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Supplementary material
Appendix Table 1. Naloxone distribution model parameters.
Input name Base case (range) Justification Source
Markov model annual transition parameters for UK adaptations
Heroin use to nonoverdose
death (in excess of
background mortality)
0.0075 (0.0025 to
0.0125)
Heroin users are at excess risk for death in addition to overdose. [1]
Heroin use to overdose
First overdose
Second overdose
Subsequent
overdoses
0.09 (0.02 to 0.12)
0.22 (0.05 to 0.30)
0.34 (0.27 to 0.60)
Findings from international studies in North America and Australia demonstrate a high rate of
overdose among young heroin users, that less than 75% of users ever overdose, and that there is a
higher risk for overdose among those who have overdosed previously. A UK study demonstrated
23% of heroin users had ever overdosed and that the mean number of overdoses was 3.6 [2].
[1]
1
Input name Base case (range) Justification Source
Annual relative reduction in
risk for first overdose
0.933 (0.900 to
1.000)
An additional approach used to calibrate the model to extant Australian epidemiologic findings was
to decrease the likelihood of a first-time overdose such that for those who had never overdosed, risk
for first-time overdose was half after 10 years of use; this does not affect the likelihood of repeat
overdoses. The parameter was exponentiated by Coffin and Sullivan to the years elapsed and the
result multiplied by its reference parameter to reduce the likelihood of the event over time.
[1]
Heroin use to discontinuation
of heroin use
0.06 (0.01 to 0.10) The rate of discontinuing heroin use was taken by Coffin and Sullivan from large prospective North
American cohorts.
[1]
Discontinuation of heroin use
to heroin use
0.070 (0.056 to
0.084)
The risk for relapse to heroin use was based on a US study showing 50% relapse over 5 years, with
an age-based reduction in risk for relapse such that relapse was half as likely after 10 years,
resulting in a median duration of heroin use of 15 years.
[1]
Annual relative reduction in
risk for relapse
0.933 (0.900 to
1.000)
This parameter acted as the age-based reduction in the risk for relapse. The parameter was
exponentiated to the preceding number of model cycles and the result multiplied by its reference
parameter to reduce the likelihood of the event over time.
[1]
2
Input name Base case (range) Justification Source
Overdose to discontinuation
of heroin use
0.062 (0.028 to
0.113)
A United States study, examining rates of discontinuing drug use after overdose, found that 26% of
injection drug users sought substance-abuse treatment within 30 days of an overdose event, 75% of
whom enrolled, suggesting an increase in discontinuation of heroin use related to the overdose
event. Coffin and Sullivan thus assumed a relative 10% increase in the likelihood of discontinuing
heroin use after an overdose, ranging on sensitivity analysis from half to double the rate of
discontinuation if there was not an overdose.
[1]
Decision-tree parameters (proportions) used in the UK adaptations
Joint probability that
distributed naloxone is used
each year
0.172 This parameter is calculated from parameters in the next five rows.
Proportion of heroin users
prescribed naloxone
0.30 (0.05 to 0.60) In Scotland (where a publicly-funded naloxone take-home policy is in place) the target is for one
third coverage of injecting drug users, we therefore assumed a distribution of naloxone that reached
30% of heroin users.
Assumption
based on
Reference 3
3
Input name Base case (range) Justification Source
Proportion of overdoses
witnessed
0.85 (0.32 to 0.94) Coffin estimated a base case of 85% of overdoses being witnessed based on United States and
Australian evidence [1]. A UK study demonstrated that 81% of those in the community and not in
treatment and 85% of those in treatment had a witnessed overdose [4]. The lower limit was based
on a US study that showed a lower rate of witnessed overdose (32%) [5] and the upper limit was a
10% increase on the base case.
[1,4,5]
4
Input name Base case (range) Justification Source
Proportion of witnessed
overdoses where naloxone is
available (i.e. hasn’t been lost
or not with the victim at the
time of the overdose)
0.75 (0.40 to 0.85) Evidence from Scotland’s national take-home naloxone program suggests that in 2014/2015 11% of
all naloxone kits supplied was because the previous kit supplied had been lost (739 kits issued out
of 6498 were due to previous kits lost) [6] and from the Welsh national take-home naloxone
program 12% of kits supplied in 2013/2014 were due to lost kits (538 resupplied of which 41%
were due to lost kits – 221 kits out of a total supply of 1802) [7]. Furthermore, a UK prospective
cohort study showed that only 18.5% of heroin users prescribed naloxone actually carry it with
them [8]. Based on a review of evidence and likely real-life scenarios, the N-ALIVE trial being
conducted in the United Kingdom has assumed that only 75% of current or former heroin injectors
on release from prison would still have their naloxone after 4 weeks [9]. Based on these data we
assume that 75% of heroin users who have been prescribed naloxone would be in possession of it at
an overdose.
