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Injection career trajectories among illicit drug users in Vancouver, Canada Werb, Dan 2013

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!INJECTION!CAREER!TRAJECTORIES!AMONG!ILLICIT!DRUG!USERS!IN!VANCOUVER,!CANADA!!!by##Dan#Werb##M.Sc.,#The#University#of#British#Columbia,#2010##B.A.,#McGill#University,#2002##A#THESIS#SUBMITTED#IN#PARTIAL#FULFILLMENT#OF##THE#REQUIREMENTS#FOR#THE#DEGREE#OF##Doctor#of#Philosophy##in###The#Faculty#of#Graduate#and#Postdoctoral#Studies#(Health#care#and#epidemiology)##THE#UNIVERSITY#OF#BRITISH#COLUMBIA##(Vancouver)##October#2013##?#Dan#Werb,#2013#! !!! !# ii#ABSTRACT!!Background:!Though#vast#resources#have#been#allocated#toward#the#prevention#of#illicit# drug# use,# the# prevalence# of# injection# drug# use# remains# high# globally.# This#thesis# therefore# sought# to# identify# factors# that# influence# the# natural# history# of#injection#drug#use#by:#systematically#reviewing#the#epidemiologic# literature#on#the#prevention# of# injecting# initiation;# identifying# the# role# of# drugYrelated# and#personalityYbased# risk# factors# in# increasing# the# risk# of# injecting# initiation;# and#evaluating# the# role# of# harm# reduction# interventions# in# potentially# modifying# the#likelihood#of#injecting#cessation#among#injection#drug#users#(IDU).###Methods:! StreetYinvolved# youth# and# IDU# participating# in# ongoing# prospective#observational# cohorts# in# Vancouver,# Canada,# completed# semiYannual# interviewerYadministered#questionnaires.#Longitudinal#epidemiologic#methods#were#applied# to#assess# the# association# between# selected# drugYrelated,# personalityYbased# (e.g.,#sensation# seeking# level),# and# structural# factors# on# the# outcomes# of# interest,#while#controlling# for# a# variety# of# potential# sociodemographic# and# behavioural#confounders.#!Results:!The#systematic#review#found#that#a#limited#set#of#interventions#to#prevent#injecting#has#been#scientifically#evaluated#and#implemented.#A#longitudinal#analysis#of# injecting# initiation# found# that# nonYinjection# crystal#methamphetamine# use#was#significantly# associated#with# injecting# initiation# among# streetYinvolved# youth.# The#adaptation# of# a# sensation# seeking# scale# for# use# in# a# related# longitudinal# analysis#found# that#higher#sensation#seeking#was#associated#with# injecting#and#risk# factors#for#injection#initiation.#Finally,#in#a#longitudinal#analysis#conducted#over#a#span#of#15#years,# rates# of# injecting# cessation# among# a# cohort# of# IDU# increased# significantly#despite# a# substantial# expansion# in# needle# and# syringe# program# (NSP)#implementation.#!Conclusions:! This# thesis# identified# gaps# in# current# responses# to# preventing#injection# drug# use.# A# set# of# drugYrelated# and# personalityYbased# factors# associated#with# increased# risk# of# injecting# initiation# among# streetYinvolved# youth# was# also#identified,# including# nonYinjection# crystal# methamphetamine# use# and# higher#sensation#seeking.#Further,#an#increase#in#the#rate#of#injecting#cessation#among#IDU#occurred#during#a#period#of#substantial#expansion#of#NSP#sites#in#Vancouver.#These#results# suggest# that# resources# should# be# allocated# towards# the# development# of#interventions#to#prevent#injection#initiation,#and#that#harm#reduction#interventions#should# be# considered# complementary# to# broader# efforts# to# reduce# both# injection#drug#use#and#related#harms.### ## iii#PREFACE!! This#statement#certifies#that#the#work#presented#in#this#thesis#was#conceived,#conducted,#written#and#disseminated#by#Dan#Werb#(DW).#All#research#described#in#this# dissertation# was# conducted# under# the# University# of# British#Columbia/Providence#Health#Care#Research#Ethics#Board#approval#(certificate#H12Y02419).#The#coYauthors#of#the#manuscripts,#including#Dr.#Evan#Wood#(EW),#Dr.#Jane#Buxton#(JB),#Dr.#Jeannie#Shoveller#(JS),#Dr.#Chris#Richardson#(CR),#Dr.#Thomas#Kerr#(TK),#Dr.#Julio#Montaner#(JM),#and#Mr.#Greg#Rowell#(GR)#made#contributions#only#as#is# commensurate# with# supervisory# committee,# collegial# or# coYinvestigator# duties.#The#principal#investigators#of#the#ARYS#study#(EW)#and#the#VIDUS#study#(TK),#from#which# the#dataYdriven# analyses#were#derived,# had# access# to# all# of# the#data# and# as#corresponding#authors#take#full#responsibility#for#the#integrity#of#the#results#and#the#accuracy#of#the#statistical#analyses.#With#substantive#input#from#coYsupervisors#EW#and# JB,# DW#designed# the# studies# and#wrote# the# research# protocol.#With# guidance#and# input# from# EW,# JB,# JS,# CR,# TK,# and# JM,# DW# performed# the# research# and#conducted#all#statistical#analyses#described#in#Chapters#4,#5#and#6.#DW#designed#and#led# the# systematic# review# presented# in# Chapter# 3# and,# in# collaboration# with# GR,#conducted#the#search#strategy#and#selected#eligible#studies#for#final#inclusion.#EW,#JB,#JS,#CR,#and#GR#reviewed#the#material#presented#in#Chapter#3#and#approved#the#final#version# of# the#manuscript# for# submission.# EW,# JB,# JS,# CR,# TK,# and# JM# contributed#scientific# input# to# the#material# in#Chapter#4# and#approved# the# final# version#of# the#manuscript#for#submission.#EW,#JB,#JS,#CR,#TK,#and#JM#provided#scientific#input#and#approved#the#final#version#of#the#manuscript#presented#in#Chapter#5.##EW,#JB,#JS,#CR,#TK,# and# JM# provided# scientific# input# and# approved# the# final# version# of# the#manuscript# presented# in# Chapter# 6.# All#manuscripts# contained# in# this# thesis#were#prepared,#written#and#edited#by#DW.#Final#drafts#of#the#manuscripts#were#prepared#following# the# inclusion# of#material# based# on# comments# from# all# coYauthors# listed#above,# the# journal# editors# and# external# peer# reviewers.# The# analysis# presented# in#Chapter#6#is#currently#in#press:### iv#1. Werb#D,#Kerr#T,#Buxton#J,#Shoveller#J,#Richardson#C,#Montaner#J,#Wood#E.# Patterns# of# injection# drug# use# cessation# during# an# expansion# of#syringe# exchange# services# in# a# Canadian# setting.# Drug% and% Alcohol%Dependence,#2013.###The#analyses#presented#in#Chapters#3,#4#and#5#are#under#review:## 1. Werb# D,# Buxton# J,# Shoveller# J,# Richardson# C,# Rowell# G,# Wood# E.#Strategies# for# preventing# the# initiation# of# injection# drug# use:# A#systematic#review.#Under#review.##2. Werb#D,#Kerr#T,#Buxton#J,#Shoveller#J,#Richardson#C,#Montaner#J,#Wood#E.# Crystal# methamphetamine# and# injecting# initiation# among# streetYinvolved#youth#in#a#Canadian#setting.#Under#review.##3. Werb#D,#Richardson#C,#Kerr#T,#Buxton#J,#Shoveller#J,#Montaner#J,#Wood#E.# Development# of# a# brief# substance# use# sensation# seeking# scale:#Validation#and#prediction#of#injection#drug#use.#Under#review.#### ## v#TABLE!OF!CONTENTS!!Abstract#..........................................................................................................................................................#ii#Preface#..........................................................................................................................................................#iii#Table#of#contents#........................................................................................................................................#v#List#of#tables#................................................................................................................................................#ix#List#of#figures#...............................................................................................................................................#x#Acknowledgments#....................................................................................................................................#xi#Dedication#.................................................................................................................................................#xiii#Chapter#1:#Background,#rationale#and#objectives#........................................................................#1#1.1## The#epidemiology#of#injection#drug#use#and#bloodYborne#diseases#........................#1#1.2## Modifying#injection#drug#use#patterns#.................................................................................#3#1.3## Research#aims#.................................................................................................................................#4#1.4## Study#setting#....................................................................................................................................#6#1.5## Conceptual#framework#................................................................................................................#8#1.5.1#Risk#environment#theory#..........................................................................................................#8#1.5.2#Personality#theory:#Sensation#seeking#.......................................................................#10#1.5.3#Life#course#theory#...............................................................................................................#11#1.6## Study#objectives#and#hypotheses#.........................................................................................#12#1.7## Study#design#and#methods#......................................................................................................#14#1.8## Summary#........................................................................................................................................#16#Chapter#2:#The#natural#history#of#injection#drug#use#..............................................................#19#2.1#Introduction#....................................................................................................................................#19#2.2#Methods##...........................................................................................................................................#20## vi#2.2.1#Search#Strategy#.....................................................................................................................#20#2.3#Results#...............................................................................................................................................#20#2.3.1#Initiation#of#injection#drug#use#......................................................................................#20#2.3.2#Longitudinal#patterns#of#injecting#drug#use#............................................................#24#2.3.3#InjectionYrelated#mortality#..............................................................................................#28#2.4#Discussion#........................................................................................................................................#30#Chapter#3:#A#systematic#review#of#interventions#to#prevent#injection#drug#use#.........#34#3.1#Introduction#....................................................................................................................................#34#3.2#Methods#............................................................................................................................................#34#3.2.1#Eligibility#criteria#.................................................................................................................#35#3.2.2#Information#sources#...........................................................................................................#35#3.2.3#Study#selection#.....................................................................................................................#36#3.2.4#Data#collection#process#.....................................................................................................#36#3.2.5#Quality#assessment#.............................................................................................................#36#3.2.6#Risk#of#publication#bias#.....................................................................................................#36#3.3#Results#...............................................................................................................................................#37#3.3.1#Study#selection#and#characteristics#.............................................................................#37#3.3.2#Methodological#quality#assessment#............................................................................#37#3.3.3#Results#of#individual#studies#..........................................................................................#38#3.4#Discussion#........................................................................................................................................#42#Chapter#4:#Crystal#methamphetamine#injecting#initiation#among#streetYinvolved#youth#in#a#Canadian#setting##...............................................................................................................#48#4.1#Background#.....................................................................................................................................#48## vii#4.2#Methods#............................................................................................................................................#48#4.3#Results#...............................................................................................................................................#50#4.4#Discussion#........................................................................................................................................#52#Chapter#5:#The#development#of#a#brief#substance#use#sensation#seeking#scale:#Validation#and#prediction#of#injection#drug#use#........................................................................#61#5.1#Introduction#....................................................................................................................................#61#5.2#Methods##...........................................................................................................................................#64#5.2.1#Scale#Development#and#Evaluation#.............................................................................#64#5.2.2#Hypothesis#Testing#.............................................................................................................#66#5.3#Results#...............................................................................................................................................#68#5.4#Discussion#........................................................................................................................................#71#Chapter#6:#Patterns#of#injection#drug#use#during#an#expansion#of#syringe#exchange#services#in#Vancouver#...........................................................................................................................#82#6.1#Introduction#....................................................................................................................................#82#6.2#Methods##...........................................................................................................................................#84#6.3#Results#...............................................................................................................................................#87#6.4#Discussion#........................................................................................................................................#89#Chapter#7:#Discussion,#future#research,#conclusions#............................................................#100#7.1## Summary#of#findings#..............................................................................................................#100#7.2# Study#contributions#.................................................................................................................#103#7.3# Study#strengths#and#limitations#.........................................................................................#105#7.4# Recommendations#....................................................................................................................#106#7.5# Future#research#.........................................................................................................................#108## viii#7.6## Conclusions#................................................................................................................................#111#References##..............................................................................................................................................#115### ## ix#LIST!OF!TABLES!!Table# 1.# Summary# of# studies# evaluating# interventions# to# prevent# the# initiation# of#injection# drug# use.???????????????????????????????????# 47#Table#2.#Baseline#characteristics#of# injectionYna?ve#streetYinvolved#youth#according#to#nonYinjection#crystal#methamphetamine#use#in#Vancouver,#Canada???????#58#Table# 3.# Unadjusted# and# adjusted# hazard# ratios# for# factors# related# to# initiation# of#injection#drug#use# among# streetYinvolved# youth# in#Vancouver,# Canada,# 2005Y2010#??????????????????????????????????????????????#59#Table#4.#Items#for#a#modified#brief#substance#use#sensation#seeking#scale?????#77#Table# 5.# Correlations# between# modified# sensation# seeking# scale# score# and#sociodemographic,#drugYrelated,#and#behavioural#variables#????????????#78#Table#6.#Adjusted#odds#ratios#for#multivariate#models#on#factors#related#to#sensation#seeking#score#on#a#modified#brief#scale#among#streetYinvolved#youth#in#Vancouver,#Canada,# 2005Y2010# ??????????????????????????????????# 80#Table#7.#Univariate# correlates#of# injecting# cessation#among# injection#drug#users# in#Vancouver,#1996#?#2010#????????????????????????????????#95#Table# 8.# Multivariate# generalized# estimating# equation# analysis# of# correlates# of#injecting#cessation#among#injection#drug#users#in#Vancouver????????????#96#!! !# x#LIST!OF!FIGURES!!Figure# 1.! Conceptual#model# to# investigate# injection# transition# events# among# illicit#drug# users# in# Vancouver#???????????????????????????????#18#Figure#2.!Flow#chart#of#screening#and#selection#process???????????????#46#Figure# 3.# Cumulative# hazard# of# injection# initiation# among# streetYinvolved# youth#stratified#by# crystal#methamphetamine#use# in#Vancouver,# Canada,#October#2005#?#December#2010?????????????????????????????????????#60#Figure#4.#Scree#plot#for#modified#sensation#seeking#scale??????????????.#81#Figure#5.#Annual#proportion#of#injection#drug#users#reporting#injection#cessation#in#past#6#months#in#Vancouver,#1996#?#2010#??????????????????????.#97#Figure#6.#Annual#proportion#of#injection#drug#users#reporting#injecting#cessation#and#crude#number#of#sterile#syringes#distributed#in#Vancouver,#1996#?#2010#?????#98#Figure#7.#Approximate# location#of#needle# and# syringe#programmes# in#Vancouver?s#downtown#eastside#neighbourhood,#2010#?????????????????????...##99!%###!! !# xi#ACKNOWLEDGMENTS!!! The# research# contained# in# this# dissertation# would# not# have# been# possible#without# the# contribution# of# the# participants# of# the# AtZRisk# Youth# Study# and# the#Vancouver# Injection# Drug# Users# Study.# I# am# indebted# to# their# contribution# to#improving# the# health# and# wellZbeing# of# people# who# use# drugs# in# Vancouver# and#elsewhere# through# their# participation# in# these# studies.# It# is# my# hope# that# the#findings#presented#in#this#dissertation#can#contribute,# in#some#way,#to#this#effort.# I#would# also# like# to# thank# all# past# and#present# study# interviewers,# field# staff,# study#nurses,#and#staff#at#the#BC#Centre#for#Excellence#in#HIV/AIDS#for#their#contributions,#and# in# particular# Caitlin# Johnston,# Deborah# Graham,# Peter# Vann,# Carmen# Rock,#Jennifer#Matthews#and#Tricia#Collingham,#as#well#as#the#study#coZinvestigators#and#my#coZauthors.### Support# for# this# dissertation# was# generously# provided# by# the# Trudeau#Foundation,# as# well# as# by# the# Canadian# Institutes# for# Health# Research# through# a#Banting#and#Best#Canada#Graduate#Scholarship.# In#addition,# I# thank# the#BC#Centre#for# Excellence# in#HIV/AIDS# for# salary# support# during# the# entirety# of#my# graduate#studies.### The# advice# and# guidance# of# my# colleagues# and# student# peers# has# proved#invaluable#throughout#the#development#of#this#work.#In#particular,#Ms.#Danya#Fast,#Dr.# MZJ# Milloy,# Dr.#Will# Small,# Dr.# Brandon#Marshall,# and# Dr.# Lindsey# Richardson#provided# sage# advice# and# encouragement# throughout# my# studies,# and# I# am# truly#indebted#to#them#for#their#ongoing#friendship#and#support.### xii## My#committee#members,#Drs.# Jeannie#Shoveller#and#Chris#Richardson,#have#gone# far# beyond# in# their# training,# support# and# guidance# and# I# offer# them# my#heartfelt#thanks.#My#coZsupervisor,#Dr.#Jane#Buxton,#has#been#an#exceptional#source#of# mentorship# and# guidance# throughout# my# entire# graduate# studies,# and# has#consistently#provided#me#with#invaluable#insight#into#the#policy#implications#of#my#work,#and#for#that#I#thank#her#deeply.#I#also#extend#my#endless#thanks#and#gratitude#to#Dr.#Thomas#Kerr,#who#has#been#involved#in#my#studies#and#career#development#since#the#beginning.#I#deeply#value#his#hard#work#in#helping#me#develop#my#capacity#to# become# an# independent# investigator.# Finally,#my# coZsupervisor# Dr.# Evan#Wood#has#been#an#unshakeable# foundation#throughout#my#studies,#and#the#depths#of#his#commitment#to#my#development,#as#well#as#his#patience#and#mentorship,#know#no#bounds.#I#cannot#thank#him#enough.## Beyond#my#colleagues,# I# have#been# supported#by#a#wide#network#of# family#and#friends,#all#of#whom#have#provided#me#with#invaluable#support#throughout#my#studies.#In#particular,#I#would#like#to#thank#my#parents#Ron#and#Elly#Werb#for#their#endless#faith#in#me,#as#well#as#my#brother#Justin#Werb,#my#sister#Jessica#Werb,#and#my# extended# family# for# their# friendship# and# love.# I# would# also# like# to# thank# my#friends# Pat# Placzek,# Luke# Bryant,# A.J.# Bond,# and# Rich# Maerov# for# the# deep#friendships# that#we#have#built# together# and# that# sustain#me#daily.# Finally,# I# thank#Miranda#Elliott#for#her#affection#and#patience.#! !# xiii#DEDICATION! %%%For%my%parents# ## 1#CHAPTER!1:!BACKGROUND,!RATIONALE!AND!OBJECTIVES!1.1!! The!epidemiology!of!injection!drug!use!and!bloodQborne!diseases!# Beginning# in# the# early#19th# century,# techniques# to# synthesize#waterZsoluble#crystalline# salts#were# applied# to# the# production# of#many#pharmacotherapies,# thus#facilitating# injection# of# these# substances# directly# into# the# bloodstream.1# This#technological# advance# spurred# the# popularization# and# standardization# of#intravenous# drug# administration,# vastly# improving# the# efficiency# of#pharmacotherapy#delivery.1#The#practice#of#administering#psychotropic#substances#through#injection#outside#of#a#clinical#therapeutic#context#was,#subsequently,#taken#up# by# illicit# drug# users# in# a# variety# of# settings,# particularly# among# those# using#stimulants#and#opioids.2,#3# Internationally,# this#behaviour#now#represents#a# critical#source#of#health#and#social#harm.4##Despite# the# introduction# of# international# criminal# sanctions# aimed# at#suppressing# illicit# drug# markets,5# interdiction# strategies,6# and# a# variety# of#preventive# interventions,7,# 8# injection# drug# use*#is# at# historically# high# levels# in#settings#across#the#globe.9#A#global#estimate#published#in#2008#suggested#that#there#are# approximately# 16# million# people# who# inject# drugs# (IDU)# worldwide,10# the#majority# of# whom# are# located# in# China,# the# United# States,# and# the# Russian#Federation.# The# United# Nations# Office# on# Drugs# and# Crime# estimates# that# the#number# of# countries# reporting# injection# drug# use# has# increased# over# the# past#########################################################*#For#the#remainder#of#this#thesis,#?injection#drug#use?#refers#to#the#illicit#intravenous#administration#of#psychotropic#substances#outside#of#a#clinical#therapeutic#context## 2#decade,9#with#roughly#75%#of#the#world?s#200#countries#now#reporting#this#behavior#among#their#populations.10##The# spread# of# injection# drug# use# represents# a# major# challenge# to# public#health# systems# given# the#many# serious#health#harms# associated#with# this# activity,#particularly# the# dramatically# heightened# risk# of# human# immunodeficiency# virus#(HIV)# and# hepatitis# C# (HCV)# transmission,11,# 12# fatal# drug# overdose,13# drug#dependence,14,# 15# and# infections# at# injection# puncture# sites.16Z18# Indeed,# injection#drug# use# has# been# implicated# in# approximately# oneZthird# of# all# HIV# infections#outside# of# SubZSaharan# Africa,# which# has# resulted# in# an# estimated# 3# million# IDU#infected# worldwide,# with# some# settings# particularly# impacted# by# injectionZdriven#HIV# epidemics.19# In# China,# the# United# States# and# the# Russian# Federation,# HIV#prevalence# among# IDU# exceeds# 10%.10# Further,#HIV#prevalence# also# remains# high#among# IDU# in# Latin# America# (29%# of# IDU# infected),# Eastern# Europe# (27%),# and#Southeast# Asia# (17%).9# Additionally,# IDU# are# burdened# with# unacceptably# high#levels#of#HCV#infection,#with#estimates#suggesting#that#over#50%#of#IDU#are#infected#with#HCV#across#49#countries#and#territories,#with#IDU#populations#in#some#settings#experiencing# HCV# prevalence# of# up# to# 95%.20# In# response# to# these# ongoing#epidemics,#a#large#body#of#scientific#literature#has#identified#a#number#of#risk#factors#for#bloodZborne#disease#transmission#among#IDU#populations,#and#as#a#result,#a#set#of# evidenceZbased# international# guidelines# have# been# developed# in# an# effort# to#reduce#the#global#burden#of#disease#experienced#by#IDU.21### 3#1.2!! Modifying!injection!career!trajectories!# In#recognition#of#the#negative#health# impacts#associated#with# injection#drug#use,#experts#have#long#called#for#the#prioritization#of#the#prevention#of#injecting#and#the# expansion# of# strategies# to# reduce# injecting,# such# as# addiction# treatment.4,# 22#Despite# these# calls,# governments# often# continue# to# allocate# resources# towards#ineffective# abstinenceZoriented# antiZdrug# education# and# social# marketing#campaigns,7,#8#with#substantially#less#effort#devoted#to#develop,#implement#or#bring#to#scale#proven#interventions#to#modify#the#incidence#of#injection#transition#events#(e.g.,# decreasing# initiation# and# increasing# cessation# of# injection# drug# use)# or# the#risks#associated#with#ongoing#injection.#This#situation#persists#despite#the#fact#that#experts#have#called#for#the#prioritization#of#interventions#to#prevent#the#initiation#of#injection# drug# use# and# related# harms.4,# 22# For# example,# clinical,# evidenceZbased#interventions# such# as# methadone# maintenance# therapy# have# been# shown# to#promote# injection#cessation#and#contribute# to#reductions# in# the# length#of# injection#trajectories,23,# 24# while# also# reducing# HIV# risk# behaviours# such# as# used# syringe#sharing24Z26# and# improving#uptake#of#HIV#antiretroviral# therapy.27Z29#Despite# these#positive# outcomes,# however,# the# provision# of# methadone# maintenance# therapy#remains#low#globally.