hospital data, along with mortality data) and may assess

the impact of the intervention on public health and

participants’ behaviour (incidence of overdose, management

of witnessed overdose, outcome of overdoses, naloxone

provision and naloxone refill).

New initiatives have emerged quickly over recent years in

various regions of the world. This is driven in part by the

epidemic of opioid-related deaths (heroin and non-heroin) in

the USA. In Europe, naloxone programmes are now broadly

available. Since September 2013, Estonia has had a naloxone

programme to tackle the alarming increase in deaths caused

by illicit use of fentanyl. Most recently, Norway began a pilot of

a nasal spray naloxone programme.

I Discussion

I Summary of the main results

Improving knowledge on opioid overdose and enabling preparedness to intervene

This outcome included knowledge about signs of overdose,

the correct management of patients and naloxone use; and

attitudes (willingness to use naloxone, confidence in and

acceptability of naloxone). The educational and training

intervention with naloxone provision seems to be effective in

improving knowledge about signs of overdose, the correct

management of patients and naloxone use in all the retrieved

studies, including the randomised trial and the uncontrolled

pre–post studies. The one randomised trial also suggests that

attitudes towards the use of naloxone have improved. The

management of witnessed overdoses seems to be positively

influenced by the educational and training intervention in

patients who returned for naloxone refill or who were not lost

at follow-up.

Management of witnessed overdose (naloxone administration)

Naloxone was administered in a median of 67 % of overdoses

witnessed by participants who returned for naloxone refill or

who were not lost at follow-up (Table 2). The data come only

from uncontrolled studies.

Death due to overdose and survival rate

The risk of opioid-related overdose fatalities was significantly

lower in communities providing naloxone distribution and

overdose management education than in communities

without programme implementation. This was shown in an ITS

analysis of more than 2 900 subjects from 19 communities

with a follow-up of 7 years (Walley et al., 2013b). Furthermore,

all the other studies found a high survival rate.

I Potential bias in the review process

It was not possible to assess the risk of publication bias using

a funnel plot because a meta-analysis was not performed.

Unpublished studies were searched on websites of

conference proceedings, ongoing trials were searched,

comprehensive bibliographic searches of many databases,

unrestricted by date or language, were undertaken and

reference lists of retrieved studies and narrative reviews were

inspected. For these reasons the probability that relevant


12 / 37

been trained and issued with take-home naloxone kits for

distribution will fall into the intervention group. Patients

attended to by paramedics following usual practice (until they

receive their training and take-home naloxone kits) will fall into

the control group. Many outcomes will be assessed, with the

aim of defining the primary outcome of the definitive trial.

This overview reached similar conclusions to those of a

recently published review (Clark et al., 2014) that included 19

of the 21 studies in our work, including the RCT by Williams et

al. (2014), which probably contributed to our more confident

conclusions.

With regard to guidelines to support the implementation of

naloxone availability outside the healthcare system, the World

Health Organization published a document for global use.

Some European countries have national guidelines; these can

be found in the EMCDDA’s Best practice portal.

In this context, the rapid identification and dissemination of

the available evidence can be helpful to refine these

programmes, if needed, or to scale up their implementation

and coverage.

Furthermore, some studies are ongoing and their results will

greatly contribute to the body of evidence. These include the

N-ALIVE trial (Strang et al., 2013), which plans to involve 5 600

prisoners on release in the initial pilot randomised phase then

extend to its randomised sample size of 56 000 for the full

trial. Participants will receive emergency naloxone with

instructions for it to be given by the much simpler

intramuscular route. The PATHFINDER feasibility study South

Wales (Moore, ongoing) aims to assess whether it is possible

for paramedics to supply take-home naloxone kits to patients

whom they have treated and who have subsequently

recovered from an opioid overdose. Paramedics will be

randomly allocated to training over the first 4 months of the

12-month trial. Patients attended to by paramedics who have


13 / 37

I Included studies

1. Bennett, A. S., Bell, A., Tomedi, L., Hulsey, E. G. and Kral, A. H. (2011), ‘Characteristics of an overdose

prevention, response, and naloxone distribution program in Pittsburgh and Allegheny County,

Pennsylvania’, Journal of Urban Health 88, pp. 1020–1030.

2. Bennett, T. and Holloway, K. (2012), ‘The impact of take-home naloxone distribution and training on

opiate overdose knowledge and response: an evaluation of the THN Project in Wales’, Drugs:

Education Prevention and Policy 19, pp. 320–328.

3. Dettmer, K., Saunders, B. and Strang, J. (2001), ‘Take home naloxone and the prevention of deaths

from opiate overdose: two pilot schemes’, BMJ 322, pp. 895–896.

4. Doe-Simkins, M., Walley, A. Y., Epstein, A. and Moyer, P. (2009), ‘Saved by the nose: bystander-

administered intranasal naloxone hydrochloride for opioid overdose’, American Journal of Public

Health 99, pp. 788–791.

5. Enteen, L., Bauer, J., McLean, R., et al. (2010), ‘Overdose prevention and naloxone prescription for

opioid users in San Francisco’, Journal of Urban Health 87, pp. 931–941.

6. Galea, S., Worthington, N., Piper, T. M., Nandi, V. V., Curtis, M. and Rosenthal, D. M. (2006), ‘Provision

of naloxone to injection drug users as an overdose prevention strategy: early evidence from a pilot

study in New York City’, Addictive Behaviors 31, pp. 907–912.

7. Gaston, R. L., Best, D., Manning, V. and Day, E. (2009), ‘Can we prevent drug related deaths by

training opioid users to recognise and manage overdoses?’, Harm Reduction Journal 6, p. 26.

8. Heller, D.I. and Stancliff, S. (2007), ‘Providing naloxone to substance users for secondary

administration to reduce overdose mortality in New York City’, Public Health Reports 122, pp.

393–397.

9. Leece, P. N., Hopkins, S., Marshall, C., et al. (2013), ‘Development and implementation of an opioid

overdose prevention and response program in Toronto, Ontario’, Revue Canadienne de Santé

Publique 104, pp. e200–e204.

10. McAuley, A., Lindsay, G., Woods, M. and Louttit, D. (2010), ‘Responsible management and use of a

personal take-home naloxone supply: a pilot project’, Drugs: Education, Prevention, and Policy 17,

pp. 388–399.

11. Maxwell, S., Bigg, D., Stanczykiewicz, K. and Carlberg-Racich, S. (2006), ‘Prescribing naloxone to

actively injecting heroin users: a program to reduce heroin overdose deaths’, Journal of Addictive

Diseases 25, pp. 89–96.

12. Piper, T. M. , Stancliff, S., Rudenstine, S., et al. (2008), ‘Evaluation of a naloxone distribution and

administration program in New York City’, Substance Use & Misuse 43, pp. 858–870.

13. Seal, K. H., Thawley, R., Gee, L., et al. (2005), ’Naloxone distribution and cardiopulmonary

resuscitation training for injection drug users to prevent heroin overdose death: a pilot intervention

study’, Journal of Urban Health 82, pp. 303–311.

14. Strang, J., Manning, V., Mayet, S., et al. (2008), ‘Overdose training and take-home naloxone for

opiate users: prospective cohort study of impact on knowledge and attitudes and subsequent

management of overdoses’, Addiction 103, pp. 1648–1657.

15. Tobin, K. E., Sherman, S. G., Beilenson, P., Welsh, C. and Latkin, C. A. (2009), ‘Evaluation of the

Staying Alive programme: training injection drug users to properly administer naloxone and save

lives’, International Journal of Drug Policy 20, pp. 131–136.

16. Wagner, K. D., Valente, T. W., Casanova, M., et al. (2010), ‘Evaluation of an overdose prevention and

response training programme for injection drug users in the Skid Row area of Los Angeles, CA’,

International Journal of Drug Policy 21, pp. 186–193.

17. Walley, A. Y., Doe-Simkins, M., Quinn, E., Pierce, C., Xuan, Z. and Ozonoff, A. (2013a), ‘Opioid

overdose prevention with intranasal naloxone among people who take methadone’, Journal of

Substance Abuse Treatment 44, pp. 241–247.

References


14 / 37

18. Walley, A. Y., Xuan, Z., Hackman, H. H., et al. (2013b), ‘Opioid overdose rates and implementation of

overdose education and nasal naloxone distribution in Massachusetts: interrupted time series

analysis’, BMJ 346, p. f174.

19. Wheeler, E., Davidson, P. J., Jones, T. S. and Irwin, K. S. (2012), ‘Community-based opioid overdose

prevention programs providing naloxone — United States, 2010’, Morbidity and Mortality Weekly

Report 61, pp. 101–104.

20. Williams, A. V., Marsden, J. and Strang, J. (2014), ‘Training family members to manage heroin

overdose and administer naloxone: randomized trial of effects on knowledge and attitudes’,

Addiction 109, pp. 250–259.

21. Yokell, M. A., Green, T. C., Bowman, S., McKenzie, M., Rich, J. D. (2011), ‘Opioid overdose prevention

and naloxone distribution in Rhode Island’, Medicine and Health Rhode Island 94, pp. 240–242.

I Excluded studies (articles)

1. Anonymous (2010), ‘Naloxone distribution saves more than 400 lives in SF overdose project’, DATA:

The Brown University Digest of Addiction Theory & Application 29, pp. 4–5.

2. Anonymous (2012), ‘Community-based opioid overdose prevention programs providing naloxone

— United States, 2010’, Morbidity and Mortality Weekly Report 61, pp. 101–105.

3. Ashton, H. and Hassan, Z. (2006), ‘Best evidence topic report. Intranasal naloxone in suspected

opioid overdose’, Emergency Medicine Journal 23, pp. 221–223.

4. Ashworth, A. J. and Kidd, A. (2001), ‘Take home naloxone for opiate addicts. Apparent advantages

may be balanced by hidden harms’, BMJ 323, p. 935.

5. Baca, C. T. and Grant, K. J. (2005), ‘Take-home naloxone to reduce heroin death’, Addiction 100, pp.

1823–1831.

6. Bigg, D. (2002), ‘Data on take home naloxone are unclear but not condemnatory’, BMJ 324, p. 678.

7. Blackwood, G. (2001), ‘Take home naloxone for opiate addicts. Figures in Jersey give no support to

scheme’s effectiveness’ BMJ 323, pp. 934–935; author reply p. 935.

8. Campopiano, M. (2009), ‘Overdose prevention and naloxone prescribing in a narcotic addiction

treatment program (NATP)’, Substance Abuse 30, p. 90.

9. Darke, S. (1999a), ‘Attacking overdose on the home front’, Addiction 94, pp. 205–206; discussion p.

207.

10. Darke, S. (1999b), ‘Comments on Strang et al’s “Preventing opiate overdose fatalities with take-

home naloxone: pre-launch study of possible impact and acceptability” attacking overdose on the

home front’, Addiction 94, pp. 205–206.

11. Davis, C., Webb, D. and Burris, S. (2013), ‘Changing law from barrier to facilitator of opioid overdose

prevention’, Journal of Law, Medicine & Ethics 41(Suppl 1), pp. 33–36.

12. George, S. and Moreira, K. (2008), ‘A guide for clinicians on take home naloxone prescribing’,

Addictive Disorders & Their Treatment 7, pp. 163–167.

13. George, S., Boulay, S. and Begley, D. (2010), ‘“I saved a life”: a heroin addict’s reflections on

managing an overdose using “take home naloxone”’, BMJ Case Reports p. ii, bcr0520102986.

14. Graham, C. A., McNaughton, G. W., Ireland, A. J. and Cassells, K. (2001), ‘Take home naloxone for

opiate addicts. Drug misusers may benefit from training in cardiopulmonary resuscitation’, BMJ

323, p. 934; author reply p. 935.

15. Green, T. C., Heimer, R. and Grau, L. E. (2008), ‘Distinguishing signs of opioid overdose and

indications for naloxone: an evaluation of six overdose training and naloxone distributions programs

in the United States’, Addiction 103, pp. 979–989.

16. Hill, D. and Mcauley, A. (2012), ‘A comparative study of stakeholder views on take-home naloxone

services’, Journal of Substance Use 17, pp. 430–441.

17. Hurley, R. (2011), ‘Pilot scheme shows that giving naloxone to families of drug users would save

lives’, BMJ 343, p. d5445.


15 / 37

18. Jones, J. D., Roux, P., Stancliff, S., Matthews, W. and Comer, S. D. (2014), ‘Brief overdose education

can significantly increase accurate recognition of opioid overdose among heroin users’,

International Journal of Drug Policy 25, pp. 166–170.

19. Kerr, D., Dietze, P., Kelly, A. M. and Jolley, D. (2008), ‘Attitudes of Australian heroin users to peer

distribution of naloxone for heroin overdose: perspectives on intranasal administration’, Journal of

Urban Health 85, pp. 352–360.

20. Lagu, T., Anderson, B. J. and Stein, M. (2006), ‘Overdoses among friends: drug users are willing to

administer naloxone to others’, Journal of Substance Abuse Treatment 30, pp. 129–133.

21. Lenton, S. (2008), ‘Case for peer naloxone further strengthened — commentary’, Addiction 103, pp.

1658–1659.

22. Lenton, S. and Hargreaves, K. (2000a), ‘A trial of naloxone for peer administration has merit, but will

the lawyers let it happen?’, Drug and Alcohol Review 19, pp. 365–369.

23. Lenton, S. R. and Hargreaves, K. M. (2000b), ‘Should we conduct a trial of distributing naloxone to

heroin users for peer administration to prevent fatal overdose?’, Medical Journal of Australia 173,

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24. Lenton, S. R., Dietze, P. M., Degenhardt, L., Darke, S. and Butler, T. G. (2009), ‘Now is the time to take

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25. Lenton, S., Dietze, P., Van Beek, I., Lintzeris, N. and Wiggins, N. (2010), ‘Symposium — policy and

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26. Mountain, D. (2001), ‘Take home naloxone for opiate addicts. Big conclusions are drawn from little

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29. Seal, K. H., Downing, M., Kral, A. H., et al. (2003), ’Attitudes about prescribing take-home naloxone to

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Toxicology 46, pp. 353–354.