Assumption
based on
References
[6–9]
5
Input name Base case (range) Justification Source
Proportion of witnesses with
naloxone who attempt to use it
0.90 (0.77 to 0.99) A UK survey of heroin users showed that 89% would use naloxone if they witnessed an overdose
and it had been available [4]. A UK prospective cohort study showed that 77% of heroin users
would administer naloxone in an overdose situation (after training in overdose management and
naloxone provision this figure rose to 99%) [8]. The evaluation of the Welsh naloxone take-home
program found that 88% of drug users and friends and family would be willing to administer
naloxone pre-training and 99% post training [10]. Based on these data we assumed 90% of
witnesses would attempt to use naloxone.
Assumption
based on
References
[4,8,10]
Social network modifier (used
in sensitivity analysis)
1.0 (0.5 to 1.5) Coffin and Sullivan used this assumption to reflect other data points. The point estimate for this
parameter relies on the other parameters, and the range allows for a broader range of error in the
related variables (that is, if heroin users in a given community are more or less likely to use in
groups, this variable would be higher or lower, respectively).
[1]
Proportion who call an ambulance
Proportion who call an
ambulance (no naloxone use)
0.60 (0.30 to 0.80) The evaluation of the Welsh naloxone take-home program found that in the absence of naloxone
distribution an ambulance was called in approximately 60% of overdoses [10].
[10]
6
Input name Base case (range) Justification Source
and then go to accident and
emergency
1.0 (0.50 to 1.0) Table 3.69 of the ‘Overdose and Poisoning’ chapter of the Joint Royal Colleges Ambulance Liaison
Committee United Kingdom Ambulance Services Clinical Practice Guidelines 2016 states that
‘Transfer to further care’ should occur for ‘All patients suffering an opioid overdose whether or not
they have responded to naloxone – the effects of respiratory depression opioid overdose can last 4-5
hours’ [11].
[11]
Proportion who call an
ambulance call after naloxone
use
0.85 (0.55 to 0.95) The evaluation of the Welsh naloxone take-home program found that after naloxone administration
an ambulance was called in approximately 85% of overdoses [10].
[10]
and then go to accident and
emergency
1.0 (0.50 to 1.0) Table 3.69 of the ‘Overdose and Poisoning’ chapter of the Joint Royal Colleges Ambulance Liaison
Committee United Kingdom Ambulance Services Clinical Practice Guidelines 2016 states that
‘Transfer to further care’ should occur for ‘All patients suffering an opioid overdose whether or not
they have responded to naloxone – the effects of respiratory depression opioid overdose can last 4-5
hours’ [11].
[11]
Proportion who survive overdose
7
Input name Base case (range) Justification Source
Proportion who survive an
unwitnessed overdose
0.90 (0.80 to 0.94) Based on the evidence that 90% of overdoses result in survival without emergency medical care or
administration of naloxone by nonmedical first responders.
[13]
Reduction in survival for
second overdose
0.015 (0.000 to
0.020)
To account for the decrease in survival for subsequent overdoses. [1]
Reduction in survival for
subsequent overdoses
0.015 (0.000 to
0.020)
To account for the decrease in survival for subsequent overdoses. [1]
Proportion who survived a
witnessed overdose (no
naloxone or ambulance)
0.918 (0.800 to
0.940)
To account for the increase in survival when an overdose is witnessed the model set survival to
91.8% for a witnessed overdose where no ambulance was called or naloxone used [1]. This was in
line with UK studies suggesting a fatality rate of witnessed overdose of 7% [3].
[1]
Relative increase in survival
during a witnessed overdose
when an ambulance was
called (no naloxone)
1.013 (0.980 to
1.035)
This accounts for the relative increase in survival from the baseline of surviving an unwitnessed
overdose (i.e. 90%). The absolute value is 0.930, in line with UK studies suggesting a fatality rate
of witnessed overdose of 7% [3].
Assumption
based on
Reference
[3]
8
Input name Base case (range) Justification Source
Relative increase in survival
during a witnessed overdose
with naloxone
1.067 (1.035 to
1.089)
This accounts for the relative increase in survival from the baseline of surviving an unwitnessed
overdose (i.e. 90%). The absolute value is 0.980. Studies in the United Kingdom and Germany
suggest that 95% (21 out of 22) [14] to 100% [8,12] of cases where naloxone is used result in
survival. This is in line with assumptions made by Coffin and Sullivan.
Assumption
based on
References
[1,8,12,14]
UK model costs
IM naloxone (1 mg/mL, 2 mL
prefilled syringe of
Prenoxad®)
£15.30 is the price
for one
Kit costs incurred after each overdose where naloxone was administered and biannually among
active heroin user to account for naloxone going out of date and for losses.
Prenoxad used as it is licensed for use in the community.
[15]
Distribution £8.50 Distribution into drug services. Coffin and Sullivan assumed in addition to drug costs were other
component costs ($3) and staff time and distribution ($10).