#In#the#United#States,#for#instance,#it#is#estimated#that#less#than#1# in# 8# opioidZdependent# IDU# have# access# to# some# form# of# opioid# substitution#treatment,#while#in#China,#it#is#estimated#that#only#1#in#33#IDU#have#access.30#In#the#Russian# Federation,# the# use# of# methadone# is# illegal,# with# dire# consequences,# as#outlined#above.#Similarly,#while#needle#and#syringe#programmes#(NSPs)#have#been#shown#to#contribute# to#reductions# in#used#syringe#sharing#and#thereby#reduce#the## 4#risks# associated# with# ongoing# injection,# coverage# of# these# services# worldwide# is#critically#low,#with#an#average#of#22#sterile#syringes#distributed#annually#per#IDU#in#the#United#States,#32#sterile# syringes#distributed#annually#per# IDU# in#China,# and#4#sterile#syringes#distributed#annually#per#IDU#in#the#Russian#Federation.30#The# development# and# implementation# of# interventions# to#modify# injection#careers,# including# those# that# reduce# the# harms# associated#with# ongoing# injection,#represent# urgent# public# health# priorities.# In# addition# to# barriers# related# to# the#implementation# of# currently# available# effective# interventions,# many# scientific#challenges#remain.#For#example,#while#clinical#treatment#exists#for#opioid#users#(e.g.,#opioid#agonist# therapy),#no#equivalent# treatment#options#have#been#developed# for#stimulant# users,# including# individuals# experiencing# amphetamine# and# cocaine#dependence.4# This# has# implications# for# a# range# of# injectionZrelated# harms,#particularly#among#stimulant#users.31,#32#A#further#complication#arises#from#the#fact#that#IDU#experience#a#set#of#complex,#evolving#risks#across#their#injection#drugZusing#careers,#ranging#from#varied#levels#of#HIV#risk#behaviours#associated#with#differing#injection# career# trajectories,14,# 15,# 33# to# the# potential# that# ongoing# injecting# among#established#IDU#may#facilitate#injecting#initiation#among#nonZinjecting#drug#users.31,#34,#35##1.3!! Research!aims!# Despite#the#existing#research#in#this#area,#major#gaps#remain#in#the#scientific#evidence# base# regarding# injection# transition# events,# defined# as# the# initiation# and#cessation#of#injection#use.#First,#a#relatively#small#body#of#quantitative#literature#has## 5#investigated#factors#that#heighten#the#risk#of#injection#initiation,22,#31,#36Z42#with#most#of#these#largely#restricted#to#examinations#of#the#impact#of#sociodemographic#(e.g.,#gender#and#ethnicity)#and#specific#drugZrelated#risk#factors#(e.g.,#frequency#of#heroin#and#cocaine#use).31,#35,#36,#43Z47#However,#the#potential#impact#of#the#use#of#other#drugs,#such#as#crystal#methamphetamine,#as#well#as#psychosocial#factors,#such#as#sensation#seeking,# on# the# risk# of# injection# initiation# among# streetZbased# drugZusing#populations# remains# obscure.# This# situation# persists# despite# the# U.S.# National#Institute#of#Drug#Abuse#having#identified#research#into#psychosocial#risk#factors#for#drugZrelated#harms#as#a#priority#research#area.48,#49#Second,#studies#have#suggested#that# established# IDU# may# play# roles# in# modifying# the# likelihood# of# injection#transition# events# among# their# peers# ?# both# with# respect# to# initiation31,# 35# and#cessation50#of#injection#?#though#more#research#into#the#nature#of#this#phenomenon#is# required.# Third,# ongoing# injection# careers# are# marked# by# risk# behaviours#associated# with# HIV# and# HCV# transmission.15,# 51# Reducing# such# risk# behaviours#remains#a#public#health#priority,#and#the#implementation#of#harm#reduction#services#such# as# NSPs# has# repeatedly# shown# to# be# effective# in# this# regard.52Z55# Fourth,#evaluating#the#risk#for#injection#cessation#events#within#the#context#of#an#expansion#of#NSPs# is# therefore# necessary# to# address# unproven# concerns# that#NSPs#may# lead#IDU#to#prolong#their#injection#drug#use#or#result#in#other#drugZrelated#harms#such#as#overdose# fatality.56,# 57# As# such,# further# research# into# the# impact# of# NSP#implementation#on#the#likelihood#of#injection#drug#use#cessation#is#required.#Collectively,# the# aforementioned# four# fields# of# inquiry# represent# an#important#program#of#research#that#has#the#potential#to#inform#public#health#efforts## 6#to# reduce# bloodZborne# disease# transmission# and# other# negative# health# outcomes#associated#with#the#injection#career#trajectories#experienced#by#IDU#populations.#It#is#hoped#that#this#dissertation#may#therefore#be#valuable#for#policymakers#seeking#to# implement#comprehensive#approaches# to# injectionZrelated#harm#by#considering#predictors# of# injection# transition# events# and# the# risks# associated# with# ongoing#injection.# This# is# done#within# a# conceptual# framework# that# takes# into# account# the#changing#risks#experienced#by#drug#users#at#different#stages#of#their#injection#drug#use# careers.# The# aim# of# this# dissertation# is# therefore# to# investigate#sociodemographic,# drugZrelated,# psychosocial,# peerZbased# and# policy# factors#associated#with# injection# transition# events#within# a# risk# environment# framework,#and#to#assess#how#interventions#to#reduce#the#risks#of#ongoing#injection#may#impact#the#likelihood#of#these#transition#events#among#streetZbased#drugZusing#populations.##1.4!! Study!setting!! Vancouver,#Canada#is#the#site#of#one#of#North#America?s#largest#openZair#illicit#drug#markets.#Located#in#the#downtown#eastside#neighbourhood#of#Vancouver,#this#area#is#marked#by#high#levels#of#poverty,#ready#access#to#illicit#drugs,#high#levels#of#drug#dependence,#and#a#disproportionately#high#prevalence#of#drugZrelated#harms#including#HIV# and#HCV# transmission,# and# fatal# overdose.58# Beginning# in# the# early#1990s,#the#absence#of#effective#and#accessible#health#interventions#such#as#NSPs#for#people#who#use#drugs#in#Vancouver,#coupled#with#a#shift#from#the#injection#of#heroin#to#the#injection#of#cocaine,#contributed#to#a#rapidly#escalating#HIV#epidemic#among#the# city?s# IDU#population.59# This# crisis# reached# its# peak# in# the#midZ1990s,#when# a## 7#public#health#emergency#was#declared#in#Vancouver#after#data#demonstrated#an#HIV#incidence#rate#of#approximately#19#per#100#personZyears#among#the#city?s#IDU.60#In#response,#Vancouver#implemented#a#large,#centralized#needle#exchange#program#in#an#effort#to#reduce#injectionZdriven#HIV#incidence.#However,#despite#the#presence#of#this# intervention,#HIV# incidence# remained# high.60# Researchers# concluded# that# this#ongoing#crisis#pointed#to# the#need# for# further#expanding#access# to#sterile# injecting#equipment# and# the# implementation# of# a# comprehensive# set# of# public# health# and#harm# reduction# measures# to# control# the# HIV# epidemic# among# the# city?s# IDU#population.60#However,# critics#opposed# to#harm#reduction#approaches#argued# that#the# ongoing# high# rates# of#HIV# incidence#were# evidence# that# harm# reduction# itself#was#ineffective#policy.61## Since# that# time,# Vancouver# has# experimented# with# a# variety# of# harm#reductionZoriented# interventions# including#decentralizing#and#expanding# its#NSP,62#implementing#a#medically#supervised#injection#facility,63#and#expanding#methadone#maintenance#therapy#and#opioid#substitution#programs.64,#65#This#has#been#coupled#with#the#provision#of#highly#active#antiretroviral#therapy#(HAART)#free#of#charge#to#all#eligible#HIVZseropositive#individuals#in#British#Columbia,#as#well#as#more#recent#provincial# efforts# to# aggressively# seek# out,# test,# treat# and# retain# marginalized#populations#of#HIVZpositive#individuals#such#as#IDU#in#HAART.66#These#efforts#have#been# supported# by# evidence# from#observational# cohort# studies# of# IDU# and# streetZinvolved#youth# located# in#and#around#Vancouver.32,#60#Research# from#these#studies#has# demonstrated# that# Vancouver?s# evolving# public# healthZoriented# approach# has## 8#led#to#decreasing#HIV#incidence#and#reduced#incidence#of#risk#behaviours#for#bloodZborne#disease#transmission#(e.g.,#syringe#sharing)#among#Vancouver?s#IDU.62### Additionally,# levels# of# amphetamineZtype# stimulant# use,# including#methamphetamine#use,#have#risen#globally,#with#amphetamineZtype#stimulants#now#the# second# most# widelyZused# class# of# drug# worldwide.9# In# Vancouver,# this# has#manifested# in#particularly#high# levels# of# crystal#methamphetamine#use# among# the#city?s# streetZinvolved# youth.58# To# date,# research# has# demonstrated# that# crystal#methamphetamine# use# is# associated#with# a# variety# of# harms,67Z70# and# preliminary#research# from# Vancouver# has# suggested# that# crystal# methamphetamine# may# be#associated#with#an# increased# risk#of# initiation#of# injection#among# the# city?s# streetZinvolved#youth,71,#72#though#more#research#is#needed#to#clarify#this#phenomenon.#1.5!! Conceptual!framework!This# research# project# is# primarily# grounded# in# the# risk# environment#framework,# with# important# modifications# incorporating# two# complementary#approaches;#namely,#aspects#of#personality#theory#(e.g.,#sensation#seeking)#and#life#course# theory.# It# is# hoped# that# this# conceptual# approach# will# facilitate# a# more#comprehensive#portrait#of#the#factors#that#influence#injection#transition#events#and#related# harms# across# individuals?# injection# careers.# Figure# 1# presents# a# visual#depiction#of#the#conceptual#framework#employed#in#this#dissertation.##1.5.1%Risk%environment%framework%The# risk#environment# framework,#originally#developed#by#Rhodes,73# allows#for#the#investigation#of#the#social#and#structural#environment#experienced#by#people## 9#who#use#drugs#and#an#identification#of#how#this#environment#may#modify#the#range#of#choices#that#individuals#are#able#to#make#regarding#drugZrelated#behaviours#and#other#related#outcomes.#Within# this#conceptual# framework,# investigations#of#drugZrelated# risk# and# service# utilization# consider# a# range# of# social,# structural,# policy,#economic,#and#geographic#factors#and#their#intersection#with#individualZlevel#factors#at#the#micro,74,#75#meso71,#76#and#macro77,#78#levels#to#delineate#how#these#mediate#the#capacity# of# IDU# to# refrain# from# engaging# in# risky# behavior# (e.g.,# used# syringe#sharing79#or#drug#overdose80)#or#from#accessing#a#range#of#health#services#including#NSPs.81# This# approach# is# particularly# useful# in# delineating# how# the# application# of#policies# and# responses# to# the# risks# experienced# by# streetZlevel# drugZusing#populations# are# constrained# by# environmental# factors.82# This# approach# has#previously# been# employed# to# demonstrate# how# the# implementation# of# policies# of#streetZbased#drug#law#enforcement,#as#well#as#structural#factors#such#as#unsanitary#public# settings,# intersect# with# individualZlevel# safety# concerns# among# IDU# to#increase# the#risk#of#unsafe# injection#practices#such#as#rushed# injecting.76#Similarly,#Rhodes#et#al.#have#demonstrated#how#a#lack#of#sterile#syringe#distribution#as#a#result#of# government# policies# can# heighten# the# risk# of# unsafe# injection# practices,# while#situational# factors# such# as# a# fear# of# streetZlevel# police# enforcement# can# further#impede# IDU# from# injecting# safely.74#The#model# of# the# risk# environment# applied# to#this#dissertation#is#presented#in#Figure#1.## Of#note,#while#investigations#utilizing#the#risk#environment#framework#have#considered# individualZlevel# variables# such# as# the# types# of# drugs# used,83# social#network# features,84,# 85# and# sociodemographic# factors,79# no# such# study# has# yet# to## 10#consider#the#psychosocial#factor#of#sensation#seeking#among#streetZinvolved#youth,#which#has#previously#been#shown#to#heighten#the#risk#of#drug#use.#Chapter#5#of#this#dissertation# therefore# includes# an# investigation# of# sensation# seeking# as# one#individualZlevel#factor#that#may#intersect#with#environmental#factors#to#heighten#the#risk#of#injection#drug#use#among#streetZinvolved#youth#(see#Figure#1).##1.5.2%Personality%Theory:%Sensation%Seeking%# To#complement#the#risk#environment#framework,#this#dissertation#draws#on#personality# theory,# and# on# the# concept# of# sensation# seeking# in# particular,# which#posits#that# individuals#possess#an#underlying#personality#trait#that#influences#their#innate# desire# for# experiences# that# are# varied,# complex# and# intense,# the# pursuit# of#which# often# involves# a# measure# of# riskZtaking.86# Researchers# have# broadly#characterized# individuals# as# either# low# or# high# sensation# seekers,# with# high#sensation# seekers# more# likely# to# engage# in# a# variety# of# risky# behaviours;87,#88additionally,# young# people# generally# report# higher# sensation# seeking# scores#compared# with# the# older# general# population.89,# 90# While# scientific# literature#spanning#five#decades#has#examined#the#role#of#sensation#seeking#in#determining#the#risk#of#an# individual?s# involvement# in#a#range#of#potentially#dangerous#activities,86,#90Z94##to#our#knowledge#no#studies#have#yet#assessed#the#impact#of#sensation#seeking#among#streetZbased#drugZusing#populations#such#as#streetZinvolved#youth#within#a#risk# environment# framework.# Individual# differences# in# the# personality# trait# of#sensation# seeking# are# considered# within# the# risk# environment# framework# in# an#investigation#of# the# impact#of# this#psychosocial# factor#on#the#risk#of# injection#drug## 11#use#and#risk#factors#for#injection#initiation#experienced#by#streetZinvolved#youth,#as#outlined#in#Chapter#4.#1.5.3%Life%course%theory%The# investigation# of# the# natural# history# of# injection# drug# use# can# be#conceptualized# as# a# natural# extension#of# the# ?life# course?# approach# to# sociological#research,#developed# in# the#1960s#by#Mannheim#and#others#as#a#way# to#assess# the#impact# of# a# structural# context,# social# change,# or# personal# events# on# individual#trajectories.95,# 96# Formally,# the# life# course# is# defined# as# ?a# sequence# of# socially#defined#events#and#roles#that#the#individual#enacts#over#time,?96#and#is#particularly#suited# to# investigating# causal# linkages# between# distal# events.# This# approach# has#been#employed#by#social#epidemiologists,#as#it#offers#a#way#of#conceptualizing#how#underlying#sociodemographic#or#structural#factors#experienced#at#various#transition#stages# can# impact# health# outcomes# or# alter# personal# trajectories# across# an#individual?s#life#course.97##As#outlined#in#Figure#1,#the#risk#environment#framework#has#been#extended#in#two#important#ways#for#this#dissertation.!First,# it# incorporates#personality#traits#in#the#form#of#individual#differences#in#sensation#seeking#within#the#range#of#factors#that# restrict# decisionZmaking# around#drugZrelated#behaviours.# Second,# it# explicitly#seeks#to#consider#injection#transition#events#and#injection#trajectories#over#time#as#sociallyZdefined#events,#consistent#with#life#course#theory.#This# includes#a#focus#on#peerZbased#factors# impacting#risk#across# injection#careers.#With#respect# to#specific#chapters# of# this# dissertation,# the# risk# environment# framework#will# guide# variable## 12#selection#and#methodological#approaches#of#all# the#analyses#presented#in#Chapters#4Z6,# with# the# psychosocial# trait# of# sensation# seeking# investigated# in# Chapter# 5.#Furthermore,#life#course#theory#will#be#employed#primarily#in#Chapters#4,#6#and#7#to#conceptualize#how#the#risk#environment#may#vary#over#time,#with#a#particular#focus#on# exploring# how# injection# transition# events# are# sociallyZdefined# through# peer#influence#between#individuals#at#varying#stages#of#their#injection#careers.!It#is#hoped#that# this# conceptual# framework# will# inform# a# more# comprehensive# overall#understanding# of# how# factors# associated#with# one# stage# of# the# natural# history# of#injection#drug#use#may#impact#other#stages.##1.6!! Study!objectives!and!hypotheses!This#project#thus#has#four#main#objectives:#1. To! systematically! review! the! scientific! literature! on! interventions! to!prevent!the!initiation!of! injection!drug!use,!and!to!critically!assess!the!effectiveness!of!these!interventions!among!vulnerable!populations!such!as!streetQinvolved!youth.#To#address#this#objective,#Chapter#3#presents#the#results# of# a# systematic# review# of# peerZreviewed# studies# that# evaluated#interventions#to#prevent#injection#initiation.##2. To!examine!the!impact!of!crystal!methamphetamine!use!on!the!risk!of!injection! drug! use! initiation! among! streetQinvolved! youth,! and! to!present! microQsetting! characteristics! of! injection! initiation! events.!Despite# high# levels# of# crystal#methamphetamine# use# in# a# range# of# settings#including#Vancouver,9#little#is#still#known#regarding#the#impact#of#the#use#of## 13#this#drug#on#the#risk#of#injection#initiation.#Furthermore,#data#delineating#the#specific# characteristics# of# injection# initiation# events# may# help# to#contextualize#efforts#to#determine#the#risk#factors#that#contribute#to#injection#initiation.# The# analyses# presented# in# Chapter# 4# will# therefore# test# the#hypothesis#that#use#of#crystal#methamphetamine#is#independently#associated#with#the#risk#of#initiation#of#injection#drug#use#among#streetZinvolved#youth#in#Vancouver.#3. To! adapt! and! validate! a! psychometric! tool! to! assess! the! impact! of!sensation! seeking! on! the! risk! of! injection! drug! use! among! vulnerable!drugQusing! individuals.!While#high#sensation#seeking#has#been#previously#identified#as#a#predictive#factor#for#drug#use#among#the#general#population,98#little#is#known#regarding#its#role#as#a#determinant#of#risky#behaviours#among#drugZusing# populations,# and# in# particular# among# streetZinvolved# youth.#Additionally,#although#a#wide#range#of#sociodemographic,#behavioural,#social#and#structural#risk#factors#for#injectionZrelated#harms#have#been#identified#in#the# epidemiologic# literature,# the# impact# of# sensation# seeking# on# the# risk# of#injection#drug#use#among#vulnerable,#drugZusing#individuals#remains#unclear.#The# analysis# presented# in#Chapter#5#will# therefore# test# the#hypothesis# that#participant# score# on# a# modified# substance# useZspecific# brief# sensation#seeking#scale#is#associated#with#injection#drug#use,#crystal#methamphetamine#use,# and# other# risky# drugZrelated# behaviours# among# a# cohort# of# streetZinvolved#youth#in#Vancouver.## 14#4. To! investigate! the! incidence! of! injection! drug! use! cessation! within! a!highQrisk! setting,! and! to! determine! the! impact! of! an! expansion! of!syringe!distribution! services!on! this! setting!over! time.# #A# large#body#of#literature# has# demonstrated# that# NSPs# are# effective# in# reducing# the# risk# of#used#syringe#sharing,#which#remains#a#primary#mode#of#bloodZborne#disease#transmission# among# IDU# in#many# settings.99,#100# However,# concerns# remain#among#policymakers#and# the#general#public# regarding# the#potential#of# such#interventions#to#cause#IDU#to#delay#the#cessation#of#injection.56#This#concern#has# contributed# to# low# levels# of# implementation# of# these# interventions#internationally.30#The#analysis#presented# in#Chapter#6#seeks# to#address# this#concern#by#investigating#the#incidence#of#injection#cessation#among#a#cohort#of# IDU# in#a#highZrisk#setting# in#Vancouver#characterized#by#an#expansion#of#NSP#sites.##1.7!! Study!design!and!methods!! The#analyses#presented#in#Chapters#4Z6#of#this#dissertation#employ#data#from#ongoing,# linked# studies# of# streetZinvolved# youth# and# IDU# in# Vancouver,# Canada.#While#the#analytic#approaches#differ#for#each#chapter#and#will#be#described#therein,#the# data# sources# and#methodological# commonalities# are# delineated# here# to# avoid#duplication.#Vancouver%Injection%Drug%Users%Study%# The# Vancouver# Injection# Drug# Users# Study# (VIDUS)# is# an# ongoing,#prospective# communityZrecruited# cohort# study# of# IDU# that# has# been# in# operation## 15#since#1996.#Beginning#in#May#of#that#year,#recruitment#began#for#IDU#who#reported#injecting# drugs# in# the# previous# month# and# resided# in# the# Greater# Vancouver#region,60#and#this#recruitment#has#been#undertaken#on#an#ongoing#basis#since#that#time.# All# participants# are# recruited# through# street# outreach# and# selfZreferral,# and#provide# written# informed# consent# prior# to# entering# the# study.# At# baseline# and#regular# semiZannual# follow# up# visits,# study# participants# complete# interviewerZadministered# questionnaires,# provide# blood# samples# for# diagnostic# testing,# and#undergo#physical#examination#from#a#trained#research#nurse#to#inspect#for#stigmata#of# drug# injecting.# Participants# are# provided#with# a# $20# CND# honorarium# for# each#visit#and,#when#appropriate,#are#referred#to#additional#health#care#services.#Ethical#approval# for# VIDUS,# as# well# as# for# the# analysis# undertaken# in# Chapter# 6# of# this#dissertation#project#that#employs#VIDUS#data,#have#been#granted#by#the#University#of#British#Columbia/Providence#Health#Care#Ethics#Review#Board.#AtIRisk%Youth%Study%The#AtZRisk#Youth#Study#(ARYS),#established#in#2005,#is#an#open#and#ongoing#prospective# cohort# of# streetZinvolved# youth# aged# 14# to# 26# based# in# Vancouver,#Canada.32# All# ARYS# participants# are# recruited# through# street# outreach# and# selfZreferral,#and#participants#are#eligible# if# they#reported#using# illicit#drugs#other#than#marijuana#in#the#30#days#prior#to#recruitment.#Once#enrolled,#participants#complete#an# interviewerZadministered# questionnaire# at# baseline,# as# well# as# physical# and#mental# health# assessments,# including# blood# sampling# for# diagnostic# testing,# and#assessment# for# physical# stigmata# of# drug# injecting.# Subsequently,# participants#complete#physical#examination#and#interviewerZadministered#questionnaires#semiZ# 16#annually,#which#solicit#basic#sociodemographic#and#drug#use#data,#along#with#data#on# other# relevant# behaviours# including# drug# injecting.# Participants# are# provided#with# a# $20# CND# honorarium# at# each# visit# and,# when# appropriate,# are# referred# to#additional# health# care# services.# The# study,# along#with# the# analyses# undertaken# in#Chapters#4#and#5#of#this#dissertation#that#employ#ARYS#data,#have#been#approved#by#the# University# of# British# Columbia/Providence# Health# Care# Ethics# Review# Board,#and#all#study#participants#provided#written#consent#prior#to#enrolment.#1.8!! Summary!# This#dissertation#includes#seven#chapters.#The#introductory#chapter#provides#an#overview#of#the#evidence#pertaining#to#injectionZrelated#harm,#with#a#particular#focus#on#describing#the#current#research#gaps#related#to#the#initiation#and#cessation#of#injection#drug#use#as#well#as#the#conceptual#framework#employed#throughout.#It#also#identifies#limitations#in#the#existing#scientific#literature#on#the#natural#history#of#injection#drug#use,#and#frames#how#this#dissertation#will#contribute#to#the#scientific#literature#in#this#area.#Chapter#2#provides#a#narrative#overview#of#the#natural#history#of# injection# drug# use# in# order# to# contextualize# empirical# analyses# undertaken# in#Chapters# 4Z6.# Chapter# 3# presents# the# results# of# a# systematic# review# describing#scientifically#evaluated#interventions#to#prevent#the#initiation#of#injection#drug#use.#Chapters#4#to#6#present#the#quantitative#empirical#analyses#of#this#dissertation.#First,#the#impact#of#crystal#methamphetamine#use#on#the#risk#of#injection#initiation#among#streetZinvolved#youth,#as#well#as#microZsetting#characteristics#of#injection#initiation#events#are# investigated# in#Chapter#4.#The#adaptation#and#validation#of#a#substance## 17#useZspecific#sensation#seeking#scale,#and#an#investigation#of#how#sensation#seeking#may# impact# the# risk# of# injection# drug# use# and# risk# factors# for# injection# initiation#among#streetZinvolved#youth# is#presented# in#Chapter#5.#Finally,#an# investigation#of#the#risk#environment# influencing# injection#drug#use#cessation#among#IDU#during#a#period# of# substantial# expansion# of# NSPs# is# presented# in# Chapter# 6.# Chapter# 7#summarizes#and#synthesizes# the#key# findings#of# this#dissertation.#The# implications#of#the#findings#are#discussed,#particularly#within#the#context#of# informing#new#and#ongoing# efforts# to# comprehensively# address# the# incidence# of# injection# transition#events# and# injectionZrelated# harms.# The# limitations# of# the# methodological# and#conceptual#approaches#employed#in#this#work#are#also#described.#Finally,#Chapter#7#provides#a#set#of#key#recommendations#for#future#research.!!! 18!Individual-Level Factors ? Gender!? Age!? Ethnicity!? Drugs used!? Drug dependence!? Sensation seeking!? Trauma!!Macro-Structural Environment ?  Drug policies!?  Housing policies!?  Economic policies!Intermediate Pathways ? Access to preventive interventions!? Access to harm reduction services (NSPs)!? Drug dealing!? Sex trade!? Public drug use!Primary outcomes ? Injection initiation!? Injection cessation!Micro-Social/Physical Environment ? Initiation event setting!? Interactions with police!? Income acquisition strategies!? Social/sexual relationships!? Clean drug equipment!!Meso-Social/Physical Environment ? Spatial distribution of services!? Spatial distribution of treatment !? Spatial distribution of networks!? Housing availability !? Illicit drug availability !? Intensity of policing !? Availability of prevention Individual)level+and+psychosocial+factors+interact+with+macro)structural,+meso)+and+micro)social/physical+environments+to+determine+socially)defined++events+and+roles+that+facilitate+injection+transition+events+via+intermediate+pathways+and+outcomes!(Adapted(from(Rhodes,(2002,(2009;Mannheim,(1928;(Elder,(1998)(Intermediate Outcomes ? Sensation seeking!? Crystal methamphetamine !? Exposure to injecting!Figure'1.'Conceptual'model'to'investigate'injection'transition'events'among'illicit'drug'users'in'Vancouver''' ! 19!CHAPTER(2:(THE(NATURAL(HISTORY(OF(INJECTION(DRUG(USE(2.1(( Introduction(Beyond!blood,borne!disease! transmission!and!drug!overdose,101! a! range!of!other! health! and! social! harms! are! associated! with! injection! drug! use,! including!cellulitis,16! abscesses,17! incarceration,102! and! engagement! in! acquisitive! and! drug!market,related! crime.103,!104!However,! these! harms! are! not! static! over! individuals?!injection! drug,using! careers,! and! IDU! at! different! stages! of! their! drug! use! exhibit!varying! levels! of! risk.! For! instance,! studies! have! shown! that! young! and! recently,initiated!IDU!have!a!higher!risk!of!overdose!and!blood,borne!disease!transmission!compared! with! older! or! more! established! IDU.105,! 