33. Sporer, K. A. and Kral, A. H. (2007), ‘Prescription naloxone: a novel approach to heroin overdose

prevention’, Annals of Emergency Medicine 49, pp. 172–177.

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36. Strang, J., Darke, S., Hall, W., Farrell, M. and Ali, R. (1996), ‘Heroin overdose: the case for take-home

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Journal of Drug Policy 11, pp. 437–445.

39. Strang, J., Manning, V., Mayet, S., et al. (2008), ‘Family carers and the prevention of heroin overdose

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I Moore, C. ‘Paramedic Administered Take Home kits: Feasible Intervention for Naloxone Distribution

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controlled trial’. Available at: www.controlled-trials.com (doi: 10.1186/ISRCTN98216498, last

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overdose deaths after prison release: rationale and practicalities for the N-ALIVE randomized trial’,

Journal of Urban Health 90, pp. 983–996.

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approaches’, International Journal of Drug Policy (doi: 10.1016/j.drugpo.2014.01.005).

I Lenton, S. R., Dietze, P. M., Degenhardt, L., Darke, S. and Butler, T. G. (2009), ‘Naloxone for

administration by peers in cases of heroin overdose’, Medical Journal of Australia 191, p. 469.


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19 / 37

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-ho

me

nal

oxo

ne

pa

ckP

OIN

T p

rog

ram

in

Toro

nto

Can

ad

aE

du

cati

on

: sig

ns

and

sym

pto

ms

of

ove

rdo

seM

ed

ical

eva

luat

ion

Trai

nin

g: m

anag

em

en

t of

ove

rdo

se, u

se o

f nal

oxo

ne

Nal

oxo

ne

pro

visi

on

Kn

ow

led

ge

rete

nti

on

, ex

pe

rie

nce

s re

late

d t

o

ove

rdo

se a

nd

ove

rdo

se

resp

on

se, w

illin

gn

ess

an

d

con

fide

nce

to

ad

min

iste

rn

alo

xon

e, b

arri

ers

to

im

ple

me

nti

ng

the

resu

scit

atio

n p

roto

col,

and

ri

sky

dru

g u

se b

eh

avio

urs

8 m

on

ths

McA

ule

y et

al

. (2

01

0)

Pro

spe

ctiv

e u

nco

ntr

olle

d s

tud

y as

sess

ing

pro

gra

mm

e im

ple

me

nta

tio

n

19

clie

nts

tra

ine

d a

nd

pro

vid

ed

wit

h a

ta

ke-h

om

e n

alo

xon

e p

ack

17 (

89

%)

asse

sse

d a

t act

ive

follo

w-u

p

Lan

arks

hir

e N

alox

one

(Nar

can)

pilo

tS

cotl

and

, U

KE

du

cati

on

: sig

ns,

sym

pto

ms

and

ri

sk f

act

ors

of o

verd

ose

Trai

nin

g: m

anag

em

en

t of

ove

rdo

se (

bas

ic li

fe s

up

po

rt),

use

o

f nal

oxo

ne

Nal

oxo

ne

pro

visi

on

Ove

rdo

se w

itn

ess

ed

Man

age

me

nt o

f ove

rdo

seD

eat

hN

alo

xon

e u

seK

no

wle

dg

eA

ttit

ud

es

6 m

on

ths

Ma

xwe

ll et

al

. (2

00

6)

Pro

spe

ctiv

e u

nco

ntr

olle

d s

tud

y as

sess

ing

pro

gra

mm

e im

ple

me

nta

tio

n

Nu

mb

er

of p

arti

cip

ants

no

t re

po

rte

dE

very

we

ek

Ch

icag

o R

eco

very

Alli

ance

’s

ou

tre

ach

wo

rke

rs d

ire

ctly

co

nta

ct o

ver

34

0 ID

Us,

wh

o h

ave

go

ne

on

to

re

ach

an

a

dd

itio

nal

78

0 p

eo

ple

sin

ce 2

00

1

Ch

icag

o R

ecov

ery

Alli

ance

nal

oxon

e p

roje

ctU

SA

Sta

nd

ard

ise

d e

du

cati

on

ab

ou

t o

verd

ose

an

d n

alo

xon

eO

verd

ose

re

vers

ed

8 y

ear

s

Pip

er

et a

l. (2

00

8)

Pro

spe

ctiv

e u

nco

ntr

olle

d s

tud

y as

sess

ing

pro

gra

mm

e im

ple

me

nta

tio

n

12

2 o

pio

id-d

ep

en

de

nt p

arti

cip

ants

tr

ain

ed

an

d p

rovi

de

d w

ith

nal

oxo

ne

No

ne

lost

at a

ctiv

e fo

llow

-up

bu

t det

aile

d

info

rmat

ion

on

ly o

n 5

0 o

verd

ose

s w

itn

ess

ed

SK

OO

P (

Ski

lls a

nd

K

now

led

ge

on O

verd

ose

Pre

ven

tion

) in

New

Yor

k C

ity

US

AE

du

cati

on

: sig

ns,

sym

pto

ms

and

ri

sk f

act

ors

of o

verd

ose

Trai

nin

g: m

anag

em

en

t of

ove

rdo

se, u

se o

f nal

oxo

ne

Nal

oxo

ne

pro

visi

on

Ove

rdo

se w

itn

ess

ed

Man

age

me

nt o

f ove

rdo

seD

eat

hN

alo

xon

e u

seN

alo

xon

e re

fill

Att

itu

de

s

8 m

on

ths

Se

al e

t al.

(20

05

)C

ase

seri

es

24

IDU

s tr

ain

ed

an

d p

rovi

de

d w

ith

n

alo

xon

eN

on

e lo

st a

t act

ive

follo

w-u

p

Pilo

t ov

erd

ose

pre

ven

tion

an

d

man

agem

ent p

rog

ram

me

in S

an F

ran

cisc

o

US

AE

du

cati

on

: sig

ns,

sym

pto

ms

and

ri

sk f

act

ors

of o

verd

ose

Trai

nin

g: m

anag

em

en

t of

ove

rdo

se, u

se o

f nal

oxo

ne

Nal

oxo

ne

pro

visi

on

Ove

rdo

se w

itn

ess

ed

Man

age

me

nt o

f ove

rdo

seK

no

wle

dg

e

6 m

on

ths

Str

ang

et a

l. (2

00

8)

Pro

spe

ctiv

e u

nco

ntr

olle

d s

tud

y2

39

op

iate

use

rs t

rain

ed

an

d p

rovi

de

d

wit

h n

alo

xon

eA

sse

sse

d a

t po

st t

rain

ing

: 20

2 (

84

.5 %

)A

sse

sse

d a

t act

ive

follo

w-u

p: 1

86

(7

7.8

%)

Nat

ion

al in

itia

tive

to

pro

vid

e tr

ain

ing

in t

he

man

agem

ent o

f ove

rdos

e

En

gla

nd

, U

KE

du

cati

on

: sig

ns,

sym

pto

ms

and

ri

sk f

act

ors

of o

verd

ose

Trai

nin

g: m

anag

em

en

t of

ove

rdo

se, u

se o

f nal

oxo

ne

Nal

oxo

ne

pro

visi

on

Ove

rdo

se w

itn

ess

ed

Nal

oxo

ne

use

Kn

ow

led

ge

Att

itu

de

s

3 m

on

ths

Tob

in e

t al.

(20

09

)P

rosp

ect

ive

un

con

tro

lled

stu

dy

asse

ssin

g p

rog

ram

me

imp

lem

en

tati

on

25

0 in

div

idu

als

trai

ne

d a

nd

pro

vid

ed

wit

h

nal

oxo

ne

85

ass

ess

ed

at a

ctiv

e fo

llow

-up

Sta

yin

g A

live

(SA

) p

rog

ram

, Bal

tim

ore

US

AE

du

cati

on

: sig

ns,

sym

pto

ms

and

ri

sk f

act

ors

of o

verd

ose

Trai

nin

g: m

anag

em

en

t of

ove

rdo

se, u

se o

f nal

oxo

ne

Nal

oxo

ne

pro

visi

on

Ove

rdo

se w

itn

ess

ed

Man

age

me

nt o

f ove

rdo

seN

alo

xon

e u

seK

no

wle

dg

eA

ttit

ud

es

6 m

on

ths


21 / 37

Au

thor

(y

ear)

Stu

dy

des

ign

Par

tici

pan

tsN

ame

of t

he

pro

gra

mm

eC

oun

try

Inte

rven

tion

Ou

tcom

e m

easu

res

Len

gth

of

follo

w-u

p

Wag

ne

r et

al

. (2

01

0)

Pro

spe

ctiv

e u

nco

ntr

olle

d s

tud

y as

sess

ing

pro

gra

mm

e im

ple

me

nta

tio

n

93

dru

g u

sers

tra

ine

d a

nd

pro

vid

ed

wit

h

nal

oxo

ne

66

(71

.5 %

) e

nro

lled

in t

he

stu

dy

47

(5

0.5

%)

asse

sse

d a

t act

ive

follo

w-u

p

Ove

rdos

e p

reve

nti

on a

nd

re

spon

se t

rain

ing

pro

gra

m in

Los

An

gel

es

US

AE

du

cati

on

: sig

ns,

sym

pto

ms

and

ri

sk f

act

ors

of o

verd

ose

Trai

nin

g: m

anag

em

en

t of

ove

rdo

se, u

se o

f nal

oxo

ne

Nal

oxo

ne

pro

visi

on

Ove

rdo

se w

itn

ess

ed

Man

age

me

nt o

f ove

rdo

seN

alo

xon

e u

seD

eat

hK

no

wle

dg

eA

ttit

ud

es

Nal

oxo

ne

refil

l

3 m

on

ths

Wal

ley

et a

l. (2

01

3a)

Pro

spe

ctiv

e u

nco

ntr

olle

d s

tud

y as

sess

ing

pro

gra

mm

e im

ple

me

nta

tio

nF

rom

Se

pte

mb

er

20

08

an

d D

ece

mb

er

20

10

1 5

53

par

tici

pan

ts t

akin

g m

eth

ad

on

eO

verd

ose

Ed

uca

tion

an

d

Nal

oxon

e D

istr

ibu

tion

(O

EN

D)

Pro

gra

m

US

AE

du

cati

on

: sig

ns,

sym

pto

ms

and

ri

sk f

act

ors

of o

verd

ose

Trai

nin

g: m

anag

em

en

t of

ove

rdo

se, u

se o

f nal

oxo

ne

Nal

oxo

ne

pro

visi

on

Ove

rdo

se w

itn

ess

ed

Nal

oxo

ne

use

27

mo

nth

s

Wal

ley

et a

l. (2

01

3b)

Inte

rru

pte

d t

ime

-se

rie

s an

alys

is f

rom

2

00

2 t

o 2

00

9

2 9

12

op

ioid

use

rs a

t ris

k fo

r o

verd

ose

, so

cial

se

rvic

e ag

en

cy s

taff

, fam

ily a

nd

fr

ien

ds

of o

pio

id u

sers

in 1

9 c

om

mu

nit

ies

Ove

rdos

e E

du

cati

on a

nd

N

alox

one

Dis

trib

uti

on

(OE

ND

) P

rog

ram

, M

assa

chu

sett

s

US

AE

du

cati

on

: sig

ns,

sym

pto

ms

and

ri

sk f

act

ors

of o

verd

ose

Trai

nin

g: m

anag

em

en

t of

ove

rdo

se, u

se o

f nal

oxo

ne

Nal

oxo

ne

pro

visi

on

An

nu

al o

pio

id-r

ela

ted

rat

es

of o

verd

ose

fat

alit

ies

7 y

ear

s

Wh

ee

ler

et

al. (

20

12

)P

rosp

ect

ive

un

con

tro

lled

stu

dy

asse

ssin

g p

rog

ram

me

imp

lem

en

tati

on

53

03

2 p

arti

cip

ants

tra

ine

d a

nd

pro

vid

ed

w

ith

a t

ake

-ho

me

nal

oxo

ne

pa

ck4

8 p

rog

ram

mes

in U

SA

US

AO

pio

id o

verd

ose

ed

uca

tio

nO

verd

ose

re

vers

al14

ye

ars

Will

iam

s et

al

. (2

014

)R

and

om

ise

d c

linic

al

tria

l1

87

ran

do

mis

ed

, 12

3 (

65

%)

asse

sse

d a

t fo

llow

-up

Em

erg

ency

rec

over

y p

roce

du

res

and

ta

ke-h

ome

nal

oxon

e ad

min

istr

atio

n t

rain

ing

UK

Ed

uca

tio

n: o

ral p

rese

nta

tio

n o

n

ove

rdo

se m

anag

em

en

t an

d

nal

oxo

ne

ad

min

istr

atio

n; 8

-min

ute

fil

m w

hic

h d

ram

atis

es

real

op

ioid

o

verd

ose

sto

rie

sTr

ain

ing

: man

age

me

nt o

f o

verd

ose

, use

of n

alo

xon

eN

alo

xon

e p

rovi

sio

n

Ove

rdo

se w

itn

ess

ed

Nal

oxo

ne

use

Kn

ow

led

ge

Att

itu

de

s

3 m

on

ths

Yoke

ll et

al.

(20

11)

Pro

spe

ctiv

e u

nco

ntr

olle

d s

tud

y as

sess

ing

pro

gra

mm

e im

ple

me

nta

tio

n

12

0 in

div

idu

als

trai

ne

d a

nd

pro

vid

ed

wit

h

nal

oxo

ne

10

(0

.08

3 %

) vo

lun

tari

ly r

etu

rne

d a

nd

we

re

asse

sse

d a

t fo

llow

-up

PO

NI (

Pre

ven

tin

g O

verd

ose

and

Nal

oxon

e In

terv

enti

on),

Rh

ode

Isla

nd

US

AE

du

cati

on

: sig

ns,

sym

pto

ms

and

ri

sk f

act

ors

of o

verd

ose

Trai

nin

g: m

anag

em

en

t of

ove

rdo

se, u

se o

f nal

oxo

ne

Nal

oxo

ne

pro

visi

on

Ove

rdo

se w

itn

ess

ed

N

alo

xon

e u

se3

mo

nth

s

IDU

, in

ject

ing

dru

g u

ser.


