HEROIN ADDICTION & Regular article RELATED CLINICAL Heroin Addict Relat Clin Probl 2018; 20(5): 35-49 PROBLEMS www.europad.org Pacini Editore & AU CNS www.wftod.org

Comparing neurocognitive function in individuals receiving chronic methadone or buprenorphine for the treatment of opioid dependence: A systematic review. Duncan Hill1,2, Daniel Garner3, and Alex Baldacchino3,4

1. Addictions Services, NHS , , , UK 2. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, UK 3. School for Medicine, University of St Andrews, Fife, Scotland, UK 4. NHS Fife, Queen Margaret Hospital, Whitefield Road, Dunfermline, Fife, Scotland, UK

Summary Introduction: Agonist Opioid Treatments (AOT) have been, in comparison to healthy controls, associated with neuro- cognitive impairment in different domains. This review identifies differences in neurocognitive function as a result of treatment with either buprenorphine or methadone. Method: A qualitative and systematic literature review of published articles from 1946 to 29/2/2016 on neurocognitive function of patients prescribed buprenorphine or methadone and com- pared with healthy patients utilising the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Results: The limited data demonstrate buprenorphine as presenting with fewer neurocognitive impairments, in cognitive impulsivity, cognitive flexibility and attention domains when compared with methadone. However both treatments mo- dalities presented with more impairments in neurocognitive function domains, including short term memory, attention, cognitive flexibility, cognitive impulsivity, motor impulsivity and non planning impulsivity, when compared with healthy control groups. Discussion: The lack of published papers in comparing neurocognitive impairment between the treatment modalities limit interpretation of this systematic review. Conclusion: Further methodologically rigid and higher quality research into the neurocognitive effects of these treatment modalities in the opioid dependent populations, especially when in treatment, is urgently required. Key Words: Neurocognitive Impairment; buprenorphine; methadone; treatment; opioid dependence

11. Introduction also display psychological dependence by altering the brains behavioural circuits. The receptors affected by Treatment for opioid (and opiate) addiction us- opioids, are located through the brain and spinal cord, ing agonist opioid treatments (AOT) (i.e. methadone including the thalamus, hypothalamus, hippocampus, and buprenorphine) have been associated with neuro- amygdala and the cerebral cortex [12],which are im- cognitive impairment in comparison to healthy con- portant for neurocognitive function, but are also con- trols. nected to the reward and reinforcement area in the For the purposes of this review we will use the brain, the nucleus accumbens. term opioids to encompass both opiates and opioids. Opioid use has been demonstrated in the brain to Opioids are widely used both legally in treatment, for increase oxidative stress, which contributes to neuro- their analgesic effects, and illicitly, for the psycho- toxicity leading to neurocognitive impairment [7, 33]. tropic effects. The neurocognitive impairments asso- In the review by Büttner and Mall, they noted re- ciated with opioid use have already been documented duced neuronal density in majority of patients dying [4] from heroin overdoses due to respiratory depression Opioids are known to alter receptor sensitivity and associated brain hypoxia [6]. and expression, demonstrating a tolerance effect, but Consideration of other contributing factors other

Corresponding author: Duncan Hill, Specialist Pharmacist in Substance Misuse, NHS Lanarkshire, Airbles Road Centre, 49-59 Airbles Road, ML1 2TP, Motherwell, Scotland, UK Phone: 01698266717; Mobile: 07920711131; E-mail: [email protected],nhs.uk 35 Heroin Addiction and Related Clinical Problems 20(5): 35-49 than the direct opioid toxic effects on neurocognitive ability to recall and make new memories. The Atkin- impairment needs to be considered. This can include son-Shiffrin model of memory proposes three distinct bacterial and viral infection and other potential neu- ‘stores’ of memory: sensory memory (lasting a few ropathological insults [10]. These factors will not be milliseconds: providing a buffer for sensory informa- reviewed in this systematic review. tion and allows us to address information when re- To measure neurocognitive function in individu- quired), short-term memory (lasting 12-30 seconds als the precise function being tested must be defined. without rehearsal: primarily auditory in nature, can Muriel Lezak, the author of the first book exploring store around seven chunks of information for a few neuropsychological assessment, wrote ‘Direct obser- seconds without rehearsal [22] duration of storage vation of the fully integrated functioning of living hu- can be increased with the use of a phonological loop), man brains will probably always be impossible’ [18]. and long term memory which can be indefinite (abil- Therefore, to assess neuropsychological function in ity to store information for a lifetime [2] and can be the context of assessment, three domains (and sub- further split into declarative memory requiring con- sequent sub-domains based on neurocognitive tests) scious though and procedural memory requiring no need to be clearly defined to allow the objective ob- thought). servation of neurocognitive function in individuals: A recent meta analysis looking at the effects of • Intelligence chronic methadone use identified global impairments • Executive Function in neurocognitive function relative to healthy partici- • Memory and Learning pants [5]. The use of an intelligence assessment allows an This article aims to determine if there are dif- estimate the premorbid IQ of an individual. A vocab- ferences in the effects on the neurocognitive function ulary test is the primary assessment method use, e.g of patients being treated with either buprenorphine or Shipley Institute of Living Scale (SILS) or Wechsler methadone. Adult Intelligence Scale – Revised & III [31, 38]. High level neurocognitive functions, known as 12. Methods Executive functions, allow for the control of behav- iour to achieve a targeted outcome, this includes cog- 12.1. Literature Search nitive flexibility, cognitive planning, cognitive impul- sivity, working memory and attention [5, 11, 36]. A literature review identified articles relating Memory and learning assesses an individual’s to the neurocognitive effects of either buprenorphine

Table 1: Inclusion and exclusion criteria for studies used in the review

Inclusion Exclusion Participants aged eighteen or over with chronic opioid de- Cohorts with current uncontrolled poly-drug use (nicotine pendence and currently engaged in an opioid maintenance excluding). programme Individuals needed to be compared to either healthy Cohorts with a diagnosis of any Axis-1 psychiatric ill- controls, abstinent individuals or another maintenance pro- ness (excluding substance related disorders) as defined gramme (methadone vs. buprenorphine) through the use of by DSM-IV/V (American Psychiatric Association 2000; validated neuropsychological assessments. American Psychiatric Association 2013).