106! As! such,! while! a! variety! of!interventions! to! reduce! the! harms! of! injection! drug! use! have! been! developed,!challenges! remain! in! ensuring! that! these! interventions!both! address! the!needs!of,!and! are! effective! at! delivering! services! to,! IDU! at! various! stages! of! their! injecting!careers.!!The! investigation! of! the! natural! history! of! injection! drug! use! requires!research! focused! on!multiple! stages! of! injection! careers:! the! identification! of! risk!factors! for! injecting! initiation;! the! characterization! of! specific! injection! career!trajectories!and!injection!cessation!patterns;!and!the!evaluation!of!injection,related!morbidity! and! mortality.! Despite! a! substantial! literature! examining! these! issues!individually,! there! do! not! appear! to! be! any! published! reviews! summarizing! this!research! in! the! context! of! the! overall! natural! history! of! injection! drug! use.! The!present! narrative! review! seeks! to! address! this! gap! by! broadly! describing! the!scientific!literature!in!this!area.!! 20!2.2(( Methods(2.2.1$$ Search$strategy$We! searched! the! following! 10! electronic! databases:! PubMed,! PsycINFO,!EMBASE,!Cochrane!CENTRAL,!CINAHL,!Web!of!Science,!TOXNET,!AIDSLINE,!AMED!and!ERIC.!We!also!searched!the!internet!(Google,!Google!Scholar),!relevant!academic!conference!abstract!lists,!and!scanned!the!references!of!potentially!eligible!studies.!Each! database! was! searched! for! English! language! articles! from! its! inception! to!January! 4,! 2013.! We! reviewed! all! studies! and! included! the! most! representative!examples!to!illustrate!the!state!of!research!on!this!topic.!Keywords!included!?natural!history! of! injection! drug! use?,! ?injection! initiation?,! ?mortality?,! ?injection! career!trajectory?,!?injection!drug!use?,!?injecting!trends?!and!?injecting!pattners?.!!2.3(( Results(2.3.1$$ Initiation$of$injection$drug$use$$Street,involved!youth!are!at!highest!risk!of!initiating!injection!drug!use,31,!40,!46!and!research!into!injecting!initiation!has!thus!focused!almost!exclusively!on!this!population.!In!a!study!of!data!from!a!prospective!cohort!of!street,involved!youth!in!Montreal,! researchers! investigated! predictors! of! injection! initiation! among! cohort!participants! that! reported!never!having! injected!at!baseline! (n$=!415).26!After! five!years! (1995,2000),! 74! of! the! street! youth! had! initiated! injection! for! an! incidence!rate!of!8.2!per!100!person!years.!Further,!the!researchers!identified!key!structural!and!peer,based!factors!that!significantly!increased!the!risk!of!initiation.!In!particular,!having!been!homeless!in!the!last!6!months!was!associated!with!the!largest!increase!in! risk! of! initiating! injection! among! all! study! participants.! Among! female!! 21!participants,!however,!having!an!IDU!friend!was!associated!with!an!even!greater!?!fourfold! ?! risk! of! initiating! injection.! Other! factors! that! significantly! increased!initiation! risk! included! being! under! 18! years! old,! use! of! heroin! in! the! previous!month,!and!having!experienced!extra,familial!sexual!abuse.26!!Similarly,! a! qualitative! study! undertaken! by! Harocopos! et! al.! found! that,!among!a!cohort!of!newly,initiated!New!York!City,based! IDU!(n$=!54),!decisions! to!begin! injecting!were! influenced!by!exposure!to! injecting.38!Within!this!context,! the!authors! describe! how,! among! newly,initiated! IDU,! exposure! to! injecting! was!associated!with!a!decrease! in!the! fear!of! injecting!and!a!corresponding! increase! in!the! acceptability! and,! in! certain! cases,! feeling! of! inevitability! regarding! injection!initiation.38! Further,! despite! the! oft,reported! unwillingness! of! established! IDU! to!initiate!injection,na?ve!individuals,!the!authors!describe!the!tenacity!of!many!newly,initiated! IDU! in! seeking! help! in! initiating! injection! from! IDU! in! their! social!networks.38!!In! an! effort! to! determine! the! impact! of! spatial,! network,! and!sociodemographic! factors! on! the! age! of! injecting! initiation,! Baltimore,based! IDU!were!enrolled! in! the!REACH! II! study!between! July!1997!and!May!1999! (n$=!144).!Researchers! then! investigated! the! impact! of! neighbourhood! characteristics! (e.g.,!employment! level,! poverty! level,! education! level,! and! ethnic! composition),!participation! in!a!high,risk!drug,using!network,!and! IDU!ethnicity!on! initiation.! In!logistic! regression! analysis,! injecting! before! the! age! of! 21! years! old! was,! among!African,American! participants,! significantly! associated! with! residing! in! a!neighbourhood! with! a! large! minority! population! and! low! levels! of! education.!!! 22!Further,!after!adjustment!for!neighbourhood!effects,!those!who!initiated!prior!to!the!age!of!21!were,!after!initiation,!subsequently!more!likely!to!participate!in!a!high,risk!network! within! two! years.! This! association! between! neighbourhood! of! residence!and!risk!of!injecting!has!been!identified!in!other!settings.71,!107!Recent! research! has! identified! specific! drug,related! behaviours! that! also!appear! to! place! individuals! at! higher! risk! of! injecting.! For! example,! Trenz! and!colleagues,! noting! that! early! onset! polysubstance! use! has! been! identified! as! a!predictor! of! subsequent! substance!use!problems,! sought! to! investigate! the! role! of!polysubstance!use!on!subsequent!risk!of!injection!initiation!among!IDU!and!non,IDU!using!cross,sectional!and!retrospective!data!from!the!Baltimore,based!NEURO,HIV!cohort!study.108!After!adjustment!for!a!variety!of!potential!confounders,!the!authors!found! that! reporting!early!onset!polysubstance!use! (e.g.,!15!years!old!or!younger)!was!significantly!associated!with!reporting! injection!drug!use.! In!a!separate!study,!researchers! in! Vancouver! conducted! an! investigation! of! drug,related! factors!potentially!associated!with!early!adolescent!initiation!of!injection!drug!use!(e.g.,!16!years!or!younger)!among!participants!in!the!Vancouver!Injection!Drug!Users!Study!(described! in! full! in!section!1.7).109! In!multivariate!analysis,! the!proportion!of! IDU!that!initiated!injecting!in!early!adolescence!was!greater!among!those!that!reported!binge! drug! use,! involvement! in! the! sex! trade,! and! a! history! of! incarceration.109!Additionally,!a!separate!study!from!Des!Jarlais!and!colleagues!examined!the!impact!of!the!implementation!of!needle!exchange!programs!on!the!risk!of!injecting.110!The!authors! found!that,!among!the!roughly!2,000!patients!entering!a!methadone!clinic!annually!in!New!York!City!for!treatment,!the!period!during!and!after!the!large,scale!! 23!implementation! of! needle! exchange! programs! was! associated! with! a! decreased!number!of!patients!reporting!opioid! injecting!at!admission,!and!an! increase! in! the!number!of!those!reporting!intranasal!opioid!use!(p$<!0.001).!The!authors!therefore!concluded! that! the! implementation! of! needle! exchange! programs! in! the! study!setting!was!unlikely!to!have!resulted!in!an!increase!in!injecting.!The! vast! majority! of! studies! on! injection! initiation! are! undertaken! among!youth!residing!in!urban!studies.!However,!one!recent!study!investigated!risk!factors!for! injection! initiation! among! a! cohort! of! rural! drug!users! residing! in! and! around!Appalachia,!a!region!of!the!United!States!that!spans!the!southern!edge!of!New!York!state! to!northern!Alabama,!Mississippi,!and!Georgia.47!Among! this!cohort! (IDU!n$=!394;! non,IDU!n$=!109),! illicit! use! of! the! prescription! opioid!OxyContin,! as!well! as!other!prescription!opioids,!was!associated!with!a!significantly! increased!hazard!of!injection!drug!use.47!While! research! regarding! personality,based! risk! factors! for! injection!initiation! is! limited,! a! small! evidence! base! has! investigated! this! association.! For!instance,! Semple! and! colleagues! employed! measures! of! sensation! seeking,!impulsivity,!depression,!self,perceived!stigma,!and!self,perceived!social!support!as!potential! predictors! of! injection! drug! use! among! a! cohort! of! crystal!methamphetamine,using!men! who! have! sex! with!men.92! The! authors! found! that,!while! sensation! seeking! score! or! depression! were! not! significantly! different!between!those!who!did!and!did!not!report! injecting,! injection!drug!users!reported!significantly!higher!levels!of!impulsivity!and!stigma,!and!significantly!lower!levels!of!social!support.! !It!should!be!noted,!however,!that!the!sensation!seeking!scale!items!! 24!employed! were! restricted! to! a! subscale! measuring! risk,taking,! one! of! the! four!domains!underlying!sensation!seeking.!Similarly,!a!Baltimore,based!study!of!young!recently,initiated! IDU! using! REACH! data! found! that! the! majority! of! participants!(43%)! reported! initiating! injection! as! a! result! of! curiosity! or! thrill,seeking,111!though!this!was!measured!using!a!single!questionnaire!item.!Interestingly,!a!greater!proportion! of! female! participants! (48%)! than! male! participants! (38%)! reported!curiosity/thrill,seeking!as!the!primary!motivation!to!initiate.!!2.3.2$$ Longitudinal$patterns$of$injecting$drug$use$$Because! of! the! many! harms! of! ongoing,! untreated! injection! drug! use,!identifying! the!major! longitudinal!patterns!of! injecting! is! of! central! importance! to!public!health!efforts!to!reduce!the!incidence!of!this!behaviour.!To!that!end,!research!from!the!AIDS!Linked! to! the! Intravenous!Experience!(ALIVE)!study,!a!community,based! cohort! of! IDU! in! Baltimore! (n$=! 1,176),! has! identified! five! major! injection!trajectories:! early! cessation! (e.g.,! sharp! decline! in! injecting! within! five! years),!delayed!cessation!(e.g.,! less!steep!decline!within!10!years),! late!cessation!(e.g.,! less!steep!decline!within!15!years),!frequent!relapse!(e.g.,!relatively!consistent!injecting!within! 15! years! and! decline! thereafter),! and! persistent! injection! (e.g.,! high! and!sustained! level!of! injection!drug!use).51!Using!data!collected!over! the!study!period!(1988! to! 2008),! ALIVE! researchers! assessed! the! frequencies! of! these! five!trajectories,! and! found! that,! among! Baltimore! IDU,! persistent! injection! was! most!commonly!reported!(32%),!followed!by!early!cessation!(19%),!late!cessation!(18%),!delayed! cessation! (16%),! and! frequent! relapse! (16%)! (n! for! each! trajectory! not!! 25!reported).!In!an!adjusted!model,!those!participants!exhibiting!early!cessation!were!significantly!more!likely!to!exclusively!inject!heroin,!report!non,injection!heroin!use,!and!have!injected!for!fewer!years!at!baseline!compared!with!those!exhibiting!late!or!delayed!cessation!patterns.!They!were!also!significantly!less!likely!to!report!having!had!sex!with!an!IDU!partner!or!having!been!incarcerated.51!Additionally,!those!who!ceased! injecting! early!were!more! likely! to! report! a! history!of! addiction! treatment!compared! with! individuals! in! the! persistently! injecting! or! relapse! groups.!!Interestingly,!neither!age!nor!HIV,serostatus!differed!significantly!between!injection!trajectories.!!! The!Drug!Abuse!Treatment!Outcome!Study!(DATOS)!is!a!longitudinal!multi,site! cohort! of! illicit! drug! users! located! in! eight! US! cities.15! In! a! five! year! study!restricted! to! IDU! enrolled! in! the! cohort! (n$ =! 1,393),! researchers! investigated!injection!risk! trajectories!using!growth!mixture!modeling! to! identify! latent!classes!by! slope! or! trajectory.15! Using! this! approach,! the! study! authors! identified! four!distinct!injection!risk!trajectories,!including!low!and!stable!injecting!risk!(n$=!1,100,!79%),!moderate!and!stable! risk! (n$=!176,!13%),!high!and!decreasing! risk! (n$=!69,!5%),!and!high!and!increasing!risk!(n$=!48,!3%).!Compared!to!all!other!participants,!those! individuals! reporting! high! and! increasing! risk! of! injection! exhibited! higher!levels! of! incarceration,! mental! illness,! residential! and! outpatient! drug! treatment!experience,!and!receipt!of!HIV/AIDS,related!services!of!any!kind.15!The!authors!did!not!detect! significant!differences! in! level!of!mean! income!between!participants!by!trajectory!type.!Participants!reporting!high!and!moderately!high!risk!of!injection!did,!however,!report!higher!levels!of!heroin!use,!while!those!with!low!and!stable!risk!of!! 26!injection! reported! higher! levels! of! cocaine! use.! The! study! authors! reported! that!these! differences! remained! consistent! after! five! years,! though! injection! risk! and!related!behaviours!declined!among!all!trajectory!groups!over!this!period.!Relatedly,!a!study!of!syringe!sharing!conducted!by!Brook!and!colleagues!found!that!male!IDU!in!New!York!City! that!reported!higher!sensation!seeking!(based!on!responses! to!a!single!questionnaire!item)!were!more!likely!to!report!sharing!used!syringes,!which!may! signal! an! increased! risk! of! HIV! transmission! among! this! subgroup.94! Among!female! IDU,! however,! sensation! seeking! was! not! significantly! associated! with!syringe! sharing.93! In! a! separate! study! conducted! by! Fenaughty! and! colleagues,!measures! of! sensation! seeking! were! also! significantly! associated! with! high,risk!sexual! activity! (e.g.,! having! multiple! partners,! inconsistent! condom! use! and!involvement!in!the!sex!trade)!among!a!cohort!of!IDU!in!Anchorage,!Alaska.91!! A!study!by!Bruneau!et!al.! investigated!sustained!cessation!of! injection!drug!use!among!a!cohort!of!IDU!in!Montreal,!Canada!(n$=!1,004)!over!a!four!year!period,!with! sustained! cessation! defined! as! at! least! seven! consecutive! months! of! no!injection! drug! use.33! In! total,! 186! (19%)! IDU! participants! reported! a! sustained!cessation! event! during! the! study! period.! In! logistic! regression,! initiating! injection!drug! use! after! 35! years! of! age! and! crack! cocaine! use! were! both! significantly!associated! with! cessation,! while! HIV,seropositivity,! a! greater! reliance! on! illegal!income!versus!legal!income,!and!a!higher!cumulative!time!spent!incarcerated!were!all! significantly! inversely! associated! with! cessation.! The! authors! also! identified! a!trend!wherein!greater!intensity!of!injection!was!associated!with!a!lower!likelihood!of!injection!cessation,!though!this!did!not!reach!statistical!significance.!The!authors!! 27!therefore!suggest!that!it!is!likely!that!IDU!who!inject!intensely!are!at!higher!risk!of!continuing! to! inject! in! the! near! future.33! Consistent! with! prior! research,112! non,injection! crack! use! was! also! associated! with! injection! cessation! in! this! study,33!which! highlights! the! role! that! the! use! of! specific! drugs! may! play! in! personal!decisions! concerning!mode! of! drug! administration.! Further,! a! 4,strata! categorical!measure!of! addiction! treatment!uptake,! ranging! from!zero! time! to! over!24!weeks!enrolled!in!treatment,!was!not!significantly!associated!with!injection!cessation.!The!authors! suggest! that! this! finding,! ?illustrates! the! spontaneity! of! the! occurrence! of!injection!cessation!among!IDUs!in!this!study!and!its!independence!from!previous!or!current!drug!treatment,?!while!also!suggesting!that!this! lack!of!association!may!be!the! result! of! a! high! proportion! of! cocaine! users! in! the! cohort,! a! group! for!whom!effective!clinical!treatment!modalities!remain!largely!elusive.113!!Additionally,! in! a! subanalysis! restricted! to! those! reporting! sustained!injection! cessation,! in! which! participants! were! stratified! by! sources! of! syringe!acquisition,! those! IDU! that! injected!at! least!once!daily!and!acquired!syringes! from!NSPs! or! pharmacies!were!more! likely! to! report! sustained! cessation! events.33! The!authors!suggest!that!this!may!be!because!NSPs!and!pharmacies!provide!counseling,!HIV!testing!and!formal!referral!to!addiction!treatment!in!their!study!setting,!which!likely!increases!the!capacity!of!frequent!IDU!to!initiate!addiction!treatment!and!thus!cease! injecting.! This! finding! should,! however,! be! considered!within! the! context! of!the! lack! of! significance! between! addiction! treatment! enrolment! and! cessation!events!observed!in!the!larger!adjusted!regression!model.!! 28!! Finally,!a!study!by!Latkin!and!colleagues!specifically!investigated!the!impact!of!peer!influence!on!the!injection!career!trajectories!of!IDU!enrolled!in!the!Stop!AIDS!For! Everyone! (SAFE)! cohort! (n$ =! 338),! which! was! nested! within! the! Baltimore!ALIVE!cohort.114!The!SAFE!study!investigated!HIV!risk!behaviours!among!IDU!who!were! randomly! enrolled! in! either! a! six,session! cognitive,behavioural! HIV/AIDS!preventive! intervention!or! standard!HIV! testing! and! counseling!on! risk! reduction.!Further,!all!participants!underwent!a! ?network! interview?!and!were!asked!to!bring!two!members!of! their!drug,using!network! to! the!study!site.!These!protocols!were!put!in!place!to!determine!the!characteristics!of!participants?!drug,using!and!support!networks.!This! information!was! then! integrated! into!a!single!variable! that!defined!an!individual?s!network!characteristics!based!on!the!relative!proportion!of!contacts!they!have!in!their!drug!use!network,!sexual!network,!and!support!network.!After!5!months!of!follow,up,!participants!that!reported!ceasing!injection!were!found!to!have!a! significantly! smaller! drug,using! network! relative! to! the! size! of! their! sexual! or!support!networks.114!Finally,! the!authors! found!no!association!between!enrolment!in!detoxification!programs!and!likelihood!of!ceasing!injection!drug!use,!though!they!did! observe! a!marginally! significant! association! (p$=! 0.06)! between! enrolment! in!methadone!maintenance!therapy!and!injection!drug!use!cessation.!2.3.3$$ Injection;related$mortality$A!number!of!studies!have!investigated!excess!mortality!among!cohorts!of!IDU,!with!some!research!documenting!death!rates!among!samples!of!IDU!more!than!10!times!that!expected!among!age,matched!non,drug,using!populations.115,118!!! 29!Degenhardt!and!colleagues!recently!conducted!a!series!of!systematic!reviews!and!meta,regressions!on!mortality!data! from!cohorts!of! individuals!using!opioids,!cocaine,! amphetamines,! and! benzodiazepines,! many! of! whom! were! IDU.119,122!Across! all! studies! assessing! mortality! among! heroin! users! (n$ =! 58),! 36! (62%)!reported!on!injection,related!mortality!outcomes.! In!total,! the!authors!calculated!a!standardized!mortality!ratio!(SMR)!of!14.66!(95%!CI:!12.82,16.50)!for!opioid!users,!with!the!SMR!of!female!opioid!users!higher!than!that!of!male!opioid!users.!Causes!of!death!varied,!with! fatal!overdose!being!the!most!common!cause!of!mortality!(0.65!deaths! per! 100! person,years),! followed! by! trauma! (0.25! deaths! per! 100! person,years)!and!suicide!(0.12!deaths!per!100!person,years).120!!While! results! of! a! systematic! review! of! cocaine,related! mortality! were!limited! (n$ =! 7),! injection! cocaine,related! causes! of! death! were! reported! for! the!ALIVE! cohort! of! IDU! in! Baltimore! and! the! Vancouver! Injection! Drug! Users! Study!(VIDUS).119!Among!ALIVE!participants!that!reported!injecting!cocaine,!the!majority!of! deaths! (35.4%,! 95%! CI:! 24.4,46.4)! were! due! to! AIDS,related! illnesses,! while!among! VIDUS! participants,! these! were! responsible! for! the! second,largest!proportion! of! all! deaths! (20.0%,! 95%! CI:! 12.2,27.8).! Overdose! mortality! was!responsible! for! the!second,largest!proportion!of!deaths!among!ALIVE!participants!that! only! reported! using! cocaine! (11.4%,! 95%!CI:! 6.1,16.7),! and!was! the! primary!cause!of!death!among!all!VIDUS!participants!(35.5%,!23.8,!46.9).!!The!results!of! the!other! two!systematic!reviews!undertaken!by!Degenhardt!and!colleagues!suggest!that!there!exists!a!dearth!of!scientific!research!on!mortality!among!people!who!use!amphetamines!and!benziodiazepines.121,!122!! 30!Researchers!have!also!examined!the!risk!of!mortality!among!IDU!at!different!stages! of! their! injecting! career.! For! example,! Vlahov! and! colleagues! found! that! a!sample!of!IDU!in!Baltimore!that!had!initiated!injection!drug!use!within!the!previous!two! years! (n$ =! 256)! experienced! significantly! increased! levels! of! mortality!compared!with!demographically,similar,! established! IDU.123!Davoli! and! colleagues!also! assessed! mortality! longitudinally! among! IDU! in! Rome! (n$ =! 4,200)! between!1980!and!1992,!and!found!that!the!age,adjusted!all,cause!mortality!rate! increased!from!7.8/1,000!person,years! in! 1980! to!27.7/1,000!person,years! in! 1992.124!This!persistent! increase! in! the! mortality! rate! among! IDU! was! attributed! primarily! to!AIDS,related!illnesses.!The!cumulative!risk!of!death!among!cohort!participants!was!29.3%!by!the!age!of!40.124!!!2.4(( Discussion(! Decades! of! research! on! the! predictors! of! injection,related! behaviours! have!enabled! the! identification! of! long,term! patterns! of! injection! drug! use,! and,! by!extension,! have! allowed! researchers! to! delineate! the! natural! history! of! injection!drug! use! in! a! variety! of! settings.! Research! conducted! to! date! in! this! area! has!highlighted! the! role! of! structural,! social,! personality,based! and! sociodemographic!factors!in!modifying!the!risk!of!injection!initiation,!including!the!impact!of!ethnicity,!neighbourhood!of! residence,!and! IDU!peer! influence!on!risk!of! initiation;! common!injecting! trajectories! (some! of! which! are! associated! with! increased! blood,borne!disease!transmission!risk);!and!major!causes!of! injection,related!mortality!such!as!AIDS,related!illnesses!and!fatal!overdose.!!! 31!! These! results! have! implications! for! the! development! of! interventions! that!seek! to! limit! drug! use! and! drug,related! harms! including! mortality! across! an!individual?s! injecting! career.! For! example,! those! IDU! that! exhibit! a! high! and!increasing!risk!of!injecting!have!been!shown!to!be!at!higher!risk!of!engaging!in!risky!behaviours! such! as! syringe! sharing.33! However,! as! noted! above! in! the! study! by!Bruneau! and! colleagues,! IDU! that! injected! frequently! and! attended! a! NSP! were!significantly!more!likely!to!cease!injecting!compared!to!non,attenders.!Interestingly,!similar!results!were!not!observed!among!IDU!that!attended!a!NSP!but!injected!less!frequently.! This! may! suggest! that,! in! certain! settings,! more! frequent! exposure! to!NSPs! may! result! in! a! greater! uptake! of! secondary! public! health! services! such! as!addiction! treatment,! as! may! have! been! the! case! in! the! study! undertaken! by! Des!Jarlais!and!colleagues!in!New!York!City.110!Though!counterintuitive!in!some!respects,!these! results! suggest! that! interventions! such! as! NSPs! may! have! the! potential! to!provide! a! range! of! services! to! hard! to! reach! subpopulations,! and! should! be!considered!within! the! continuum!of! interventions! to! reduce!ongoing! injection.4,!21,!125! As!is!evident!from!the!literature!described!above,!the!vast!majority!of!studies!on!the!natural!history!of!injection!drug!use!are!undertaken!with!data!from!cohorts!of! individuals!that!are!already!actively! injecting!at!baseline.!As!such,!there!are!few!longitudinal! studies! on! the! natural! history! of! injection! drug! use! involving!populations!at!risk!of!initiating!injection,!such!as!street,involved!youth.!Conversely,!studies! of! injecting! initiation! have! generally! structured! this! event! as! a! discrete!! 32!outcome,! rather! than! exploring! initiation!within! the! context! of! an! emerging!drug,using!career.!!Research!has!identified!exposure!to!injecting!as!a!key!predictor!of!initiation!of! injection! drug! use! among! populations! at! risk,! such! as! street,involved! youth.34!Similarly,! as! described! above,! the! composition! and! magnitude! of! an! individual?s!injecting!network!may!play!a!key!role!in!enabling!injecting!initiation!or!prolonging!an!individual?s!injecting!career,114!as!has!been!found!with!other!sources!of!ill!health!such! as! tobacco! smoking! and! obesity.126,! 127! In! both! these! cases,! research!demonstrates! that! tobacco! smoking! and! obesity!may! both! arise! as! a! result! of! the!selection!of!individuals!in!an!individual?s!social!network,!which!may!then!reinforce!an!individual?s!behavior.128,!129!Structural!interventions!such!as!supervised!injection!facilities,!which!have!the!potential!to!both!reduce!community!exposure!to!injecting!and! facilitate! the! entry! of! IDU! into! the! addiction! treatment! continuum,! may!therefore!be!effective!in!disrupting!high,frequency!injecting!trajectories.63,!125!Finally,! high! rates! of! mortality! among! IDU! point! to! the! urgent! need! to!develop! effective! interventions! in! this! area.! Indeed,! with! respect! to! AIDS,related!illnesses,! the! adoption! of! expanded! access! to! antiretroviral! therapy! among! IDU!populations! as! part! of! a! ?seek,! test,! treat,! and! retain?! strategy! has! the! potential! to!dramatically! reduce! AIDS,related! mortality! among! IDU! population,! while! also!reducing! the! incidence! of! HIV! transmission.66,! 130! Additionally,! the! ongoing! high!incidence!of!overdose!experienced!by!IDU!highlights!the!need!for!the!dissemination!of!primary!response!interventions!such!as!take!home!naloxone,!both!in!isolation!and!as! part! of! a! comprehensive! package! of! interventions! to! reduce! drug,related!! 33!morbidity! and! mortality.131,133! In! this! regard,! research! has! demonstrated! the!potential!of!supervised!injecting!facilities!in!reducing!neighbourhood,level!overdose!mortality!among!IDU.134!In!sum,!this!review!described!a!variety!of!studies!relevant!to!the!delineation!of! the!natural! history!of! injection!drug!use.!While! individual!patterns!of! use! vary,!researchers! have! identified! a! variety! of! factors! that! impact! the! risk! of! injecting!initiation,!along!with!primary!injecting!patterns,14,!15!and!major!causes!of!injection,related!mortality.!In!light!of!accumulating!evidence,!policymakers!should!prioritize!interventions!that!comprehensively!seek!to!prevent!injecting,114!address!immediate!drug,related!harms!(e.g.,!NSPs!and!other!harm!reduction!interventions),21!and!work!to! modify! long,term! high,risk! injecting! trends! (e.g.,! methadone! maintenance!therapy).24!(! (! 34!CHAPTER( 3:( A( SYSTEMATIC( REVIEW( OF( INTERVENTIONS( TO( PREVENT(INJECTION(DRUG(USE(3.1(( Introduction(Street,involved! youth! and! newly,initiated! IDU! are! at! particularly! high! risk!for!a!variety!of!drug,related!harms.!For!example,!young!IDU!populations!have!been!shown! to! engage! in! high! levels! of! needle! and! syringe! sharing,105,! 135,! 136! and! as! a!result! are! at! elevated! risk! of! HIV! and! HCV! transmission.! Research! has! also!demonstrated! that! street,involved! youth! who! begin! injecting! are! more! likely! to!experience!overdose,!violence,!lack!of!education!about!drug!use,!mental!illness,31,!37,!137,! 138! and! to! engage! in! polysubstance! use,108! highlighting! the! challenges! in!developing! public! health! and! harm! reduction! interventions! tailored! to! this!population.4,! 22,! 139! As! outlined! in! Chapter! 2,! while! studies! have! demonstrated! a!range!of!risk!factors!for!injection!initiation,!interventions!to!prevent!injection!drug!use!have!not!been!subjected!to!systematic!review!and!impact!assessment.!!We! therefore! sought! to! systematically! search! the! existing! peer,reviewed!scientific! literature! in! order! to! identify! and! assess! interventions! to! prevent! the!initiation!of!injection!drug!use.!3.2(( Methods(We! employed! the! Preferred! Reporting! Items! for! Systematic! Reviews! and!Meta,Analyses!