22 / 37

I Ann

ex 2

I Eff

ects

of

the

inte

rven

tion

s

Au

thor

(ye

ar)

Res

ult

sS

urv

ival

/ad

vers

e ev

ents

/dea

thN

alox

one

refi

ll/lo

st/s

tole

n/

con

fisc

ated

Au

thor

s’ c

oncl

usi

ons

and

qu

alit

y of

evi

den

ce

(wh

en a

vaila

ble

)

Ove

rdo

se w

itn

ess

ed

/at

titu

de

s/kn

ow

led

ge

Ove

rdo

se m

anag

em

en

t: n

alo

xon

e a

dm

inis

trat

ion

, re

cove

ry p

osi

tio

n a

nd

CP

R

Be

nn

ett e

t al.

(20

11)

Ove

rdo

se w

itn

ess

ed

: no

t re

po

rte

dA

ttit

ud

es:

89

/141

(6

3.1

%)

use

d n

alo

xon

eK

no

wle

dg

e [a

pp

rop

riat

e u

se

of n

alo

xon

e (o

verd

ose

cau

sed

b

y o

pio

ids)

]: 9

8 %

Nal

oxo

ne:

24

9 (e

pis

od

es

ad

min

iste

red

by

89

pe

rso

ns)

Re

cove

ry p

osi

tio

n: n

o

info

rmat

ion

CP

R: 1

52

/24

9 (

61

%)

Am

bu

lan

ce c

all:

25

/24

9

(10

%)

Su

rviv

al: 9

6 %

Ad

vers

e e

ven

ts: n

o

info

rmat

ion

De

ath

: 0.8

%U

nkn

ow

n o

utc

om

e:

3.2

%

Re

fill:

141

/42

6 (

33

.1 %

) R

efil

l fo

r re

aso

n d

iffe

ren

t fro

m

ove

rdo

se: 5

2, o

f wh

ich

n

alo

xon

e lo

st 4

8.1

%;

con

fisca

ted

by

po

lice

12

%;

sto

len

4 %

, oth

er

reas

on

s (3

7 %

)

The

maj

ori

ty (

96

%)

of p

arti

cip

ants

re

po

rte

d p

osi

tive

o

utc

om

es

(e.g

. pe

rso

n li

ved

, was

no

t in

a c

om

a an

d d

id n

ot

hav

e b

rain

dam

age)

in t

he

ove

rdo

se s

itu

atio

ns

wh

ere

th

ey

ad

min

iste

red

nal

oxo

ne

to a

pe

er.

This

ind

icat

es

the

feas

ibili

ty o

f de

velo

pin

g p

rog

ram

me

s th

at e

qu

ip a

ctiv

e d

rug

use

rs w

ith

th

e sk

ills

to p

reve

nt,

reco

gn

ise

and

re

spo

nd

to

an

o

verd

ose

in c

om

mu

nit

y se

ttin

gs.

Trai

nin

g in

th

e e

ffe

ctiv

e a

dm

inis

trat

ion

of n

alo

xon

e ca

n b

e p

rovi

de

d t

o d

rug

use

rs in

a c

om

mu

nit

y se

ttin

g an

d c

an

pre

ven

t ove

rdo

se f

atal

itie

s.P

arti

cip

ants

wh

o u

sed

nal

oxo

ne

rep

ort

ed

ve

ry f

ew

p

rob

lem

s, a

nd

on

ly t

wo

fat

alit

ies

we

re r

eco

rde

d

Be

nn

ett a

nd

H

ollo

way

(2

01

2)

Ove

rdo

se w

itne

sse

dE

xpe

rim

en

tal:

no

t re

po

rte

dC

on

tro

l: 3

8A

ttitu

de

sW

illin

gn

ess

to

use

nal

oxo

ne:

p

re 8

8 %

, po

st 9

8 %

(p

< 0

.00

1)

Will

ing

ne

ss t

o d

o m

ou

th-t

o-

mo

uth

re

susc

itat

ion

: pre

79

%,

po

st 8

8 %

(p

< 0

.00

1)

Will

ing

ne

ss p

ut i

n r

eco

very

p

osi

tio

n: p

re 9

6 %

, po

st 9

9 %

(p

= 0

.00

7)

Will

ing

ne

ss t

o p

ho

ne

em

erg

en

cy s

erv

ice

s: p

re 9

7 %

, p

ost

99

% (

p=

0.2

67

)K

no

wle

dg

eR

ela

tive

ch

ang

e in

co

rre

ctly

id

en

tifie

d r

esp

on

ses

bef

ore

an

d a

fte

r tr

ain

ing

Ove

rdo

se r

isk

fact

ors

: +1

2.7

%S

ign

s o

f op

iate

ove

rdo

se:

+12

.5 %

Man

age

me

nt o

f ove

rdo

se:

+11

.3 %

Use

of n

alo

xon

e: +

6.4

%M

eth

od

fo

r a

dm

inis

teri

ng

nal

oxo

ne:

+1

3.4

%

Na

loxo

ne

Exp

eri

me

nta

l: 2

8C

on

tro

l: 3

8R

eco

very

po

sitio

nE

xpe

rim

en

tal:

21

/28

(8

1 %

)C

on

tro

l: 14

/38

(40

%)

CP

RE

xpe

rim

en

tal:

10

/28

(40

%)

Co

ntr

ol:

18

/38

(5

3 %

)A

mb

ula

nce

ca

llE

xpe

rim

en

tal:

23

/28

(8

5 %

)C

on

tro

l: 2

1/3

8 (

60

%)

Su

rviv

al: 2

7/2

8

(96

.5 %

)A

dve

rse

eve

nts

: no

in

form

atio

nD

ea

thE

xpe

rim

en

tal:

1 (4

%)

Co

ntr

ol:

1 (

3 %

)

Re

fill:

28

/52

5 (

5.3

%)

Trai

nin

g in

ove

rdo

se m

anag

em

en

t an

d t

he

use

of n

alo

xon

e ca

n s

ign

ifica

ntl

y im

pro

ve k

no

wle

dg

e an

d w

illin

gn

ess

to

tak

e a

ctio

n. T

ake

-ho

me

nal

oxo

ne

trai

nin

g h

elp

ed

dru

g u

sers

to

u

se n

alo

xon

e su

cce

ssfu

lly in

ove

rdo

se e

ven

ts


23 / 37

Au

thor

(ye

ar)

Res

ult

sS

urv

ival

/ad

vers

e ev

ents

/dea

thN

alox

one

refi

ll/lo

st/s

tole

n/

con

fisc

ated

Au

thor

s’ c

oncl

usi

ons

and

qu

alit

y of

evi

den

ce

(wh

en a

vaila

ble

)

Det

tme

r et

al.

(20

01

, Be

rlin

)O

verd

ose

wit

ne

sse

d: 2

9A

ttit

ud

es:

no

info

rmat

ion

Kn

ow

led

ge:

no

info

rmat

ion

Nal

oxo

ne:

22

/29

(7

6 %

)R

eco

very

po

siti

on

: no

in

form

atio

nC

PR

: no

info

rmat

ion

Am

bu

lan

ce c

all:

9/2

9 (

31

%)

Su

rviv

al: 1

00

%A

dve

rse

eff

ect

s: in

3

4 %

of i

nst

ance

s n

alo

xon

e p

rovo

ked

a

sud

de

n o

nse

t of

op

iate

wit

hd

raw

al; n

o

oth

er

sid

e-e

ffe

cts

we

re r

ep

ort

ed

No

info

rmat

ion

Ear

ly r

ep

ort

s ar

e e

nco

ura

gin

g. N

o d

eat

hs

hav

e b

ee

n

rep

ort

ed

, an

d 1

0 %

of d

istr

ibu

ted

nal

oxo

ne

has

sav

ed

live

s. A

st

ud

y o

f th

e w

ide

r d

istr

ibu

tio

n o

f tak

e-h

om

e n

alo

xon

e is

no

w

req

uir

ed

Det

tme

r et

al.

(20

01

, Je

rse

y)O

verd

ose

wit

ne

sse

d: n

ot

rep

ort

ed

Att

itu

de

s: n

o in

form

atio

nK

no

wle

dg

e: n

o in

form

atio

n

Nal

oxo

ne:

5 o

verd

ose

s o

ut o

f 1

01

dru

g u

sers

.R

eco

very

po

siti

on

: no

in

form

atio

nC

PR

: no

info

rmat

ion

Am

bu

lan

ce c

all:

no

in

form

atio

n

Su

rviv

al: 1

00

%A

dve

rse

eve

nts

: no

a

dve

rse

con

seq

ue

nce

s o

the

r th

an w

ith

dra

wal

sy

mp

tom

s o

f re

susc

itat

ion

re

po

rte

dD

eat

h: n

on

e

No

info

rmat

ion

Ear

ly r

ep

ort

s ar

e e

nco

ura

gin

g. N

o d

eat

hs

hav

e b

ee

n

rep

ort

ed

, an

d 1

0 %

of d

istr

ibu

ted

nal

oxo

ne

has

sav

ed

live

s. A

st

ud

y o

f th

e w

ide

r d

istr

ibu

tio

n o

f tak

e-h

om

e n

alo

xon

e is

no

w

req

uir

ed

Do

e-S

imki

ns

et a

l. (2

00

9)

Ove

rdo

se w

itn

ess

ed

: 74

/27

8

(26

.6 %

) A

ttit

ud

es:

no

info

rmat

ion

Kn

ow

led

ge:

no

info

rmat

ion

Nal

oxo

ne:

74

(10

0 %

)R

eco

very

po

siti

on

: no

in

form

atio

nC

PR

: no

info

rmat

ion

Am

bu

lan

ce c

all:

21

/74

(2

8.4

%)

Su

rviv

al: 1

00

%A

dve

rse

eve

nts

: tw

o

wit

hd

raw

al s

ymp

tom

sD

eat

h: n

on

e

Re

fill:

57/

274

(2

0.8

%)

Sto

len

: 2 (

3.5

%)

Co

nfis

cate

d: 2

(3

.5 %

)

Ove

rdo

se p

reve

nti

on

ed

uca

tio

n w

ith

dis

trib

uti

on

of

intr

anas

al n

alo

xon

e is

a f

eas

ible

pu

blic

he

alth

inte

rve

nti

on

to

a

dd

ress

op

ioid

ove

rdo

se

En

tee

n e

t al.

(20

10

)O

verd

ose

wit

ne

sse

d: n

o d

ata

Att

itu

de

s: n

o d

ata

Kn

ow

led

ge:

no

dat

a

Nal

oxo

ne:

39

9R

eco

very

po

siti

on

: no

in

form

atio

nC

PR

: no

info

rmat

ion

Am

bu

lan

ce c

all:

116

/39

9

(29

%)

Re

vers

ion

du

e to

n

alo

xon

e: 3

33

/39

9

(83

%):

Un

kno

wn

ou

tco

me:

3

6/3

99

(9

%)

Ad

vers

e ev

ents

Se

izu

re:1

%V

om

itin

g:1

3 %

Vic

tim

was

an

gry

or

‘do

pe

sick

’: 9

%D

eat

h: 6

(1.5

%)

Pat

ien

ts r

etu

rne

d f

or

nal

oxo

ne

refil

l: 4

70

/19

42

(2

4 %

)N

um

be

r o

f re

fills

: 1 0

20

Lost

: 49

9/1

02

0 (4

9 %

)C

on

fisca

ted

: 12

2/1

02

0

(12

%)

Re

fill f

or

nal

oxo

ne

ad

min

istr

atio

n: 3

99

/1 0

20

(4

0 %

)

Par

tici

pat

ion

has

gro

wn

ste

ad

ily a

mo

ng

ind

ivid

ual

s at

hig

h

risk

of w

itn

ess

ing

ove

rdo

se e

ven

ts, a

nd

fin

din

gs

ind

icat

e th

at p

arti

cip

ants

are

mo

tiva

ted

to

re

ceiv

e re

fills

fo

llow

ing

nal

oxo

ne

loss

or

use

. Am

on

g tr

ain

ed

par

tici

pan

ts w

ho

re

po

rt

usi

ng

nal

oxo

ne,

9 in

10

re

po

rt p

osi

tive

ou

tco

me

s. F

ew

se

rio

us

sid

e-e

ffe

cts

or

de

ath

s w

ere

re

po

rte

d.