Neuropsychological assessments needed to be identi- Cohorts with previous serious head injury. fied and validated to allow for them to be classified into domains. If novel assessments were used a description of the cognitive functions assessed was used to classify by comparison to a defined assessment. Identified papers need to be of adequate quality match- Articles with poor quality methodology, ing the control/abstinent group to the maintained cohort, matching criteria should include: age, sex, years of educa- tion and years of heroin dependence Papers needed to report separate results for each cohort Cohorts including participants who were HIV serotype and test, papers which combined maintenance cohorts positive were excluded as it was not possible to extract the results required.

- 36 - D. Hill et al.: Comparing neurocognitive function in individuals receiving chronic methadone or buprenorphine for the treatment of opioid dependence: A systematic review.

Table 2: Search Subject Headings

opioid related neuropsychological tests/impair- methadone OR disorders OR ments/deficits substance related disorders OR OR buprenorphine OR chronic drug AND AND dependence OR Subutex OR neurocognitive tests/deficits/im- substance pairments withdrawal syn- Suboxone drome or methadone on patients receiving Agonist Opioid function were used from articles comparing either of Treatment (AOT) for opioid dependence. The cohorts the two therapeutic intervention against a healthy pa- chosen where either direct comparison between indi- tient control group. The results of these studies were viduals treated with methadone or buprenorphine or used to comment on the potential for neurocognitive those compared against a healthy control group. The impairment from the treatment with ORT against a Meta-analysis of Observational Studies in Epidemi- control group. ology (MOOSE) guidelines were employed and the inclusion and exclusion criteria used have been tabu- 13.2. Assessment of study quality lated in Table 1. An electronic based search using a number of The vast majority of selected articles for this re- databases and incorporating articles published from view were assessed as fair in quality using the NIH 1946 to 29/2/2016 were used. The databases used Quality Framework for case-control studies (Table 3) where Ovid MEDLINE (1946 to 29/2/2016); EM- (NIH 2014) with others ranging in quality from poor BASE (1974 to 29/2/2016); PUBMED (1964 to (2 articles) to good (1 article). All studies were obser- 29/2/2016); PsychINFO (1980 to 29/2/ 2016). There vational case control studies. were no language constraints employed. The articles were identified using the search 13.3. Number of articles identified headings in Table 2. The search terms ‘neuropsychological tests’ and The initial literature search identified 426 ar- ‘neurocognitive tests’ were then replaced with the ticles from literature and other sources. Once du- sub-titles of neurocognitive domains e.g. Short Term plicates were removed the total number of relevant Memory, Long Term Memory, Attention, Cognitive manuscripts was reduced to 179. Titles and abstracts Flexibility, Cognitive Impulsivity, Motor Impulsivity of 31 articles included in the accepted abstracts were and Non-Planning Impulsivity. screened for eligibility with an additional six articles As this article is a literature review there was included in the full text screening (Figure 1: QUO- no requirement for ethical approval in relation to the RUM). The full text of the remaining 36 articles was study. assessed using the inclusion and exclusion criteria on Table 1. This assessment excluded a further 20 arti- 13. Results cles which failed to meet the inclusion criteria in the full text with the remaining 16 articles included in 13.1. Data analysis and study detail this review.

The literature search provided very few articles 13.4. Cohorts identified published on the comparison of effects of treatment on the neurocognitive function of patients being treat- The included articles described results from the ed with buprenorphine or methadone. direct comparison of 60 buprenorphine maintained With the very limited number of published arti- individuals to 74 methadone maintained individu- cles offering direct comparisons (3 articles identified) als from 3 published articles. When the search was between buprenorphine and methadone, a wider but extended to compare either methadone or buprenor- indirect comparison of the effects on neurocognitive phine maintained patients to a healthy control, there

- 37 - Heroin Addiction and Related Clinical Problems 20(5): 35-49

(IQ) RST3) WCST Measured WAIS-III; WAIS-III; TT15; DR2; logical Tests logical Tests DSST; TMT DSST; (A&B); 2BT; (A&B); 2BT; GT; ST; SILS ST; GT; Neuropsycho - WMSR (PAL- Q1; FAT; LL5; Q1; FAT; I& II, VR-I & II I& II, RCFT; COWAT; COWAT; RCFT; subtests); CVLT; subtests); CVLT; ART-2020 (MAT; (MAT; ART-2020 92.6 94.0 (2.8) Mean (-11.1) IQ (sd) 11.7 12.1 Educa - tion (yrs) / / Sex Sex 12F 11F (intelligence) 18M 10M (nM/nF) Healthy Controls Healthy Age 35.2 34.9 (yrs) Mean Matched for age, sex and score in MAT and score in MAT Matched for age, sex N 30 21 78.6 45.7 67.2 dose done (mg) daily Mean metha - 1.55 3.78 (yrs) dian) 5 (me - Metha - done use 4.28 15.3 Mean mum) Opioid 5 (mini - Use (yrs) IQ n/a (sd) 91.5 87.4 (2.7) Mean (10.4) Methadone Group yrs tion 11.2 11.8 ment High Junior attain - Modal School Educa - / / / 6F 9M 7M Sex Sex 12F 11F 18M (nM/nF) Age 35.8 25.8 37.6 (yrs) Mean N 30 15 18 ity Fair Fair Fair Qual - States