(PRISMA)!guidelines!for!the!development!of!systematic!reviews.140!! 35!3.2.1$$ Eligibility$criteria$In!order!to!be!eligible!for!inclusion,!studies!had!to!be!peer,reviewed!and!had!to!assess!a!specific!intervention!to!prevent!the!initiation!of!injection!drug!use!among!non,injectors.! Studies! that! did! not! assess! original! data! (i.e.,! reviews)! were! not!eligible!for!inclusion.!Randomized!controlled!trials!(RCTs)!and!observational!studies!were!both!eligible!for!inclusion.!However,!studies!that!identified!risk!factors!for!the!initiation! of! injection! drug! use! but! did! not! identify! or! evaluate! an! intervention! to!prevent! injecting! were! not! eligible! for! inclusion.! Further,! studies! that! assessed!interventions! to! reduce! the! frequency! of! ongoing! injecting! or! those! that! seek! to!transition!current!injectors!into!non,injection!or!abstention!from!drug!use!were!not!eligible!for!inclusion.!!!3.2.2$ $Information$sources$We! searched! the! following! 10! electronic! databases:! PubMed,! PsycINFO,!EMBASE,!Cochrane!CENTRAL,!CINAHL,!Web!of!Science,!TOXNET,!AIDSLINE,!AMED!and!ERIC.!We!also!searched!the!internet!(Google,!Google!Scholar),!relevant!academic!conference!abstract!lists,!and!scanned!the!references!of!potentially!eligible!studies.!!We!searched!all!English,language!studies!and!abstracts!and!set!no!date!limits.!Search!terms!included!?initiation,?!?injection!drug!use,?!?prevention,?!?intervention,?!and! ?injecting.?! The! terms! were! searched! as! keywords! and! mapped! to! database!specific! subject! headings/controlled! vocabulary! terms! when! available,! including!MeSH!terms!for!PubMed!searches.!Each!database!was!searched!from!its!inception!to!its!most!recent!update!as!of!December!1st,!2012!for!English!language!articles.!! 36!3.2.3$ $Study$selection$! Two! investigators! (DW,! GR)! conducted! the! search! independently! and! in!duplicate!using! a!predefined!protocol.!The! investigators! scanned!all! abstracts! and!obtained!full!texts!of!articles!that!potentially!met!the!eligibility!criteria.!Validity!was!assessed!in!duplicate!based!on!eligibility!criteria.!After!all!potentially!eligible!studies!were!collected,!consensus!was!achieved!by!comparing!the!two!review!datasets.!Any!differences!were! reviewed! by! two! investigators! (DW,! GR)! and! a! final! decision! to!include!or!exclude!was!then!made.!3.2.4$$ Data$collection$process$! Between!December!1st,!2011!and!June!1st,!2012,!data!were!extracted!using!a!standardized! form! that! solicited! information! on! study!design,! setting,! sample! size!and!characteristics,!study!length,!type!of!intervention,!and!measures!of!effectiveness.!The!data!were!then!entered!into!an!electronic!database.!!3.2.5$$ Quality$assessment$! The! methodological! quality! assessment! checklist! developed! by! Downs! &!Black! was! employed! to! evaluate! the! relative! quality! of! reporting! for! all! studies!included!in!the!review.!This!approach!evaluates!studies!with!respect!to!five!different!areas:! reporting! of! hypotheses,! outcomes,!measurement,! results,! and! conclusions;!external! validity;! controlling! for! potential! bias;! controlling! for! potential!confounders;!and!statistical!power.!Studies!are!given!a!score!between!1!and!18,!with!18!representing!a!perfect!score.141!!3.2.6$$ Risk$of$publication$bias!! 37!! The!scientific! literature!on!anti,drug! interventions!such!as!education,based!prevention!campaigns!has!been!shown!to!be!affected!by!publication!bias!through!a!lack!of!publication!of!studies!with!negative!or!null!findings.142!Given!the!similarity!in!outcomes! between! these! interventions! and! those! designed! to! prevent! injecting!initiation,! a! similar! bias! may! affect! the! publication! of! studies! relevant! to! this!systematic!review.!3.3(( Results!3.3.1$$ Study$selection$and$characteristics$As!shown!in!Figure!1,!the!initial!search!yielded!384!studies,!of!which!78!met!the!eligible!criteria.!Sixty,one!studies!were!excluded!because! they!did!not!directly!evaluate!an!intervention!to!prevent!injecting!initiation,!while!nine!additional!studies!were!excluded!because!they!consisted!of!reviews!and!did!not!present!original!data.!Eight! studies! (combined! n$=! 2,414),! published! between! 1992! and! 2011,! met! the!eligibility!criteria!and!were!included!in!the!review.!!3.3.2$$ Methodological$quality$assessment$Out!of!a!possible!score!of!18,!the!Downs!&!Black!scores!for!individual!study!quality! ranged! from!10! to!17,!with! a!median! score!of! 13.5! (IQR!=!11.0! ?!16.5).141!Lower! scores!were!most!often! related! to! a! lack!of! reporting! study! characteristics,!with! only! 5! studies! (62.5%)! providing! full! details! on! sample! characteristics,!outcome!measures,! analytic! approaches,! and! findings.! Additionally,! only! 4! studies!(50.0%)!provided!information!on,!or!adequately!adjusted!for,!potential!confounders.!! 38!Only! one! study! (12.5%)! provided! detailed! information! such! as! intervention!implementation!and!materials/processes!used.!3.3.3$$ Results$of$individual$studies$! Eligible!studies!are!presented!in!Table!1.!As!shown,!sample!sizes!ranged!from!86! to! 900! participants! (Median! =! 125,! Interquartile! Range! [IQR]:! 91! ?! 682).! Five!studies!(62.5%)!were!conducted!in!North!America,!and!one!each!(12.5%)!in!Europe,!Australia,! and! Central! Asia.! Four! major! types! of! preventive! interventions! were!evaluated! in! the!studies:!social!marketing,143!peer,based!behavior!modification,144,146! addiction! treatment,147! and! deterrent/enforcement,based! interventions.148,150!Seven! studies! (87.5%)! employed! quantitative! methods;! one! study! (12.5%)!employed!qualitative!methods.143!Of! the! seven!quantitative! studies,! three! (42.9%)!employed!a!longitudinal!observational!design,146,!147,!150!two!studies!(28.6%)!used!a!RCT!design,144,!145!and!two!(28.6%)!employed!a!lagged!cross,sectional!design.148,!149!Among! longitudinal! studies,! the!median!study!period!was!18!months! (IQR!=!4.5!?!78.3).! The!majority! of! studies! (75.0%)! involved! human! participants! and! assessed!rates! of! injecting! initiation! via! self,report.! Two! studies! (25.0%)! employed! US!metropolitan! centers! as! the! unit! of! measurement! and! extrapolated! annual!metropolitan,specific! rates! of! injection! drug! use! based! on! surveillance! and!administrative!data.148,!149!Social$marketing$$! One!study!evaluated!the!impact!of!a!social!marketing!intervention!to!prevent!injecting! initiation.143!This!study! involved! the! targeted!dissemination!of!addiction,! 39!themed!posters!to!Montreal!street!youth!over!the!period!of!two!and!a!half!months.!Each! poster! communicated! a! unique! injection,related! harm! (e.g.,! increased! drug!dependence,!blood,borne!disease! transmission,! sex! trade! involvement)! and!public!postering!was!undertaken!in!and!around!61!participating!establishments!known!to!cater! to! street,involved! youth! in! Montreal.143! Data! from! in,depth! qualitative!interviewing!suggested!that!campaign!penetration!was!high,!and!the!vast!majority!of! study! participants! (84,93%)! agreed! with! the! statement! that! the! posters! were!effective!in!preventing!young!people!from!initiating!injection.143!!Peer;based$behavior$modification$! Three! studies! assessed! the! impact! of! peer,based! behavior!modification! on!risk! of! injecting! initiation,144,146! and! tested! the! hypothesis! that! peer! injectors!contribute!substantially!to!the!initiation!of!injection,na?ve!drug!users.!Two!of!these!studies!evaluated!an!intervention!dubbed!?Break!the!Cycle?!in!the!United!Kingdom,!Uzbekistan! and! Kyrgyzstan.145,! 146! Break! the! Cycle! involves! engaging! with! peer!injectors!to!reduce!injection,na?ve!drug!users?!exposure!to,!and!to!provide!education!regarding!the!harms!of,! injecting.145!The!first!study!evaluating!?Break!the!Cycle?!in!the!United!Kingdom!(n$=!86)!found!that!IDU!had!a!significantly!lower!likelihood!of!reporting!having!injected!in!front!of!non,IDU!in!the!3!months!after!the!intervention!(p$=!0.047).!Further,!requests!to! initiate!non,IDU!dropped!by!more!than!half,! from!36!to!15,!in!the!3!months!after!exposure!to!the!intervention!(p$=!0.038).!Additionally,!there! was! a! significant! association! between! exposure! to! the! intervention! and! a!decreased! likelihood! of! IDU! reporting!willingness! to! initiate! non,IDU! (p$<! 0.001).!The! second! ?Break! the!Cycle?! study! conducted! in!Uzbekistan!and!Kyrgyzstan! (n$=!! 40!856)!reported!similar!findings:!after!exposure!to!the!intervention,!the!proportion!of!IDU! that! reported! helping! non,IDU! initiate! injection! decreased! significantly! from!23.2%!of!the!cohort!to!9.8%!(p$<!0.001),!and!the!authors!estimated!that!the!overall!number! of! new! injecting! initiates! decreased! from! 67! in! the! year! prior! to! the!intervention!to!30!in!the!year!after!implementation.146!The!third!study!assessed!the! impact!of!a!social! learning!program!on!risk!of!injecting!initiation!among!a!cohort!of!intranasal!heroin!users!(i.e.,!heroin!?sniffers?)!in!New!York!City!(n$=!104).144!The!intervention!consisted!of!four!AIDS!education!and!injecting!prevention!sessions,!which!participants!were!randomly!selected!to!attend!four! times! over! a! period! of! two! weeks,! and! which! included! group! discussion,!informational!materials,!and!skill,building!to!avoid!injecting.!The!control!condition!involved! basic! AIDS! education! and! HIV! antibody! test! counseling.! At! a! 9,month!follow,up,! approximately! twice! as! many! control! arm! participants! had! initiated!injection! compared! to! experimental! arm! participants! (33%! vs.$ 16%),! and! those!participants! in! the! experimental! arm!were! found! to! be! significantly! less! likely! to!report!injecting!drugs!despite!adjustment!for!potential!confounders!(Adjusted!Odds!Ratio![AOR]!=!0.51,!95%!Confidence!Interval![CI]:!0.27!?!0.99,!p$<!0.05).144!!Treatment$One! study! examined! the! impact! of! addiction! treatment! access! on! injecting!initiation!among!a!cohort!of!intranasal!heroin!users.147!The!authors!employed!a!two,stage!design;!initially,!a!case,control!approach!was!used!in!which!intranasal!heroin!users,!newly,initiated!injection!heroin!users,!and!established!injection!heroin!users!were! grouped! separately,! and! compared! on! their! reported! access! to! heroin!! 41!addiction!treatment.!The!second!stage!of!the!analysis!investigated!whether!access!to!addiction! treatment! during! the! period! of! intranasal! heroin! use! affected! transition!patterns! into! injecting.! In! a! Cox! regression! analysis,! the! authors! found! that! an!increased! number! of! times! in! treatment! was! significantly! associated! with! a!decreased! likelihood! of! injecting! (Adjusted! Hazard! Ratio! [AHR]:! 0.72,! p$<! 0.001),!suggesting!that!access!to!treatment!may!increase!the!length!of!time!that!individuals!avoid!injecting.147!!Deterrence$Three!studies!examined!the!impact!of!drug!law!enforcement!on!the!initiation!of! injection! drug! use.148,150! Two! of! these! studies! investigated! the! long,term!deterrent!impact!of!legal!repressiveness!on!the!prevalence!of!injecting!initiation!in!metropolitan! centers! in! the!United! States.! In! the! first,148! legal! repressiveness!was!measured! by! the! number! of! drug,related! arrests! per! metropolitan! center,! the!number!of!police!employees!per!capita,!and!expenditures!on!corrections!per!capita!for!the!years!1994!to!1997.!The!overall!annual!prevalence!of!IDU!in!the!year!1998!was! the! dependent! variable.! Despite! adjustment,! the! authors! found! no! significant!association!between!any!of!the!measures!of!legal!repressiveness!and!the!subsequent!prevalence! of! IDU.! However,! the! authors! did! observe! a! significant! association!between!the!measures!of!legal!repressiveness!and!increased!HIV!prevalence!among!IDU! (all! three! p$ <! 0.05).! In! a! follow,up! study,149! the! authors! examined! the!prevalence!of! injection!drug!use! among!93!US!metropolitan! centers! from!1992! to!2002! that!employed!similar!surveillance!data!on! injection!drug!use!and!measured!legal! repressiveness! through! the! rate! of! ?hard! drug?! arrests! (e.g.! arrests! for! the!! 42!unlawful! possession! of! opium! or! cocaine! or! their! derivatives,! such! as! morphine,!heroin,!or!codeine)!per!metropolitan!center.!Consistent!with!their!initial!study,!they!found! that! the! rate! of! hard! drug! arrests! per! metropolitan! center! was! not!significantly! associated! with! changes! in! the! prevalence! of! IDU! over! the! study!period.149!!The!third!study!investigated!the!impact!of!decreased!availability!of!heroin!in!Australia,151,! 152! which! was! attributed! by! some! to! targeted! enforcement,based!supply!reduction.153!The!authors!employed!Australian!government!surveillance!data!on!the!annual!prevalence!of!heroin! injectors,! the!prevalence!of! treatment,enrolled!heroin! injectors,! heroin,related! arrests,! and! fatal! overdoses! across! the! country.!These!data!were!used! to! estimate! the! total! reduction! in! the! incidence!of! injecting!initiation! among! heroin! users.! The! authors! estimated! that! between! 2,745! and!10,560!individuals!did!not!initiate!heroin!injection!as!a!result!of!the!heroin!shortage.!However,! the! authors! observed! an! increase! in! the! number! of! new! injectors! of!amphetamine,! and! stated! that! it! was! unclear! how!much! of! the! reduction! in! new!heroin!injectors!was!offset!by!an!increased!incidence!of!amphetamine!injection.150!!3.4(( Discussion(! This!systematic!review!included!all!English,language!peer!reviewed!studies!that!evaluated! interventions! to!prevent! injecting! initiation.!The!number!of!eligible!studies!was!limited.!Those!studies!included!in!the!final!review!evaluated!four!major!types! of! interventions:! social! marketing,! peer,based! behavior! modification,!addiction! treatment,! and! deterrent/enforcement,based! interventions.! The! eligible!! 43!studies!employed!a!variety!of!methodological!approaches!and!included!data!from!a!diverse!set!of!regions.!Four!studies!(50.0%)!reported!a!significant!positive!impact!of!peer,based! behavior! modification! and! treatment,based! interventions! on! the!prevention!of!injecting!initiation.144,147!! The! small! number! of! studies! eligible! for! this! review! suggest! that! the!development! and! evaluation! of! interventions! to! prevent! injecting! remains!underserved!as!an!area!of!research,!despite!the!well,known!harms!of!injection!drug!use!and!expert! calls! to!prevent! this!phenomenon.4,!22!This! is!of! concern,! given! the!estimated! 16! million! individuals! worldwide! who! engage! in! injection! drug! use.10!Further,! while! this! review! outlines! preventive! interventions! that! appear! to! be!effective,! none! of! these! have! been! resourced! to! scale.! Indeed,! aside! from!enforcement,based!interventions,!only!?Break!the!Cycle,?!which!has!been!adapted!to!three!settings,146!appears!to!currently!be!implemented.!!Despite! the! limited! number! of! studies,! these! results! have! implications! for!efforts! to! reduce! injecting.! Several! studies! included! in! this! review!highlighted! the!influence! of! social! networks! on! initiation! risk,! as! previously! noted! in! Chapter! 2.!Indeed,! exposure! to! injectors! and! injecting! environments! appears! to! increase! risk!for! initiation.154,156! Expanding! access! to! addiction! treatment! and! behavior!modification! interventions! among! established! injectors! may! thereby! reduce!exposure!to!injecting!among!injection,na?ve!drug!users.!However,!interventions!that!provide! access! to! addiction! treatment! among! established! injectors147!may! have! a!greater!overall! impact!on!community,level! injection,related!harms,!given! that! this!approach!may!have!the!secondary!effect!of!reducing!the!total!number!of!injectors.!If!! 44!brought! to! scale,! such! interventions!would!be! supplementary! to! current!efforts! to!reduce!both!drug!use!and!drug,related!harm.!However,!the!present!lack!of!a!strong!evidence! base! to! support! the! scale,up! of! addiction! treatment! represents! a!substantial! barrier! to! pursuing! this! hypothesis.! Given! the! many! serious! harms!associated! with! injecting,! however,! the! development! of! new! modalities! to!investigate!and!modify!the!risk!of!injection!initiation!posed!by!exposure!to!injecting!should! be! prioritized.! These! should! take! into! account! the! fact! that! a! variety! of!intersecting! economic! concerns! and! vulnerabilities! can! influence! drug! injectors?!decisions! to! initiate! others! into! injecting,157! which! may! limit! the! impact! of!interventions! that! rely! on! individual! behaviour! modification,! such! as! Break! the!Cycle.! As! such,! access! to! evidence,based! treatment!modalities! such! as!methadone!maintenance!therapy,!and!other!clinical!treatment!options!should!be!investigated!as!potential!approaches!to!preventing!the!incidence!of!injecting!initiation.!By!contrast,!the! results! of! this! review! suggest! that! approaches! relying! on! legal! repressiveness!are!likely!to!be!ineffective!deterrents.148,!149!This! review! has! a! number! of! limitations.! First,! there! was! a! limited! peer,reviewed!literature!that!evaluated!interventions!to!prevent!injecting!initiation,!and!the!systematic!review!was!thus!restricted!to!eight!studies.!Those!studies!that!were!included!in!the!review!utilized!a!diverse!set!of!methodologies!to!evaluate!a!variety!of!interventions!in!a!wide!range!of!settings.!Second,!experts!have!demonstrated!the!potential!for!publication!bias!in!studies!evaluating!education,based!interventions!to!prevent!drug!use,142!as!well!as!in!studies!evaluating!the!overall!effectiveness!of!drug!law!enforcement! in!reducing!drug,related!harms.158,!159! It! is!possible!that!a!similar!! 45!bias!exists!in!the!scientific!literature!on!the!prevention!of!injecting!initiation,!which!would! have! skewed! our! results! away! from! null! findings.! Third,! some! studies!included! in! the! review! assessed! the! indirect! effects! of! interventions! on! levels! of!injecting! initiation,!which! limits! the! conclusions! that! can! be! drawn! regarding! the!causal!linkages!between!these!interventions!and!patterns!of!injecting!initiation.!To!conclude,!this!review!found!that!those!interventions!that!seek!to!limit!the!exposure! of! injection,na?ve! drug! users! to! injecting! environments,! either! through!peer,based!behavior!modification!or!enrolment!of!drug!users!in!addiction!treatment,!may! be! effective! in! reducing! the! incidence! of! injecting! initiation.! By! contrast,!interventions! that! rely! on! drug! law! enforcement! to! produce! a! deterrent! effect!appear!to!be!ineffective.!However,!the!peer,reviewed!literature!on!this!topic!is!quite!limited,!with! the!development!of! interventions! to!prevent! injection!representing!a!critically!underserved!area!of!research.!!! !! 46!!Not!sure!what!happened!to!the!table!as!in!my!computer!didn?t!make!sense.!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Figure 2.  Flow chart of screening and selection process (!384!poten*al!studies!iden*fied!in!electronic!databases!!!!306!excluded!based!on!exclusion!criteria!!!61!papers!excluded!(no!direct!evalua*on!of!injec*ng!preven*on!interven*ons) !!!!9!papers!excluded!(no!original!data)!!!!!8!paper!included!in!systema1c!review!!5!studies!from!North!America!!1!study!from!Europe!!1!study!from!Australia!!1!study!from!Central!Asia!! !!!384!poten*al!studies!iden*fied!in!electronic!databases!!!!306!excluded!based!on!exclusion!criteria!!!61!papers!excluded!(no!direct!evalua*on!of!injec*ng!preven*on!interven*ons) !!!!9!papers!excluded!(no!original!data)!!!!!8!paper!included!in!systema1c!review!!5!studies!from!North!America!!1!study!from!Europe!!1!study!from!Australia!!1!study!from!Central!Asia!! !!! 47!Author''&'Year' Location' N" Study'period' Study'Design' Participant'Characteristics'' Intervention' Proportion'Exposed' Main'Findings' Quality'Score'!! !! !! !! !! Mean'age'(range)' %'Female' Ethnicity' '' '' !! ''Hunt!et!al.,!1998! Kent,!UK! 86! 3!months! RCT!! 29.8! 22%! NR! Peer>based!behaviour!modification! 100%! Participants!injected!with!fewer!non>injectors!after!exposure!(97!vs.!49).!Initiation!requests!fell!(36!to!15)!and!the!number!of!initiates!decreased!(6!to!2).!11!Roy!et!al.,!2007! Montreal,!Canada! 146! ! Cross>sectional!observational!study,!qualitative!interviews!19!(15>23)! 25%! NR! Anti>injection!media!campaign! 92%?! Participants!reported!believing!campaign!was!effective.!A!certain!number!of!young!people!testified!to!the!dissuasive!effect!the!campaign!had!had!on!them!directly.!13!Des!Jarlais!et!al.,!1992! New!York,!US! 104!! 8.9!months! RCT! 27.3!(16>48)! 30%! 51%!white! Peer>based!behaviour!modification!! 48%!(40)! Being!in!the!experimental!group!for!this!study!was!associated!with!a!lower!probability!of!injecting!(AOR!=!0.51;!95%!CI:!0.27!>!0.99)!15!Friedman!et!al.,!2006! US!MSAs! 89!US!MSAs! 1!year!(1993)! Lagged!cross>sectional!analysis! >>! >>! >>! Drug!law!enforcement! 100%! No!association!between!injection!drug!use!and!police!deterrence.! 17!Friedman!et!al.,!2011! US!MSAs! 96!US!MSAs! 1992>2002! Longitudinal!observational!study! >>! >>! >>! Drug!law!enforcement! 100%! No!association!between!injection!drug!use!and!police!deterrence.! 17!Kelley!et!al.,!2004! South!Florida,!US! 900!! July!1997!>!August!1999! Longitudinal!observational!study! Sniffers:!34.7!//!New!injectors:!32.1!//!Established!injectors:!43.0!Sniffers:!30.1!//!New!injectors:!30.7!//!Established!injectors:!32.0!Sniffers:!24.2%!white!//!New!injectors:!27.6%!white!//!Established!injectors:!30.6%!white!Addiction!treatment! Mean!treatment!days:!heroin!sniffers:!237.6!//!injection!initiators:!191.6!The!number!of!times!that!heroin!sniffers!(n!=!604)!were!in!treatment!was!inversely!associated!with!a!time!to!injecting!(AHR!=!0.73,!p&<!0.001).!14!Day!et!al.,!2006! Australia! 158!! 1996>2004! Longitudinal!observational!study! !!!NR!!!!NR!!!!NR!Heroin!drought! 100%! 2,745>10,560!young!people!may!have!averted!heroin!injecting!in!2001.!Potentially!offset!by!amphetamine!injecting.!11!Gray,!2008! Uzbekistan!and!Kyrgyzstan! 856! April!2006>April!2008! Longitudinal!observational!study! NR! NR! NR! Peer>based!behaviour!modification! 100%! Injectors!initiated!by!established!IDU!decreased!from!67!to!30!(2006>2008)! 10!  Table 1. Studies evaluating interventions to prevent the initiation of injection drug use Note:&RCT&=&randomized&controlled&trial;&MSA&=&metropolitan&statistical&area;&IDU&=&injection&drug&user;&AOR&=&adjusted&odds&ratio;&AHR&=&adjusted&hazard&ratio&NR&=&not&reported!!! 48!CHAPTER(4:(CRYSTAL(METHAMPHETAMINE(AND(INJECTING(INITIATION(AMONG(STREET5INVOLVED(YOUTH(IN(A(CANADIAN(SETTING(4.1(( Background(As! described! in! Chapter! 3,! there! are! few! evidence7based! strategies! specifically!proven!to!prevent! injecting! initiation!among!street7involved!youth.!This! is! in! large!part!because! little! is! known! regarding! the! risk! factors! for! injecting! initiation! among! this!population,!though!Chapter!2!noted!that!crack!and!powder!cocaine!use,!along!with!early7onset!polysubstance!use,!may!play!a!role!in!heightening!risk.31,!108,!160!However,!much!less!is!known!regarding!how!the!use!of!specific!synthetic!drugs,!such!as!methamphetamine,!may!impact!an!individual?s!risk!of!initiating!injection.32!This!is!of!concern!given!that!the!United! Nations! Office! on! Drugs! and! Crime! recently! reported! that! amphetamine7type!stimulants!are!now!the!second!most!commonly!used!illicit!drug!globally.161!Research!also!suggests! that! the! use! of! drugs! including! amphetamines! may! be! associated! with!subsequent!reductions!in!spatial!working!memory,!increased!disinhibition,!and!a!range!of!impaired! cognitive! function.1627165! Given! growing! concerns! regarding! increasing!methamphetamine!use!globally!and!in!the!present!study!setting,32,!67!as!well!as!the!harms!of! injecting!drug!use!as!delineated! in!Chapter!1,!we!sought! to! investigate! the! impact!of!crystal! methamphetamine! use! on! risk! of! injecting! initiation! among! a! cohort! of! street7involved!youth!in!Vancouver.(4.2(( Methods(! These!analyses!employed!data!from!the!At7Risk!Youth!Study!(ARYS),!described!in!full! in! section! 1.7.32! For! the! present! study,! data! from! ARYS! participants! who! were!!! 49!injection!na?ve,!enrolled!in!the!cohort!between!October!1,!2005!and!November!30,!2010,!and!completed!at!least!one!follow!up!interview!were!used.!The!outcome!of!interest!was!defined!as!the!first!episode!of!any!injection!drug!use.!The!primary!independent!variable!of!interest!was!defined!as!any!non7injection!crystal!methamphetamine!use!(i.e.,!smoking!and/or! intranasal!use)! in! the!previous!six!months.!Potential!confounders! included:!age,!gender!(e.g.,!male!vs.!female!or!male!to!female!transgender),!Aboriginal!ancestry!(yes!vs.!other),!recent!non7injection!heroin!use,!recent!powder!cocaine!use!(i.e.,!smoking!and/or!intranasal! use),! recent! crack! cocaine! smoking,! recent! cannabis! use,! and! recent! alcohol!use.! Aboriginal! ancestry! was! considered! given! the! extensive! literature! from! the! study!locale!indicating!a!higher!risk!profile!among!Aboriginal!people!who!use!illicit!drugs.1667168!All! drug7related! variables! refer! to! behaviours! in! the! previous! 6! months! and! all! were!lagged! by! one! follow7up! questionnaire! to! protect! against! reverse! causality! (e.g.,! the!potential! that! participants! began! using! specific! types! of! drugs! as! a! consequence! of!initiating!injection!drug!use).!First,! Kaplan7Meier! methods! were! used! to! calculate! the! cumulative! hazard! of!injecting!initiation.!We!then!employed!an!a!priori!two7step!approach!as!recommended!by!Greenland.169! First,! univariate! Cox! regression! analyses! were! conducted! to! determine!whether! the! independent! variable! of! interest! and! potential! confounders! predicted!initiation! of! injection! drug! use! at! the! p!<! 0.05! level.! Next,! a! multivariate! confounding!model! was! constructed! that! included! all! potential! confounders,! which! were! removed!sequentially! using! a! backward! selection! approach! to! produce! restricted! models.! The!relative!coefficient!change!for!crystal!methamphetamine!use!was!then!calculated!among!these! restricted! models! and! those! variables! that,! once! removed,! changed! the! model!!! 50!coefficient! by!more! than! 5%! relative! to! the! full!model!were! included! in! a! final!model.!Finally,! a! retrospective! subanalysis! investigating! circumstances! of! first! injection! was!undertaken!among!all!ARYS!participants!that!reported!ever!injecting!drugs!at!baseline!or!during! study! follow7up! in! an! effort! to! identify! specific! micro7setting! phenomena!accompanying! injecting! initiation! events.! All! statistical! analyses!were! performed! using!SPSS!software!version!17.0!(SPSS,!Chicago,!IL).!4.3(( Results(! A! total! of! 991!participants! completed! the!ARYS!baseline! questionnaire! between!October! 2005! and! December! 