The

find

ing

s p

rese

nte

d h

ere

ad

d t

o a

gro

win

g b

od

y o

f e

vid

en

ce t

hat

su

pp

ort

s th

e p

osi

tive

imp

act

of n

alo

xon

e p

resc

rip

tio

n p

rog

ram

me

s as

an

inte

rve

nti

on

to

pre

ven

t p

ote

nti

ally

fat

al o

verd

ose

eve

nts

Gal

ea

et a

l. (2

00

6)

Ove

rdo

se w

itn

ess

ed

: 26

(in

form

atio

n o

n 1

7);

amb

ula

nce

cal

led

: 9/1

1 (

82

%)

Att

itu

de

s: 1

5/2

0 (

75

%)

felt

co

mfo

rtab

le o

r ve

ry

com

fort

able

usi

ng

nal

oxo

ne;

1

2/2

0 (

60

%)

kep

t nal

oxo

ne

wit

h t

he

m a

t all

tim

es

or

in

the

ir h

ou

se, w

he

re t

he

y u

sual

ly u

sed

dru

gs

Nal

oxo

ne:

10

/17

(5

9 %

)R

eco

very

po

siti

on

: no

in

form

atio

nC

PR

: no

info

rmat

ion

Am

bu

lan

ce c

all:

9/1

1 (

82

%)

Ove

rdo

se r

eve

rse

d:

10

0 %

No

ad

vers

e e

ffe

cts

rep

ort

ed

Sto

len

: 4/2

0 (

20

%)

This

init

ial e

vid

en

ce s

ug

ge

sts

that

nal

oxo

ne

ad

min

istr

atio

n

by

inje

ctin

g d

rug

use

rs a

s p

art o

f a c

om

pre

he

nsi

ve o

verd

ose

p

reve

nti

on

str

ate

gy

is f

eas

ible

in N

ew

Yo

rk C

ity

and

may

be

a p

ract

icab

le m

ean

s o

f re

du

cin

g o

verd

ose

de

ath

s o

n a

larg

er

scal

e. P

arti

cip

ants

in t

his

ass

ess

me

nt r

ep

ort

ed

hig

h le

vels

of

com

fort

wit

h n

alo

xon

e a

dm

inis

trat

ion

an

d n

o a

dve

rse

con

seq

ue

nce

s fo

llow

ing

ad

min

istr

atio

n. A

ll in

stan

ces

of

nal

oxo

ne

use

du

rin

g th

is b

rief

pe

rio

d o

f ass

ess

me

nt

app

ear

ed

to

be

app

rop

riat

e an

d a

sso

ciat

ed

wit

h n

ear

-im

me

dia

te r

eve

rsal

of t

he

op

iate

ove

rdo

se. Th

e lim

ite

d

avai

lab

le e

vid

en

ce in

th

is r

eg

ard

co

ncu

rs t

hat

th

ere

are

fe

w

com

plic

atio

ns

or

pro

ble

ms

wit

h n

alo

xon

e a

dm

inis

trat

ion

in

this

co

nte

xt


24 / 37

Au

thor

(ye

ar)

Res

ult

sS

urv

ival

/ad

vers

e ev

ents

/dea

thN

alox

one

refi

ll/lo

st/s

tole

n/

con

fisc

ated

Au

thor

s’ c

oncl

usi

ons

and

qu

alit

y of

evi

den

ce

(wh

en a

vaila

ble

)

Gas

ton

et a

l. (2

00

9)

Ove

rdo

se w

itn

ess

ed

: 16

by

9

ind

ivid

ual

sA

ttit

ud

es:

mo

st p

arti

cip

ants

d

id n

ot c

arry

nal

oxo

ne

wit

h

the

m c

on

sist

en

tly

and

, co

nse

qu

en

tly,

it w

as g

en

era

lly

no

t ava

ilab

le if

th

ey

wit

ne

sse

d

an o

verd

ose

Kn

ow

led

ge

Me

an s

core

Re

cog

nit

ion

of o

verd

ose

: b

ase

line

5.5

, fo

llow

-up

6.0

(p

< 0

.05

)A

ctio

ns

to t

ake

in c

ase

of

ove

rdo

se e

ven

ts: b

ase

line

5.6

, fo

llow

-up

9.3

(p

< 0

.00

1)

Nal

oxo

ne:

0/1

6R

eco

very

po

siti

on

: 2/1

6C

PR

: mo

uth

to

mo

uth

: 2/1

6A

mb

ula

nce

cal

l: 3

/16

Su

rviv

al: 6

/16

Ad

vers

e ev

ents

De

ath

: 1/1

6 (

fou

nd

al

rea

dy

de

ad

)N

o in

form

atio

n: 9

Lost

: 3/7

0 (

6.5

%)

Trai

nin

g o

pia

te u

sers

in t

he

reco

gn

itio

n a

nd

man

age

me

nt o

f o

pia

te o

verd

ose

s h

ad

a s

ign

ifica

nt i

mp

act

on

th

eir

aw

are

ne

ss, k

no

wle

dg

e an

d c

on

fide

nce

, an

d in

cre

ase

d t

he

ir

like

liho

od

of i

nte

rve

nin

g in

hig

h-r

isk

situ

atio

ns

He

ller

and

S

tan

cliff

(2

00

7)

Ove

rdo

se w

itn

ess

ed

: no

t sp

eci

fied

Att

itu

de

s: n

o in

form

atio

nK

no

wle

dg

e: n

o in

form

atio

n

Nal

oxo

ne:

no

info

rmat

ion

Re

cove

ry p

osi

tio

n: n

o

info

rmat

ion

CP

R: n

o in

form

atio

nA

mb

ula

nce

cal

l: n

o

info

rmat

ion

Re

vers

al r

ate:

9 %

(1

62

/1 8

00

) at

1

8-m

on

th f

ollo

w-u

p

No

info

rmat

ion

The

loca

l su

cce

ss a

chie

ved

in r

apid

pro

gra

mm

e d

eve

lop

me

nt a

nd

imp

lem

en

tati

on

re

lied

on

th

e co

llab

ora

tive

an

d c

om

ple

me

nta

ry e

ffo

rts

of a

ll st

ake

ho

lde

rs. Th

e in

terv

en

tio

n n

ow

sh

ow

s p

rom

ise

for

ad

dre

ssin

g an

d

red

uci

ng

ove

rdo

se m

ort

alit

y vi

a co

mm

un

ity-

bas

ed

, pu

blic

an

d m

ed

ical

sys

tem

s o

f car

e in

Ne

w Y

ork

Cit

y

Lee

ce e

t al.

(20

13

)N

alo

xon

e a

dm

inis

trat

ion

: 17

/20

9 (

8.1

3 %

)N

alo

xon

e a

dm

inis

trat

ion

: 17

(8

.13

%)

Re

cove

ry p

osi

tio

n: n

o

info

rmat

ion

CP

R: n

o in

form

atio

nA

mb

ula

nce

cal

l: n

o

info

rmat

ion

Su

rviv

al, a

dve

rse

eve

nts

: no

info

rmat

ion

De

ath

: no

ne

No

info

rmat

ion

The

auth

ors

are

en

cou

rag

ed

by

the

init

ial d

eve

lop

me

nt a

nd

im

ple

me

nta

tio

n e

xpe

rie

nce

wit

h t

he

nal

oxo

ne

pro

gra

mm

e an

d it

s p

ote

nti

al t

o s

ave

live

s in

To

ron

to. A

n o

utc

om

es

and

p

roce

ss e

valu

atio

n is

pla

nn

ed

fo

r th

e fu

ture

McA

ule

y et

al.

(20

10

)O

verd

ose

wit

ne

sse

d: 3

17 c

lien

ts (

89

%)

we

re

follo

we

d u

p a

t 2 m

on

ths:

16

(9

4 %

) cl

aim

ed

to

sti

ll h

ave

nal

oxo

ne,

12

(7

5 %

) w

itn

ess

ed

by

key

wo

rke

rs17

clie

nts

(8

9 %

) w

ere

fo

llow

ed

up

at 6

mo

nth

s: 1

7

(10

0 %

) cl

aim

ed

to

sti

ll h

ave

nal

oxo

ne,

15

(8

8 %

) w

itn

ess

ed

by

key

wo

rke

rsK

no

wle

dg

eC

um

ula

tive

sco

re m

ean

(S

D):

pre

7.0

3 (

2.2

7);

2-m

on

th

follo

w-u

p 1

0.5

4 (1

.94

); 6

-mo

nth

fo

llow

-up

10

.33

(2

.42

)A

ttitu

de

s (c

on

fiden

ce)

Cu

mu

lati

ve m

ean

sco

re (

SD

): p

re 1

9.6

3 (

5.4

0);

2-m

on

th

follo

w-u

p 2

8 (

2.4

1);

6-m

on

th

follo

w-u

p 2

9.6

0 (

0.8

9)

Nal

oxo

ne:

2 (

67

%)

Re

cove

ry p

osi

tion

an

d C

PR

Bas

ic li

fe s

up

po

rt in

itia

ted

: 3

(10

0 %

)A

mb

ula

nce

cal

l: 3

(10

0 %

)

Sav

es

(1):

2 (

67

%)

De

ath

: 1 (

33

%)

No

info

rmat

ion

The

se d

ata

sug

ge

st t

hat

Sco

ttis

h d

rug

use

rs c

an b

e tr

ain

ed

to

ide

nti

fy a

nd

re

spo

nd

to

an

op

iate

ove

rdo

se u

tilis

ing

bas

ic

life

sup

po

rt a

nd

nal

oxo

ne

ad

min

istr

atio

n s

kills

.Th

ese

re

sult

s su

gg

est

th

at a

maj

ori

ty o

f op

iate

use

rs c

an

resp

on

sib

ly m

anag

e th

eir

ow

n p

ers

on

al t

ake

-ho

me

nal

oxo

ne

sup

ply

wh

en

tra

ine

d a

pp

rop

riat

ely


25 / 37

Au

thor

(ye

ar)

Res

ult

sS

urv

ival

/ad

vers

e ev

ents

/dea

thN

alox

one

refi

ll/lo

st/s

tole

n/

con

fisc

ated

Au

thor

s’ c

oncl

usi

ons

and

qu

alit

y of

evi

den

ce

(wh

en a

vaila

ble

)

Ma

xwe

ll et

al.

(20

06

)O

verd

ose

wit

ne

sse

d: n

o

info

rmat

ion

Att

itu

de

s: n

o in

form

atio

nK

no

wle

dg

e: n

o in

form

atio

n

Nal

oxo

ne

pre

scri

pti

on

: 3 5

00

d

ose

sR

eco

very

po

siti

on

: no

in

form

atio

nC

PR

: no

info

rmat

ion

Am

bu

lan

ce c

all:

no

in

form

atio

n

Re

vers

ed

: 31

9A

dve

rse

eff

ect

s: 1

vo

mit

; 1 s

eiz

ure

s [a

lpra

zola

m u

se

(6–

8 m

g/d

ay)]

; on

e re

scu

er

rep

ort

ed

u

sin

g fi

ve s

eq

ue

nti

al

do

ses

(0.4

mg

ea

ch),

ea

ch h

avin

g a

par

tial

re

vivi

ng

eff

ect

, bef

ore

fu

ll re

vers

al w

as

ach

ieve

dD

eat

h: 1

No

info

rmat

ion

Par

tici

pan

ts w

ere

ed

uca

ted

, an

d n

alo

xon

e p

resc

rib

ed

, th

rou

gh

ou

t an

ext

en

sive

har

m r

ed

uct

ion

ou

tre

ach

net

wo

rk.

Ap

pro

xim

ate

ly 3

50

0 1

0-d

ose

via

ls o

f nal

oxo

ne

we

re

pre

scri

be

d.

No

clin

ical

, le

gal

or

liab

ility

re

pe

rcu

ssio

ns

en

sue

d.

The

re w

ere

re

po

rts

of 3

19

pe

er

reve

rsal

s, w

ith

on

ly o

ne

un

succ

ess

ful r

eve

rsal

re

po

rte

d.

On

ly t

wo

re

po

rts

of a

dve

rse

eve

nts

hav

e b

ee

n r

ece

ive

d: o

ne

case

of s

eve

re o

pia

te a

bst

ine

nce

syn

dro

me

(OA

S)

and

on

e ca

se o

f se

izu

res

(in a

par

tici

pan

t wit

h h

igh

-do

se a

lpra

zola

m

use

)

Pip

er

et a

l. (2

00

8)

Ove

rdo

se w

itn

ess

ed

: no

t re

po

rte

dO

verd

ose

cau

sed

by

he

roin

: 4

4/5

0 (

88

%)

Att

itu

de

s: 9

7 (

82

.2 %

) sa

id

the

y fe

lt c

om

fort

able

or

very

co

mfo

rtab

le u

sin

g n

alo

xon

e if

ind

icat

ed

; 31

(2

7.0

%)

rep

ort

ed

hav

ing

kep

t th

e n

alo

xon

e w

ith

th

em

at a

ll ti

me

s o

r in

th

eir

ho

use

, wh

ere

th

ey

usu

ally

use

d d

rug

s

Nal

oxo

ne:

82

Re

cove

ry p

osi

tio

n: 3

6/5

0

(72

%)

CP

R: 2

7/5

0 (

54

%)

Am

bu

lan

ce c

all:

37/

50

(74

%)

Re

vers

ed

: 68

(8

3.0

%)

Ou

tco

me

un

kno

wn

: 14

(17.

1 %

)

Re

fille

d m

ore

th

an o

nce

: 3

6/1

22

(3

0 %

)S

tole

n: 2

8/1

22

(2

4 %

)

Dru

g u

sers

can

be

trai

ne

d t

o r

esp

on

d t

o h

ero

in o

verd

ose

w

ith

nal

oxo

ne

and

sav

e liv

es.

Nal

oxo

ne

ad

min

istr

atio

n b

y in

ject

ing

dru

g u

sers

may

be

use

d a

s p

art o

f a

com

pre

he

nsi

ve o

verd

ose

pre

ven

tio

n s

trat

eg

y fo

r re

du

cin

g o

verd

ose

de

ath

s o

n a

larg

er

scal

e. P

arti

cip

ants

in t

his

e

valu

atio

n r

ep

ort

ed

hig

h le

vels

of c

om

fort

wit

h n

alo

xon

e a

dm

inis

trat

ion

an

d n

o a

dve

rse

con

seq

ue

nce

s fo

llow

ing

ad

min

istr

atio

n

Se

al e

t al.