United Austria Country Australia Study Schin - (2000) (2004) al (2002) dler et al. Mintzer et Abbreviations: n= Number of Participants; yrs = Years; nM/nF= Number Male/ Number Female; IQ = Intelligence quotient; sd= standard deviation; mg= milligrams; WAIS-III = Wechsler Wechsler = WAIS-III mg= milligrams; nM/nF= Number Male/ Female; IQ = Intelligence quotient; sd= standard deviation; Years; yrs = n= Number of Participants; Abbreviations: learning test; RCFT; California verbal Reproduction; CVLT= Visual VR-I&II= Associate Learning; Paired PAL-I&II= Memory Scale-Revised; Weschler WMSR; Adult Intelligence Scale; DSST= Tast; Scale; GT= Gambling Institute of Living SILS= Shipley Test; Card Sorting Wisconsin WCST= association test; Controlled oral word COWAT= Test; Figure Complex Rey Reten - Visual Benton BVRT= Adult Intelligence Scale - Revised; Wechsler WAIS-R= Test; ST= Stroop Test; Back Two 2BT= Test; Making Trail TMT= Test; Digit Symbol Substitution Semantic SAVF= Test; RRLET= Remote and Recent Life Event Test; Sequence Learning Word WSLT= Test; SOMT= Six Object Memory Test; CPT= Continuous Performance Test; tion FTT= Time; Reaction CRT=Choice Test; CBT= Corsi Block World;; Three Dimensional Block Construction Model; SpTW= Spot the Real 3DBCM= Fluency; Verbal Association of AGN= Task; CGT= Cambridge Gambling Test; Adult Reading National NART= Attention; SS= Stop Signal; PES= Post Error Slowing; of Variables of Test TOVA= Test; Tapping Finger Act ART-2020= Test; Gambling Animals; IGT= Iowa Fruits and FAS= Test; Digit FDT= Five Austine Maze; n/a= not available; AM= Go/No Go; SOC= Stockings of Cambridge; Affective Structuring Visual for Test LL5= Attention Flexibility, for Test intelligence), Q1=Attention Under Monotonous Circumstances, FAT= (non-verbal Test Matricies System (MAT= Test React ART-90= Test); Stress Environment, RST3= Reactive in a Dynamic Driving DR2= Decision and Reaction Behaviour Ability, Perception Traffic-specific Measuring the TT15=Test Ability, Test, Stess Attention Under Monotonous Circumstances, RST3= Reactive Q1= Ability, specific Perception Traffic- Measuring the TT15=Test Test, Vision (PVT= Peripheral Test Act React Scale. KMSK= Kreek–McHugh–Schluger–Kellogg in a Dynamic Environment) DR2= Decision and Reaction Behaviour Darke et al. Darke Characteristics of articles identified comparing methadone maintenance patients to healthy controls. 3: Characteristics of articles identified comparing methadone maintenance patients to healthy Table

- 38 - D. Hill et al.: Comparing neurocognitive function in individuals receiving chronic methadone or buprenorphine for the treatment of opioid dependence: A systematic review. IGT. DR2) BVRT WCST SS; PES 3DBCM arithmetic, R(digit span, COWAT; ST; ST; COWAT; WAIS-R (IQ); WAIS-R SAVF; WAIS- SAVF; Test; Proverbs ART-90 (PVT; (PVT; ART-90 WAIS-III (IQ); WAIS-III BVRT; WCST; WCST; BVRT; SOMT; WSLT; WSLT; SOMT; SILS (IQ); GT; SILS (IQ); GT; symbol); Reitan BVRT; RRLET; RRLET; BVRT; TT15; Q1;RST3; NART (IQ); NART AGN; CGT; SOC n/a n/a n/a 104 92.1 12.2 (3.39) (-13.2) (-3.42) 118 (5.1) 9.3 13.6 15.5 10.9 15.4 (n=9) attain - Modal school leaving leaving general ment was ment was certificate 15.4 / / / / / 8F 7F 1F 0F n/a 11F 21M 14M 14M 22M 64M 28M / 0F 37 34 34 34 29.8 36.8 24.1 19 29 21 25 23 64 28 66 56 36 45 61.6 73.8 55.8 n/a 0.5 8.3 0.5 6.44 1.73 mum) (mini - 1.3 11 0.5 15.1 15.5 13.9 14.3 mum) (mini - 8.8 85 n/a n/a n/a 83.8 8.05 (9.7) (2.19) 109 (7.6) 13 8.6 was was “O” 12.2 8.37 10.3 ment levels levels attain - Modal (n=10) 10.6 / / / / / 6F 1F 8F 1F 0F n/a 23M 29M 16M 26M 65M 29M / 0F 35 32 42.3 37.9 36.8 40.2 27.3 18 29 30 24 27 65 29 Fair Fair Fair Fair Fair Poor Good Italy States States United United Taiwan Taiwan Germany - ham- (2004) (2011) (2012) (2014) Rother Lin et al. Pirastu et al. (2006) al. (2006) Prosser et Liao et al. Abbreviations: n= Number of Participants; yrs = Years; nM/nF= Number Male/ Number Female; IQ = Intelligence quotient; sd= standard deviation; mg= milligrams; WAIS-III = Wechsler Wechsler = WAIS-III mg= milligrams; nM/nF= Number Male/ Female; IQ = Intelligence quotient; sd= standard deviation; Years; yrs = n= Number of Participants; Abbreviations: learning test; RCFT; California verbal Reproduction; CVLT= Visual VR-I&II= Associate Learning; Paired PAL-I&II= Memory Scale-Revised; Weschler WMSR; Adult Intelligence Scale; DSST= Tast; Scale; GT= Gambling Institute of Living SILS= Shipley Test; Card Sorting Wisconsin WCST= association test; Controlled oral word COWAT= Test; Figure Complex Rey Reten - Visual Benton BVRT= Adult Intelligence Scale - Revised; Wechsler WAIS-R= Test; ST= Stroop Test; Back Two 2BT= Test; Making Trail TMT= Test; Digit Symbol Substitution Semantic SAVF= Test; RRLET= Remote and Recent Life Event Test; Sequence Learning Word WSLT= Test; SOMT= Six Object Memory Test; CPT= Continuous Performance Test; tion FTT= Time; Reaction CRT=Choice Test; CBT= Corsi Block World;; Three Dimensional Block Construction Model; SpTW= Spot the Real 3DBCM= Fluency; Verbal Association of AGN= Task; CGT= Cambridge Gambling Test; Adult Reading National NART= Attention; SS= Stop Signal; PES= Post Error Slowing; of Variables of Test TOVA= Test; Tapping Finger Act ART-2020= Test; Gambling Animals; IGT= Iowa Fruits and FAS= Test; Digit FDT= Five Austine Maze; n/a= not available; AM= Go/No Go; SOC= Stockings of Cambridge; Affective Structuring Visual for Test LL5= Attention Flexibility, for Test intelligence), Q1=Attention Under Monotonous Circumstances, FAT= (non-verbal Test Matricies System (MAT= Test React ART-90= Test); Stress Environment, RST3= Reactive in a Dynamic Driving DR2= Decision and Reaction Behaviour Ability, Perception Traffic-specific Measuring the TT15=Test Ability, Test, Stess Attention Under Monotonous Circumstances, RST3= Reactive Q1= Ability, specific Perception Traffic- Measuring the TT15=Test Test, Vision (PVT= Peripheral Test Act React Scale. KMSK= Kreek–McHugh–Schluger–Kellogg in a Dynamic Environment) DR2= Decision and Reaction Behaviour Fuller et al. Soyka et al. Soyka Characteristics of articles identified comparing methadone maintenance patients to healthy controls. 3: Characteristics of articles identified comparing methadone maintenance patients to healthy Table Baldac - chino et al. (2014)