2010,! among! whom! 395! (39.9%)! reported! using! crystal!methamphetamine! at! baseline! and! 390! (39.4%)! reported! injecting! drugs! at! baseline.!Those!with! a! history! of! injection! drug! use! at! baseline!were!more! likely! to! use! crystal!methamphetamine! than! those!without! a! history! of! injecting! (47%! vs.!34%,!p!<! 0.001).!Among! the! 601! individuals! who! were! injection7na?ve! at! baseline,! 395! (65.7%)! had! a!follow!up!visit!to!assess!for!injecting!initiation!and!were!therefore!eligible!for!inclusion!in!the!present!study.!!The!overall!recruited!ARYS!sample!did!not!differ!significantly!in!age,!gender,!ethnicity!or!baseline!crystal!methamphetamine!use!compared!to!those!injection7na?ve!participants!that!were!included!in!the!analysis.!Among!eligible!participants!(n!=!395),!126!(31.9%)!were!female!and!85!(21.5%)!reported!Aboriginal! ancestry.!Median! participant! age! at! baseline!was! 22! (Interquartile!range! [IQR]:! 20! ?! 23),! and! the!median! follow7up! time!was! 21!months! (IQR:! 13! ?! 26).!Overall,!141!(35.7%)!participants!reported!non7injection!crystal!methamphetamine!use!at!baseline.!!!! 51!Sixty7four! (16.2%)!participants! reported! initiating! injection!drug!use!during! the!study!period! for!an! incidence!density!of!21.7! (95%!Confidence! Interval!1.7!?!41.7)!per!100! person! years.! The! median! age! of! first! non7injection! drug! use! among! those! who!subsequently!initiated!injection!drug!use!was!14!(IQR:!12!?!16),!while!among!persistently!injection7na?ve!participants!it!was!12!(IQR:!10!?!13).!Table!2!presents!characteristics!of!study!participants!stratified!by!non7injection!crystal!methamphetamine!use!at!baseline.!Figure!3!shows!the!results!of!a!Kaplan7Meier!analysis!of!time!to!injecting!initiation!stratified!by!crystal!methamphetamine!use!among!the!study!sample.!As!shown!here,!after!36!months! the! cumulative!hazard!of! injecting! initiation!was!33.0%!among!participants!that! reported! crystal! methamphetamine! use! compared! with! 13.3%! among! those!participants!that!did!not!report!crystal!methamphetamine!use!(p!=!0.010).!!! The! results! of! the! univariate! Cox! regression! analyses! and! the! final!multivariate!confounding!model! are! presented! in! Table! 3.! As! shown! here,! in!multivariate! analysis,!recent! crystal! methamphetamine! use! (Adjusted! Hazard! Ratio! [AHR]! =! 1.78,! 95%!Confidence!Interval![CI]:!1.24!?!2.56,!p!=!0.002)!and!recent!heroin!use!(AHR!=!1.89,!95%!CI:!1.22!?!2.93,!p!=!0.004)!were!associated!with!an!increased!risk!of!injecting!initiation.!By!contrast,!recent!cannabis!use!(AHR!=!0.63,!95%!CI:!0.40!?!0.99,!p!=!0.046)!was!negatively!associated! with! risk! of! injecting! initiation,! though! this! association! approached! non7significance.!!! Among!ARYS!participants!that!reported!ever!injecting!drugs!at!baseline!or!during!follow7up!(n!=!369),!almost!half!(46.9%)!reported!receiving!their!first!injected!drug!as!a!gift.! The! drugs! of! first! injection! were! most! commonly! heroin! (25.7%)! and! crystal!methamphetamine! (24.1%),! followed! by! cocaine! (20.1%).! Roughly! two7thirds! of!!! 52!participants!(36.6%)!reported!that!they!did!not!believe!that!their!use!of!drugs!was!out!of!control! prior! to! first! injection.! Further,! 49.6%! of! participants! reported! that! they! had!never!considered!injecting!prior!to!the!initiation!event.!!While! participants! reported! diverse! injecting! initiation! micro7settings,! 39.8%!reported! initiating! injection! in! an!outdoor!public! space.! In! terms!of! geographic! setting,!the! largest! proportion! of! participants! reported! initiating! injection! in! Vancouver?s!downtown! eastside! neighbourhood! (19.0%),! the! site! of! a! large! open7air! illicit! drug!market,! while! 17.9%! reported! initiating! injection! in! the! downtown! south,! an! adjacent!neighbourhood! previously! identified! as! a! potential! geographic! area! of! transition! into!increased!drug!use! among! street7involved!youth.71,!72,!170! Further,! participants! reported!that!a!variety!of!individuals!were!present!at!initiation!events,!including!friends!(44.4%),!family! members! (8.4%),! and! strangers! (4.1%).! However,! 7.5%! of! initiates! reported!initiating! injection!alone.!Almost! three!quarters! (72.6%)!of!participants! reported!being!injected! by! someone! else! during! their! injection! initiation! event.! During! their! first!injection! experiences,! 18! initiates! (4.9%)! reported! sharing! needles.! Finally,! 80.8%! of!participants!reported!subsequently!becoming!regular!injectors!within!5!years.!4.4(( Discussion(! Among! a! sample! of! street7involved! youth! in! a! Canadian! setting,! recent! non7injection!crystal!methamphetamine!use!was!independently!associated!with!an!increased!risk! of! subsequent! initiation! of! injection! drug! use.! First7time! injectors!were! also!more!likely! to! inject! crystal! methamphetamine! compared! to! other! drugs.! A! substantial!proportion!of!the!subsample!of!initiates!reported!having!been!injected!by!someone!else!!! 53!during! initiation! events,! and!nearly! all! reported! that! they!had!not! considered! injection!drug! use! prior! to! first! injection.! Half! of! the! subsample! reported! receiving! the! injected!drug!as!a!gift.!!Canadian! surveillance! data! suggest! that! reported! levels! of! crystal!methamphetamine! use! among! street7involved! youth! in! Canada! rose! significantly! from!2.5%! in! 1999! to! 9.5%! in! 2005.171! This! is! consistent! with! global! patterns! of! elevated!crystal!methamphetamine! use,161! as!methamphetamine! remains!widely! available,! with!levels!of!use!particularly!high!among!youth!in!Southeast!Asia!and!North!America.161!This!likely! reflects! the! relative! ease! with! which! amphetamine7type! stimulants! can! be!produced.!!!The!data!presented!here!have!immediate!policy! implications.!For! instance,!while!previous!research!has!identified!a!variety!of!serious!health!harms!associated!with!crystal!methamphetamine!use,67!the!current!study!identifies!use!of!this!drug!as!a!potential!risk!factor!for!injecting!initiation.!This!has!implications!for!current!approaches!to!curtail!the!supply! of! amphetamine7type! stimulants! and! precursor! chemicals,! which! appear! to! be!largely! ineffective! in! the! North! American! context,! given! the! persistent! widespread!availability! of! this! drug.9,! 58,! 171! In! this! context,! the! findings! of! this! study! indicate! that!resources!dedicated! to! supply! reduction!may!be!better! spent!on!proven!approaches! to!reduce!methamphetamine7related!harms.!!!Specifically,! given! the!previously7identified!harms!of!methamphetamine!use! and!the! findings! presented! in! this! Chapter,67! policymakers! should!work! to! implement! and!scale! up! evidence7based! treatment! for! methamphetamine7dependent! individuals.!However,! it! is! important! to! note! that! a! recent! review! of! clinical! treatment! for!!! 54!methamphetamine!dependence!noted! the!dearth!of! effective! treatment!options! for! this!drug,!and!stated!that!one!barrier!to!the!development!of!treatment!has!been!inadequate!research! on! the! characteristics! and! consequences! of! use! of! this! drug.172! Therefore,! a!policy! recommendation! to! come! out! of! this! research! is! to! expand! research! into! novel!treatments! for! methamphetamine! addiction.1737175! Given! that! this! study! identified!established!IDU!as!facilitators!of!injection!initiation!events,!an!avenue!for!future!research!could!include!how!structural!interventions,!such!as!supervised!consumption!facilities,176!may! reduce! population! mixing! effects! that! increase! the! exposure! of! non7IDU! to!established!IDU.!!Contrary!to!a!study!of!injecting!initiation!among!street!youth!in!Montreal,31!which!found! an! increased! risk! of! initiation! among! street! youth! that! used! crack! and! powder!cocaine,! the! current! analysis! found! no! significant! association! between! recent! powder!cocaine! or! crack! use! and! injecting! initiation.! In! this! regard,! the! current! findings! also!diverge! from! those! of! a! study! of! IDU! in! Baltimore! that! observed! a! protective! effect! of!powder!cocaine!use!on!risk!of!injecting!initiation.160!Clearly,!further!research!is!required!to! develop! and! test! evidence7based! interventions! to! prevent! injecting! in! ways! that!accommodate! the! complexities! of! polysubstance! use! and! other! micro7environmental!features! that!modify! risk! in! the! lives!of!young!street7based!drug!users.!With! respect! to!our! findings! concerning! the! fact! that!participants!perceived! that!drug!dependence!was!not! a!motivation! for! their! decisions! to! initiate! injection,! these! are! consistent!with!data!from! studies! such! as! the! Collaborative! Injection! Drug! Users! Study! (CIDUS)! and! the!Montreal! Street! Youth! Cohort,! both! of! which! have! noted! that! drug! dependence! is! not!commonly!cited!as!a!factor!by!individuals!in!their!decisions!to!initiate!injection.177!These!!! 55!studies! also! concluded! that! individuals! identified! as! at! high! risk! of! initiating! injection!drug!use!require!more!network7!and!peer7delivered!information!regarding!the!negative!consequences!of! injection!drug!use.31,!35!To! that! end,! some! studies!have! suggested! that!older!IDU!should!be!enlisted!in!efforts!to!educate!young!people!who!use!drugs!regarding!the!harms!of!transitioning!into!injection!drug!use.178!!In! this! context,! the! current! study?s! findings! regarding! the! micro7setting!characteristics!of!injecting!initiation!events!elucidate!the!context7specific!roles!that!other!injectors! likely! play! in! determining! risk! of! injecting! initiation! among! street7involved!youth.! Specifically,! roughly! half! of! the! sample! of!ARYS! injectors! reported! receiving! the!injected!drug!as!a!gift!and!almost!three!quarters!of!participants!reported!being!injected!by!someone!else!during!their!initiation!event.!These!findings!suggest!that,!consistent!with!the!research!presented! in!Chapters!2!and!3,!drug7using!peers!and!established! injectors!likely!play!a! critical! role! in! initiating! street7based!young!people! into! injection!drug!use!through!a!variety!of!roles.!By!extension,!they!may!also!represent!untapped!potential!for!preventing! injecting! initiation,! as! they! represent! a! source! of! peer! education! on! the!negative! health! and! social! impacts! of! injecting! initiation! among! injection7na?ve! drug!users,145! though! the! evidence! base,! as! noted! in! Chapter! 3,! is! limited! in! this! regard.!However,! one! potential! avenue! to! mitigate! the! impact! of! established! injectors! in!increasing! risk! of! injecting! initiation!may!be! increasing! community! access! to! addiction!treatment,! as! described! in! the! study! by! Kelley! and! colleagues! in! Chapter! 3,147! or!implementing! supervised! consumption! facilities,! which! may! work! to! minimize! the!exposure! to! injecting!and! the! influence!of!established! injectors! that!appear! to! facilitate!injection!transition!events.!!! 56!This! study! has! limitations! consistent! with! observational! studies! of! drug7using!populations.!First,!although!the!ARYS!cohort!reflects!many!characteristics!representative!of! street7involved! youth! living! in!Vancouver,179! the! lack! of! registries! of! street7involved!youth!meant!that!the!sample!was!not!randomly!recruited.!Second,!illicit!drug!use!remains!highly!stigmatized!and!this!may!have!affected!participant!responses,180!although!this!bias!may!not!have!affected! the!response!patterns!of! initiators!and!non7initiators!differently.!Third,! we! cannot! rule! out! the! potential! for! confounding! as! a! result! of! exposures! or!participant!traits!that!were!not!measured!as!part!of!the!present!study.!!For!instance,!illicit!stimulant!use!has!been!associated!with!psychiatric!disorders!including!Attention!Deficit!Hyperactivity! Disorder! (ADHD).181,! 182! Unfortunately,! standardized! assessment! of!psychiatric!disorders!was!not!undertaken!as!part!of! the!ARYS!study.! !Similarly,! there! is!increasing!recognition!of!genetic! factors!which!may!predispose! individuals! to!addictive!disorders! and! high7risk! drug! use,183! including! sensation! seeking,98,! 184! and! these! data!were! also! not! available! in! the! present! study! because! of! concerns! regarding! statistical!power,!though!the!role!of!this!personality!trait!is!investigated!in!Chapter!5.!!Nevertheless,!the!present!study!identified!a!strong!association!between!crystal!methamphetamine!use!and!subsequent!injection!drug!use,!a!finding!with!immediate!policy!implications.!Finally,!data!were!not!available!on!the!circumstances!of!injecting!for!all!incident!cases!of!injection!initiation.! Future! research! should! seek! to! better! elucidate! the! specific! mechanism! by!which!crystal!methamphetamine!use!may! increase! the!risk!of! initiation,!by!considering!whether!use!of!this!drug!may!interact!with,!or!mediate!the!relationship!between!injection!initiation!and!other!potential!risk!factors!such!as!childhood!trauma!or!latent!personality7based!factors!such!as!sensation!seeking.!(!! 57!! In! sum,! this! study! found! that! non7injection! crystal! methamphetamine! use! was!independently! associated! with! an! increased! risk! of! injecting! initiation! among! ARYS!participants,! despite! adjustment! for! sociodemographic! and! drug7related! confounders.!Further,!in!a!subanalysis!of!circumstances!of!first!injection,!the!second!largest!proportion!of! participants! reported! initiating! injection! with! crystal! methamphetamine! use,! and!established! injectors!appeared! to!play!a!critical! role! in! initiation!events.!These! findings!highlight! the!need!to!address! the!dual! impact!of!crystal!methamphetamine!use!and!the!presence! of! established! injectors! in! increasing! the! risk! of! injecting! initiation! among!injection7na?ve! street7involved! youth.4,! 22! Considered! within! the! context! of! the! review!presented!in!Chapter!3,!the!development!and!evaluation!of!appropriate!interventions!to!prevent!injection!among!crystal!methamphetamine!users!is!critically!needed.!!!! 58!!Table 2. Baseline characteristics of injection-na?ve street-involved youth according to non-injection crystal methamphetamine use in Vancouver, Canada (n = 395).  Characteristic  Crystal Methamphetamine Use Total (%) No (%) Yes (%) (n = 395)! (n =254) (n = 141) Sociodemographic factors    Median age (IQR)* 21.6 (19.6 - 23.3) 21.7 (19.5 - 23.6) 21.4 (19.7 ? 22.8)  Male gender 269 (68.1) 177 (65.8) 92 (34.2) Aboriginal ancestry 85 (21.5) 64 (25.2) 21 (14.9)  Drug-related behaviors     Recent heroin use 63 (15.9) 31 (49.2) 32 (50.8) Recent cocaine use 194 (49.1) 127 (65.5) 67 (34.5) Recent crack use 221 (55.9) 137 (62.0) 84 (38.0) Recent cannabis use 355 (96.2) 252 (64.8) 137 (35.2) Recent alcohol use 69 (17.5) 50 (72.5) 19 (27.5) Note: All drug use variables refer to non-injection use in the preceding six months * IQR = Interquartile Range    !! 59! Table 3. Unadjusted and adjusted hazard ratios for factors related to initiation of injection drug use among street-involved youth in Vancouver, Canada, 2005-2010 (n = 395). Characteristic Unadjusted HR (95% CI) Adjusted HR (95% CI) p value* Recent crystal methamphetamine use 1.51 (1.19 - 1.99) 1.78 (1.24 - 2.56)  0.002 Participant age (per year younger) 0.91 (0.86 - 0.97) -- -- Male gender 0.61 (0.42 - 0.88) -- -- Aboriginal vs. other 1.02 (0.69 ? 1.52) 1.67 (0.87 ? 3.23) 0.122 Recent cocaine use 0.94 (0.73 - 1.21) 0.81 (0.54 - 1.22) 0.305 Recent crack use 1.20 (0.93 - 1.56) 0.93 (0.63 - 1.37) 0.704 Recent heroin use 1.39 (1.06 - 1.82) 1.89 (1.22 - 2.93) 0.005 Recent cannabis use 0.94 (0.67 - 1.26) 0.63 (0.40 - 0.99) 0.046 Recent alcohol use 1.02 (0.77 - 1.37)  0.93 (0.58 - 1.50) 0.759  Note: All drug use variables refer to non-injection use in the preceding six months and are lagged by one follow-up Note: HR = hazard ratio; CI = confidence interval * p value for adjusted hazard ratio  !! !!      !! 60!Cumulative hazard of injection initiation (%) Time from recruitment (in months)Figure 3. Cumulative hazard of injection initiation among street-involved youth stratified by crystal methamphetamine use in Vancouver, Canada, October 2005 - December 2010 (n = 395)!! 61 CHAPTER( 5:( THE( DEVELOPMENT( OF( A( BRIEF( SUBSTANCE( USE( SENSATION(SEEKING(SCALE:(VALIDATION(AND(PREDICTION(OF(INJECTION(DRUG(USE(5.1(( Introduction(! Sensation! seeking,! a! personality! trait! first! identified! in! the! 1950s! and!frequently! measured! using! the! Sensation! Seeking! Scale! (SSS)! developed! by!Zuckerman,! can! be! briefly! defined! as! a! desire! for! novel! and! potentially! risky!experiences.185!A!large!body!of!scientific!literature!has!demonstrated!that!sensation!seeking! increases! dramatically! between! the! ages! of! 12! to! 14,! remains! relatively!stable!throughout!young!adulthood!(e.g.,!until!approximately!25!years!old),!and!then!declines!slightly!as!individuals!age.90!While!consisting!of!four!subdomains,!sensation!seeking!has! been!modeled! as! a! single! unidimensional! trait,! and!past! research!has!shown!sensation!seeking! to!be!a!reliable!measure!of!an! individual?s!willingness! to!engage!in!risky!behaviours.86,!98,!186K188!In!particular,!the!SSS!has!been!employed!as!a!tool! to! identify! individuals! who! may! be! at! higher! risk! of! substance! use.98! For!instance,! antiKdrug! public! service! announcements! have! been! designed! for! an!audience! of! high! sensation! seekers! in! order! to! reduce! the! initiation! of! drug! use!among! this! group.189,! 190! A! recent! randomized! controlled! trial! also! found! that!cognitiveKbehavioural!interventions!that!worked!to!lower!sensation!seeking!among!youth!were!efficacious!in!reducing!levels!of!alcohol!misuse.191!Additionally,!changes!in!sensation!seeking!have!been!associated!with! the!escalation!of!adolescent!use!of!alcohol,! marijuana! and! tobacco,! with! those! youth! who! experienced! a! less! rapid!variance!in!sensation!seeking!level!over!time!also!less!likely!to!rapidly!increase!their!use!of!marijuana!or!tobacco!compared!with!youth!who!experienced!rapid!changes!in!sensation! seeking! level.184! This! may! be! related! to! the! fact! that! higher! sensation!!! 62 seeking!among!adolescents!has!shown!to!be!associated!with!childhood!sexual!abuse,!which!in!turn!has!been!shown!to!be!a!risk!factor!for!injection!initiation.192!As!such,!an! investigation! of! sensation! seeking! among! streetKbased! drugKusing! populations!may! contribute! to! a! greater! understanding! of! the! linkages! between! distal! factors!and! psychosocial! variables! that!may! heighten! the! risk! of! drugKrelated! behaviours!such!as!injecting.!!!! !Kalichman! and! colleagues! suggest! that! sensation! seeking! may! act! as! a!mediating! factor! in! sexual! transmission! of! HIV,! but! that! the! SSS! may! be! an!inappropriate!tool!for!individuals!in!subpopulations!at!high!risk!because!many!scale!items! refer! to! behaviours! that! are! irrelevant! or! not! suitable! for! certain!subpopulations!(e.g.,! the!SSS! item!regarding!a!willingness! for!?Discussing!your!sex!life!with!friends?!would!likely!not!be!a!valid!measure!of!sensation!seeking!among!a!cohort! of! individuals!who! report! engaging! in! sexual! riskKtaking;! similarly,! ?Trying!the!drug!LSD?!would!not!accurately!measure!a!desire!for!riskKtaking!among!a!cohort!of! experienced! illicit! drug! users).193,!194! To! address! this! limitation,! Kalichman! and!colleagues! adapted! a! brief! version! of! the! SSS! to! specifically!measure! sexual! riskKtaking! among! a! cohort! of! gay!men!with! a! history! of! high! risk! sexual! activity.! The!authors! found! that! their! adapted! SSS! consistently! predicted! sexual! riskKtaking!among! the! sample,! as! indicated! by! higher! frequency! of! unprotected! sexual!intercourse!and!a!greater!number!of!sexual!partners.195!!! !This! thesis!outlines!a!variety!of! risk! factors! for! initiation!(see!section!2.3.1!and!Chapter!4),32,!36,!46,!177,!192,!196,!197!and!in!the!present!Chapter!seeks!to!employ!the!risk!environment!framework!to!consider!not!only!social,!structural,!economic,!peerKbased!and!policy!factors,!but!also!to!specifically!consider!the!underlying!personality!!! 63 trait! of! sensation! seeking.( In! this!way,! it! is! hoped! that! researchers!will! be! able! to!provide! a! more! comprehensive! portrait! of! the! suite! of! factors! that! may! impact!decisions!surrounding!injecting.!Though!prior!studies!have!been!undertaken!among!IDU! samples! incorporating! the! SSS,91,! 93! these! have! not! ensured! the! cultural!appropriateness! of! the! scale! for! this! streetKbased!drugKusing!population! and!have!not!sought!to!modify!this!scale!to!correct!this!potential!source!of!error.!Experts!have!also!previously!suggested!that!future!research!in!the!area!of!sensation!seeking!and!drugKrelated! riskKtaking! requires! a! clinicallyKvalidated! scale.198! Indeed,! to! our!knowledge,! no! research! has! been! conducted! on! the! role! of! sensation! seeking! in!increasing!the!risk!of!injection!drug!use!among!streetKinvolved!youth.!!Given! the! findings! presented! in! Chapter! 3! identifying! crystal!methamphetamine!use!as!a!risk!factor! for! initiation!among!ARYS!participants,! it! is!important! to!determine!whether! sensation! seeking!may!be! associated!with!use!of!this! particular! drug! among! streetKinvolved! youth! in! Vancouver.! Additionally,! as!delineated!in!Chapter!2,!both!polysubstance!use!and!binge!drug!use!have!previously!been!identified!as!potential!predictors!of! injection!drug!use.108,!109!Determining!the!association!between! these!behaviours!and!sensation!seeking!may! further! improve!our!understanding!of!the!role!of!sensation!seeking!in!youth!drug!use!behaviour!and!ultimately!contribute!to!the!development!of! interventions!that!prevent!injection!in!this! population.! We! therefore! sought! to! modify! and! validate! a! brief! SSS! for! use!among! streetKinvolved!youth!and! to! then!examine! its!potential!utility! in! assessing!the!risk!of! injection!drug!use,!use!of!crystal!methamphetamine,!polysubstance!use,!and!binge!drug!use!among!a!sample!of!streetKinvolved!youth.!!!! 64 5.2(( Methods(! This!study!included!individuals!enrolled!in!the!AtKRisk!Youth!Study!(ARYS),!as!described!in!section!1.7.32!For!the!present!study,!ARYS!participants!completed!an!interviewerKadministered! questionnaire! soliciting! sociodemographic,! behavioural,!and!drug!use!data,!including!data!on!drug!injecting,!and!also!completed!the!modified!SSS!during!one!follow!up!interview.!!5.2.1% %Scale%Development%and%Evaluation%! The!modified!SSS!was!developed!by!adapting! items!from!the!SSS!FormKV185!using!a!fourKstage!process.!First,!11!items!in!the!SSS!FormKV!that!were!amenable!to!adaptation! for! a! highKrisk! drugKusing! population! were! identified.! Second,! item!modification!was!undertaken!in!consultation!with!experts! in!psychology,!drug!use,!and! youth! behavior! to! ensure! that! the! modified! scale! items! reflected! themes!relevant!to!a!streetKinvolved!youth!population.!!The! modified! scale! was! then! administered! to! ARYS! participants! and!exploratory!factor!analysis!(EFA)!was!conducted!on!these!data!in!order!to!assess!the!dimensionality!of! the!modified! scale.!Confirmatory! factor! analysis! (CFA)!was! then!undertaken!to!assess!the!internal!validity!and!reliability!of!the!modified!scale.!!! With!respect!to!the!EFA,!this!was!undertaken!to!ensure!that!the!modified!SSS!was! essentially! unidimensional,! consistent! with! the! original! SSS.199! To! do! so,! we!engaged!in!a!series!of!tests!to!determine!the!optimal!number!of!factors!to!retain!in!the!measurement!model,!as!previously!recommended.200!To!accommodate!potential!skewing,! the! ordinal! nature! of! the! item! responses,! and! to! allow! for! correlated!factors,!robust!EFA!was!performed.!This!is!because!the!estimated!correlation!matrix!derived! through! classical! EFA! techniques! is! susceptible! to! bias! in! cases!when! the!!! 65 distribution! of! data! departs! from! normality.201! To! account! for! nonKnormal!distributions,! robust! EFA! employs!Weighted! Least! Squares! Estimation!with!Mean!and! Variance! Adjustment! (WLSMV)! with! a! GEOMIN! rotation! supporting! oblique!factors,!which!is!less!susceptible!to!influence!from!outliers!and!skewed!data.201!This!was!done!using!Mplus!Version!6!(Mplus,!Los!Angeles,!CA).202!!! Evaluating! the! results! of! the! EFA! involved! a! series! of! a% priori%determined!steps,!including!generating!a!scree!plot!of!eigenvalues!and!comparing!the!size!of!the!largest!eigenvalue!relative!to!that!of!the!next!largest!eigenvalue.!A!parallel!analysis!approach! suitable! for! ordinal! data!was! employed! as! previously! recommended! by!experts!in!the!field.200,!203!Specifically,!this!technique!uses!a!Monte!Carlo!simulation!modeling!approach,204!in!which!the!eigenvalues!derived!from!an!original!dataset!are!compared!with!eigenvalues!extracted!from!a!series!of!random!datasets!matched!to!the!original!on!the!number!of!cases!and!scale!items.203!The!mean!eigenvalues!of!the!random!data!generated!at!a!desired!percentile,!generally!recommended!as!the!95th!percentile,! then! serve! as! the! comparative!baseline! to! assess! the!dimensionality! of!the! scale.203! Those! eigenvalues! generated! from! the! scale! data! are! subsequently!retained! if! they! are! greater! than! the! corresponding! eigenvalues! generated! by! the!random! dataset,! and! the! number! of! eigenvalues! retained! by! this! process! is!interpreted!as! the!number!of! factors!measured!by! the!scale! items.!When!only!one!eigenvalue! is! retained,! this! indicates! that! the! pool! of! items! being! assessed! is!essentially! unidimensional.203! This! calculation! was! performed! using! a! macro!package!developed!by!O?Connor!for!use!in!SPSS!20.0!(IBM,!New!York,!NY).203!% The!CFA!approach!involves!the!use!of!statistical!methods!to!assess!the!fit!of!the!model!derived!from!the!EFA,!and!also!provides!a!measure!of!construct!validity!!! 66 for! the! scale.! As! with! the! EFA,!WLSMV!was! employed! to! accommodate! potential!skewing! and! the! ordinal! nature! of! the! data.202! Construct! reliability! was! then!calculated! according! to! the! approach! recommended! by! Gerbing! and! Anderson,205!which! assesses! reliability! based! on! the! variance! across! items! explained! by! one!underlying! latent! construct! (e.g.,! sensation! seeking).! This! approach! is! used! for!measuring! scale! reliability! in! cases! wherein! scale! items! load! onto! the! same!construct! but! have! loadings! unequal! in!magnitude.205,!206! In! addition! to! assessing!construct!reliability,!the!Comparative!Fit!Index!(CFI),207!and!the!Root!Mean!Square!Error!of!Approximation!(RMSEA)!were!used!to!evaluate!the!fit!of!the!CFA!model.208,!209!The!CFA!was!performed!using!Mplus!Version!6!(Mplus,!Los!Angeles,!CA).202!5.2.2%% Hypothesis%Testing% %First,! correlations! between! sensation! seeking! score! and! a! range! of!sociodemographic,!drugKrelated,!and!psychosocial! factors!were!generated! in!order!to!determine!whether!higher!sensation!seeking!scores!were!associated!with!specific!sociodemographic! factors! or! behaviours.! These! included:! ethnicity! (Aboriginal!Ancestry!vs.