(20

05

)O

verd

ose

wit

ne

sse

d: 2

0K

no

wle

dg

e>

50

% c

orr

ect

re

spo

nse

sId

en

tify

ing

a h

ero

in o

verd

ose

: b

ase

line

0 (

0),

follo

w-u

p 1

3

(53

%);

p <

0.0

01

Ris

k fa

cto

rs f

or

he

roin

o

verd

ose

: bas

elin

e 2

(8

%),

follo

w-u

p 1

6 (

68

%);

p =

0.0

03

He

roin

ove

rdo

se p

reve

nti

on

st

rate

gie

s: b

ase

line

1 (

6 %

), fo

llow

-up

8 (

32

%);

p =

0.0

40

Co

rre

ct u

ses

of n

alo

xon

e:

bas

elin

e 2

1 (

91

%),

follo

w-u

p

23

(9

5 %

); p

= 1

.00

0

Nal

oxo

ne:

15

/20

(7

5 %

)R

eco

very

po

siti

on

: no

in

form

atio

nC

PR

: 16

/20

(8

0 %

)A

mb

ula

nce

cal

led

: 5/2

0

(25

%)

De

ath

: no

ne

No

info

rmat

ion

Inje

ctin

g d

rug

use

rs c

an b

e tr

ain

ed

to

re

spo

nd

to

he

roin

o

verd

ose

em

erg

en

cie

s b

y p

erf

orm

ing

CP

R a

nd

a

dm

inis

teri

ng

nal

oxo

ne

. Fu

ture

re

sear

ch is

ne

ed

ed

to

e

valu

ate

the

eff

ect

ive

ne

ss o

f th

is p

ee

r in

terv

en

tio

n t

o

pre

ven

t fat

al h

ero

in o

verd

ose


26 / 37

Au

thor

(ye

ar)

Res

ult

sS

urv

ival

/ad

vers

e ev

ents

/dea

thN

alox

one

refi

ll/lo

st/s

tole

n/

con

fisc

ated

Au

thor

s’ c

oncl

usi

ons

and

qu

alit

y of

evi

den

ce

(wh

en a

vaila

ble

)

Str

ang

et a

l. (2

00

8)

Ove

rdo

se w

itn

ess

ed

: 18

Kn

ow

led

ge

1. R

isk

fact

ors

fo

r o

pia

te

ove

rdo

se:

Par

tici

pan

ts c

orr

ect

ly

reco

gn

isin

g al

l se

ven

ris

k fa

cto

rs: p

re-t

rain

ing

31

.9 %

, p

ost

tra

inin

g 6

3.8

%N

um

be

r o

f co

rre

ctly

ide

nti

fied

ri

sk f

act

ors

: pre

-tra

inin

g m

ean

5

.3 (

SD

1.6

7),

po

st-t

rain

ing

me

an 6

.1 (

SD

1.5

); p

< 0

.00

12

. Sig

ns

of o

pia

te o

verd

ose

Me

an c

orr

ect

an

swe

rs (o

ut o

f 8

): p

re-t

rain

ing

5.6

(S

D =

1.3

), p

ost

-tra

inin

g 6

.7 (

SD

= 1

.2);

p <

0.0

01

3. A

pp

rop

riat

e a

ctio

ns

to t

ake

in a

n o

pia

te o

verd

ose

si

tuat

ion

Me

an s

core

(ma

xim

um

11

): p

re-t

rain

ing

5.9

(S

D =

2.3

), p

ost

-tra

inin

g 8

.6 (

SD

= 2

.1);

p <

0.0

01

Ove

rall

kno

wle

dg

e o

f o

verd

ose

Me

an s

core

(ma

xim

um

26

): p

re-t

rain

ing

16

.7 (

SD

= 3

.7),

po

st-t

rain

ing

21

.4 (

SD

= 3

.4);

p <

0.0

01

Kn

ow

led

ge

of n

alo

xon

eN

alo

xon

e o

nly

fo

r th

e re

vers

al

of o

pia

te o

verd

ose

: bef

ore

tr

ain

ing

77

% (1

59

of 2

06

), af

ter

trai

nin

g 9

6 %

(19

1 o

f 2

00

)N

alo

xon

e d

oe

s n

ot r

eve

rse

coca

ine,

am

ph

etam

ine

s,

alco

ho

l, b

en

zod

iaze

pin

es

ove

rdo

se: b

efo

re t

rain

ing

80

%, a

fte

r tr

ain

ing

bet

we

en

9

5 %

an

d 9

8 %

Att

itud

es

Will

ing

ne

ss t

o a

dm

inis

ter

nal

oxo

ne:

bef

ore

tra

inin

g,

77

% (1

51/1

96

), af

ter

trai

nin

g 9

9 %

; n =

19

2/1

94

(p

< 0

.00

1)

Thre

e fo

llow

-up

resu

ltsK

no

wle

dg

e o

f sig

ns

of

ove

rdo

se: p

ost

-tra

inin

g 6

.6

(SD

1.2

), fo

llow

-up

6.5

(1.1

); p

= 0

.47

Nal

oxo

ne:

12

/18

(6

6.6

%)

Re

cove

ry p

osi

tio

n a

nd

cal

ling

an a

mb

ula

nce

: N/A

Su

rviv

al: 1

2/1

2

(10

0 %

)A

dve

rse

eve

nts

: 1

pre

cip

itat

ion

of o

pia

te

wit

hd

raw

al o

r h

ost

ility

at

ab

rup

t op

iate

re

vers

alD

eat

h: 1

(nal

oxo

ne

no

t use

d)

No

info

rmat

ion

Wit

h o

verd

ose

man

age

me

nt t

rain

ing

, op

iate

use

rs c

an b

e tr

ain

ed

to

exe

cute

ap

pro

pri

ate

act

ion

s to

ass

ist t

he

succ

ess

ful r

eve

rsal

of p

ote

nti

ally

fat

al o

verd

ose

. Wid

er

pro

visi

on

may

re

du

ce d

rug

-re

late

d d

eat

hs

furt

he

r. F

utu

re

stu

die

s sh

ou

ld e

xam

ine

wh

eth

er

pu

blic

po

licy

on

wid

er

ove

rdo

se m

anag

em

en

t tra

inin

g an

d n

alo

xon

e p

rovi

sio

n

cou

ld r

ed

uce

th

e ex

ten

t of o

pia

te o

verd

ose

fat

alit

ies,

p

arti

cula

rly

at t

ime

s o

f re

cog

nis

ed

incr

eas

ed

ris

k


27 / 37

Au

thor

(ye

ar)

Res

ult

sS

urv

ival

/ad

vers

e ev

ents

/dea

thN

alox

one

refi

ll/lo

st/s

tole

n/

con

fisc

ated

Au

thor

s’ c

oncl

usi

ons

and

qu

alit

y of

evi

den

ce

(wh

en a

vaila

ble

)

Kn

ow

led

ge

of a

pp

rop

riat

e a

ctio

ns:

po

st t

rain

ing

8.6

(S

D

2.1

), fo

llow

-up

9.4

(1.2

); p

< 0

.00

1A

ttitu

de

sC

on

fide

nce

in t

he

use

of

nal

oxo

ne

Co

nfid

en

t in

th

eir

ab

ility

to

re

cog

nis

e an

op

iate

ove

rdo

se:

98

% (1

69

of 1

73

)A

ble

to

man

age

an o

verd

ose

si

tuat

ion

: 97

% (1

67/

172

)W

ou

ld c

all f

or

an a

mb

ula

nce

: 9

8 %

(16

8/1

72

)

Tob

in e

t al.

(20

09

)O

verd

ose

witn

ess

ed

Nu

mb

er

of o

verd

ose

s n

ot

rep

ort

ed

, nu

mb

er

of p

atie

nts

re

po

rtin

g w

itn

ess

ing

an

ove

rdo

se p

re a

nd

po

st: 4

3C

ha

ng

e in

kn

ow

led

ge

Kn

ow

led

ge

of n

alo

xon

e:

imp

rove

d f

rom

bas

elin

e 3

9/8

5 (4

6 %

); g

oo

d a

t bo

th

tim

e p

oin

ts 1

6/8

5 (1

9 %

); n

ot

imp

rove

d o

r d

ecr

eas

ed

30

/85

(3

5 %

)C

ha

ng

e in

att

itud

es

Leve

l of c

om

fort

: im

pro

ved

fr

om

bas

elin

e 2

1/8

5 (

25

%);

go

od

at b

oth

tim

e p

oin

ts

38

/85

(45

%);

no

t im

pro

ved

or

de

cre

ase

d 2

7/8

5 (

32

%)

Nal

oxo

ne:

19

/43

(44

%)

Re

cove

ry p

osi

tio

n: n

o

info

rmat

ion

CP

R: p

re 8

/43

(19

%),

po

st

23

/49

(2

3 %

)A

mb

ula

nce

cal

l: p

re 2

8/4

3

(65

%),

po

st: 2

1/4

3 (4

9 %

)

Nal

oxo

ne

lost

: no

ne

Nal

oxo

ne

sto

len

: no

ne

This

stu

dy

ind

icat

es

that

th

e S

tayi

ng

Aliv

e (S

A)

pro

gra

mm

e w

as e

ffe

ctiv

e in

incr

eas

ing

the

use

of n

alo

xon

e d

uri

ng

op

iate

o

verd

ose

s, r

esu

ltin

g in

22

re

vers

als

by

19

ind

ivid

ual

s. O

n

ave

rag

e, t

he

fre

qu

en

cy o

f in

app

rop

riat

e re

spo

nse

s (l

eav

ing

the

vict

im o

r ap

ply

ing

pai

n) d

ecr

eas

ed

.Th

is s

tud

y p

rovi

de

s a

dd

itio

nal

evi

de

nce

to

su

pp

ort

th

e e

ffe

ctiv

en

ess

of o

verd

ose

pre

ven

tio

n t

rain

ing

pro

gra

mm

es

that

incl

ud

e sk

ills

bu

ildin

g fr

om

dru

g u

sers

to

ad

min

iste

r n

alo

xon

e

Wag

ne

r et

al.

(20

10

)O

verd

ose

s w

itn

ess

ed

: 35

by

22

ind

ivid

ual

sK

no

wle

dg

eO

vera

ll kn

ow

led

ge

ind

ex:

bas

elin

e m

ean

76

.5 (

SD

15

.4),

follo

w-u

p: 9

1.5

(S

D 9

.6);

p <

0.0

00

1A

sta

tist

ical

ly s

ign

ifica

nt

incr

eas

e w

as o

bse

rve

d f

or

thre

e it

em

s ab

ou

t th

e ap

pro

pri

ate

use

an

d e

ffe

cts

of

nal

oxo

ne

. No

sig

nifi

can

t ch

ang

es

we

re o

bse

rve

d in

it

em

s ab

ou

t ris

k fa

cto

rs f

or

ove

rdo

se o

r o

verd

ose

sy

mp

tom

s

Nal

oxo

ne:

28

/35

(8

0 %

)R

eco

very

po

siti

on

: no

in

form

atio

nC

PR

: 23

/35

(6

5.7

%)

Am

bu

lan

ce c

all:

21

/35

(6

0 %

)

Fat

al o

verd

ose

s4

/35

(11

.4 %

)R

efil

l: 14

/47

(2

9.8

%)

Lost

or

sto

len

: 6C

on

fisca

ted

: 4O

the

r: 4

This

stu

dy

con

trib

ute

s to

th

e g

row

ing

lite

ratu

re s

ug

ge

stin

g th

at o

verd

ose

pre

ven

tio

n a

nd

re

spo

nse

tra

inin

g p

rog

ram

me

s fo

r d

rug

use

rs m

ay b

e as

soci

ate

d w

ith

ch

ang

es

in k

no

wle

dg

e an

d o

verd

ose

re

spo

nse

be

hav

iou

r, w

ith

fe

w n

eg

ativ

e co

nse

qu

en

ces

and

th

e p

oss

ibili

ty o

f u

nfo

rese

en

be

ne

fits

such

as

red

uct

ion

s in

dru

g u

se o

r in

cre

ase

d e

ng

age

me

nt w

ith

dru

g tr

eat

me

nt


28 / 37

Au

thor

(ye

ar)

Res

ult

sS

urv

ival

/ad

vers

e ev

ents

/dea

thN

alox

one

refi

ll/lo

st/s

tole

n/

con

fisc

ated

Au

thor

s’ c

oncl

usi

ons

and

qu

alit

y of

evi

den

ce

(wh

en a

vaila

ble

)

Att

itud

es

No

sig

nifi

can

t ch

ang

es

we

re

ob

serv

ed

in a

ttit

ud

es

abo

ut

ove

rdo

se r

esp

on

se, i

ncl

ud

ing

like

liho

od

of a

dm

inis

teri

ng

nal

oxo

ne,

like

liho

od

of c

allin

g e

me

rge

ncy

se

rvic

es

or

wo

rry

abo

ut a

rre

st a

fte

r ca

llin

g e

me

rge

ncy

se

rvic

es

(all

p >

0.0

5)

Wal

ley

et a

l. (2

01

3a)

Ove

rdo

se w

itn

ess

ed

: no

t re

po

rte

dN

alo

xon

e: 3

27

Re

cove

ry p

osi

tio

n, C

PR

an

d

amb

ula

nce

cal

l: n

o

info

rmat

ion

Ove

rdo

se r

esc

ue

s: 9

2

rep

ort

ed

by

62

e

nro

lee

s w

ho

re

po

rte

d t

akin

g an

y m

eth

ad

on

e in

th

e p

ast 3

0 d

ays

Re

fill:

28

6 (

fro

m a

su

bsa

mp

le

of 1

55

3 p

atie

nts

tak

ing

met

ha

do

ne

fro

m S

ep

tem

be

r 2

00

8 t

o D

ece

mb

er

20

10

)

OE

ND

tra

inin

g fo

r in

div

idu

als

wh

o t

ake

met

ha

do

ne

can

be

succ

ess

fully

imp

lem

en

ted

in a

var

iety

of s

etti

ng

s. P

eo

ple

w

ho

tak

e m

eth

ad

on

e h

ave

hig

h r

ate

s o

f ove

rdo

se r

isk

fact

ors

an

d h

igh

exp

osu

re t

o w

itn

ess

ed

ove

rdo

se, a

nd

can

u

se n

alo

xon

e to

re

vers

e an

ove

rdo

se

Wal

ley

et a

l. (2

01

3b)

Ove

rdo

se w

itn

ess

ed

: 32

7O

pio

id-r

ela

ted

de

ath

rate

s Lo

w im

ple

me

nte

r co

mm

un

ity

vs. n

o im

ple

me

nta

tio

n:

ad

just

ed

RR

0.7

3, 9

5 %

CI

0.5

7–

0.9

1H

igh

imp

lem

en

ter

com

mu

nit

y vs

. no

imp

lem

en

tati

on

: a

dju

ste

d R

R 0

.54

, 95

% C

I 0

.39

–0

.76

No

n-f

ata

l op

ioid

ove

rdo

se-

rela

ted

acu

te c

are

ho

spita

l u

tilis

atio

ns

Low

imp

lem

en

ter

com

mu

nit

y vs

. no

imp

lem

en

tati

on

: a

dju

ste

d R

R 0

.93

, 95

% C

I 0

.80

–1

.08

Hig

h im

ple

me

nte

r co

mm

un

ity

vs. n

o im

ple

me

nta

tio

n:

ad

just

ed

RR

0.9

2, 9

5 %

CI

0.7

5–

1.1

3

Nal

oxo

ne,

re

cove

ry p

osi

tio

n,

CP

R a

nd

am

bu

lan

ce c

all:

no

in

form

atio

n

N/A

N/A

De

ath

rat

es

fro

m o

pio

id o

verd

ose

we

re r

ed

uce

d in

co

mm

un

itie

s w

he

re a

n o

verd

ose

ed

uca

tio

n a

nd

nal

oxo

ne

dis

trib

uti

on

pro

gra

mm

e w

as im

ple

me

nte

d c

om

par

ed

wit

h

no

imp

lem

en

tati

on

. This

pro

vid

es

ob

serv

atio

nal

evi

de

nce

th

at a

n o

verd

ose

ed

uca

tio

n a

nd

nas

al n

alo

xon

e d

istr

ibu

tio

n

pro

gra

mm

e is

an

eff

ect

ive

pu

blic

he

alth

inte

rve

nti

on

to

a

dd

ress

th

e e

pid

em

ic o

f fat

al o

pio

id o

verd

ose

. OE

ND

im

ple

me

nta

tio

n s

ee

me

d t

o h

ave

a d

ose

-re

late

d im

pa

ct,

wh

ere

th

e h

igh

er

the

cum

ula

tive

rat

e o

f OE

ND

im

ple

me

nta

tio

n, t

he

gre

ate

r th

e re

du

ctio

n in

de

ath

rat

es.