- 39 -

Heroin Addiction and Related Clinical Problems 20(5): 35-49

Measured

logical Tests Tests logical

- Neuropsycho Ruff DR2) RST3) ART-90 ART-90 RBANS WAIS-III WAIS-III Q1;RST3; FAT; LL5; FAT; ART-2020 ART-2020 COG; DT; COG; DT; (MAT; Q1; (MAT;

BNT; VFT; VFT; BNT; TAVT; VIG TAVT; TT15; DR2; (IQ); BVRT; (IQ); BVRT;

WCST; IGT; IGT; WCST; (PVT; TT15; (PVT; RAVLT; CTT; CTT; RAVLT;

Mean IQ (sd) IQ Mean n/a n/a n/a

104

(-3.39) Education (yrs) Education n/a 10.9 11.5 (n=9) attain -

Modal school leaving leaving general

ment was ment was certificate Sex (nM/nF) Sex / / / / (intelligence) 7F 7F

6F 11F

14M 27M 84M 114M Mean Age (yrs) Age Mean

34

35.7 29.8 37.1 n Matched for age, sex and score in MAT and score in MAT Matched for age, sex

21 34 25 90 Healthy Controls Healthy

dose (mg) dose buprenorphine buprenorphine

9 Mean daily daily Mean 10

7.7 6.78 10.4

use (yrs) use Buprenorphine Buprenorphine

5.4 5.5 0.93 0.67 0.19

Use (yrs) Use Mean Opioid Opioid Mean

n/a 13.3 3.63 12.8 11.6 Mean IQ (sd) IQ Mean n/a n/a n/a n/a

89.3

(-3.45) Education (yrs) Education 11 n/a 8.72 High (n=9) (n=9) Junior attain -

Modal school or “O” School leaving leaving general

tainment tainment Level at - Level ment was ment was Modal at - certificate Sex (nM/nF) Sex / / / / /

1F 3F 2F

5M 10F 11F 17M 15M 11M 28M Mean Age (yrs) Age Mean

25 33

36.5 34.2 36.6 n

15 18 18 22 11 Buprenorphine Group Quality

Fair Fair Fair Fair Poor Country Italy

Greece Austria

Germany Germany Study (2006) (2011) al. (2004) al. (2009) Shmygalev Shmygalev Messinis et Abbreviations: n= Number of Participants; yrs= Years; nM/nF= Number Male/ Number Female; IQ= Intelligence Quotient; sd= Standard Deviation; mg- Milligrams; WAIS-III= Wechsler Wechsler WAIS-III= mg- Milligrams; nM/nF= Number Male/ Female; IQ= Intelligence Quotient; sd= Standard Deviation; Years; yrs= n= Number of Participants; Abbreviations: Matricies System (MAT= Test Act React ART-2020= Task; Gambling IGT= Iowa Task; Card Scoring Wisconsin WCST= Test; Retention Visual Benton Adult Intelligence Scale; BVRT= Measuring the TT15=Test Ability, Structuring Visual for Test LL5= Attention Flexibility, for Test intelligence), Q1=Attention Under Monotonous Circumstances, FAT= (non-verbal Test Test (PVT= Peripheral Act React ART-90= Test); Stress Environment, RST3= Reactive in a Dynamic Driving DR2= Decision and Reaction Behaviour Ability, Perception Traffic-specific Test, DR2= Decision and Reaction Stess Attention Under Monotonous Circumstances, RST3= Reactive Q1= Ability, Perception Traffic-specific Measuring the TT15=Test Test, Vision Selec - Ruff=Ruff Test; Trails CTT=Color Test; Learning Verbal Auditory RAVLT=Rey Test; Fluency Verbal VFT= Test; BNT= Boston Naming in a Dynamic Environment); Behaviour Available. n/a= Not Test; VIG=Vigilance Perception; TAVT=Tachistoscopic DT=Determination Test; Attention Test; COG= Attention Test; tive Soyka et al. Soyka Schindler et et al. (2011) Pirastu et al. Characteristics of articles identified comparing buprenorphine maintenance patients to healthy controls. buprenorphine maintenance patients to healthy 4: Characteristics of articles identified comparing Table

- 40 - D. Hill et al.: Comparing neurocognitive function in individuals receiving chronic methadone or buprenorphine for the treatment of opioid dependence: A systematic review.

-

Tests Measured Tests Neuropsychological DR2) RST3) RST3) ART-90 ART-90 WAIS-III WAIS-III

Q1;RST3; FAT; LL5; FAT; ART-2020 ART-2020 FAT; LL5; FAT; ART-2020 ART-2020 (MAT; Q1; (MAT; (MAT; Q1; (MAT;

TT15; DR2; TT15; DR2; (IQ); BVRT; (IQ); BVRT; WCST; IGT. WCST; (PVT; TT15; (PVT;

done dose (mg) dose done

- metha daily Mean

66 56

45.7 52.7 Methadone Use (yrs) Use Methadone

8.3 0.4 1.55 1.94

(yrs) Mean Opioid Use Use Opioid Mean

11

4.28 6.09 15.53 Mean IQ (sd) IQ Mean

85 n/a n/a n/a Education (yrs) Education n/a 8.37 High Methadone Group levels levels Junior Modal Modal (n=10) School

was “O” was

attainment attainment Sex (nM/nF) Sex / / / /

6F 1F 8F

9M 7M 13F 29M 16M Mean Age (yrs) Age Mean

35 32

25.8 27.9 n

15 30 20 24

(mg) prenorphine dose dose prenorphine

9 - Mean daily bu daily Mean 10

13.4 10.4

(yrs) Buprenorphine use use Buprenorphine

5.4 0.93 1.43 0.19

(yrs) Mean Opioid Use Use Opioid Mean

5.8

3.63 11.6 13.28 Mean IQ (sd) IQ Mean n/a n/a n/a

89.3

(-3.45) Education (yrs) Education n/a 8.72 Buprenorphine Group High (n=9) (n=9) Junior attain -

Modal school or “O” School leaving leaving general

tainment tainment Level at - Level ment was ment was Modal at - certificate Sex (nM/nF) Sex / / / /