[1]
Training costs for users,
family and friends
£124 per kit for
first-time
administration
Training the individuals (one to one about 10 to 30 mins): Drug services – community (per-care
contact).
[16]
9
Input name Base case (range) Justification Source
Ambulance £233 Cost of see, treat, convey. [17]
Accident and emergency visit £278 VB03Z: emergency medicine, category 3 investigation with category 1–3 treatment. [17]
Utility values
Heroin user 0.80 (0.73 to 0.90) Estimates from Coffin and Sullivan derived from a United States paper involving clients at a
midwestern United States substance-abuse treatment-intake centre, which included a 6-month
follow-up survey that may have captured those not actively seeking treatment and documented a
utility of 0.80 by SF-6D methodology and a 6.5% improvement for those who achieved interim
abstinence.
[1]
Relative increase in utility for
heroin user in recovery
1.07 (1.00 to 1.13) To be consistent and conservative, Coffin and Sullivan used the 6.5% improvement in utility from
the study outlined above, although the SF-6D methodology has been found to be poorly responsive
to changes in drug use and a study of opioid maintenance therapy found a relative improvement of
16% in utility for a heroin user. Utility was coded to never exceed 1.0 when values were set to
upper extremes simultaneously.
[1]
SF-6D, short form-6 domains
10
References
[1] Coffin PO, Sullivan SD. Cost-effectiveness of distributing naloxone to heroin users for lay overdose
reversal. Ann Intern Med 2013;158:1–9.
[2] Gossop M, Griffiths P, PowisB, etal. Frequency of non-fatal heroin overdose: survey of heroin users
recruited in non-clinical settings. BMJ 1996;313:402.
[3] Bird SM, Parmar MKB, Strang J. Take-home naloxone to prevent fatalities from opiate-overdose:
protocol for Scotland’s public health policy evaluation, and a new measure to assess impact. Drugs
2015;22:66–76.
[4] Strang J, Powis B, Best D. Preventing opiate overdose fatalities with take-home naloxone: pre-launch
study of possible impact and acceptability. Addiction 1999;94:199–204.
[5] Davidson PJ, McLean RL, Kral AH, et al. Fatal heroin-related overdose in San Francisco, 1997–2000:
a case for targeted intervention. J Urban Health 2003;80:261–73.
[6] National Health Service Scotland Information Services Division. National Naloxone Programme
Scotland—Monitoring Report 2014/15. Edinburgh, Scotland: Scotland Information Services Division,
2015.
[7] Public Health Wales. Take home naloxone 2013–14. 2014. Available from:
http://www2.nphs.wales.nhs.uk:8080/SubstanceMisuseDocs.nsf/Public/
ECF9E1D7909A8ABC80257E0A0059E887/$file/Naloxone%20report%202014%20FINAL.pdf?
OpenElement. [Accessed August 25, 2016].
[8] Strang J, Manning V, Mayet S, et al. Overdose training and take-home naloxone for opiate users:
prospective cohort study of impact on knowledge and attitudes and subsequent management of overdoses.
Addiction 2008;103:1648–57.
[9] Strang J, Bird SM, Parmar MKB. Take-home emergency naloxone to prevent heroin overdose deaths
after prison release: rationale and practicalities for the N-ALIVE randomized trial. J Urban Health
2013;90:983–96.
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[10] Bennett T, Holloway K. The impact of take-home naloxone distribution and training on opiate
overdose knowledge and response: an evaluation of the THN Project in Wales. Drugs (Abingdon Engl)
2012;19:320–8.
[11] Joint Royal Colleges Ambulance Liaison Committee, Association of Ambulance Chief Executives.
UK Ambulance Services Clinical Practice Guidelines. London: Joint Royal Colleges Ambulance Liaison
Committee, 2016.
[12] Dettmer K, Saunders B, Strang J. Take home naloxone and the prevention of deaths from opiate
overdose: two pilot schemes. BMJ 2001;322:895–6.
[13] Coffin PO, Sullivan SD. Cost-effectiveness of distributing naloxone to heroin users for lay overdose
reversal in Russian cities. J Med Econ 2013;16:1051–60.
[14] Bennett T, Holloway K. Evaluation of the Take Home Naloxone Demonstration Project. Glamorgan,
Wales: University of Glamorgan, 2011.
[15] British Medical Association, Royal Pharmaceutical Society. British National Formulary (BNF) 67.
London: BMJ Group and Pharmaceutical Press, 2016.
[16] Curtis L. Unit Costs of Health and Social Care 2015. Kent, UK: Personal Social Services Research
Unit, University of Kent, 2015.
[17] Department of Health. NHS reference costs 2014 to 2015. 2015.Available from:
https://www.gov.uk/government/publications/nhs-reference-costs-2014-to-2015. [Accessed August 25,
2016].
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