Methadone Maintenance Treatment and Cognitive ...

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Methadone Maintenance Treatment and Cognitive Function: A Systematic Review Grace Y. Wang*,1,2, Trecia A. Wouldes3 and Bruce R. Russell1,2 1

School of Pharmacy, 2Centre for Brain Research, 3Department of Psychological Medicine, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand Abstract: Methadone has been used as a pharmacotherapy for the treatment of opiate dependence since the mid-1960s. Many studies examining the benefits of methadone maintenance treatment (MMT) for opiate dependence have documented a significant reduction in both criminal behavior and the use of other opiates. Nevertheless, emerging evidence suggests that MMT may impair cognitive function. However, it is unclear as to the part methadone dose, duration of MMT or plasma level may play in any observed deficits. Given the large number of people enrolled in MMT world-wide and the potential for deficits in cognitive function, a systematic review of the research investigating the association between MMT and cognitive function seemed warranted. The following databases were searched with a combination of free-text and thesaurus terms (methadone AND cognition): MEDLINE In-Process, EMBASE, PsycINFO and EBM Reviews-Cochrane Central Register of Controlled Trials. Seventy-eight articles were retrieved of which 35 met the inclusion criteria. The majority of research suggests that MMT is associated with impaired cognitive function and that deficits extended across a range of domains. However, caution is required when interpreting these results due to the methodological limitations associated with many studies. Further research that includes a combination of psychological and physiological measures within well-controlled group comparison studies is required to more accurately assess which cognitive domains are affected.

Keywords: Methadone maintenance, opiate dependence, cognition, neuropsychological test, systematic review. 1. INTRODUCTION Methadone has been used as a pharmacological treatment for opiate dependence since the mid-1960s. It is a synthetic opioid that when prescribed consists of two enantiomers present in equal amounts of a racemic mixture: L-methadone and D-methadone. L-methadone is the pharmacologically active isomer, while D-methadone is inactive but retains some pharmacological effects, such as its antitussive activity. Methadone elicits its pharmacodynamic effects by binding to mu opiate receptors as do other opiates, but it has a much slower onset and longer duration of action, partly due to its oral absorption [1, 2]. Methadone is given as an oral dose and is rapidly absorbed (being detectable in plasma 30 minutes after administration) with an elimination half-life of 24-36 hours. Normally, the peak plasma concentration occurs 2.5-4 hours after dosing, with a plasma trough level occurring 24 hours after the last dose [3]. Therefore, methadone has minimal euphoric effects compared to other opiates and is able to negate the aversive effects associated with acute opiate withdrawal [4]. However, the dose required to effectively block withdrawal varies and is dependent on individual physiological variables, such as metabolic rate and the degree of tolerance developed [5]. A national survey of MMT in the United Kingdom (UK) found the maximum daily dose of methadone prescribed for maintenance treatment ranged from 9 to 325 mg, with a mean dose of 116 mg [6]. An initial maintenance dose generally starts with 2040 mg daily and gradually increases, usually by 10 mg every *Address correspondence to this author at the School of Pharmacy, The University of Auckland, Private Bag 92019, Auckland, New Zealand; Tel: +64 9 923 2556; Fax: +64 9 3677192. E-mail: [email protected] 1874-4737/13 $58.00+.00