1F 8F

5M 10F 11F 17M 12M 11M Mean Age (yrs) Age Mean

25 33 27

34.2 n

15 18 20 22 Quality Fair Fair Fair Poor

- Country

Ger Italy many

Austria Austria Study dler wert Bae - et al. et al. et al. et al. Soyka Soyka ing Ability, TT15=Test Measuring the Traffic- specific Perception Ability, DR2= Decision and Reaction Behaviour in a Dynamic Driving Environment, RST3= Reactive Stress Test); Stress Environment, RST3= Reactive in a Dynamic Driving DR2= Decision and Reaction Behaviour Ability, specific Perception Traffic- Measuring the TT15=Test Ability, (PVT= ing Test Act React ART-90= Test; Gambling IGT= Iowa Test; Card Sorting Wisconsin WCST= Test; Retention Visual Benton Adult Intelligence Scale; BVRT= Weschler WAIS-III= Test, DR2= Decision and Stess Attention Under Monotonous Circumstances, RST3= Reactive Q1= Ability, Perception Traffic-specific Measuring the TT15=Test Test, Vision Peripheral Available. n/a= Not in a Dynamic Environment); Reaction Behaviour Abbreviations: n=Number of Participants; yrs= Years; nM/nF= Number Males/Number Females; IQ= Intelligence Quotient; sd= Standard Deviation; mg=Milligrams; ART-2020= Act ART-2020= mg=Milligrams; nM/nF= Number Males/Number Females; IQ= Intelligence Quotient; sd= Standard Deviation; Years; yrs= n=Number of Participants; Abbreviations: Structur Visual for Test LL5= Attention Flexibility, for Test intelligence), Q1=Attention Under Monotonous Circumstances, FAT= (non-verbal Test Matricies System (MAT= Test React Schin - (2004) (2006) (2007) (2011) Pirastu Characteristics of articles identified comparing buprenorphine maintenance patients to methadone patients. 5: Characteristics of articles identified comparing Table

- 41 - Heroin Addiction and Related Clinical Problems 20(5): 35-49

Records identified Records identified through literature through other sources. search. (n=208) (n=218)

Records Excluded (n=142)

Abstracts screened after duplicates removed. Poly Drug Use (n=23) (n=179) No Control (n=25) Participants Under 18 (n=14) Current Heroin Users (n=3) HIV Positive (n=17) Axis-1 Illness (n=4) No Neuropsychological Tests (n=23) No Maintenance Therapy (n=21) No English Article Available (n=2) Full-text Articles Assessed for Eligibility Animal Study (n=1) (n=37) Acute Effects of Opioids (n=9)

Articles Excluded (n=20)

Poly Drug Use (n=7) Head Injury (n=3) Mixed Results Group (n=3) No Control (n=2) Acute Effects (n=2) Control Group Seeking Psychological Treatment for Pain (n=1) No English Article Available (n=1) Only Abstract Available (n=1)

Articles included in the Final Review N= 16

Methadone Vs. Methadone Vs. N =Buprenorphine 17 Vs. Buprenorphine Vs. Buprenorphine Vs. Healthy Control Abstinence Healthy Control Abstinence Methadone

n = 10 n = 4 n = 5 n = 1 n = 3

Figure 1. QUORUM were the neurocognitive assessments of 279 metha- In the articles directly comparing patients on done maintained individuals from 10 published arti- ORT treatment [1, 25, 34], all except one domain cles and 84 individuals maintained on buprenorphine (cognitive impulsivity) showed no significant differ- compared to healthy controls from 5 published papers ences between cognitive functioning in methadone [34], although one article is included in each com- and buprenorphine treated individuals. parison in the table as it compared healthy controls against methadone and buprenorphine and in ad- 13.5.1. Cognitive impulsivity dition a direct comparison between methadone and Buprenorphine maintained individuals scored buprenorphine groups. significantly better (p<0.05) on measures of cognitive The papers included are shown in table 6. impulsivity than methadone maintained individuals in all three selected studies [1, 25, 34]. This is also 13.5. Neurocognitive impairments between groups supported by all other selected studies measuring this