%other),! gender,! age,!nonKinjection!crystal!methamphetamine!use,!nonKinjection!heroin!use,!nonKinjection!powder!cocaine!use,!nonKinjection!crack!cocaine!use,!injection!use!of!any!drugs,!binge!drug!use,!polysubstance!use,!overdose,!alcohol!use,! childhood! sexual! abuse,! CESKD! Depression! Scale! score,! SelfKEfficacy! to! Avoid!Injecting!Scale!score,!and!Limiting!HIV!Risk!Behaviours!Scale!score.!All!behavioural!variables! refer! to! the! previous! six! months.! Pearson?s! test! of! significance! was!conducted!for!all!correlations.!Second,! the! hypothesis! that! the!modified! SSS! scores! predict! injection! drug!use! and! drugKrelated! behaviours! identified! as! risk! factors! for! injection! initiation!!! 67 among! streetKinvolved! youth! was! tested! using! a! series! of! generalized! estimating!equation! (GEE)! models.! This! approach! allows! for! the! determination! of! factors!independently! associated! with! injection! drug! use! among! participants! throughout!the!study!period.210!It!also!provides!modified!standard!errors!adjusted!by!multiple!observations!per!person!using!a!firstKorder!autoregressive!correlation!structure.210!!Specifically,! four! multivariate! GEE! models! were! constructed,! all! of! which!included!participant!score!on!the!modified!SSS!as!the!primary!independent!variable!of! interest.! The! dependent! outcomes! for! the! four!models!were! defined! as:! recent!(e.g.,! in! the!six!months!previous! to! followKup! interview)! injection!drug!use,! recent!crystal!methamphetamine!use,!recent!polysubstance!use,!and!recent!binge!drug!use.!Injection!drug!use!was!defined!as! illicit! injection!of! any!drug.!Binge!drug!use!was!defined!as!using!more!drugs! than!normal! in! the!previous!six!months.211!Length!of!drugKusing! career! was! included! in! all! four! models! as! a! withinKsubject! variable.!Sociodemographic! and! drugKrelated! variables! potentially! associated!with! the! four!outcome! variables! and! included! in! the! analyses! were:! age,! gender,! Aboriginal!ancestry! (yes! vs.% other),! recent! nonKinjection! heroin! use,! recent! nonKinjection!powder! cocaine! use,! recent! nonKinjection! crack! cocaine! use,! and! recent! nonKinjection!crystal!methamphetamine!use.!All!drugKrelated!variables!except!for!length!of!drugKusing!career!refer!to!behaviours!undertaken!in!the!previous!six!months,!and!all!were!lagged!by!one!followKup!questionnaire!to!protect!against!reverse!causality!whereby!factors!associated!with!the!outcome!variable!may!instead!result!from!this!behaviour.!The!multivariate!model!was!fit!using!an!a%priori%defined!model!building!protocol! of! adjusting! for! all! variables! that!were! statistically! significant! at! the!p%<!!! 68 0.05! level! in! bivariate! analyses! along!with! basic! sociodemographic! variables! (e.g.,!age,!gender,!and!ethnicity).!!All! statistical! analyses! for! hypothesis! testing! were! performed! using! SAS!software!version!9.2!(SAS!Institute!Inc.,!Cary,!North!Carolina,!USA).!All!pKvalues!are!twoKsided.!!5.3(( Results(Overall,! between! October! 2005! and! May! 2012,! 226! ARYS! participants!completed!the!SSS!and!were!eligible!for!the!present!study.!This!sample!included!73!(32.3%)! female! participants,! and! 66! (29.2%)! participants! reporting! Aboriginal!ancestry.!Median!age!at!baseline!was!22!years!(Interquartile!Range![IQR]:!20!?!23).!!Median!follow!up!was!33!months!(IQR:!27!?!46).!!One! hundred! and! sixtyKthree! (72.1%)! participants! reported! injection! drug!use!during! the! study!period.!Compared! to! the!overall!ARYS! sample! (n%=!991),! the!subsample! of! ARYS! participants! that! completed! the! modified! SSS! did! not! differ!significantly!on!age,!Aboriginal!ancestry,!frequency!of!injecting!at!baseline,!or!length!of!drugKusing!career.!Frequency%distribution%of%scale%responses%Table!4!presents! the!modified!SSS! items!and!potential! responses!measured!on!a!5Kpoint!Likert!scale.!Among!ARYS!participants,!median!SSS!score!was!21!(IQR!=!15!?!27,!Standard!Deviation![SD]!=!8).!While!the!test!statistics!for!the!distribution!of!scale! items! 2! and! 10! suggest! that! these! were! particularly! rightKskewed,! the!skewness! for! the! test! statistic!assessing! the!distribution!of! responses! for! the! total!score!was! 0.75! (Standard! Error! [SE]! =! 0.16),! denoting!moderate! skewing! and! an!approximately! symmetrical! distribution.212! Additionally,! the! computation! of!!! 69 kurtosis! suggested! that! the! distribution! of! scale! items! 3! and! 10! were! highly!leptokurtic! (i.e.,!data!points! lie!close! to! the!mean),! though!the! test!statistic! for! the!distribution!of!responses!for!the!total!score!was!0.73,!suggesting!that!the!frequency!distribution! approached! mesokurtosis! (i.e.,! the! distribution! approached!normality).213%Exploratory%Factor%Analysis%Figure! 4! shows! a! scree! plot! delineating! the! eigenvalues! from! the! EFA!solution.!!As!can!be!seen,!the!plot!contains!a!sharp!drop!in!eigenvalues!between!the!first! and! second! factors,!with! the! eigenvalue! for! the! first! factor! almost! five! times!larger! than! the! eigenvalue! for! the! second! largest! factor.! Furthermore,! in! parallel!analysis,203! the! first! eigenvalue! generated! at! the! 95th! percentile! of! the! random!dataset!was!1.37.!By!contrast,!the!eigenvalue!associated!with!the!first!factor!in!the!EFA!for!the!modified!SSS!dataset!was!5.43,!while!the!eigenvalue!associated!with!the!second!factor!was!1.19.!The!second!eigenvalue!associated!with!the!95th!percentile!of!the! random!dataset!was! 1.27,! and! thus! exceeded! that! associated!with! the! second!factor!in!the!dataset!of!responses!to!the!modified!SSS.!The!results!of!the!scree!plot!and!parallel!analysis!therefore!support!a!oneKfactor!or!unidimensional!solution!for!the!modified!SSS!items.203!!Confirmatory%Factor%Analysis%!!A!construct!reliability!estimate!of!0.804!was!derived!for!the!unidimensional!model.214,!215!The!CFI!suggested!an!acceptable!level!of!agreement!between!the!model!and!the!data!(CFI!=!0.914),216!and!while!the!point!estimate!for!the!RMSEA!was!high,!the!range!estimate!approached!the!cutoff!point! indicating!acceptable! fit! (RMSEA!=!0.111,!95%!CI:!0.093!?!0.129).207,!208!!!! 70 Hypothesis%Testing%%% Table!5!presents!correlations!between!sensation!seeking!score!and!a!range!of!sociodemographic,!drugKrelated! factors!and!psychosocial!variables.!As! shown,!age,!male! gender,! nonKinjection! powder! cocaine! use,! nonKinjection! crack! cocaine! use,!nonKinjection!crystal!methamphetamine!use,! alcohol!use,!polysubstance!use,!binge!drug!use,! childhood!sexual!abuse,!CESKD!Depression!Scale!score,!and!Limiting!HIV!Risk! Behaviours! Scale! score! were! all! significantly! associated! with! participant!sensation!seeking!score!(p%<!0.05).!!Table!6!presents!results!from!the!four!multivariate!GEE!models!investigating!the! association! between! participant! SSS! score! and! injection! drug! use,! crystal!methamphetamine!use,!polysubstance!use,!and!binge!drug!use.!As!shown,!total!SSS!score! was! significantly! associated! with! injection! drug! use! (Adjusted! Odds! Ratio![AOR]! =! 1.04,! 95%! CI:! 1.02! ?! 1.05! [per! one! unit! score! increase]),! nonKinjection!crystal!methamphetamine!use! (Adjusted!Odds!Ratio! [AOR]!=!1.03,! 95%!CI:! 1.00!?!1.07![per!one!unit!score!increase]),!polysubstance!use!(Adjusted!Odds!Ratio![AOR]!=!1.06,! 95%! CI:! 1.03! ?! 1.09! [per! one! unit! score! increase]),! and! binge! drug! use!(Adjusted! Odds! Ratio! [AOR]! =! 1.03,! 95%! CI:! 1.01! ?! 1.05! [per! one! unit! score!increase])! (all! p% <! 0.05),! despite! adjustment! for! potential! confounders.! These!correspond! to! an! AOR! of! 1.37! for! injection! drug! use,! an! AOR! of! 1.27! for! crystal!methamphetamine!use,!an!AOR!of!1.59!for!polysubstance!use,!and!an!AOR!of!1.!27!for!binge!drug!use,!for!each!one!standard!deviation!increase!(i.e.,!8!point!increase)!in!total!score.!!! 71 5.4( Discussion(The! present! study! sought! to! develop! a! brief! SSS! suitable! for! use! among! a!streetKbased! drugKusing! population.! The! results! of! the! EFA! and! CFA! provided!preliminary!support!for!the!reliability!and!validity!of!the!modified!SSS.!Furthermore,!despite! adjustment! in!multivariate! confounding! GEE!models,! participant! score! on!the! modified! SSS! was! independently! associated! with! injection! drug! use,! nonKinjection!crystal!methamphetamine!(a!risk!factor!for!injection!initiation!identified!in!Chapter!3),!polysubstance!use!and!binge!drug!use,!both!also!previously!identified!as!predictors!of!initiation!of!injection!drug!use.108,!109!Additionally,!while!the!AORs!for!sensation! seeking! and! all! four! drugKrelated! outcomes! were! relatively! small! for! a!oneKunit! increase! in! total! score,! the! differences! between! scores! one! standard!deviation! apart! were! substantial.! As! such,! there!may! be! a! role! for! the! use! of! the!modified! SSS! to! assess! the! impact! of! the! intersection! of! sensation! seeking! and!traditional! risk! factors! for! injection! drug! use! within! investigations! focusing! on!specific!drugs!or! the!socioKstructural! context!of!drug!use.69,!73,!177! In!particular,! the!inclusion! of! the! modified! SSS! in! epidemiologic! analyses! of! the! risk! environment!experienced! by! streetKbased! drugKusing! populations! could! extend! the! range! of!potential!risk! factors! for! initiation!or!other!drugKrelated!risks! to! include!sensation!seeking,!given!that!this!psychosocial!trait!appears!to!limit!the!capacity!of!individuals!to!avoid!such!highKrisk!drug!behaviours.!!The! association! between! sensation! seeking! and! a! range! of! drugKrelated!behaviours!also!offers!a!potential!avenue!for!both!future!research!and!intervention!development.!These! findings!suggest! that! those!who!score!higher!on! the!modified!SSS! are! also! more! likely! to! be! nonKinjection! crystal! methamphetamine! users,!!! 72 involved! in! the! drug! trade,! and! engaged! in! risky! drugKrelated! behaviours.!Furthermore,! in! bivariate! analysis,! higher! sensation! seeking! score! was! also!associated! with! reporting! lower! scores! for! selfKefficacy! in! avoiding! HIV! risk!behaviours.!Taken!together,!these!findings!appear!to!place!higher!sensation!seekers!at!heightened!risk!of!a!variety!of!drugKrelated!harms,!and,!in!particular,!of!injection!initiation.! Indeed,! the! streetKinvolved! youth! population! in! our! study! setting! is!marked!by!high!levels!of!crystal!methamphetamine!and!polysubstance!use,68!ready!access!to!drugs,58,!69,!217!a!high!level!of!exposure!to!injecting,34!ongoing!structural!and!social!barriers!to!housing,218!overdose,196!and!high!levels!of!involvement!in!the!illicit!drug! trade.219! These! intersecting! factors! increase! the! risk! of! negative! health!outcomes,! most! notably! injection! initiation.31,! 35,! 36,! 38,! 109,! 160,! 220! Future! research!should! determine! whether! preventing! these! behaviours,! and! in! turn! injection!initiation,!may!be!achieved!by!reducing!the!level!of!sensation!seeking!among!highKrisk!streetKbased!drug!users.!Additionally,!previous!research!has!found!that!among!a!sample! of! polysubstance! users! in! Chicago,! high! sensation! seeking!was! associated!with! risky! sexual!practices! among!HIVKseropositive!participants,221!while!multiple!studies! of! gay! men! have! found! that! sensation! seeking! partially! accounts! for! the!association!between!drug!use!and!highKrisk!sexual!behaviours.222,!223!!More!research!is!therefore!needed!to!determine!what!specific!role!sensation!seeking!may!have!on!risks!related! to! injection! initiation,!and!whether!behavioural!interventions,! or! the! use! of! particular! drugs,! may! impact! the! expression! of! this!personality! trait.! In! particular,! future! research! should! seek! to! disentangle! the!association! between! nonKinjection! crystal!methamphetamine,! as!well! as! the! other!drugKrelated! risk! behaviours! identified! in! this! chapter,!which! are! both! associated!!! 73 with!sensation!seeking!and!with!an!increased!risk!of! injection!initiation.!Of!critical!importance!in!this!regard!is!determining!the!direction!of!causality!between!drug!use!and! sensation! seeking,! given! that! research! has! demonstrated! that! use! of!amphetamines! and! other! stimulants! by! youth! may! increase! levels! of! sensation!seeking.224!This,!then,!presents!multiple!potential!causal!pathways!for!injection!drug!use! related! to! sensation! seeking! and! crystal! methamphetamine! use:! first,! the!relationship!between!sensation!seeking!and!injection!initiation!may!be!mediated!by!ccrystal! methamphetamine! use! among! streetKinvolved! youth.164! Second,! crystal!methamphetamine!use!might!cause!neurological!changes!that!may!then!impact!the!degree! of! sensation! seeking! and! riskKtaking! that! streetKinvolved! youth! engage! in,!which!in!turn!may!precipitate!the!initiation!of!injection!drug!use.!!Prior! research! has! also! demonstrated! that! sensation! seeking! may! be! a!mediating! factor! between! childhood! sexual! abuse! and! increased! HIV! risk! among!adolescents.225,! 226! Importantly,! the! ARYS! sample! of! streetKinvolved! youth! is,!consistent!with!streetKinvolved!youth!samples! in!other!settings,31!characterized!by!high! levels! of! childhood! sexual! abuse.227! Interestingly,! reporting! childhood! sexual!abuse!and!sensation!seeking!score!were!negatively!correlated!in!bivariate!analysis.!This! association! should! be! explored! in! efforts! to! further! refine! the!modified! SSS.!Indeed,!while! childhood! sexual! abuse! has! been! shown! to! be! positively! associated!with! sensation! seeking,225! future! research! should! focus! on! ensuring! the!divergent!validity! of! the! modified! SSS! from! closely! related! psychosocial! constructs! such! as!impulsivity,90,!184!given! that!both!have!been! found! to!be!associated!with!childhood!sexual!abuse.228,!229!!! 74 These! findings! have! implications! for! the! development! of! interventions! to!prevent!injection!initiation,!which!have!been!largely!overlooked!by!policymakers,!as!described! in!Chapter!3.22! If! future!research! further!confirms!that! the!modified!SSS!can!reliably!identify!streetKinvolved!youth!at!high!risk!for!injecting!initiation,!it!may!aid! in! the! development! of! novel,! evidenceKbased! preventive! interventions! for! this!highKrisk!population.(For!example,!recent!research!has!demonstrated!the!potential!effectiveness!of! interventions!specifically! focused!on!reducing!an! individual?s! level!of! sensation! seeking! through! cognitive!behavioral! therapy,191,!230! and! studies!have!also! examined! the! impact! of! sensation! seeking! on! retention! in! addiction!treatment.187,! 231,! 232! Additionally,! from! a! life! course! perspective,! preventive!interventions!may!benefit!from!identifying!high!sensation!seeking!youth!at!an!early!stage!of!development.!This!may!entail!standardized!testing!of!sensation!seeking!and!complementary! psychosocial! factors! such! as! impulsivity,! selfKesteem,! depression,!and! resilience! among! youth! in! preK! and! early! adolescence.233! This! approach!may!then! facilitate! the! development! of! preventive! interventions! tailored! to! those! at!highest! risk! of! problematic! drug! use,! such! as! injection! initiation! or! related! risk!factors! like!crystal!methamphetamine!use,!polysubstance!use,! and!binge!drug!use.!Such! interventions! should!be! informed!by!a!public!health!approach!and,! crucially,!should! not! replicate! previously! employed! social! marketing! and! educational!interventions!that!have!proven!ineffective.7,!89!Developing!the!necessary!tailored!or!stepped! interventions! presents! substantial! challenges! as! interventions! need! to! be!established! across! a! number! of! geographic! and! temporal! settings! along! the! drugKusing!trajectories!of!streetKinvolved!youth.!In!this!regard,!interventions!established!in!settings!characterized!by!either!large!number!of!streetKinvolved!youth!or!public!!! 75 injecting! settings,!or!both,71,!72! should!be!considered!a!priority.! Such! interventions!should!be!designed!to!provide!harm!reduction!materials,!and!referrals!to!addiction!treatment,!vocational!training!and!other!services!relevant!for!this!population.!(This! study! has! limitations.! First,! it! should! be! noted! that! the! modified! SSS!presented! in! this! study! represents! a! first! step! in! this! scale?s! development.!Additionally,! the!EFA!and!CFA!reported!in!this!study!were!performed!on!the!same!dataset! in! order! to! maximize! the! amount! of! information! obtained! on! the!performance!of!the!modified!SSS.!Additional!studies!are!therefore!needed!to!further!evaluate!the!scale?s!reliability!and!validity!in!independent!samples.!In!particular,!the!less! than! optimal! CFA! results! and! skewed! response! patterns! for! several! items!indicate! that! additional! revisions! to! the! SSS! involving! item! wording,! response!options!and!the!addition!of!new!items!should!be!considered!by!researchers!working!to! further! refine! this! tool.( Second,! the! relatively! small! sample! size! may! have!impacted!the!results!of!the!analyses.!However,!recent!research!on!the!evaluation!of!scale!dimensionality!suggests!that!the!results!of!the!parallel!analysis!conducted!for!this!study!are! likely!unaffected!by!the!size!of! the!ARYS!sample!or! the!skewness!of!the! data.236! Third,! the! nature! of! the! data! set! and! a! low! incidence! of! individuals!transitioning! into! injecting! during! the! study! period! precluded! the! option! of!conducting!a!longitudinal!survival!analysis,!such!as!that!as!undertaken!in!Chapter!4,!to!test!the!association!between!participant!SSS!score!and!the!incidence!of!initiation!into! injection!drug!use.!As!such,!we!caution!against! inferring!a!causal! relationship!between!higher!participant!SSS!score!and!the!initiation!of!drug!injection.!Fourth,!as!noted!in!Chapter!4,!ARYS!is!not!a!randomlyKselected!sample!and!its!generalizability!to!the!broader!population!of!streetKinvolved!youth!in!Vancouver!cannot!be!assumed,!!! 76 though!the!existence!of!comparative!datasets!suggest!similarities!between!ARYS!and!other! samples! of! streetKinvolved! youth! in! Vancouver.179,! 237! Fifth,! as! noted!previously,! because!we! relied! on! selfKreport,! and! given! the! stigmatized! nature! of!drug!use! and!of! injection!drug!use! in!particular,! these!behaviours!may!have!been!underreported.238K240! Finally,! though! previous! research! has! demonstrated! that!sensation! seeking! is! generally! stable! among! individuals! aged! 14! to! 25,90! future!research!should!examine!the!stability!of!scores!on!the!modified!SSS!over!entire!drug!using!careers.!!! In! sum,! the! results! of! the! explanatory! and! confirmatory! factor! analyses!provide!preliminary!support!for!the!reliability!and!validity!of!the!modified!SSS!as!a!tool! to!measure! sensation! seeking! among! streetKinvolved!youth.! Further,! analyses!suggested!that!participant!SSS!score!is!independently!associated!with!injection!drug!use,! as! well! as! with! crystal! methamphetamine! use,! binge! drug! use,! and!polysubstance! use,! all! of!which! have! been! shown! to! increase! the! risk! of! injection!initiation.!While! the! intersection!of! sociodemographic,! structural,!policy!and!peerKbased! factors!heavily! influence! the! risk!environment!within!which! streetKinvolved!youth! make! decisions! regarding! injection! drug! use,! the! results! of! this! study!nevertheless! suggest! that! sensation! seeking! may! independently! heighten! risk! of!participation! in! drugKrelated! behaviours! previously! identified! as! predictors! of!injection! initiation.! While! preliminary,! these! results! may! be! useful! for! future!research!seeking!to!prevent!such!behaviours!through!the!development!of! targeted!interventions!for!streetKinvolved!youth!exhibiting!high!sensation!seeking.(!(( (!! 77 Table 4. Items for a modified brief sensation seeking scale ! !!! 78 !Table 5. Correlations between modified sensation seeking scale score and sociodemographic, drug-related, and behavioural variables Correlation  Gender Pearson Correlation .139** p-value .000 Ethnicity (Aboriginal vs. Other) Pearson Correlation -.008 p-value .770 Age Pearson Correlation .055* p-value .048 Recent non-injection crystal methamphetamine use Pearson Correlation .110** p-value .000 Recent non-injection powder cocaine use Pearson Correlation .062* p-value .024 Recent non-injection crack cocaine use Pearson Correlation .040 p-value .149 Recent non-injection heroin use Pearson Correlation .045 p-value .106 Recent injection drug use Pearson Correlation .092** p-value .001 Recent binge drug use Pearson Correlation .087** p-value .002 Recent polysubstance use Pearson Correlation .145** p-value .000 Recent overdose Pearson Correlation .006 p-value .828 Recent alcohol use Pearson Correlation .061* p-value .028 !! 79 Table 5. Correlations between modified sensation seeking scale score and sociodemographic, drug-related, and behavioural variables Correlation  Childhood sexual abuse Pearson Correlation -.120** p-value .000 CES-D Scale score Pearson Correlation .101** p-value .000 Self-Efficacy to Avoid Injecting Scale score Pearson Correlation -.040 p-value .162 Limiting HIV Risk Behaviours Scale score Pearson Correlation -.077** p-value .006 ** Correlation is significant at the 0.01 level (2-tailed) *  Correlation is significant at the 0.05 level (2-tailed) !   !! 80 Table 6. Adjusted odds ratios and 95% confidence intervals for multivariate models on factors related to sensation seeking score on a modified brief scale among street-involved youth in Vancouver, Canada, 2005-2010 (n = 226). Characteristic Model 1:                         Injection Drug Use Model 2:              Crystal Methamphetamine Use Model 3:               Polysubstance Use Model 4:                  Binge Drug Use Sensation Seeking Score 1.04 (1.02 ? 1.05)* 1.03 (1.00 ? 1.07)* 1.06 (1.03 - 1.09)* 1.03 (1.01 - 1.05)* Age (Per Year Older) 0.99 (0.94 ? 1.03) 1.01 (0.87 ? 1.17) 0.93 (0.87 - 0.99)* 0.98 (0.93 - 1.04) Female Gender 1.75 (1.34 ? 2.29)* 1.25 (0.73 ? 2.05) 1.37 (0.91 - 2.05) 0.91 (0.66 - 1.25) Aboriginal Ancestry vs. Other 0.88 (0.68 ? 1.16) 0.74 (0.49 ? 1.13) 0.78 (0.53 - 1.15) 0.90 (0.65 - 1.24) Recent Crystal Methamphetamine Use 1.14 (0.88 ? 1.47) -- 1.64 (1.21 - 2.23)* -- Recent Heroin Use 1.46 (1.04 ? 2.06)* -- 2.30 (1.35 - 3.91)* -- Recent Powder cocaine Use 0.45 (0.34 ? 0.60)* -- 1.86 (1.36 - 2.55)* 1.14 (0.87 - 1.51) Recent Crack Use 1.06 (0.83 ? 1.37) -- 1.75 (1.27 - 2.41)* 2.28 (1.70 - 3.06)* Note: All drug use variables refer to non-injection use in the previous six months and are lagged by one follow-up. Note: Models adjust for length of drug-using career as a within-subject variable *significant at p < 0.05    ! ! ! ! !!! 81 ( (Figure 4. Scree plot for modified brief sensation seeking scale !Number of Eigenvalues Number of Factors !! 82 (CHAPTER(6:(INJECTION(CAREER(TRAJECTORIES(AND(CESSATION(DURING(AN(EXPANSION(OF(SYRINGE(EXCHANGE(SERVICES(IN(VANCOUVER(6.1( Introduction(! Once! individuals! have! initiated! injection! drug! use! and! entered! into! an!injection!drugKusing!trajectory,!the!concerns!of!public!health!practitioners!focus!on!both!reducing!the!harms!of!ongoing!injection!drug!use!and!ensuring!that!the!length!of! these! injection!drugKusing! careers! is! limited.!Regarding! the! latter,! research!has!identified!a!range!of!structural,!drugKrelated,!and!social!factors!that!modify!the!risk!environment!for!the!cessation!of!injection!drug!use,!as!outlined!in!Chapter!2.!These!include! access! to! methadone! maintenance! therapy,! which! has! been! shown! to!increase!the!likelihood!of!injection!cessation.50!NonKinjection!crack!cocaine!use!has!also! been! shown! to! increase! the! likelihood! of! injection! cessation! in! certain!settings,33! while! exposure! to! IDU! has! been! shown! to! delay! injection! cessation.114!With!respect!to!reducing!the!harms!of!ongoing!injection,(decades!of!research!have!demonstrated!that!needle!and!syringe!programmes!(NSPs)!are!effective!in!reducing!HIV!and!HCV!incidence,100,!241!and!that!they!are!also!highly!costKeffective!compared!to! other! preventive! approaches! among! IDU! populations.242! As! a! result,! the!implementation!of!NSPs!is!a!key!recommendation!of!international!guidelines!for!the!prevention!of!bloodKborne!disease!transmission!among!IDU.4,!21,!243!(Yet,!despite! this!evidence!base!and!ongoing! injectionKdriven!epidemics! in!a!number!of!settings!internationally,10,!244!NSPs!have!not!been!implemented!to!scale.30!This! is!partially!related!to!the!fact!that,!while!research!indicates!that!NSPs!are!not!associated! with! increased! drug! injecting,99! some! concerns! persist! regarding! the!possibility! that! NSPs! may! enable! or! encourage! injection! drug! use,! prolong! the!!! 83 injection!drug!use! careers! of! their! clients,! and/or!discourage! clients! from! seeking!addiction!treatment.56!This!may!be!related!to!findings!of!early!studies!that!found!an!association!between!NSP!use!and!HIV!risk,60,!245!subsequently!explained!by!the!fact!that!NSPs!attract!high!risk!IDU.246!However,!as!described!in!Chapter!1,!global!scale!up!of!NSPs!has!been!greatly!impeded,!and!only!an!estimated!5%!of!drug!injections!worldwide! are! conducted! using! sterile! equipment.30,! 247! This! lack! of! scale! up! has!implications!for!the!risk!environment!experienced!by!IDU!throughout!the!course!of!their!injection!drug!use!careers.!In!settings!where!they!are!implemented,!structural!interventions! such!as!NSPs! can! serve! as! a! first!point! of! contact! for! IDU! to! engage!with!the!health!care!continuum.248!As!described!in!Chapter!2,!such!contact!can!then!increase!access!to!a!range!of!health!and!social!services!which!may!impact!both!the!length,! of! and! risks! inherent! in,! ongoing! injection! trajectories.33!!In! the! absence! of!NSPs! and! other! harm! reduction! services,! however,! emergency! health! care!responders,! police,! and! the! criminal! justice! system! represent! the! most! frequent!sources!of!contact!for!IDU.249K251!The!harms!of!contact!between!IDU!populations!and!the! criminal! justice! system! have! been! wellKestablished,! and! have! been! shown! to!expose!IDU!to!risk!environments!which!increase!their!likelihood!of!engaging!in!HIV!risk! behaviours! and! experiencing! other! negative! drugKrelated! health! and! social!outcomes.18,!148,!252K256!!! Addressing! concerns! related! to! the! impact! of! NSPs! on! the! injection! career!trajectories! of! IDU! could! help! to! support! approaches! to! reducing! injectionKdriven!bloodKborne!disease!transmission!in!a!number!of!settings!marked!by!such!harms.257!For! example,! in! some! U.S.! cities! (e.g.,! Washington,! D.C.)! where! HIV! rates! are!particularly! high! among! IDU,! NSPs! have! been! recently! scaled! back! or! closed,258!!! 84 despite! research! demonstrating! that! increased! access! to! NSPs! improves! use! of!sterile!syringes!among!IDU.259!Similarly,!in!Russia,!with!an!IDU!population!estimated!at! 1.8! million,4! policymakers! continue! to! oppose! harm! reduction! measures,!including!NSPs.260!In!Thailand,!where!less!than!1%!of!IDU!have!access!to!NSPs,30!the!government?s! State! Council! recently! ruled! that! a! notification! in! support! of! harm!reduction! by! the! country?s! Department! of! Disease! Control! was! in! breach! of!Thailand?s!1979!Narcotic!Act,!on!the!basis!that!syringe!distribution!encourages!drug!use.261! Additionally,! although! the! President?s! Emergency! Plan! for! AIDS! Relief!