Qu

alit

y a

sse

ssm

ent

Cle

ar d

efin

ed

po

int i

n t

ime

wh

en

th

e in

terv

en

tio

n o

ccu

rre

dTh

ree

dat

a p

oin

ts b

efo

re, a

nd

th

ree

afte

r, th

e in

terv

en

tio

nIn

terv

en

tio

n o

ccu

rre

d in

de

pe

nd

en

tly

of o

the

r ch

ang

es

ove

r ti

me

Inte

rve

nti

on

un

like

ly t

o a

ffe

ct d

ata

colle

ctio

n (e

.g. s

ou

rce

s an

d m

eth

od

s o

f dat

a co

llect

ion

we

re t

he

sam

e b

efo

re a

nd

af

ter

the

inte

rve

nti

on)

Exp

licit

sta

tem

en

t by

auth

ors

th

at t

he

pri

mar

y o

utc

om

e va

riab

les

we

re a

sse

sse

d b

lind

ly o

r th

e o

utc

om

e va

riab

les

we

re o

bje

ctiv

e, e

.g. l

en

gth

of h

osp

ital

sta

y, d

rug

leve

ls a

s as

sess

ed

by

a st

and

ard

ise

d t

est

Un

cle

ar c

om

ple

ten

ess

of d

ata

set (

com

par

e al

so w

ith

A

nn

ex 5

)

Wh

ee

ler

et a

l. (2

01

2)

Ove

rdo

se r

eve

rsal

: 10

171

Nal

oxo

ne

dis

trib

ute

d t

o

53

03

2 p

ers

on

s

Nal

oxo

ne,

re

cove

ry p

osi

tio

n,

CP

R a

nd

am

bu

lan

ce c

all:

no

in

form

atio

n

Re

vers

ed

: 10

171

No

info

rmat

ion

To a

dd

ress

th

e h

igh

rat

es

of o

pio

id d

rug

ove

rdo

se d

eat

hs,

p

ub

lic h

eal

th a

ge

nci

es

cou

ld, a

s p

art o

f a c

om

pre

he

nsi

ve

pre

ven

tio

n p

rog

ram

me,

imp

lem

en

t co

mm

un

ity-

bas

ed

o

pio

id d

rug

ove

rdo

se p

reve

nti

on

pro

gra

mm

es,

incl

ud

ing

trai

nin

g an

d p

rovi

din

g n

alo

xon

e to

po

ten

tial

ove

rdo

se

wit

ne

sse

s, a

nd

sys

tem

atic

ally

ass

ess

th

e im

pa

ct o

f th

ese

p

rog

ram

me

s


29 / 37

Au

thor

(ye

ar)

Res

ult

sS

urv

ival

/ad

vers

e ev

ents

/dea

thN

alox

one

refi

ll/lo

st/s

tole

n/

con

fisc

ated

Au

thor

s’ c

oncl

usi

ons

and

qu

alit

y of

evi

den

ce

(wh

en a

vaila

ble

)

Will

iam

s et

al.

(20

14)

Ove

rdo

se w

itn

ess

ed

: ex

pe

rim

en

tal 7

, co

ntr

ol 6

Nal

oxo

ne

use

d: e

xpe

rim

en

tal

2/7

(2

8 %

), co

ntr

ol:

0/6

Ch

ang

e in

kn

ow

led

ge

(OO

KS

): ex

pe

rim

en

tal 6

.47

(9

5 %

CI

5.0

9–

7.8

5),

con

tro

l: 0

.81

(9

5 %

CI –

0.9

6 t

o –

2.5

7)

Bet

we

en

-gro

up

diff

ere

nce

in

chan

ge:

4.0

8 (

95

% C

I 2

.10

–6

.06

)C

han

ge

in a

ttit

ud

es:

ex

pe

rim

en

tal 1

4.1

0 (

95

% C

I 0

.73

–17

.47

), co

ntr

ol 7

.18

(9

5 %

CI 3

.48

–1

0.8

7)

Bet

we

en

-gro

up

diff

ere

nce

in

chan

ge:

7.4

7 (

95

% C

I 1

3–

11.8

2)

Na

loxo

ne

Exp

eri

me

nta

l: 2

/7 (

28

%)

Co

ntr

ol:

0/6

Re

cove

ry p

osi

tio

n: m

ost

ly

(dat

a n

ot r

ep

ort

ed

)C

PR

: no

info

rmat

ion

Am

bu

lan

ce c

all:

mo

stly

(dat

a n

ot r

ep

ort

ed

)

N/A

N/A

Take

-ho

me

nal

oxo

ne

trai

nin

g fo

r fa

mily

me

mb

ers

of h

ero

in

use

rs in

cre

ase

s o

pio

id o

verd

ose

-re

late

d k

no

wle

dg

e an

d

com

pet

en

ce a

nd

th

ese

be

ne

fits

are

we

ll re

tain

ed

aft

er

3

mo

nth

s.Q

ua

lity

ass

ess

men

tS

ele

ctio

n b

ias:

ran

do

m s

eq

ue

nce

ge

ne

rati

on

— lo

w r

isk

of

bia

sS

ele

ctio

n b

ias:

allo

cati

on

co

nce

alm

en

t — lo

w r

isk

of b

ias

Pe

rfo

rman

ce b

ias:

blin

din

g o

f par

tici

pan

ts a

nd

pro

vid

ers

(s

ub

ject

ive

and

ob

ject

ive

ou

tco

me

s) —

hig

h r

isk

of b

ias

Det

ect

ion

bia

s: b

lind

ing

of o

utc

om

e as

sess

or

(su

bje

ctiv

e an

d o

bje

ctiv

e o

utc

om

es)

— u

ncl

ear

ris

k o

f bia

s(c

om

par

e al

so w

ith

An

nex

5)

Yoke

ll et

al.

(20

11)

Ove

rdo

se w

itn

ess

ed

: 10

Kn

ow

led

ge:

five

use

d t

he

ir

ove

rdo

se r

esp

on

se t

rain

ing

and

did

no

t fin

d it

ne

cess

ary

to a

dm

inis

ter

nal

oxo

ne

The

pas

sive

nat

ure

of P

ON

I’s

rep

ort

ing

syst

em

lim

ite

d t

he

colle

ctio

n o

f par

tici

pan

t fo

llow

-up

dat

a an

d c

ou

ld b

e th

e re

aso

n f

or

the

very

hig

h

rate

of p

atie

nts

lost

at

follo

w-u

p

Nal

oxo

ne:

5/1

0 (

50

%)

Re

cove

ry p

osi

tio

n: n

o

info

rmat

ion

CP

R: n

o in

form

atio

nA

mb

ula

nce

cal

l: n

o

info

rmat

ion

N/A

N/A

PO

NI i

s th

e fir

st o

pio

id o

verd

ose

pre

ven

tio

n p

rog

ram

me

in

Rh

od

e Is

lan

d a

nd

has

met

wit

h g

reat

su

cce

ss in

th

e tr

ain

ing

of t

he

first

12

0 p

arti

cip

ants

. The

maj

or

chal

len

ge

face

d b

y P

ON

I has

be

en

its

limit

ed

siz

e. E

xpan

din

g P

ON

I wo

uld

p

rovi

de

crit

ical

, lif

e-s

avin

g kn

ow

led

ge

to o

pio

id u

sers

an

d

the

ir f

rie

nd

s an

d f

amili

es,

wh

ich

co

uld

ult

imat

ely

ave

rt

cou

ntl

ess

op

ioid

ove

rdo

ses

and

su

bse

qu

en

t de

ath

s

(1)

A ‘s

ave’

is a

ny

situ

ati

on

wh

ere

th

e am

bu

lan

ce s

erv

ice

ob

serv

ed

an

d c

on

firm

ed

th

at

the

ad

min

iste

red

nal

oxo

ne

was

th

e ke

y e

lem

en

t in

sav

ing

the

pe

rso

n’s

life

.C

PR

, car

dio

pu

lmo

nar

y re

susc

ita

tio

n; N

/A, n

ot

app

licab

le; O

EN

D, O

verd

ose

Ed

uca

tio

n a

nd

Nal

oxo

ne

Dis

trib

uti

on

; OO

KS

, Op

ioid

Ove

rdo

se K

no

wle

dg

e S

cale

; PO

NI,

Pre

ven

tin

g O

verd

ose

an

d N

alo

xon

e In

terv

en

tio

n.


30 / 37

I Ann

ex 3

I Nal

oxon

e p

rog

ram

mes

in E

uro

pe

(Oct

ober

20

14

— T

ech

nic

al m

eeti

ng

on

nal

oxon

e p

rovi

sion

) d

ata

from

per

son

al c

omm

un

icat

ion

s n

ot c

hec

ked

wit

h o

ther

so

urc

es

Cou

ntr

yP

rog

ram

me/

stu

dy

Org

anis

atio

n, (

tim

efra

me)

an

d m

ain

com

pon

ents

, loc

atio

n

Ger

man

yA

th

ree

-ye

ar m

od

el p

roje

ct o

f tak

e-h

om

e n

alo

xon

e in

Ge

rman

yF

ixp

un

kt (1

99

8–

19

99

)C

om

po

ne

nts

: firs

t-ai

d t

rain

ing

and

nal

oxo

ne

dis

trib

uti

on

fo

r o

pia

te u

sers

in B

erl

in

Den

mar

kN

alo

xon

e p

rog

ram

me

Sta

te fi

nan

ced

(2

01

3–

15

) C

om

po

ne

nts

: nal

oxo

ne

pro

gra

mm

e in

fo

ur

Dan

ish

mu

nic

ipal

itie

s w

ith

op

en

dru

g sc

en

es

Nor

way

Nas

al n

alo

xon

e p

rog

ram

me

No

rwe

gia

n M

inis

ter

of H

eal

th (

Ap

ril 2

014

–)

Co

mp

on

en

ts: n

atio

nal

ove

rdo

se p

reve

nti

on

str

ate

gy

incl

ud

ing

the

intr

od

uct

ion

of t

ake

-ho

me

nal

oxo

ne

nas

al s

pra

y (f

or

use

rs, r

ela

tive

s an

d s

taff

in lo

w-t

hre

sho

ld f

aci

litie

s), O

slo

an

d B

erg

en

Est

onia

Take

-ho

me

nal

oxo

ne

pro

gra

mm

eN

atio

nal

Inst

itu

te f

or

He

alth

De

velo

pm

en

t (2

01

3–

) C

om

po

ne

nts

: tak

e-h

om

e n

alo

xon

e p

ilot p

rog

ram

me,

Est

on

ia

Sco

tlan

d, U

KTa

ke-h

om

e n

alo

xon

e p

rog

ram

me

The

Sco

ttis

h G

ove

rnm

en

t (2

01

0-

)C

om

po

ne

nts

: tak

e-h

om

e n

alo

xon

e p

rog

ram

me

in 2

01

0; c

urr

en

t tar

get

is t

o r

ea

ch 2

5 %

of p

rob

lem

/hig

h-r

isk

dru

g u

sers

in S

cotl

and

by

Mar

ch 2

01

5

Sp

ain

Net

wo

rk o

f dru

g ab

use

car

e ce

ntr

es

of C

atal

on

ia in

an

o

verd

ose

pre

ven

tio

n p

rog

ram

me

Cat

alo

nia

net

wo

rk o

f ce

ntr

es

Co

mp

on

en

ts: m

eth

ad

on

e p

rog

ram

me

s, c

on

sum

pti

on

ro

om

s, e

du

cati

on

an

d n

alo

xon

e d

istr

ibu

tio

n c

are

cen

tre

s an

d

har

m r

ed

uct

ion

fa

cilit

ies,

Cat

alo

nia

Ital

yN

alo

xon

e p

ee

r d

istr

ibu

tio

n p

rog

ram

me

via

ph

arm

aci

es

Nal

oxo

ne

in v

ial f

or

inje

ctio

n is

ava

ilab

le o

ver

the

cou

nte

r fr

om

ph

arm

aci

es

(Offi

cial

Ph

arm

aco

pe

ia, T

able

s II

and

IV)


31 / 37

I Ann

ex 4

I Sea

rch

str

ateg

ies

Dat

abas

eD

rug

s an

d A

lco

ho

l Gro

up

Sp

eci

aliz

ed

Re

gis

ter

(in C

RS

)