- 42 - D. Hill et al.: Comparing neurocognitive function in individuals receiving chronic methadone or buprenorphine for the treatment of opioid dependence: A systematic review. - n/a n/a n/a n/a n/a n/a n/a (Copy) ↓ - RCFT ↓ - RCFT Impulsivity Non Planning n/a n/a n/a n/a n/a n/a n/a Motor (Phase 1) (Phase 2) (Phase 3) ↓ - RST-3 ↓ - RST-3 ↓ - RST-3 ↓ - RST-3 Impulsivity n/a n/a n/a ↓ - GT ↓ - GT ↓ - GT ↓ - DR2 ↓ - DR2 Cognitive Impulsivity n/a TT15 WCST (errors) ↓ - TMT ↓ - ↓ - TT15 ↓ - ⟷ - LL5, Cognitive ↓ - WCST WCST ↓ - Flexibility — - WCST — - ↓ - COWAT, ↓ - COWAT, — - COWAT - R n/a n/a rect) — - ST — - FAT — - PVT — - PVT ↓ - DSST Attention — - WAIS- — - ↓ - Q1 (cor ↓ - DR2, Q1 ↓ - WAIS-III ↓ - n/a n/a n/a n/a n/a n/a SAVF CVLT Memory Long Term Long Term ↓ - WSMR, ↓ - — - RRLET, — - RRLET, n/a n/a Methadone Maintenance Papers SAVF CVLT, WSLT, WSLT, SOMT, SOMT, RRLET, RRLET, Memory ↓ - TT15 ↓ - — - 2BT ↓ - BVRT ↓ - BVRT Short Term Short Term ↓ - WMSR, ↓ - — - BVRT, — - BVRT, n/a — - SILS — - SILS — - MAT Intelligence ↓ - WAIS-III ↓ - ↓ - WAIS-III ↓ - ↓ - WAIS-III ↓ - — - WAIS-III - — 30 21 29 19 21 25 23 Type and Type Number (n) (See Demo - graphic Table) graphic Control Group Matched CON 30 18 23 18 15 30 24 27 Outcome Group and Number (n) 2011 2000 2002 2006 2004 2004 2006 Article Fuller et al. Darke et al. Soyka et al. Rotherham- Pirastu et al. Prosser et al. Mintzer et al. Lin et al. 2012 mance Test; WAIS-R Weschler Adult Intelligence Scale - Revised; SS= Stop Signal; PES= Post Error Slowing; FDT= Five Digit Test; Ruff= Ruff Selective Attention Test; CTT= Color Test; Attention Selective Ruff Ruff= Test; Digit FDT= Five SS= Stop Signal; PES= Post Error Slowing; Adult Intelligence Scale - Revised; Weschler WAIS-R Test; mance BNT= Making Test; TMT= Trail Card Sorting Task; Wisconsin WCST= Association Test; Controlled Word Oral COWAT= Test; Vigilance VIG= Attention Test; COG= - Affec Test; Trails AGN= Test; Tapping FTT= Finger Test; CGT= Cambridge Gambling Test; Perception; GT= Gambling Tachistoscopic TAVT= Test; Fluency Verbal VFT= Test; Boston Naming Matrices System (MAT= Test Act React ART-2020= AM=Austine Maze; SOC=Stockings of Cambridge; Test; Figure Complex RCFT= Rey Test; Go/No Go; DT=Determination tive Measuring the TT15=Test Ability, Structuring Visual for Test LL5= Attention Flexibility, for Test intelligence), Q1=Attention Under Monotonous Circumstances, FAT= (non-verbal Test Test (PVT= Peripheral Act React ART-90= Test); Stress Environment, RST3= Reactive in a Dynamic Driving DR2= Decision and Reaction Behaviour Ability, Perception Traffic-specific Test, DR2= Decision and Reaction Stress Attention Under Monotonous Circumstances, RST3= Reactive Q1= Ability, Perception Traffic-specific Measuring the TT15=Test Test Vision Selective Ruff=Ruff Test; Trails CTT=Color Test; Learning Verbal Auditory RAVLT=Rey Test; Fluency Verbal VFT= Test; BNT= Boston Naming in a Dynamic Environment); Behaviour Available. n/a= Not Test; VIG=Vigilance Perception; TAVT=Tachistoscopic DT=Determination Test; Attention Test; COG= Attention Test; Abbreviations: n= Number of Participants; MMT= Methadone Maintenance Programme; CON= Healthy Control; ABST= Protracted Abstinence; BUP= Buprenorphine Maintenance; Abstinence; BUP= ABST= Protracted Control; MMT= Methadone Maintenance Programme; CON= Healthy n= Number of Participants; Abbreviations: Memory Scale Weschler WSMR= Test; Adult Reading National NART= Test; = Matrices Scale; MAT Institute of Living Adult Intelligence Scale; SILS= Shipley Weschler WAIS-III= Test; Sequence Learning Word WSLT= Test; SOMT= Six Object Memory Test;; Retention Visual Benton BVRT= Test; Back Two 2BT= Test; Test; Learning Figure Complex RCFT= Rey - Revised; Verbal Auditory Rey RAVLT= Test Learning Verbal Californian CVLT= Fluency; Verbal Association of Semantic SAVF= Test; RRLET= Remote and Recent Life Event CPT=Continuous Perfor Test; ST= Stroop Test; Animals; DSST= Digit Symbol Substitution Fruits and Assessment of Neurological Status; FAS= Repeatable Battery for the RBANS= Schindler et al. Articles included, comparison groups and neurocognitive domain 6. Articles included, comparison groups and neurocognitive Table

- 43 - Heroin Addiction and Related Clinical Problems 20(5): 35-49 - n/a n/a n/a n/a n/a n/a n/a n/a ↓ - SOC n/a n/a n/a n/a n/a Time) Reaction (Phase 1) (Phase 2) (Phase 3) — - AGN ↓ - RST-3 ↓ - RST-3 ↓ - RST-3 — - RST3 — - RST-3 — - RST-3 ↓ - DT (Mean n/a n/a n/a ↑ - GT — - GT ↑ - DR2 ↓ - CGT — - DR2 — - DR2 n/a n/a VFT TT15 TT15 - BNT, - BNT, ⟷ - LL5, ⟷ - LL5, ↓ - TT15 — - TAVT — - WCST — - WCST n/a n/a n/a FAT - Ruff - Ruff ↓ - Q1 ↓ - PES ↑ - DR2 — - Q1, — - SS , (Correct) ↓ - CTT2 — - PVT incorrect) — - COG ↓ - Q1 (% - DR2, FAT - DR2, FAT parison Group) n/a n/a n/a n/a n/a n/a n/a n/a n/a Buprenorphine Papers n/a n/a n/a n/a n/a RBANS ↓ - TT15 ↓ - BVRT — - BVRT ↓ - RAVLT, ↓ - RAVLT, n/a n/a n/a n/a — - MAT — - MAT ↓ - NART ↓ - WAIS-III — - WAIS-III 28 64 21 34 25 30 20 90 Papers (See Demo - Comparison graphic Table) Matched CON 15 29 65 18 18 22 18 20 11 (Per- 11 (Per- protocol) Group (n) No Significant Difference in score. (Outcome Group vs. Control or Com - Score (p<0.05), ↑ Significant Higher ⟷ No Difference ↓ Significantly Lower Comparison Key: 2004 2009 2006 2011 2006 2007 al. 2014 al. 2011 Soyka et al. Soyka Pirastu et al. Pirastu et al. Shmygalev et Shmygalev Baewert et al. Baewert Messinis et al. mance Test; WAIS-R Weschler Adult Intelligence Scale - Revised; SS= Stop Signal; PES= Post Error Slowing; FDT= Five Digit Test; Ruff= Ruff Selective Attention Test; CTT= Color Test; Attention Selective Ruff Ruff= Test; Digit FDT= Five SS= Stop Signal; PES= Post Error Slowing; Adult Intelligence Scale - Revised; Weschler WAIS-R Test; mance BNT= Making Test; TMT= Trail Card Sorting Task; Wisconsin WCST= Association Test; Controlled Word Oral COWAT= Test; Vigilance VIG= Attention Test; COG= - Affec Test; Trails AGN= Test; Tapping FTT= Finger Test; CGT= Cambridge Gambling Test; Perception; GT= Gambling Tachistoscopic TAVT= Test; Fluency Verbal VFT= Test; Boston Naming Matrices System (MAT= Test Act React ART-2020= AM=Austine Maze; SOC=Stockings of Cambridge; Test; Figure Complex RCFT= Rey Test; Go/No Go; DT=Determination tive Measuring the TT15=Test Ability, Structuring Visual for Test LL5= Attention Flexibility, for Test intelligence), Q1=Attention Under Monotonous Circumstances, FAT= (non-verbal Test Test (PVT= Peripheral Act React ART-90= Test); Stress Environment, RST3= Reactive in a Dynamic Driving DR2= Decision and Reaction Behaviour Ability, Perception Traffic-specific Test, DR2= Decision and Reaction Stress Attention Under Monotonous Circumstances, RST3= Reactive Q1= Ability, Perception Traffic-specific Measuring the TT15=Test Test Vision Selective Ruff=Ruff Test; Trails CTT=Color Test; Learning Verbal Auditory RAVLT=Rey Test; Fluency Verbal VFT= Test; BNT= Boston Naming in a Dynamic Environment); Behaviour Available. n/a= Not Test; VIG=Vigilance Perception; TAVT=Tachistoscopic DT=Determination Test; Attention Test; COG= Attention Test; Abbreviations: n= Number of Participants; MMT= Methadone Maintenance Programme; CON= Healthy Control; ABST= Protracted Abstinence; BUP= Buprenorphine Maintenance; Abstinence; BUP= ABST= Protracted Control; MMT= Methadone Maintenance Programme; CON= Healthy n= Number of Participants; Abbreviations: Memory Scale Weschler WSMR= Test; Adult Reading National NART= Test; = Matrices Scale; MAT Institute of Living Adult Intelligence Scale; SILS= Shipley Weschler WAIS-III= Test; Sequence Learning Word WSLT= Test; SOMT= Six Object Memory Test;; Retention Visual Benton BVRT= Test; Back Two 2BT= Test; Test; Learning Figure Complex RCFT= Rey - Revised; Verbal Auditory Rey RAVLT= Test Learning Verbal Californian CVLT= Fluency; Verbal Association of Semantic SAVF= Test; RRLET= Remote and Recent Life Event CPT=Continuous Perfor Test; ST= Stroop Test; Animals; DSST= Digit Symbol Substitution Fruits and Assessment of Neurological Status; FAS= Repeatable Battery for the RBANS= Baldacchino et Schindler et al. Liao et al. 2014 Articles included, comparison groups and neurocognitive domain 6. Articles included, comparison groups and neurocognitive Table