(PEPFAR)! recently! released! guidelines! for! funding! NSPs! as! part! of! the! U.S.?!international!response!to!the!spread!of!HIV,262!legislation!has!since!been!introduced!in!the!U.S.!House!of!Representatives!that!bars!the!U.S.!from!funding!NSPs!in!foreign!countries.263!!Vancouver,! Canada!has!been! the! site! of! a!wellKdocumented!NSP!expansion,!beginning! in! the! year! 2000,!when! a! single! centralized! syringe! exchange! program!was!transformed!into!a!decentralized,!multiKsite!syringe!distribution!program.62!In!the! context! of! ongoing! concerns! regarding! the!potential! for!NSPs! to! encourage!or!prolong!injection!drug!use,!and!within!an!environment!that!heightens!the!likelihood!of!risky! injectionKrelated!practices!such!as!syringe!sharing!and!overdose,264,!265!we!sought! to! assess! rates!of! injecting! cessation! among!a! sample!of! IDU! in!Vancouver!during!this!period!of!NSP!expansion.!6.2(( Methods(! First,!to!describe!the!pattern!of!NSP!expansion,!reports!of!the!number!of!NSP!sites! in!Vancouver!during!the!study!period!were!obtained!from!Vancouver!Coastal!Health,! Vancouver?s! local! health! authority.266! We! then! conducted! trend! tests! to!!! 85 determine!whether!the!increase!in!NSP!sites!by!calendar!year!was!significant.!Rates!of! injecting! drug! use! cessation! (i.e.,! reporting! no! drug! injecting! in! the! prior! six!months)! and! reKinitiation! (i.e.,! a! period! of! injection! cessation! followed! by! a!resumption! of! injecting)! were! derived! from! the! Vancouver! Injection! Drug! Users!Study!(VIDUS),!described!in!full!in!section!1.7.!!! The!primary!outcome!for!the!current!study!was! injecting!cessation,!defined!as! reporting! no! injection! drug! use! in! the! previous! 6!months.! As! noted! above,!we!derived!adjusted!annual!estimates!of!the!proportion!of!cohort!participants!reporting!cessation,!and!to!control!for!a!potential!cohort!effect,267!whereby!the!number!of!IDU!reporting! drug! use! cessation! might! be! expected! to! increase! over! time,268! the!proportions!of!those!reporting!cessation!were!adjusted!for!the!number!of!years!that!individuals! were! enrolled! in! the! study.! Annual! estimates! and! 95%! confidence!intervals!were!then!generated!for!the!years!1996!to!2010.!Data!on!the!crude!number!of! sterile! syringes! distributed! annually! were! also! acquired! from! the! local! health!board,! and! overlaid! graphically! with! the! proportion! of! participants! reporting!injection! cessation! per! year.! Finally,! a! map! of! NSPs! in! Vancouver?s! downtown!eastside!neighbourhood!was!generated!for!the!year!2010!in!order!to!visually!assess!the!spatial!relations!between!the!epicenter!of!injecting!activity!in!Vancouver!and!the!geographic!coverage!of!sterile!syringe!provision.!! At!this!stage,!the!graphical!exploration!of!the!data!implied!that!the!NSP!site!expansion!coincided!with!increased!injecting!cessation.!However,!to!better!delineate!the! risk! environment! within! which! injection! transition! events! occur! among! the!study! participants,! we! conducted! generalized! estimating! equation! (GEE)! logistic!regression! analyses! to! determine!what! social,! physical,! policy,! drugKrelated,! peerK!! 86 based!and!economic!factors!were!associated!with!the!likelihood!of!cessation!during!the! study!period.! Specifically,! univariate! and!multivariate!GEE!analyses! for!binary!outcomes!were!used! to!determine! factors! independently! associated!with! injecting!cessation! among! cohort! participants.! These!methods! provided!modified! standard!errors! adjusted! by! multiple! observations! per! person! using! a! firstKorder!autoregressive! correlation! structure.210,!269!As! in! the! first! stage!of! the! analysis,!we!adjusted! for! year!of! study! recruitment! to! control! for! a!potential! cohort! effect.!We!used! the! risk! environment! framework! to! guide! the! selection! of! additional!variables,73!which!included:!age!at!study!entry,!gender,!Aboriginal!ancestry!(yes!vs.%other),! number! of! years! injecting! at! baseline,! accessing! methadone! maintenance!therapy,! accessing!other!addiction! treatment,! residency! in!Vancouver?s!downtown!eastside! neighbourhood! (the! site! of! a! large! openKair! illicit! drug! market),!homelessness,! incarceration,! accessing!Vancouver?s!medically! supervised! injection!facility! (Yes! vs.%No),! having! a! partner! who! was! injecting,! recent! heroin! injection,!recent!cocaine! injection,! recent!speedball! (i.e.,!heroin!and!cocaine! in!combination)!injection,! recent!nonKinjection!crack!use,!and! frequent! injection!drug!use!(daily!vs.%less! than! daily).! All! behavioural! variables! refer! to! behaviours! in! the! previous! 6!months.! Consistent! with! previous! studies! investigating! cessation! of! injecting,! all!timeKupdated!behavioural!variables!were!lagged!by!one!follow!up!questionnaire.50,!270! As! such,! behavioural! variables! refer! to! the! 6! months! prior! to! the! followKup!questionnaire!immediately!preceding!the!first!report!of!injecting!cessation.!! The! multivariate! GEE! model! was! fit! using! a! twoKstage! protocol.! First,! a!decision! to!enter! the!primary! independent!variable!of! interest! (i.e.,! calendar!year)!and! key! potential! confounders! (i.e.,! year! of! study! enrolment,! enrolment! in!!! 87 methadone,! and!nonKinjection! crack!use)! into! the!multivariate!model!was!made!a%priori.! All! other! independent! variables! were! entered! into! the! multivariate! model!based! on! a! finding! of! statistical! significance! at! the! p% <! 0.05! level! in! univariate!analysis.!!All! statistical! analyses! were! performed! using! SPSS! software! version! 19.0!(IBM,!New!York,!NY).!All!p%values!are!two!sided.!6.3(( Results(! In! total,! 2,551!participants!were! recruited! into! the! study! and! completed! at!least! one! follow! up! visit! between! May! 1996! and! December! 2010,! including! 856!(33.6%)! female! and! 697! (27.3%)! individuals! reporting! Aboriginal! ancestry.!Participants!contributed!10,180!personKyears!of!follow!up.!Retention!was!high,!with!87.6%!of!cohort!participants!reporting!at!least!one!followKup!visit,!and!the!median!number!of!follow!up!visits!was!5!(Interquartile!Range![IQR]!=!2!?!12).!!Throughout!the!study!period,!5,849!injecting!cessation!events!were!reported,!while!the!number!of!NSP!sites!in!Vancouver!increased!significantly!from!1!in!1996!to!29!in!2010!(p!<!0.001).! !Figure! 5! presents! a! line! graph! of! the! adjusted! proportion! of! participants!reporting!injecting!cessation!by!year!and!a!histogram!depicting!the!increase!in!the!number! of! NSP! sites! during! this! same! period.! Adjusting! for! year! of! baseline!recruitment! into! the! study,! the! proportion! of! IDU! reporting! injecting! cessation!increased! from!2.4%!(95%!Confidence! Interval! [CI]:!0.0%!?!7.0%)! in!1996! (when!eligibility!for!the!study!required!drug!injecting)!to!47.9%!(95%!CI:!46.8%!?!48.9%,!p%<! 0.001)! in! 2010.! During! the! same! period,! the! proportion! of! IDU! reporting! reKinitiation!of!injection!drug!use!increased!from!0%!in!1996!to!36.7%!(95%!CI:!19.1%!!! 88 K! 54.2%,! p% <! 0.001)! in! 2010.! Figure! 6! presents! a! line! graph! of! the! adjusted!proportion! of! participants! reporting! injection! cessation! by! year! and! a! histogram!depicting! the! crude! number! of! syringes! distributed! annually.! Finally,! Figure! 7!presents! a! map! of! NSP! coverage! in! Vancouver?s! downtown! eastside! for! the! year!2010.! This! includes! the! approximate! range! of! the! Mobile! Access! Project,! which!consists! of! a! mobile! van! that! patrols! the! Vancouver! downtown! eastside! and!surrounding! areas! and! provides! sterile! syringes,! condoms,! and! other! supplies! to!individuals!involved!in!the!sex!trade!as!well!as!IDU!and!nonKIDU.271!!! In! a! univariate! GEE! analysis,! increasing! calendar! year! was! positively!associated!with!injecting!cessation!(Odds!ratio![OR]!=!1.22,!95%!CI:!1.20!?!1.24,!p%<!0.001).!Full!univariate!results!are!presented!in!Table!6.!In!a!multivariate!GEE!model,!increasing!calendar!year!(Adjusted!Odds!ratio![AOR]!=!1.16,!95%!CI:!1.15!?!1.18,!p%<!0.001)!and!enrolment!in!methadone!treatment!(AOR!=!1.19,!95%!CI:!1.09!?!1.31,!p%<!0.001)!were!positively!associated!with!injecting!cessation.!Later!year!of!enrolment!into!the!study!(AOR!=!0.88,!95%!CI:!0.87!?!0.90,!p%<!0.001),!residence!in!Vancouver?s!downtown!eastside!(AOR!=!0.84,!95%!CI:!0.77!?!0.91,!p%<!0.001),!recent!involvement!in!the!sex!trade!(AOR!=!0.70,!95%!CI:!0.61!?!0.79,!p%<!0.001),!accessing!a!medically!supervised! injection!facility!(AOR!=!0.66,!95%!CI:!0.58!?!0.74,!p%<!0.001),!having!a!partner!who!is!an!IDU!(AOR!=!0.74,!95%!CI:!0.68!?!0.81,!p%<!0.001),!recent!heroin!injection!(AOR!=!0.47,!95%!CI:!0.43!?!0.52,!p%<!0.001),!recent!cocaine!injection!(AOR!=!0.53,!95%!CI:!0.49!?!0.59,!p%<!0.001),!recent!speedball!injection!(AOR!=!0.72,!95%!CI:!0.65!?!0.79,!p%<!0.001),!and!frequent!injection!drug!use!(AOR!=!0.79,!95%!CI:!0.74!?! 0.84,! p% <! 0.001)! were! negatively! associated! with! injecting! cessation.! Full!multivariate!results!are!presented!in!Table!7.!!! 89 6.4(( Discussion(! This! analysis! observed! a! significant! increase! in! the! proportion! of! IDU! in!Vancouver!reporting!injecting!cessation!during!a!15Kyear!period!characterized!by!a!significant! increase! in! the! number! of! NSP! sites.! This! increase! in! the! likelihood! of!injecting!cessation!over!time!persisted!even!after!adjustment!for!other!determinants!of! injecting! cessation,! including! a! possible! cohort! effect! controlled! for! by! year! of!recruitment.217! 222! Further,! while! study! participants! that! reported! accessing!methadone!maintenance! therapy!were!significantly!more! likely! to! report! injecting!cessation,! a! range! of! factors! were! associated! with! a! reduced! the! likelihood! of!injecting!cessation.!These! included!sex! trade! involvement,!having!a!sexual!partner!who! was! injecting,! residing! in! Vancouver?s! downtown! eastside,! and! reporting! a!higher!frequency!of!injecting!and!use!of!heroin,!cocaine,!or!speedballs.!!! This!study!has!limitations!consistent!with!the!use!of!observational!data.!As!a!result,!although!we!observed!that!an!NSP!site!expansion!coincided!with!increasing!rates! of! injecting! cessation,!we! are! unable! to! explain! a! causal!mechanism! for! this!shift!related!to!NSP!implementation.!However,!based!on!this!study?s!findings,!we!can!conclude! that!NSP! expansion! is! unlikely! to! delay! injecting! cessation.! Additionally,!cohort! participants! were! not! recruited! using! random! sampling! and! the! potential!exists!that!results!may!not!be!generalizable!to!the!overall!population!of! illicit!drug!users! in! our! study! setting.! However,! participant! recruitment! was! ongoing!throughout! the! study! period,! and! it! is! noteworthy! that! data! from! government!surveillance! systems! and! other! studies! undertaken! in! the! same! setting! are!consistent!with!our!own,! suggesting! that! the! cohort! is! likely! representative!of! the!broader!IDU!population!in!Vancouver.272K274!Additionally,!while! involvement! in!the!!! 90 illicit! drug! trade! and! interactions! with! police! may! have! impacted! the! odds! of!injection!cessation!among!study!participants,!these!variables!were!not!consistently!measured! across! cohort! questionnaires! throughout! the! study! period,! and! were!therefore!not!eligible!for!the!analysis.!Finally,!as!previously!noted,!it!is!possible!that!an!age!or!cohort!effect!may!have!impacted!the!observed!rate!of!injecting!cessation;55,!268!however,!increasing!rates!of!injecting!cessation!over!time!were!observed!despite!adjustment!for!age!and!year!of!recruitment!into!the!cohort.!! The!findings!presented!herein!suggest!that,!while!a!period!of!NSP!expansion!was!associated!with!an!increasing!proportion!of!IDU!reporting!injecting!cessation,!a!range! of! intersecting! factors! were! associated! with! ongoing! injection,! or! delayed!cessation.!It!is!particularly!noteworthy!that!residing!in!the!downtown!eastside,!the!epicenter!of!Vancouver?s!openKair!injecting!drug!scene,!as!well!as!reporting!having!a!sexual!partner!who!was!injecting,!were!both!associated!with!a!reduced!likelihood!of!cessation.! This! suggests! that! ongoing! exposure! to! injecting!may! prolong! injection!drugKusing!trajectories!and!sustain!injecting!risk!among!established!IDU!in!a!similar!manner! as! exposure! to! injecting!heightens! risk! for! injectionKna?ve!drug!users.34,!38!Indeed,! among! IDU! in! Baltimore,! Latkin! and! colleagues! found! cessation! to! be!strongly! associated!with! reporting! a! lower! proportion! of! social! network! contacts!who!use!drugs.114!Buchanan!and!Latkin!also! found!that,!compared!with! those! that!did!not!cease!injecting,!IDU!in!Baltimore!reporting!injection!cessation!had!a!highly!reduced!number!of!drugKusing!individuals!in!their!social!network,275!while!Shah!and!colleagues! found!a! lower! likelihood!of! injection!cessation!among! IDU! in!Baltimore!who!reported!having!an!IDU!sexual!partner.50!In!the!present!study,!results!suggest!that! accessing! Vancouver?s! supervised! injection! facility! was! independently!!! 91 associated!with! a! lower! likelihood! of! cessation.! This!may! suggest! that! the! facility!attracts!IDU!at!risk!of!ongoing!injection,!which!has!implications!for!efforts!to!reduce!communityKlevel!exposure!to!injecting,!given!that!those!that!inject!within!the!facility!do!so!alone!and!in!a!nonKpublic!setting.!!With!respect!to!neighbourhood!of!residence,!a!recent!BaltimoreKbased!study!found!that!residing!in!a!neighbourhood!characterized!by!high!levels!of!poverty!(i.e.,!more!than!30%!of!residents!reporting!living!under!the!poverty!line)!was!associated!with!a!reduced!odds!of!cessation!among!IDU.276!This!finding!is!highly!relevant!to!the!present! study! context,! given! that! Vancouver?s! downtown! eastside! is! among! the!poorest! urban! areas! in! Canada.277! Additionally,! while! the! spatial! relationship!between! IDU! and! NSPs! has! been! shown! to! restrict! access! to! sterile! injecting!equipment! in! settings! where! distribution! sites! are! distally! located,278! Figure! 5!demonstrates!the!high!level!of!coverage!of!NSPs!in!Vancouver?s!injection!drugKusing!epicenter,!with!NSPs!located!at!a!maximum!of!approximately!four!blocks!from!any!location! in! the! downtown! eastside.! This! is! consistent!with! previous! research! that!found! that! IDU! residing! in! the! downtown! eastside! reported! significantly! lower!levels! of! difficulty! accessing! syringes! compared! to! IDU! residing! in! other!neighbourhoods.279!However,!those!residing!in!the!downtown!eastside!nevertheless!were! significantly! less! likely! to! report! injection! cessation.! This! likely! reflects! a!selection!effect,!given!the!known!high!risk!profile!of!individuals!living!in!this!area.58!Nevertheless,! this! has! implications! for! the! spatial! design! of! competing! policy!responses!to!drug!use,!and!suggests!that!policymakers!should!consider!the!potential!unintended!consequences!of!service!provision!and!drug!law!enforcement!clustering!within!highKrisk!areas.!Specifically,!research!from!New!York!City!has!demonstrated!!! 92 that! streetKlevel! enforcement! of! drugKrelated! behaviours! in! areas! of! NSP!implementation!negatively! impacted!the!protective!effect!of!NSPs!and!reduced!the!likelihood! of! IDU! injecting!with! sterile! equipment.280! The! ongoing! focus! on! arrest!and! incarceration! of! IDU! in! the! downtown! eastside! may,! similarly,! contribute! to!lower!effectiveness!of!NSPs!in!this!setting,!and!should!be!reevaluated.!!! While! the!majority!of!resources!aimed!at! the!control!and!reduction!of!drug!use! are! often! allocated! towards! drugKlaw! enforcement! and! criminal! justice!interventions! (e.g.,! arrest! and! incarceration),! study! participants! reporting! recent!incarceration!did!not!have!a!higher!likelihood!of!injection!cessation.!This!finding!is!consistent!with! past! research! suggesting! that! this! approach! is! likely! ineffective! in!reducing! problematic! drug! use.148,!149,!264,!281,!282! Relatedly,! participants! enrolled! in!methadone!maintenance! therapy!were!significantly!more! likely! to! report! injection!cessation,!suggesting!that!the!provision!of!proven!clinical! treatment!modalities! for!drug!dependence!is!likely!effective,24!which!further!supports!the!steady!increase!in!the!provision!of,!and!retention!of!IDU!in,!methadone!maintenance!therapy!in!British!Columbia! since! the! midK1990s.283! These! results! also! have! implications! for! the!debate!surrounding!the!implementation!of!NSPs!in!a!variety!of!settings!and!help!to!address!a!key!concern!often!cited!by!those!opposed!to!NSPs.!Specifically,!the!present!study!demonstrates!an!increase!in!injecting!cessation!among!a!sample!of!IDU!during!a!period!of!NSP!expansion!in!Vancouver!that!saw!not!only!an!increase!in!the!number!of! NSP! sites,! but! also! operational! changes! aimed! at! increasing! sterile! syringe!availability.! These! included! longer! operating! hours! and! a! shift! to! syringe!distribution! from! a! strict! oneKforKone! syringe! exchange! system.62! This! echoes!research!undertaken!in!other!settings!that!has!found!that!these!programs!are!more!!! 93 effective!when!they!employ!a!syringe!distribution!rather!than!exchange!model.284K287!While! the! increase! in!NSP! sites!was! not! linear! throughout! the! study! period,!with!local!factors!such!as!the!consolidation!of!health!services!causing!fluctuations!in!the!number!of!NSPs,! the!results!nevertheless! imply! that!NSPs!are!unlikely! to! lengthen!drugKinjecting!careers.!!This! finding! is! consistent! with! a! recent! study! from! New! York! City! that!observed!that!largeKscale!implementation!of!NSPs!was!associated!with!a!decreased!proportion! of! methadone! treatment! clients! reporting! injection! drug! use.110! ! This!suggests!that!NSPs!may!be!complementary!to!efforts!to!retain!IDU!in!treatment!and!promote! abstention! from! injection! drug! use.! Indeed,! research! from!other! settings!suggests! that! use! of! NSPs! results! not! only! in! reducing! risk! behaviours! for! bloodKborne! disease! transmission! but! also! in! increasing! access! to! basic! health! services!among!clients,248!and!that!these!programs!have!the!capacity!to!attract!those!IDU!at!high! risk!of! a!variety!of!drugKrelated!harms.62,!100,!243!This! is!highly! relevant! to! the!present! study,!and! it! is! important! to!note! that!many! IDU! in! the!study!who!ceased!injecting!also!experienced!a!period!of! relapse.!Nevertheless,!as!shown! in!Figure!5,!this! study! suggests! that! the! proportion! of! people! who! use! drugs! who! were! not!injecting!nevertheless!increased!on!an!annual!basis.!Given!the!wellKknown!potential!for! relapse! among! IDU! seeking! to! cease! injecting,50,! 288! NSP! access! is! critical! in!reducing! bloodKborne! disease! transmission! risk! throughout! an! individual?s! drugKusing!career.!Interestingly,!in!this!study!crack!use!was!not!associated!with!injecting!cessation,! suggesting! that! IDU! who! transition! into! nonKinjection! crack! use! may!nevertheless! continue! to! inject! other! substances.! This! differs! from! previous!research!undertaken!in!other!Canadian!settings.33,!289!!!! 94 ! Finally,!the!findings!presented!in!this!chapter!suggest!that!a!variety!of!factors,!including!illicit!income!generation!via!the!sex!trade,290!the!drugKrelated!behaviours!of! peers,72,! 107! interactions! with! the! criminal! justice! system,264,! 291! and! the! wide!availability! of! drugs! such! as! heroin! and! cocaine58! heighten! the! risk! that! IDU!will!prolong! their! injection!careers.!Nonetheless,!we!observed!a! steady! increase! in! the!proportion! of! participants! reporting! injecting! cessation.! This! suggests! that!transitions! into! nonKinjection! drug! use! can! be! facilitated! through! the! provision! of!structural! interventions! in!settings!characterized!by! factors! that!may! increase!risk!for! ongoing! injection.! Policymakers! should! therefore! implement! and! expand!interventions! such! as! NSPs,! methadone! maintenance! therapy,! and! other!interventions!such!as!supervised!injection!facilities!that!have!been!shown!to!modify!injection!drug!use!patterns!towards! lowerKrisk!and!lower!frequency!trajectories.24,!27,!63,!99,!283,!292K294!! In!summary,!the!present!study!suggests!that!injection!cessation!occurred!at!a!high!level!during!a!period!characterized!by!increasing!NSP!availability!and!within!a!context!in!which!IDU!had!a!reduced!capacity!to!cease!injecting.!Given!a!large!body!of!research! demonstrating! the! positive! impacts! of! NSPs! on! the! risk! of! bloodKborne!disease!transmission!and!other!public!health!concerns,62,!100,!292,!295!as!well!as!the!low!global!coverage!of!these!intervention,30!policymakers!should!move!quickly!towards!the! provision! of! NSPs! in! conjunction! with! complementary! public! health!interventions! such!as!methadone!maintenance! treatment!and!supervised! injection!facilities!in!settings!marked!by!ongoing!highKrisk!injection!trajectories!among!drugKusing!populations.!!! 95 !! !Table 7. Univariate correlates of injecting cessation among injection drug users in Vancouver, 1996 ? 2010 (n = 2,551)* Characteristic  Injecting Cessation Event**       p value    No Yes   N = 17,220 N = 5,849 Unadjusted  n (%) n (%) Odds Ratio 95% CI Calendar year        Per Year Later  -- --  -- --  1.22 1.20, 1.24 < 0.001Age at study baseline        Median (IQR) 36 (28.3 ? 41.8) 35.7 (28.8 ? 42.1) 1.00 1.00, 1.01 0.538 Gender        Male 10,926 (63.4) 3,596 (61.5)    Female 6,294 (36.6) 2,253 (38.5) 1.17 1.02, 1.32 0.024 Ethnicity        Non-Aboriginal 11,967 (69.5) 3,889 (66.5)    Aboriginal 5,253 (30.5) 1,960 (33.5) 1.49 1.27, 1.75 < 0.001Years injecting at baseline        Median (IQR) 13.8 (5.9 ? 23.5) 13 (4.6 ? 24.1) 1.00 0.99, 1.00 0.341Year of enrolment        Median (IQR) 1996 (1996 ? 2000) 1996 (1996 ? 2000) 0.97 0.96, 0.99   0.002 DTES residence        No 6,060 (35.2) 2,953 (50.5)    Yes 11,159 (64.8) 2,896 (49.5) 0.60 0.54, 0.66 < 0.001Incarceration        No 14,024 (81.4) 5,480 (93.7)    Yes 3,195 (18.6) 369 (6.3) 0.48 0.42, 0.55 < 0.001Sexual partner injects        No 11,431 (66.7) 5,394 (92.9)    Yes 5,703 (33.3) 414 (7.1) 0.35 0.32, 0.39 < 0.001Sex trade involvement         No 14,116 (82.0) 5,527 (94.5)    Yes 3,098 (18.0) 322 (5.5) 0.36 0.30, 0.43 < 0.001Homeless        No 13,235 (76.9) 5,054 (86.4)    Yes 3,984 (23.1) 795 (13.6) 0.70 0.64, 0.78 < 0.001Insite access        No 13,525 (78.7) 5,806 (99.7)    Yes 3,650 (21.3) 15 (0.3) 0.69 0.63, 0.76 < 0.001Methadone treatment        No 11,471 (66.6) 3,744 (64.0)    Yes 5,749 (33.4) 2,105 (36.0) 2.06 1.87, 2.28  < 0.001Other addiction treatment         No 10,755 (62.5) 3,491 (59.7)    Yes 6,464 (37.5) 2,358 (40.3) 0.96 0.88, 1.05 0.355Recent heroin injection        No 6,705 (38.9) 4,791 (81.9)    Yes 10,514 (61.1) 1,058 (18.1) 0.24 0.22, 0.26 < 0.001Recent cocaine injection        No  7,015 (40.7) 4,645 (79.4)    Yes 10,204 (59.3) 1,204 (20.6) 0.27 0.25, 0.30 < 0.001Recent speedball injection?        No  9,319 (54.1) 5,018 (85.8)    Yes 7,900 (45.9) 831 (14.2) 0.42 0.38, 0.46 < 0.001Recent non-injection crack use        No 6,155 (35.7) 2,777 (47.5)    Yes 11,064 (64.3) 3,072 (52.5) 0.85 0.77, 0.95 0.003Frequent injection?        No 9,082 (52.7) 4,417 (75.5)    Yes 8,138 (47.3) 1,431 (24.5) 0.53 0.49, 0.57 < 0.001Note: CI = Confidence Interval; IQR = Interquartile Range; DTES = downtown eastside; IQR = interquartile range  *All behavioural variables refer to behaviours measured in the follow-up survey prior to the first report of cessation; **Frequencies refer to the number of events throughout study period; ?Speedball refers to heroin and cocaine in combination; ?Frequent refers to at least once daily.   !! 96 !Table 8. Multivariate generalized estimating equation analysis of correlates of injecting cessation                  among injection drug users in Vancouver (n = 2,551)*  Characteristic Adjusted Odds Ratio 95% CI       p value Calendar year        Per Year Later  1.16 1.15, 1.18 < 0.001 Year of enrolment     Per Year Later  0.88 0.87, 0.90 < 0.001 Female      Male vs. Female 1.12 0.99, 1.30 0.119 Ethnicity      Non-Aboriginal vs. Aboriginal 1.08 0.88, 1.16 0.916 Methadone treatment     Yes vs. No 1.19 1.09, 1.31 < 0.001 DTES residence    Yes vs. No 0.84 0.77, 0.91 < 0.001 Homeless    Yes vs. No 0.95 0.87, 1.05 0.303 Involvement in the sex trade     Yes vs. No 0.70 0.61, 0.79 < 0.001 Incarceration     Yes vs. No 0.91 0.81, 1.01 0.076 Partner is injecting     Yes vs. No 0.74 0.68, 0.81 < 0.001 Accessing Insite     Yes vs. No 0.66 0.58, 0.74 < 0.001 Recent heroin injection    Yes vs. No 0.47 0.43, 0.52 < 0.001 Recent cocaine injection    Yes vs. No 0.53 0.49, 0.59 < 0.001 Recent speedball injection??    Yes vs. No 0.72 0.65, 0.79 < 0.001 Recent non-injection crack use    Yes vs. No 0.95 0.90, 1.07 0.612 Frequent injection drug use?    Yes vs. No 0.79 0.74, 0.84   < 0.001 Note: CI = Confidence Interval; DTES = downtown eastside.  *All behavioural variables refer to behaviours measured in the follow-up survey prior to the first report of cessation ?Recent refers to the previous six months   ??Speedball refers to heroin and cocaine in combination ?Frequent refers to at least once daily  !! 97   ((Fin(((((((((((((((((1Figure 5. Annual proportion of injection drug users reporting injecting cessation and expansion of needle and syringe programs in Vancouver, 1996 ? 2010 (n = 2,551) 2!! 98 ( (Figure 6. Annual proportion of injection drug users reporting injecting cessation and crude number of sterile syringes distributed in Vancouver, 1996 ? 2010 (n = 2,551) !! 99 ( ((((( (Figure 7. Approximate location of needle and syringe programmes in Vancouver?s downtown eastside neighbourhood, 2010  Source: Vancouver Coastal Health  !! 100 CHAPTER(7:(DISCUSSION,(FUTURE(RESEARCH,(CONCLUSIONS(7.1(( Summary(of(findings (As! described! in! Chapters! 1! and! 2,! investigations! of! the! natural! history! of!injection! provide! insight! into! how! injectionKrelated! risks! vary! over! time.! Such!investigations! have! also! identified! key! transition! events! (e.g.,! initiation! and!cessation! of! injection),! longitudinal! patterns! of! injecting,! and! sources! of! injectionKrelated!morbidity!and!mortality.!Given!that!public!health!experts!have!called!for!the!prioritization!of!interventions!to!prevent!injection!drug!use,22!Chapter!3!consists!of!a! systematic! review! identifying! and! critically! assessing! peerKreviewed! scientific!evaluations!of!interventions!to!prevent!injecting.!Of!a!total!of!384!studies!potentially!eligible! for! inclusion! in! the! review,! eight! met! the! eligibility! criteria,143K150! which!included! the! presentation! of! original! data! and! the! evaluation! of! a! discrete!preventive! intervention.!While!eligible! studies!varied! in!methodology,! setting,! and!outcomes,!four!major!types!of!interventions!were!identified:!social!marketing,!peerKbased! behaviour!modification,! addiction! treatment,! and! drug! law! enforcement.! Of!these,! peerKbased! behaviour! modification! and! addiction! treatment! interventions!were! found! to! be! the! most! effective.! However,! the! major! finding! from! this!systematic! review! is! that! there! exists! a! lack! of! peerKreviewed! evaluations! of!interventions! to! prevent! initiation! into! injection! drug! use.! This! review! therefore!highlights! the! need! for! research! into! the! development! and! evaluation! of!interventions!to!prevent!drug!injection.!However,!results!suggest!that!interventions!that! reduce! the! exposure! of! injectionKna?ve! drug! users! to! injecting! environments!may!have! the!greatest!preventive!potential.!This! is! in! line!with!studies! identifying!exposure!to!injecting!as!a!key!modifier!of!risk!of!injection!initiation.38,!42!!!! 