Sea

rch

str

ateg

y #

1 ((

op

iat*

OR

op

ioid

* O

R h

ero

in*

OR

nar

cot*

):TI,

AB

, XD

I)#

2 ((

ove

rdo

s* O

R in

toxi

cat*

OR

po

iso

n*)

)#

3 #

1 A

ND

#2

#4

(N

arca

n O

R n

alo

xon

e)#

5 #

3 A

ND

#4

Dat

e of

sea

rch

10

/07/

20

13

Res

ult

s2

1

Dat

abas

eC

EN

TR

AL

(The

Co

chra

ne

Lib

rary

)

Sea

rch

str

ateg

y #

1

Me

SH

de

scri

pto

r: [O

pio

id-R

ela

ted

Dis

ord

ers

] ex

plo

de

all t

ree

s#

2

(op

iat*

or

op

ioid

* o

r h

ero

in*

or

nar

cot*

):ti

,ab

,kw

(W

ord

var

iati

on

s h

ave

be

en

se

arch

ed

)#

3

#1

or

#2

#

4

Me

SH

de

scri

pto

r: [

Dru

g O

verd

ose

] ex

plo

de

all t

ree

s#

5

(ove

rdo

s* o

r in

toxi

cat*

or

po

iso

n*)

:ti,a

b,k

w (

Wo

rd v

aria

tio

ns

hav

e b

ee

n s

ear

che

d)

#6

#

4 o

r #

5

#7

M

eS

H d

esc

rip

tor:

[N

alo

xon

e] e

xplo

de

all t

ree

s#

8

nal

oxo

ne:

ti,a

b,k

w (

Wo

rd v

aria

tio

ns

hav

e b

ee

n s

ear

che

d)

#9

n

arca

n:t

i,ab

,kw

(W

ord

var

iati

on

s h

ave

be

en

se

arch

ed

)#

10

M

eS

H d

esc

rip

tor:

[N

arco

tic

An

tag

on

ists

] th

is t

erm

on

ly#

11

((n

arco

tic

or

op

iate

or

op

ioid

) n

ear

/3 a

nta

go

nis

t*):

ti,a

b

#1

2

#7

or

#8

or

#9

or

#1

0 o

r #

11

#1

3

#3

an

d #

6 a

nd

#1

2

Dat

e of

sea

rch

Issu

e 7,

20

13

Res

ult

s5

0

Dat

abas

eP

ub

Me

d

Sea

rch

str

ateg

y ((

(((“

dru

g o

verd

ose

”[M

eS

H T

erm

s])

OR

ove

rdo

s*[T

itle

/Ab

stra

ct])

OR

into

xica

t*[T

itle

/Ab

stra

ct])

) A

ND

((((

op

iat*

[tia

b]

OR

o

pio

id*[

tiab

] O

R h

ero

in*[

tiab

] O

R n

arco

t*[t

iab

])))

OR

“Op

ioid

-Re

late

d D

iso

rde

rs”[

Me

SH

]))

AN

D ((

(nal

oxo

ne

[Me

SH

Te

rms]

) O

R n

alo

xon

e[T

itle

/Ab

stra

ct])

OR

nar

can

[Tit

le/A

bst

ract

])

Dat

e of

sea

rch

10

/07/

20

13


32 / 37

Res

ult

s4

71

Dat

abas

eE

MB

AS

E (e

mb

ase

.co

m)

Sea

rch

str

ateg

y ‘o

pia

te a

dd

icti

on

’/exp

op

iat*

:ab

,ti O

R o

pio

id*:

ab,ti

OR

he

roin

*:ab

,ti O

R n

arco

t*:a

b,ti

#1

OR

#2

‘dru

g o

verd

ose

’/exp

ove

rdo

s*:a

b,ti

OR

into

xica

t*:a

b,ti

#4

OR

#5

#3

AN

D #

6‘n

alo

xon

e’/e

xpn

alo

xon

e:ab

,ti O

R n

arca

n:a

b,ti

#8

OR

#9

#7

AN

D #

10

‘an

imal

’/exp

OR

‘in

vert

eb

rate

’/exp

OR

‘an

imal

exp

eri

me

nt’/

exp

OR

‘an

imal

mo

de

l’/ex

p O

R ‘a

nim

al c

ell’

/exp

OR

‘an

imal

ti

ssu

e’/e

xp O

R ‘n

on

hu

man

’/exp

‘hu

man

’/exp

OR

‘no

rmal

hu

man

’/exp

#1

2 A

ND

#1

3#

12

NO

T #

14#

11 N

OT

#1

5 A

ND

[em

bas

e]/l

im

Dat

e of

sea

rch

10

/07/

20

13

Res

ult

s6

41

Dat

abas

eC

INA

HL

Sea

rch

str

ateg

y (M

H “

Su

bst

ance

Ab

use

+”)

TI o

pia

t* O

R T

I op

ioid

* O

R T

I he

roin

* O

R T

I nar

cot*

or

AB

op

iat*

OR

AB

op

ioid

* O

R A

B h

ero

in*

OR

AB

nar

cot*

S1

OR

S2

(MM

“Ove

rdo

se”)

TI o

verd

os*

OR

TI i

nto

xica

t* O

R T

I po

iso

n*

OR

AB

ove

rdo

s* O

R A

B in

toxi

cat*

OR

AB

po

iso

n*

S4

OR

S5

(MH

“N

alo

xon

e+

”)T

X N

alo

xon

eT

X N

alo

xon

eS

7 O

R S

8 O

R S

9S

3 A

ND

S6

AN

D S

10

Lim

ite

rs -

Exc

lud

e M

ED

LIN

E r

eco

rds

Dat

e of

sea

rch

10

/07/

20

13

Res

ult

s6

1

Dat

abas

eW

eb

of S

cie

nce

Sea

rch

str

ateg

y To

pic

=((

op

iat*

OR

op

ioid

* O

R h

ero

in*

OR

nar

cot*

)) A

ND

To

pic

=(o

verd

os*

) A

ND

To

pic

=((

Nar

can

OR

nal

oxo

ne)

)Ti

me

span

=A

ll ye

ars.

Dat

abas

es=

SC

I-E

XP

AN

DE

D, S

SC

I, A

&H

CI.

Dat

e of

sea

rch

10

/07/

20

13

Res

ult

s3

02


33 / 37

I Ann

ex 5

I Cri

teri

a fo

r ri

sk o

f b

ias

asse

ssm

ent:

ran

dom

ised

con

trol

led

tri

als

Item

Ju

dg

emen

tD

escr

ipti

on

1. R

and

om s

equ

ence

gen

erat

ion

(s

elec

tion

bia

s)Lo

w r

isk

Hig

h r

isk

Un

cle

ar r

isk

The

inve

stig

ato

rs d

esc

rib

e a

ran

do

m c

om

po

ne

nt i

n t

he

seq

ue

nce

ge

ne

rati

on

pro

cess

, su

ch a

s ra

nd

om

nu

mb

er

tab

les,

co

mp

ute

r ra

nd

om

nu

mb

er

ge

ne

rato

r, co

in t

oss

ing

, sh

uffl

ing

card

s o

r e

nve

lop

es,

th

row

ing

dic

e, d

raw

ing

lots

, min

imis

atio

nTh

e in

vest

igat

ors

de

scri

be

a n

on

-ran

do

m c

om

po

ne

nt i

n t

he

seq

ue

nce

ge

ne

rati

on

pro

cess

, su

ch a

s o

dd

or

eve

n d

ate

of b

irth

, dat

e (o

r d

ay)

of

ad

mis

sio

n, h

osp

ital

or

clin

ic r

eco

rd n

um

be

r, al

tern

atio

n, j

ud

ge

me

nt o

f th

e cl

inic

ian

, re

sult

s o

f a la

bo

rato

ry t

est

or

a se

rie

s o

f te

sts,

ava

ilab

ility

of t

he

inte

rve

nti

on

Insu

ffici

en

t in

form

atio

n a

bo

ut t

he

seq

ue

nce

ge

ne

rati

on

pro

cess

to

pe

rmit

jud

ge

me

nt o

f lo

w o

r h

igh

ris

k

2. A

lloca

tion

con

ceal

men

t (s

elec

tion

bia

s)Lo

w r

isk

Hig

h r

isk

Un

cle

ar r

isk

Inve

stig

ato

rs e

nro

llin

g p

arti

cip

ants

co

uld

no

t fo

rese

e as

sig

nm

en

t be

cau

se o

ne

of t

he

follo

win

g, o

r an

eq

uiv

ale

nt m

eth

od

, was

use

d t

o c

on

ceal

al

loca

tio

n: c

en

tral

allo

cati

on

(in

clu

din

g te

lep

ho

ne,

we

b-b

ase

d a

nd

ph

arm

acy

-co

ntr

olle

d r

and

om

isat

ion)

; se

qu

en

tial

ly n

um

be

red

dru

g co

nta

ine

rs

of i

de

nti

cal a

pp

ear

ance

; se

qu

en

tial

ly n

um

be

red

, op

aq

ue,

se

ale

d e

nve

lop

es

Inve

stig

ato

rs e

nro

llin

g p

arti

cip

ants

co

uld

po

ssib

ly f

ore

see

assi

gn

me

nts

be

cau

se o

ne

of t

he

follo

win

g m

eth

od

s w

as u

sed

: op

en

ran

do

m a

lloca

tio

n

sch

ed

ule

(e.g

. a li

st o

f ran

do

m n

um

be

rs);

assi

gn

me

nt e

nve

lop

es

wit

ho

ut a

pp

rop

riat

e sa

feg

uar

ds

(e.g

. if e

nve

lop

es

we

re u

nse

ale

d, n

on

-op

aq

ue

or

no

t se

qu

en

tial

ly n

um

be

red

); al

tern

atio

n o

r ro

tati

on

; dat

e o

f bir

th; c

ase

reco

rd n

um

be

r; a

ny

oth

er

exp

licit

ly u

nco

nce

ale

d p

roce

du

reIn

suffi

cie

nt i

nfo

rmat

ion

to

pe

rmit

jud

ge

me

nt o

f lo

w o

r h

igh

ris

k. Th

is is

usu

ally

th

e ca

se if

th

e m

eth

od

of c

on

ceal

me

nt i

s n

ot d

esc

rib

ed

or

no

t d

esc

rib

ed

in s

uffi

cie

nt d

etai

l to

allo

w a

de

finit

e ju

dg

em

en

t

3. B

lind

ing

of p

arti

cip

ants

an

d

pro

vid

ers

(per

form

ance

bia

s)O

bje

ctiv

e ou

tcom

es

Low

ris

k

Hig

h r

isk

Un

cle

ar r

isk

No

blin

din

g o

r in

com

ple

te b

lind

ing

, bu

t th

e re

vie

w a

uth

ors

jud

ge

that

th

e o

utc

om

e is

no

t lik

ely

to

be

influ

en

ced

by

lack

of b

lind

ing

.B

lind

ing

of p

arti

cip

ants

an

d k

ey

stu

dy

pe

rso

nn

el i

s e

nsu

red

, an

d it

is u

nlik

ely

th

at t

he

blin

din

g co

uld

hav

e b

ee

n b

roke

nN

o b

lind

ing

or

inco

mp

lete

blin

din

g, a

nd

th

e o

utc

om

e is

like

ly t

o b

e in

flue

nce

d b

y la

ck o

f blin

din

g.

Blin

din

g o

f ke

y st

ud

y p

arti

cip

ants

an

d p

ers

on

ne

l is

atte

mp

ted

, bu

t it i

s lik

ely

th

at t

he

blin

din

g co

uld

hav

e b

ee

n b

roke

n, a

nd

th

e o

utc

om

e is

like

ly t

o

be

influ

en

ced

by

lack

of b

lind

ing

Insu

ffici

en

t in

form

atio

n t

o p

erm

it ju

dg

em

en

t of l

ow

or

hig

h r

isk

4. B

lind

ing

of p

arti

cip

ants

an

d

pro

vid

ers

(per

form

ance

bia

s)S

ub

ject

ive

outc

omes

Low

ris

kH

igh

ris

k

Un

cle

ar r

isk

Blin

din

g o

f par

tici

pan

ts a

nd

pro

vid

ers

, an

d it

is u

nlik

ely

th

at t

he

blin

din

g co

uld

hav

e b

ee

n b

roke

nN

o b

lind

ing

or

inco

mp

lete

blin

din

g, a

nd

th

e o

utc

om

e is

like

ly t

o b

e in

flue

nce

d b

y la

ck o

f blin

din

g.