- 44 - D. Hill et al.: Comparing neurocognitive function in individuals receiving chronic methadone or buprenorphine for the treatment of opioid dependence: A systematic review. cognitive domain and compared with healthy con- nificantly impaired (p<0.05) relative to healthy con- trols [3, 23, 25, 28, 30, 34]. There was however no trols in both methadone and buprenorphine cohorts. significant difference found in cognitive impulsivity Four of the identified studies found a significant im- between buprenorphine maintained individuals and pairment (p<0.05) when methadone maintained indi- healthy controls [25, 30, 34]. viduals were compared to healthy controls [3, 8, 25, 27]. Three of the studies comparing buprenorphine 13.5.2. Cognitive flexibility to healthy controls showed significant impairment In the three studies directly comparing metha- (p<0.05) in short term memory [21, 25, 34]. done to buprenorphine treatment there were no sig- nificant differences in cognitive flexibility scores 14. Discussion reported. However cognitive flexibility was more fre- quently reported as significantly impaired (p<0.05) in 14.1. Summary of findings patients maintained on methadone, than those on bu- prenorphine when compared to healthy controls. Four Buprenorphine maintained individuals demon- of the ten selected studies [8, 23, 25, 34], showed im- strate reduced impairment of cognitive impulsivity pairment for methadone maintained individuals com- compared to those maintained on methadone. This pared to healthy control. In comparison only one of was the most reliable conclusion drawn from the re- five studies that reviewed cognitive flexibility in bu- sults as a significant difference was observed both in prenorphine treated individuals identified impairment papers directly comparing methadone with buprenor- [34],with the other 4 papers finding no impairment in phine and comparisons with control groups. this domain in comparison to healthy controls. The attention domain shows that buprenorphine patients are less impaired than patients on metha- 13.5.3. Motor impulsivity done in the direct comparative studies. However, in In the three papers conducting the direct com- the articles comparing methadone or buprenorphine parison between methadone treatment and buprenor- to healthy controls, both treatments were shown to phine treatment, there were no reported differences in cause equal impairment. The differences between the motor impulsivity. However in the studies looking buprenorphine and methadone in relation to the at- at comparison to healthy controls, both methadone tention domain could be due to the increased sedation and buprenorphine treated cohorts exhibited impair- experienced with a full opioid agonist in comparison ments in motor impulsivity when compared to healthy to a partial agonist [29]. controls [32, 34]. Cognitive flexibility was reported to be sig- nificantly less impaired (p<0.05) in buprenorphine 13.5.4. Attention maintained cohorts than methadone when compared One measure (DR2) in relation to the attention to healthy controls. However this was not replicated domain found buprenorphine individuals were less in articles that directly compare the domain between impaired than methadone in the papers comparing methadone or buprenorphine maintained patients. treatments against each other directly [1]. However the same paper found no significant difference on two 14.2. Significance other assessments of attention (Q1 & FAT). Soyka [34] also found no significant difference in attention As the literature search demonstrated, using the test scores when comparing methadone to buprenor- strict criteria employed in this review, there is little phine. Five articles that compared methadone to evidence available currently to directly compare both healthy controls identified a significant impairment in buprenorphine and methadone maintenance therapies attention [8, 19, 23, 30, 34] with four buprenorphine in relation to neurocognitive function. The articles comparison papers showed an impairment (p<0.05) that have been included highlights that there are dif- in the attention domain [30, 21, 32, 34]. ferences between treatments and these may provide benefits for patients increasing the success of their 13.5.5. Short term memory treatment. However there is a lack of consistency in From the two direct comparison articles between the tests employed in the research to date. methadone and buprenorphine cohorts that reported on Short Term Memory, there was no significant dif- 14.3. Strength and Limitations ference found [25, 34]. Short term memory was sig-