101 ! In!Chapter!4,!use!of!crystal!methamphetamine!is!shown!to!be!independently!associated!with!an!increased!risk!of!injection!initiation!among!streetKinvolved!youth!enrolled! in! the!ARYS!cohort! in!Vancouver,!while! the!drug! that! cohort!participants!reported! commonly! using! in! injection! initiation! events! was! crystal!methamphetamine.! Further,! in! a! secondary! analysis! of! those! that! reported! ever!injecting,!almost!half!of!all!participants!received!the!injected!drug!as!a!gift,!and!the!vast!majority!reported!being!injected!by!someone!else.!!! Chapter!5! investigates! the! role!of! the!personality! trait! sensation! seeking! in!modifying!individual!risk!for!injection!drug!use!and!a!variety!of!other!drugKrelated!behaviours! identified! as! predictors! of! injection! initiation,! including! crystal!methamphetamine! use,! polysubstance! use,! and! binge! drug! use,! among! a! cohort!streetKinvolved!youth.!For!the!purposes!of!this!thesis,!a!modified!brief!version!of!the!sensation! seeking! scale! (SSS)! was! developed! for! use! among! a! sample! of! streetKinvolved! youth.! The! reliability! and! validity! of! the! modified! brief! SSS! was! then!explored! using! exploratory! and! confirmatory! factor! analysis.! The! hypothesis! that!participant! score! on! the! modified! SSS! was! associated! with! an! increased! odds! of!injecting!and!risk!factors!for!injection!initiation!was!then!tested!using!selfKreported!data! gathered! from! a! cohort! of! streetKinvolved! youth! in! Vancouver.! In! a! series! of!multivariate!models,!higher!SSS!score!was!associated!with!a!higher!odds!of!injecting,!of!crystal!methamphetamine!use,!of!polysubstance!use,!and!of!binge!drug!use!during!the! study!period,! despite! adjustment! for! a! variety! of! sociodemographic! and!drugKrelated!factors.!While!previous!studies!have!identified!the!role!of!sensation!seeking!in! modifying! the! risk! of! drug! use! among! the! general! youth! population,98,! 296! and!while!some!have!employed!measures!of!sensation!seeking! in! investigations!of!risk!!! 102 among!streetKbased!drugKusing!populations,91K93,!198,!297!this!is,!to!our!knowledge,!the!first!study!to!develop!a!sensation!seeking!scale!for!specific!use!among!streetKbased!drugKusing!populations!and!to!also! identify! the!role!of!higher!sensation!seeking! in!increasing! risk! of! injecting! among! streetKinvolved! youth! through! a! variety! of!potential!causal!pathways.!!! Finally,! Chapter! 6! sought! to! examine! rates! of! injection! drug! use! cessation!during!a!period!of!NSP!expansion!using!data! from!a! cohort!of! IDU!over!a!15Kyear!period! in! Vancouver.! Variable! selection! for! the! model! was! guided! by! the! risk!environment! framework.! Specifically,! factors! such! as! enrolment! in! methadone!maintenance,!access!to!a!supervised!injection!facility,!and!incarceration!were!tested,!along!with!a!range!of!economic,!spatial,!social!network,!and!policy!factors,!and!the!model!was!adjusted!for!possible!cohort!effects.!Several!factors!were!associated!with!ongoing! injecting,! including! residence! in! Vancouver?s! downtown! eastside,!involvement!in!the!sex!trade,!and!having!a!partner!who!injects.!However,!despite!the!fact! that! participants! reported! these! risks,! the! period! of! NSP! expansion! was!nevertheless! associated! with! increased! injection! cessation,! and! enrolment! in!methadone!maintenance! therapy!was! independently! associated!with! an! increased!likelihood! of! cessation.! This! finding! supports! the! conclusion! that! the!implementation!of!NSPs!does!not!prolong!the!injection!careers!of!IDU,!a!finding!that!has! been! observed! in! other! settings.33,! 110! It! also! further! suggests! that! the!coordinated! implementation!of!evidenceKbased!treatment,!public!health,!and!harm!reduction! interventions! are! likely! effective! in! reducing! both! the! harms! of! drug!injecting!and!in!facilitating!reductions!or!cessation!of!injection!drug!use.!!(!! 103 7.2( Study(contributions(( Together,!the!above!chapters!make!several!contributions!to!the!literature!on!the! natural! history! of! injection! drug! use.! Primarily,! this! dissertation! includes! the!adaptation!and!validation!of!a!psychometric!scale! to!assess! the! likelihood!of!drugKrelated! riskKtaking! among! streetKinvolved! youth.32,! 298! The! development! of! this!modified! SSS! for! the! first! time! provides! a! culturally! appropriate! assessment! of!sensation!seeking! for!a!streetKinvolved!youth!population!exhibiting!negative!drugKrelated!outcomes!at!a!higher!rate!than!other!populations!in!which!sensation!seeking!has! previously! been! studied.98,! 296! Further,! the! hypothesis! testing! exercise!undertaken! in! Chapter! 5! demonstrates! the! potential! for! extending! classical!epidemiologic! models! of! drugKrelated! risk! currently! focusing! on! behavioural,!sociodemographic!or!clinical!risk!factors!to!include!personalityKbased!risk!factors!as!well.! This! investigation! of! personalityKbased! risk! factors! is! consistent!with! recent!calls! from! the! U.S.! National! Institutes! of! Health! to! employ! individualKlevel,!neurobiological,! and!psychological! factors! in! investigations!of! drugKrelated! risk.299!In! this! regard,! Chapter! 5! represents! a! preliminary! expansion! of! the! scientific!literature! to! articulate! the! association! between! sensation! seeking! and! a! range! of!risky! drugKrelated! behaviours! highly! relevant! to! public! health! efforts! to! mitigate!drugKrelated! harm,! and! primarily! injection! drug! use.! Additionally,! the! analyses!undertaken! in! Chapter! 4! and! Chapter! 5! collectively! represent! a! relatively!comprehensive! investigation! of! the! risks! for! injection! initiation! faced! by! streetKinvolved! youth,! which! remains! an! understudied! phenomenon.! These! findings! are!highly! relevant! given! ongoing! epidemics! of! injection! drug! use! globally.10! Taken!together,! these!suggest!an!expanded!role! for!research! into! the!role!of!both!crystal!!! 104 methamphetamine!use!and! sensation! seeking! in!heightening! risk!of! initiation! into!injection.!! This! dissertation! also! includes,! in! Chapter! 3,! the! first! systematic! review! of!interventions! to!prevent! the! initiation!of! injection!drug!use.!Given!expert! calls! for!the!prioritization!of! the!prevention!of! injection! initiation,22! this! systematic! review!fills! a! gap! in! the! scientific! literature! on! this! topic,! providing! researchers! and!policymakers!with!what!is!hoped!will!be!a!useful!foundational!document!for!future!research! and! intervention! development.! Of! concern,! this! review! highlights! the!critical! dearth! of! scientifically! peerKreviewed! evaluations! of! preventive!interventions!undertaken!to!date,!and!the!concomitant!need!for!the!development!of!novel,!evidenceKbased!interventions!to!effectively!reduce!the!incidence!of! injection!initiation.!! Collectively,! this! dissertation! identifies! a! series! of! factors,! such! as! use! of!crystal!methamphetamine!(Chapter!4),!exposure!to!injecting!(Chapters!4!and!6),!and!sensation!seeking!(Chapter!5),!all!of!which!appear! to!negatively! impact! the!risk!of!injection!transitions.!Furthermore,!the!findings!presented!in!Chapter!6!suggest!that!current! efforts! to! reduce! the! harms! associated! with! ongoing! highKrisk! injection!trajectories,!which!include!the!provision!of!evidenceKbased!addiction!treatment!and!the!expanded!distribution!of!sterile! injecting!equipment,!are!unlikely!to!negatively!impact!rates!of!injection!cessation!among!IDU!populations!for!whom!these!services!are!made! available,! despite! the! fact! that! the! capacity! of! the! sample! of! IDU! under!study! in! Chapter! 6! to! cease! injecting! was! highly! restricted! by! a! range! of! social,!structural,!peerKbased!and!policy!factors.!!!! 105 7.3(( Study(strengths(and(limitations(This! dissertation! is! notable! in! that! all! dataKdriven! chapters! include!longitudinal! analyses! of! drugKrelated! risk! undertaken! among! samples! of! streetKbased! drugKusing! populations! (e.g.,! streetKinvolved! youth! and! IDU).! In! particular,!Chapter! 6! includes! an! analysis! of! 15! years! of! longitudinal! data! from! the! VIDUS!cohort.!This!dissertation!also!identifies!a!novel!source!of!increased!risk!for!injection!drug!use!and!other!risk!factors!for!injection!initiation,!in!the!form!of!high!sensation!seeking.! This! thesis! also! includes! the! first! systematic! review! identifying! and!assessing! the! scientific! literature! on! interventions! to! prevent! the! initiation! of!injection!drug!use.!With! respect! to! limitations,! and! as! noted! elsewhere,! the! analyses! reported!here!rely!on!observational!data!from!cohorts!of!streetKbased!drugKusing!populations,!and! behavioural! and! drugKrelated! data! were! collected! via! participant! selfKreport.!Given! the! stigmatized! nature! of! drug! use,! the! potential! therefore! exists! that!participants! underreported! drugKrelated! behaviours.180,! 240! However,! all!interviewers!were! trained! in!a!variety!of! techniques! to!minimize! the!possibility!of!bias!resulting! from!unreliable!selfKreport.!These! included!the!use!of!schedules!and!cue! cards! to! improve! recall,! the! staging! of! more! sensitive! questions! later! in!interviews,!and!techniques!to!build!trust!with!study!participants.!Second,!although!this! thesis! employed! multivariate! analyses,! it! is! possible! that! unmeasured!confounding! exists.! Finally,! given! that! no! populationKbased! registries! of! streetKinvolved!youth!or!IDU!exist,!the!possibility!of!constructing!probability!samples!using!a! comprehensive! registryKbased!system!was!not!available.!However,! as!previously!noted,!studies!have!demonstrated!that!the!ARYS!and!VIDUS!cohorts,!both!of!which!!! 106 employ! communityKbased! recruitment! techniques! such! as! streetKbased! and!snowball! sampling,! may! be! generalizable! to! the! broader! populations! of! streetKinvolved!youth!and!IDU!residing!in!Vancouver.179,!237,!272,!273!!7.4( Recommendations(Several!recommendations!can!be!derived!from!the!research!presented!in!this!thesis.! First,! as! described! in! Chapters! 3K5,! implementing! evidenceKbased!interventions!to!prevent!injection!initiation!among!streetKinvolved!youth!should!be!a!public!health!priority,31,!42,!231! given! that! so! few!currently!exist!and!only!one!has!been!brought!to!scale.!Second,!the!development!of!such!interventions!should!seek!to!identify! highKrisk! individuals! from! within! groups! of! vulnerable! drugKusing!populations.!(In!this!regard,!a! focus!on!the!role!of!established!IDU!in!facilitating! injection!initiation! events! is! warranted,! given! the! findings! of! the! secondary! analysis!presented! in! Chapter! 4.! There! are!multiple! interventional! options! for!minimizing!the! exposure! of! streetKinvolved! youth! to! risk! environments! for! injecting.! For!example,! lowKthreshold! housing! should! be! located! in! areas! inhabited! by! streetKinvolved! youth! in! order! to! disrupt! their! transition! into! injecting! or! further!entrenchment!in!a!streetKbased!drugKusing!scene.71,!72!As!well,!determining!whether!current! interventions! that! seek! to! reduce! the! incidence! of! injection! (such! as! the!provision! of! methadone! maintenance! therapy;24! the! provision! of! peerKbased!behavioural! interventions;144! and! comprehensive! engagement! strategies! including!harm! reduction! interventions! such! as! NSPs,4)! also! reduce! the! risk! of! injection!initiation!by!limiting!exposure!to!injecting!and!the!overall!number!of!IDU!peers!that!nonKIDU!are!exposed!to!should!be!prioritized.!Supervised!injection!facilities!may!be!!! 107 particularly! effective! in! this! regard,! given! that! they! disrupt! peer! influence! by!reducing! exposure! to! injecting! in! a! number! of!ways:! IDU! attending! such! facilities!inject! separately! from! other! clients;! clients! of! the! supervised! injection! facility! in!Vancouver!are!not!allowed!to!share!drugs!within!the!facility!(e.g.,!gifting);!injection!within!such!a!facility!reduces!community!exposure!to!injection;!and!these!facilities!do!not!accommodate!injectionKna?ve!drug!users.63!!Third,! the! analysis! presented! in! Chapter! 6! found! that! being! exposed! to!injecting!via!a!sexual!partner!was!associated!with!a!significantly!lower!likelihood!of!injection! cessation.! As! described! above,! supervised! injection! facilities!may!modify!the! risk! environment! experienced! by! individuals! at! varying! points! along! their!injection! careers! by! reducing! the! likelihood! of! public! injecting! and! thereby!potentially! mitigating! peer! influence,! with! implications! for! the! likelihood,! timing,!duration,!and!cessation!of!injection!drug!use.!However,!the!intimate!nature!of!sexual!relationships!may!be!beyond!the!capacity!of!these!structural!interventions!to!modify,!and!complementary!approaches!are!likely!therefore!required.!To!that!end,!multiple!studies!have! found! that! IDU!enrolled! in!methadone!maintenance! therapy!not!only!reduce! injecting! but! also! report! significantly! fewer! IDU! sexual! partners,300,! 301!suggesting! that! this! intervention!may! have! the! capacity! to! reduce! secondary! HIV!risk!behaviours!associated!with!ongoing!injection.!Fourth,! the! findings! presented! here! reinforce! evidence! indicating! that! the!implementation!and/or!expansion!of!NSPs!should!be!a!key!part!of!a!comprehensive!public! health! response! to! drugKrelated! harms! in! settings! characterized! by! a! high!prevalence! of! injection! drug! use.! In! short,! it! is! clear! that! interventions! aimed! at!reducing!the!incidence!of!ongoing!injecting!(e.g.,!methadone!maintenance!therapy)!!! 108 and!those!that!aim!to!reduce!the!harms!associated!with!this!activity!(e.g.,!NSPs)!do!not! necessarily! undermine! each! other! and,! as! delineated! above,! may! represent! a!potential! area!of! synergy! in! treatment!and!harm!reduction!efforts.! In! fact,!beyond!their!demonstrated! role! in! reducing!HIV! risk!among! IDU,62,!295,!302!NSPs!have!been!found! to! be! complementary! to! efforts! to! reduce! injecting! among! active! IDU! in! a!number! of! settings.33,! 110,! 303! Indeed,! it! is! noteworthy! that! in! a! study! setting!characterized! by! an! intersection! of! factors,! including! residency! in! the! downtown!eastside,!involvement!in!the!sex!trade,!and!having!a!sexual!partner!who!is!injecting,!all! of! which! significantly! reduce! the! likelihood! of! cessation,! the! period! of! NSP!expansion! was! nevertheless! characterized! by! an! increasing! annual! proportion! of!IDU!reporting!cessation.!However,! given! that!previous! research!has!demonstrated!that! streetKlevel! enforcement! can! reduce! the! protective! effect! of! NSPs,304!policymakers! should! consider! alternatives! to! drug! law! enforcement! in! settings!characterized!by!ongoing!drugKrelated!health!and!social!harms.244!7.5( Future(research(! The! use! of! psychosocial! constructs! such! as! sensation! seeking!within! a! risk!environment! framework! provides! a! starting! point! for! novel! research! into! how!personalityKbased!risk! factors! for! injectionKrelated!harm!may!be!expressed!among!streetKbased! drugKusing! populations! experiencing! a! social! and! structural! context!that!increases!the!risk!of!a!range!of!negative!health!outcomes.!In!particular,! future!testing!and!refinement!of!the!modified!sensation!seeking!scale!presented!in!Chapter!5!may! improve! capacity! to! develop! individualized! interventions! to! prevent! drugKrelated!harm!by!identifying!those!who!may!be!more!likely!to!engage!in!risky,!novel!experiences.! For! example,! binge! drug! use! and! polysubstance! use!were! associated!!! 109 with! higher! sensation! seeking! score,! and! both! behaviours! carry! attendant! harms!and! have! also! been! identified! as! risk! factors! for! injection! initiation.108,! 109! More!generally,! elevated! sensation! seeking! has! been! shown! (in! this! thesis! and!elsewhere305)! to! heighten! drugKrelated! risk.! As! such,! a! promising! area! of! future!research! may! be! to! undertake! intervention! studies! or! addiction! treatment! trials!evaluating! the! effectiveness! of! interventions! that! are! specifically! designed! to! aid!people! who! use! drugs! identified! as! high! sensation! seekers! to! reduce! riskKtaking!behaviours! such! as! crystal! methamphetamine! use,! binge! drug! use! and!polysubstance!use!or!to!reduce!their!level!of!sensation!seeking.191!Additionally,!the!causal!pathways!by!which!sensation!seeking!and!specific!types!of!drug!use!such!as!crystal!methamphetamine!use!may!impact!upon!high!risk!behavior!requires!further!research!aiming!to!identify!directions!of!causality!in!the!association!between!drugKrelated! riskKtaking! and! sensation! seeking.( More! broadly,! the! use! of! psychosocial!constructs! such! as! sensation! seeking! within! a! risk! environment! framework! may!facilitate!novel!research!into!how!personalityKbased!risk!factors!for!injectionKrelated!harm! may! intersect! with! social! and! structural! contexts! to! increase! the! risk! of! a!range!of!negative!drugKrelated!health!and!social!outcomes.!Additionally,! Chapter! 6! reconfirms! the! utility! of! methadone! maintenance!therapy! in! increasing! the! likelihood! of! injection! cessation! among! IDU,! while! also!demonstrating! that!exposure! to! injecting!via!a! sexual!partner!appears! to!decrease!the!likelihood!of!cessation.!In!the!context!of!the!findings!presented!in!Chapters!3K5,!these! results! suggest! that! the! provision! of! methadone! maintenance! therapy! may!have! both! an! individualK! and! communityKlevel! impact! on! injection! trajectories.!Specifically,! along! with! the! direct! impact! of! individual! enrolment! in! methadone!!! 110 maintenance!therapy!on!injection!cessation,!such!enrolment!may!also!lead!to!lower!communityKlevel! exposure! to! injecting! by! decreasing! a! community?s! number! of!active! injectors.! Further! investigation! of! how! addiction! treatment! provision! may!impact!the!risk!environment!experienced!by!streetKlevel!drugKusing!populations!in!our!study!setting!?!particularly!with!respect!to!sexual!partnerships!among!IDU!?!is!warranted.!!This!dissertation,!consistent!with!previous!research,!has!identified!exposure!to! injecting! as! a! risk! factor! for! initiation! and! suggests! that! it! may! contribute! to!prolonged!injection!career!trajectories.!As!such,!and!consistent!with!experts!calls!for!research! into! the! social! context! of! injection,306,! 307! future! quantitative! research!should!employ!network!analysis!tools308!in!order!to!determine!the!extent!to!which!injection!transition!events!are!associated!with!peer!behavior.!Indeed,!while!previous!research!on!injection!initiation!has!investigated!peer!influence,36,!42,!107,!306!there!is!a!dearth! of! literature! employing! formal! network! analysis! tools! to! assess! injection!transition! events.! Future!work! in! this! area! could! therefore! expand!upon! research!assessing! the! impact! of! social! influence! on! the! risk! of! bloodborne! disease!transmission!among!IDU!populations.309!!Finally,! future! research!should!explicitly!examine! the! impact!of!drug!policy!interventions! on! the! incidence! of! initiation! and! cessation! of! injection! drug! use!among! drugKusing! populations.! For! example,! drug! law! enforcement! interventions!negatively! impact! streetKbased! drugKusing! populations! disproportionately,252! and!previous! research! has! starkly! demonstrated! how! largeKscale! policy! decisions! can!increase!the!risk!of!injection!initiation!among!vulnerable!drugKusing!populations,310!while!also!compromising!the!effectiveness!of!harm!reduction!interventions!such!as!!! 111 NSPs.280! Although! the! results! of! Chapter! 3! of! this! thesis! suggest! that! drug! law!enforcement! is! ineffective! in! preventing! initiation,! the! association! between! drug!policy! and! initiation! nevertheless! remains! largely! obscure,! and! more! research! is!thus!required.!Such!research!will!likely!necessitate!methodological!approaches!that!employ!multilevel!modeling! to! account! for! the!differential! impact! of! drug!policies!across!geographic!settings!and!sociodemographic!and!structural!contexts.!This!type!of!research!could!expand!upon!the!findings!presented!in!Chapters!3,!4!and!6!of!this!dissertation!regarding! the!potential! influence!of!established! injectors! in!modifying!injection! trajectories.! For! example,! longitudinal! research! could! be! undertaken! to!investigate!the!impact!of!drug!policies!on!the!incidence!of!initiation!and!cessation!of!injection!as!mediated!through!exposure!to!other!injectors!in!a!drugKusing!network,!types!of!drugs!used,!mode!of!administration,! sensation!seeking!status,! intensity!of!drug! law! enforcement,! and! the! presence! or! absence! of! harm! reduction! or! other!public!health!interventions.!!7.6( Conclusions(( Despite! decades! of! scientific! research! on! the! harms! of! injection! drug! use,!prevailing!drug!policies!remain!largely!ineffective!in!reducing!drugKrelated!harm,!as!evidenced! in! high! ongoing! incidence! of! injectionKdriven! epidemics! of! bloodKborne!disease!and!fatal!overdose!in!a!number!of!settings.10,!149,!169,!311,!312!This!is!particularly!problematic! given! that! substantial! resources! to! control! drug! use! and! supply!continue! to! be! allocated! towards! interventions! and! policy! approaches! that! lack! a!scientific! evidence! base,! and! that! have! furthermore! been! shown! to! negatively!impact! injectionKrelated! risk! through!drug! law!enforcement! interventions! and! the!incarceration!of!people!who!use!drugs.244,!252,!313!In!this!context,! this!thesis!found!a!!! 112 relatively!limited!literature!on!the!natural!history!of!injection!drug!use,!as!well!as!a!small!number!of!scientificallyKevaluated!interventions!to!prevent!injection!initiation.!Further,! using! a! risk! environment! framework,! findings! presented! in! this! thesis!suggest!that!streetKinvolved!youth!in!Vancouver!who!use!crystal!methamphetamine!are! at! higher! risk! of! initiating! injection! drug! use,! while! those! that! report! higher!sensation!seeking!are!at!higher!risk!of! injection!drug!use,!along!with!nonKinjection!crystal!methamphetamine,!polysubstance!use!and!binge!drug!use!?!all!of!which!have!been!shown!to!contribute!to!the!risk!of!injection!initiation.!Additionally,!this!thesis!further!confirms!that!exposure!to!injecting!appears!to!influence!injection!transition!events,!both!with!respect!to!initiation!and!cessation.!Finally,!during!a!period!of!NSP!expansion,! rates!of! injection!cessation! increased!substantially,! suggesting! that! this!intervention! is! not! associated!with! reducing! injection! cessation.! It! is! important! to!note!that!this!thesis!contains!limitations!typical!of!observational!research,!as!well!as!limitations! related! to! the! development! and! preliminary! testing! of! a! novel!psychometric! scale.! Nonetheless,! the! findings! presented! suggest! that! the!development! and! implementation! of! interventions! to! prevent! injection! drug! use!should!be!considered!complementary!to!efforts!to!reduce!injectionKrelated!harms.!(Future! research! into! the!natural!history!of! injection!drug!use!research! that!focuses!on! interactions!between!a!number!of!potential! risk! factors!holds!promise.!For! example,! research! investigating! the! interaction! between! the! individual!personality! traits! of! drug! users! (e.g.,! level! of! sensation! seeking)! and! the! types! of!drugs!consumed!could!help!identify!ways!in!which!these!two!risk!factors!impact!one!another.!This!is!important!because!research!to!date!has!focused!almost!exclusively!on! a! unidirectional! association! between! sensation! seeking! and! drug! use,! though!!! 113 experts! have! found! that! adolescent! use! of! drugs! such! as! amphetamines! and!cannabis!may!impact!brain!development!and!the!expression!of!personality!traits.314!In!this!way,!determining!the!direction!of!causation!with!respect!to!sensation!seeking!and!drug!use!may!therefore!aid!in!investigations!of!drugKrelated!risk.!Additionally,!further! investigations! of! the! interaction! between! drug! users! at! various! stages! of!their! injection! careers,! and! on! the! impact! of! exposure! to! injecting,! is! required! in!order! to! further! delineate! the! impact! that! established! injectors! may! have! on!modifying! the! likelihood!of! injection! transition!events,! and! this!work!may!best!be!undertaken! by! employing! formal! network! analysis! tools.! Finally,! research!pertaining!to!the!interactions!between!policy!decisions!and!the!individual!injection!career! trajectories! of! people! who! use! drugs! would! provide! insights! into! how!potential!policy!responses!impact!drugKrelated!riskKtaking.!The! global! burden! of!HIV! and!HCV! transmission,! fatal! overdose,! and! other!health! and! social! harms! is! overwhelmingly! focused! on! streetKbased! drugKusing!populations.!Within!this!context,!describing!the!natural!history!of!injection!drug!use,!examining! the! varying! level! of! drugKrelated! risk! that! IDU! experience,! and!determining! how! individuals! at! different! stages! of! their! injection! careers! impact!injectionKrelated! risk! in! others,! becomes! increasingly! important.! This! is! because!research!of! this!kind! can!provide!evidence!highly! relevant! to!policies! that! seek! to!both!mitigate!ongoing!drugKrelated!harms!such!as!bloodKborne!disease!transmission,!and!reduce!the!incidence!of!injection!drug!use!initiation.!Given!the!lack!of!evidenceKbased! responses! that! currently! exist,! and! the! severity! of! drugKrelated! harms! in! a!variety! of! settings,! developing! comprehensive! approaches! that! can! both! prevent!!! 114 injection! drug! use! and! reduce! injectionKrelated! harms! represents! a! critical! public!health!priority.(!! 115 References:((1.! Mogey!GA.!Centenary!of!hypodermic!injection.!British!BMJ.!1953;!2(4847):!1180K5.!2.! Karch!SB.!Cocaine:!history,!use,!abuse.!Journal!of!the!Royal!Society!of!Medicine.!1999;!92(8):!393.!3.! de!Ridder!M.!Heroin:!new!facts!about!an!old!myth.!Journal!of!Psychoactive!Drugs.!1994;!26(1):!65K8.!4.! 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