Blin

din

g o

f ke

y st

ud

y p

arti

cip

ants

an

d p

ers

on

ne

l is

atte

mp

ted

, bu

t it i

s lik

ely

th

at t

he

blin

din

g co

uld

hav

e b

ee

n b

roke

n, a

nd

th

e o

utc

om

e is

like

ly t

o

be

influ

en

ced

by

lack

of b

lind

ing

Insu

ffici

en

t in

form

atio

n t

o p

erm

it ju

dg

em

en

t of l

ow

or

hig

h r

isk

5. B

lind

ing

of o

utc

ome

asse

ssor

(d

etec

tion

bia

s)O

bje

ctiv

e ou

tcom

es

Low

ris

k

Hig

h r

isk

Un

cle

ar r

isk

No

blin

din

g o

f ou

tco

me

asse

ssm

en

t, b

ut t

he

revi

ew

au

tho

rs ju

dg

e th

at t

he

ou

tco

me

me

asu

rem

en

t is

no

t lik

ely

to

be

influ

en

ced

by

lack

of b

lind

ing

.B

lind

ing

of o

utc

om

e as

sess

me

nt i

s e

nsu

red

, an

d it

is u

nlik

ely

th

at t

he

blin

din

g co

uld

hav

e b

ee

n b

roke

nN

o b

lind

ing

of o

utc

om

e as

sess

me

nt,

and

th

e o

utc

om

e m

eas

ure

me

nt i

s lik

ely

to

be

influ

en

ced

by

lack

of b

lind

ing

.B

lind

ing

of o

utc

om

e as

sess

me

nt,

bu

t lik

ely

th

at t

he

blin

din

g co

uld

hav

e b

ee

n b

roke

n, a

nd

th

e o

utc

om

e m

eas

ure

me

nt i

s lik

ely

to

be

influ

en

ced

by

lack

of b

lind

ing

Insu

ffici

en

t in

form

atio

n t

o p

erm

it ju

dg

em

en

t of l

ow

or

hig

h r

isk

6. B

lind

ing

of o

utc

ome

asse

ssor

(d

etec

tion

bia

s)S

ub

ject

ive

outc

omes

Low

ris

k

Hig

h r

isk

Un

cle

ar r

isk

No

blin

din

g o

f ou

tco

me

asse

ssm

en

t, b

ut t

he

revi

ew

au

tho

rs ju

dg

e th

at t

he

ou

tco

me

me

asu

rem

en

t is

no

t lik

ely

to

be

influ

en

ced

by

lack

of b

lind

ing

.B

lind

ing

of o

utc

om

e as

sess

me

nt i

s e

nsu

red

, an

d it

is u

nlik

ely

th

at t

he

blin

din

g co

uld

hav

e b

ee

n b

roke

nN

o b

lind

ing

of o

utc

om

e as

sess

me

nt,

and

th

e o

utc

om

e m

eas

ure

me

nt i

s lik

ely

to

be

influ

en

ced

by

lack

of b

lind

ing

.B

lind

ing

of o

utc

om

e as

sess

me

nt,

bu

t it i

s lik

ely

th

at t

he

blin

din

g co

uld

hav

e b

ee

n b

roke

n, a

nd

th

e o

utc

om

e m

eas

ure

me

nt i

s lik

ely

to

be

influ

en

ced

b

y la

ck o

f blin

din

gIn

suffi

cie

nt i

nfo

rmat

ion

to

pe

rmit

jud

ge

me

nt o

f lo

w o

r h

igh

ris

k


34 / 37

Item

Ju

dg

emen

tD

escr

ipti

on

7. In

com

ple

te o

utc

ome

dat

a (a

ttri

tion

bia

s)F

or a

ll ou

tcom

es e

xcep

t re

ten

tion

in t

reat

men

t or

dro

pou

t

Low

ris

k

Hig

h r

isk

Un

cle

ar r

isk

No

mis

sin

g o

utc

om

e d

ata

.R

eas

on

s fo

r m

issi

ng

ou

tco

me

dat

a ar

e u

nlik

ely

to

be

rela

ted

to

th

e tr

ue

ou

tco

me

(fo

r su

rviv

al d

ata,

ce

nso

rin

g u

nlik

ely

to

be

intr

od

uci

ng

bia

s).

Mis

sin

g o

utc

om

e d

ata

are

bal

ance

d in

nu

mb

ers

acr

oss

inte

rve

nti

on

gro

up

s, w

ith

sim

ilar

reas

on

s fo

r m

issi

ng

dat

a a

cro

ss g

rou

ps.

Fo

r d

ich

oto

mo

us

ou

tco

me

dat

a, t

he

pro

po

rtio

n o

f mis

sin

g o

utc

om

es

com

par

ed

wit

h o

bse

rve

d e

ven

t ris

k is

no

t en

ou

gh

to

hav

e a

clin

ical

ly r

ele

van

t im

pa

ct o

n t

he

inte

rve

nti

on

eff

ect

est

imat

e.

Fo

r co

nti

nu

ou

s o

utc

om

e d

ata,

pla

usi

ble

eff

ect

siz

e (d

iffe

ren

ce in

me

ans

or

stan

dar

dis

ed

diff

ere

nce

in m

ean

s) a

mo

ng

mis

sin

g o

utc

om

es

is n

ot

en

ou

gh

to

hav

e a

clin

ical

ly r

ele

van

t im

pa

ct o

n o

bse

rve

d e

ffe

ct s

ize

.M

issi

ng

dat

a h

ave

be

en

imp

ute

d u

sin

g ap

pro

pri

ate

met

ho

ds.

All

ran

do

mis

ed

pat

ien

ts a

re r

ep

ort

ed

/an

alys

ed

in t

he

gro

up

th

ey

we

re a

lloca

ted

to

by

ran

do

mis

atio

n ir

resp

ect

ive

of n

on

-co

mp

lian

ce a

nd

co

-in

terv

en

tio

ns

(inte

nti

on

to

tre

at)

The

reas

on

fo

r m

issi

ng

ou

tco

me

dat

a is

like

ly t

o b

e re

late

d t

o t

he

tru

e o

utc

om

e, w

ith

eit

he

r im

bal

ance

in n

um

be

rs o

r re

aso

ns

for

mis

sin

g d

ata

acr

oss

inte

rve

nti

on

gro

up

s.F

or

dic

ho

tom

ou

s o

utc

om

e d

ata,

th

e p

rop

ort

ion

of m

issi

ng

ou

tco

me

s co

mp

are

d w

ith

ob

serv

ed

eve

nt r

isk

is e

no

ug

h t

o in

du

ce c

linic

ally

re

leva

nt

bia

s in

an

inte

rve

nti

on

eff

ect

est

imat

e.

Fo

r co

nti

nu

ou

s o

utc

om

e d

ata,

pla

usi

ble

eff

ect

siz

e (d

iffe

ren

ce in

me

ans

or

stan

dar

dis

ed

diff

ere

nce

in m

ean

s) a

mo

ng

mis

sin

g o

utc

om

es

is e

no

ug

h

to in

du

ce c

linic

ally

re

leva

nt b

ias

in o

bse

rve

d e

ffe

ct s

ize

.‘A

s-tr

eat

ed

’ an

alys

is is

do

ne

wit

h s

ub

stan

tial

de

par

ture

of t

he

inte

rve

nti

on

re

ceiv

ed

fro

m t

hat

ass

ign

ed

at r

and

om

isat

ion

Insu

ffici

en

t in

form

atio

n t

o p

erm

it ju

dg

em

en

t of l

ow

or

hig

h r

isk

(e.g

. nu

mb

er

ran

do

mis

ed

no

t sta

ted

, no

re

aso

ns

for

mis

sin

g d

ata

pro

vid

ed

, nu

mb

er

of d

rop

ou

ts n

ot r

ep

ort

ed

fo

r e

ach

gro

up)

8. S

elec

tive

rep

orti

ng

(rep

orti

ng

bia

s)

Low

ris

k

Hig

h r

isk

Un

cle

ar r

isk

The

stu

dy

pro

toco

l is

avai

lab

le a

nd

all

of t

he

stu

dy’

s p

re-s

pe

cifie

d (

pri

mar

y an

d s

eco

nd

ary)

ou

tco

me

s th

at a

re o

f in

tere

st in

th

e re

vie

w h

ave

be

en

re

po

rte

d in

th

e p

re-s

pe

cifie

d w

ay.

The

stu

dy

pro

toco

l is

no

t ava

ilab

le b

ut i

t is

cle

ar t

hat

th

e p

ub

lish

ed

re

po

rts

incl

ud

e al

l exp

ect

ed

ou

tco

me

s, in

clu

din

g th

ose

th

at w

ere

pre

-sp

eci

fied

(c

on

vin

cin

g te

xt o

f th

is n

atu

re m

ay b

e u

nco

mm

on)

No

t all

of t

he

stu

dy’

s p

re-s

pe

cifie

d p

rim

ary

ou

tco

me

s h

ave

be

en

re

po

rte

d.

On

e o

r m

ore

pri

mar

y o

utc

om

es

is r

ep

ort

ed

usi

ng

me

asu

rem

en

ts, a

nal

ysis

met

ho

ds

or

sub

sets

of t

he

dat

a (e

.g. s

ub

scal

es)

th

at w

ere

no

t pre

-sp

eci

fied

.O

ne

or

mo

re r

ep

ort

ed

pri

mar

y o

utc

om

es

we

re n

ot p

re-s

pe

cifie

d (u

nle

ss c

lear

just

ifica

tio

n f

or

the

ir r

ep

ort

ing

is p

rovi

de

d, s

uch

as

an u

nex

pe

cte

d

ad

vers

e e

ffe

ct).

On

e o

r m

ore

ou

tco

me

s o

f in

tere

st in

th

e re

vie

w a

re r

ep

ort

ed

inco

mp

lete

ly s

o t

hat

th

ey

can

no

t be

en

tere

d in

a m

eta

-an

alys

is.

The

stu

dy

rep

ort

fai

ls t

o in

clu

de

resu

lts

for

a ke

y o

utc

om

e th

at w

ou

ld b

e ex

pe

cte

d t

o h

ave

be

en

re

po

rte

d f

or

such

a s

tud

yIn

suffi

cie

nt i

nfo

rmat

ion

to

pe

rmit

jud

ge

me

nt o

f lo

w o

r h

igh

ris

k


35 / 37

I Annex 6

I Criteria for risk of bias assessment: case–control studies

Selection

1) Adequate definition of the cases

a) yes, with independent validation

b) yes, e.g. record linkage or based on self-reports

c) no description

2) Representativeness of the cases

a) consecutive or obviously representative series of cases

b) potential for selection biases or not stated

3) Selection of controls

a) community controls

b) hospital controls

c) no description

4) Definition of controls

a) no history of disease (end point)

b) no description of source

Comparability

5) Comparability of cases and controls on the basis of the

design or analysis

a) study controls for the most important factor

b) study controls for any additional factor

c) no control or adjustment for potential confounders

Exposure

6) Ascertainment of exposure

a) secure record (e.g. surgical records)

b) structured interview where blind to case/control status

c) interview not blinded to case/control status

d) written self-report or medical record only

e) no description

7) Same method of ascertainment for cases and controls

a) yes

b) no

8) Non-response rate

a) same rate for both groups

b) non-respondents described

c) rate different and no designation

Criteria for risk of bias assessment: cohort studies

Selection

1) Representativeness of the exposed cohort:

a) truly representative of the average in the community

b) somewhat representative of the average in the

community

c) selected group of patients

d) no description of the derivation of the cohort

2) Selection of the non-exposed cohort

a) drawn from the same community as the exposed cohort

b) drawn from a different source

c) no description of the derivation of the non-exposed

cohort

3) Ascertainment of exposure

a) secure record

b) structured interview

c) written self-report

d) no description

4) Demonstration that outcome of interest was not present at

start of study

a) yes

b) no

Comparability

1) Comparability of cohorts on the basis of the design or

analysis

a) study controls for the most important factor

b) study controls for any additional factor

Outcome

1) Assessment of outcome

a) independent blind assessment

b) record linkage

c) self-report

d) no description

2) Was follow-up long enough for outcomes to occur?

a) yes

b) no


36 / 37

b) NOT CLEAR because it is not reported in the paper

c) Intervention was not independent of other changes over

time

Protection against detection bias (intervention is unlikely to

affect data collection)

a) Intervention is unlikely to affect data collection (e.g.

sources and methods of data collection were the same

before and after the intervention)


c) Intervention is likely to affect data collection (e.g. any

change in source or method of data collection before vs.

after the intervention)

Blinded assessment of primary outcome(s)

a) Explicit statement of authors that the primary outcome

variables were assessed blindly OR the outcome

variables are objective, e.g. length of hospital stay, drug

levels as assessed by a standardised test

b) NOT CLEAR if not specified

c) Outcomes were not assessed blindly

Completeness of data set

a) Data set covers 80–100 % of total number of

participants or episodes of care in the study

b) NOT CLEAR if not specified

c) Data set covers less than 80 % of the total number of

participants or episodes of care in the study

3) Adequacy of follow-up of cohorts

a) complete follow-up — all subjects accounted for

b) subjects lost to follow-up unlikely to introduce bias

— small number lost (< 10 % or a description provided

of those lost)

c) no statement

Criteria for risk of bias assessment: interrupted time series

Clearly defined point in time when the intervention occurred.

a) Intervention occurred at a clearly defined point in time


c) Intervention did not occur at a clearly defined point in

time

At least three data points before, and three after, the

intervention.

a) Three or more data points before and three or more data

points recorded after the intervention


c) Fewer than three data points recorded before, and three

data points after, the intervention

Protection against secular changes (the intervention is

independent of other changes).

a) Intervention occurred independently of other changes

over time


TD-AU-14-009-EN-N

I Acknowledgements

We would like to thank John Strang and Rebecca McDonald, King’s College London, and

Nick Welsh, public health physician and consultant in substance use (Cambodia and

Australia), for peer reviewing the paper. Authors: Silvia Minozzi, Laura Amato and Marina

Davoli, Cochrane Drugs and Alcohol Group.

EMCDDA project team: Marica Ferri, Lucas Wiessing, Isabelle Giraudon and Roland Simon.

About the EMCDDA

The European Monitoring Centre for Drugs and Drug Addiction is the hub of drug-related

information in Europe. Its mission is to provide the European Union and its Member States

with ‘factual, objective, reliable and comparable information’ on drugs and drug addiction

and their consequences. Established in 1993, it opened its doors in Lisbon in 1995, and is

one of the European Union’s decentralised agencies. The Centre offers policymakers the

evidence base they need for drawing up drug laws and strategies. It also helps

professionals and researchers pinpoint best practice and new areas for analysis.

Related EMCDDA publications and web information

I Mortality related to drug use in Europe: public health implications, Selected issue, 2011

I Best practice portal

I Preventing overdose deaths, Perspectives on Drugs

These and all other EMCDDA publications are available from

emcdda.europa.eu/publications

Legal notice: The contents of this publication do not necessarily reflect the official opinions of the EMCDDA’s partners, the EU Member States or any institution or agency of the European Union. More information on the European Union is available on the Internet (europa.eu).

Luxembourg: Publications Office of the European Uniondoi: 10.2810/396726 I ISBN 978-92-9168-756-5

© European Monitoring Centre for Drugs and Drug Addiction, 2015Reproduction is authorised provided the source is acknowledged.

This publication is available only in electronic format.

EMCDDA, Praça Europa 1, Cais do Sodré, 1249-289 Lisbon, PortugalTel. (351) 211 21 02 00 I [email protected] emcdda.europa.eu I twitter.com/emcdda I facebook.com/emcdda

http://www.emcdda.europa.eu

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http://www.emcdda.europa.eu/best-practice

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