- 45 - Heroin Addiction and Related Clinical Problems 20(5): 35-49

The literature search found no Randomised tems. A large degree of heterogeneity existed between Control Trials (RCTs) and all articles included are studies, e.g. mean opioid use ranged from six months case-control studies. The lack of randomized blinded to over fifteen years between methadone cohorts [25, studies limits result reliability due to the possibility of 28]. Other demographics followed similar trends, e.g. increased bias [15]. Due to methodological difficul- mean buprenorphine dose ranged from 6.78mg [21] ties, patients were not blinded to their interventional to 13.4mg [1]. There were significant differences re- group with only two articles used a single blinded ported between comparable populations within indi- methodology [1, 30]. vidual selected studies. There were discrepancies in Articles were excluded if they included indi- age, gender and educational attainment between pop- viduals affected by simultaneous illicit drug use or ulations [3, 20, 25, 27]. Significant differences in the medication that might affecting neurocognitive func- completed educational years could have a profound tion to minimise the effect of compounding factors. effect on the neurocognitive test scores reported by Most articles used different definitions of simulta- these groups in the intelligence domain. Matching neous drug use, showing a differing application of controls based on an estimate of their pre-morbid in- exclusion criteria between papers. Some conducted telligence (IQ) will reduce this bias. urinalysis over a period of months and others allowed The time between administration of the mainte- for positive urine test if the individual was not expe- nance dose and conducting the neurocognitive assess- riencing acute effects. The most commonly identified ments needs to be considered as variations in the time additional substance was benzodiazepines, which are delay may have different impairments on neurocogni- known to have effects on neurocognitive function [8, tive function due to the acute sedative effects of the 28, 34, 37]. These mitigate the acute effects of ben- treatment modality used [5]. One paper analysed the zodiazepines on the result of the neurocognitive tests difference in scores between peak levels (1.5 hours and question the cause of any reported neurocogni- after administration) and trough levels (20 hours after tive impairments in these studies. This becomes more administration) for both methadone and buprenor- important when comparing buprenorphine due to the phine. The combined results showed that individuals limited number of papers available covering this area. at trough levels performed significantly worse on the The less robust exclusion criteria used in Soyka’s [34] RST3 assessment of motor impulsivity [1]. In this re- paper reduces the reliability of the results from this view, the majority of studies included did not specify study. The results mirror those from the other three the time between administration of the last dose and papers making this comparison [1, 25, 30], reducing neuropsychological test which impacts on repeat- the likelihood that benzodiazepine use caused these ability and result interpretation. The large variation results. However it must be noted that benzodiazepine in duration of action means that individuals main- use is frequent amongst active heroin users, as well as tained on different opioids may experience the onset those enrolled in maintenance opioid agonist replace- of withdrawal symptoms, at different times which ment programmes. [16]. None of the studies consid- may affect the neurocognitive assessment. Thus, if ered the potential neurocognitive sequelae of chronic the assessment is conducted at the same time post ad- nicotine and/or cannabis use in this treatment seeking ministration; the methadone maintained cohort may population. collectively experience withdrawal symptoms earlier The selected articles sample size lack consist- than the buprenorphine maintained cohort in direct ency across the five studies investigating buprenor- comparison studies. Some studies screened for opioid phine. They included 84 individuals, contrasting to withdrawal at the time of testing ensuring participants 279 methadone maintained individuals across 10 were not in withdrawal [30, 37], whilst others con- selected studies. Potential root causes of this differ- ducted assessments well within the duration of action ence in articles identified are; (a) the limited period of treatments [3, 17]. of time that buprenorphine preparations have been Multiple different cognitive domains are de- licensed for use in opioid dependence (mid-1990s scribed and used in the literature. For the purposes of for buprenorphine as opposed to methadone’s avail- this enquiry the domains set out by Baldacchino et al. ability since the 1960s) and (b) methadone being the [4] were used. preferential use of methadone as a first line treatment Until a standardised system of domains and as- to opioid dependence [39]. sessment exists there will always be discrepancies The published articles are using small numbers and variations in the tests used and subsequent result studying individuals attending diverse treatment sys- classification, damaging the integrity of conclusions

- 46 - D. Hill et al.: Comparing neurocognitive function in individuals receiving chronic methadone or buprenorphine for the treatment of opioid dependence: A systematic review. drawn from these studies heavy machinery. However for some patients a degree It is important to consider compounding factors of cognitive impairment may be beneficial. E.g. states affecting neurocognition, including head injury, alco- of increased boredom and “problematic thoughts that hol use and overdose. Regression analysis was used can increase the risk of relapse” [35]. This observation by some papers to correct for variations of these fac- should be taken with extreme caution as this system- tors. The rigorous inclusion criteria applied to papers atic review has highlighted the urgent need to conduct is a strength of the review, and provides clear results methodologically sound, unbiased and well powered comparing methadone/buprenorphine to a control or studies to be able to identify better significant corre- each other. This allowed a large array of data to be ex- lation between observed neurocognitive impairments tracted from included papers. The majority of papers and type of agonist opioid treatment used with clini- did not directly compare methadone to buprenorphine cal practice. and further research into this area could address this factor. 15. Conclusions Decreased neurocognitive test scores for both treatments were demonstrated in comparison to In conclusion, this systematic review of pub- healthy controls. The comparison of each treatment lished literature into the neurocognitive function of option against healthy controls allows some infer- individuals on methadone or buprenorphine mainte- ence to the effects of each treatment on the neuro- nance treatment shows that there are fewer than ex- cognitive impairments experienced. The differences pected reports of impaired neurocognitive function observed between the neurocognitive impairment and when patients are prescribed buprenorphine in com- the prescribed treatment modality validates the need parison to methadone. There is a need for more rigor- for further direct comparison research between the ous and larger well matched longitudinal studies to treatment options. reduce the variances caused due to opioid withdrawal influencing the result and to measure neurocognitive 14.4. Clinical relevance impairment of pharmacologically maintained indi- viduals over time. The relevance of this review can be demonstrat- ed in the application to driving ability. It is illegal to References drive whilst impaired under the influence of any drug. England and Wales have a blood concentration limit 1. Baewert A., Gombas W., Schindler S. D., Peternell- for methadone of 500mcg/L of blood [9]. Buprenor- Moelzer A., Eder H., Jagsch R., Fischer G. (2007): phine has no defined concentration limit. Therefore Influence of peak and trough levels of opioid maintenance if supported by further research and one treatment is therapy on driving aptitude. Eur Addict Res. 13(3): 127- 135. proven to provide improved scores this could influ- 2. Bahrick H. P., Bahrick P. O., Wittlinger R. P. (1975): ence treatment choice. Therefore this review helps to Fifty Years of Memory for Names and Faces: A Cross- identify better the current knowledge base when mak- Sectional Approach. J Exp Psychol Gen. 104(1): 54-75. ing clinical decisions on choice of opioid used for 3. 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Acknowledgements The authors would like to acknowledge the Medical School at the University of St Andrews for their support in preparing the article.

Role of the funding source Financial support for the implementation of this re- view was provided by internal funds.

Contributors The authors contributed equally to this review.

Conflict of interest Authors declared no conflict of interest.

Received December 7, 2017 - Accepted March 1, 2018

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