4-7 days [4]. Research has shown that patients who take a dose of 80 mg/day or greater, and who maintain average plasma concentrations of over 400 ng/mL, show little additional drug use and good social stability [7, 8]. However, doses exceeding 200 mg/day are sometimes required for successful treatment [9, 10]. Unfortunately there is no clear agreement about the plasma level of methadone required to achieve a good response. The benefits of MMT have been demonstrated by many studies. For example, MMT has been shown to effectively reduce the use of other drugs, criminal activity, mortality, and the transmission of HIV and other blood-borne pathogens [11-14]. In addition, MMT is more cost-effective than giving placebo or not treating opiate dependence [15]. Consequently, MMT is now the most common treatment for opiate addiction in many countries, including the United States (US), Australia, the UK and New Zealand (NZ) [16, 17]. In the US 235,836 people received MMT for opiate dependence during 2005 [18]; and in the UK, 15,931 patients attended 157 centers for MMT during 2005 [6]. Estimates for NZ and Australia suggest there are 4,300 patients in NZ [17] and 32, 200 in Australia receiving MMT [19]. It was found that chronic substance abuse (opiate use) induces progressive changes in central brain regions related to reward, memory, learning, cognitive control and motivation [20-22]. The regions of the brain affected by drug addiction are interdependent and overlapping, and include the nucleus accumbens, ventral pallidum (reward), amygdala and hippocampus (memory and learning), the prefrontal cortex and dorsal anterior cingulate cortex (cognitive control), and the orbital frontal cortex (motivation) [21, 22]. These regions are affected by cellular changes which are © 2013 Bentham Science Publishers

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Current Drug Abuse Reviews, 2013, Vol. 6, No. 2

thought to disrupt neuronal circuitry. For example, it was found that chronic exposure to opiates decreases neurogenesis in the hippocampus and potentially interferes with cognitive function [22-24]. An fMRI study of chronic heroin users examined resting state networks and found increased functional connectivity between the nucleus accumbens, the anterior cingulate cortex and orbital frontal cortex and also between the amygdala and orbital frontal cortex [21]. Disrupted cerebo-cerebellar circuitry related to verbal working memory has also been identified in patients undertaking MMT [25]. When combined, much of the evidence suggests abnormal brain function is associated with cognitive demand in patients undertaking MMT. Given that a significant number of people are enrolled in MMT, it is essential that its effects on cognitive function are clearly described. A comprehensive investigation of the effects of MMT on cognitive function would provide detailed information about the long-term effects of methadone and enable improved clinical interventions for those who suffer from opiate addiction. Furthermore, it would inform prescribing practice surrounding dose-related effects. The main objective of this systematic review is to identify relationships between MMT, dose, duration of treatment and cognitive function. 2. METHODS 2.1. Data Sources and Strategy Studies were identified using searches of MEDLINE (OVID 1950-2012), EMBASE (1980-2012) PsycINFO (1806-2012) and Cochrane CENTRAL. Search terms were a combination of free-text and thesaurus terms (methadone AND cognition), such as “methadone maintenance” and “methadone”, combined with cognition-related terms such as “cognition”, “cognitive function” “cognitive defect”, “cognitive impairment”, “memory”, “attention”, “executive function” and “perception”. The different search strings were used to maximize the relevance of the returned results when searching in different databases (Appendix 1). Peer-reviewed journals and English language limits were used. 2.2. Study Selection Further inclusion/exclusion criteria were developed to assess the relevance and quality of studies. Research was selected if it met the following criteria: 1) the study population consisted of individuals with opiate dependence undertaking methadone treatment; 2) cognitive tests were used as study outcome measures; and 3) information on cognitive function related to methadone was clearly presented. The search strategy identified 32 publications from MEDLINE In-Process, 19 from PsycINFO, 20 from EMBASE, and 7 from Cochrane Central. Of the 78 articles, 38 were duplicates and 5 were excluded because of one or more of the following criteria: case study (n=1), the study did not focus on cognitive functions related to methadone (n=3), unavailable electronically (n=1). Thirty-five publications met the inclusion criteria and were included in this review. Checking the references of all publications did not result in the inclusion of any further studies.

Wang et al.

3. RESULTS 3.1. Data Extraction From the studies included, methodological characteristics (study population, study design and data analysis), participant characteristics (age, duration and dose of MMT) and data regarding cognitive performance associated with MMT were extracted and are summarized into three groups: cross-sectional studies (Table 1); randomised controlled trials (RCTs) (Table 2); and longitudinal studies (Table 3). All patients taking MMT in the reviewed studies were assumed to be in the maintenance phase unless reported otherwise. 3.2. Methodological Quality The methodological quality of the selected studies was assessed using a standardised checklist for observational epidemiological studies developed by Sanderson et al. [26]. The checklist is divided into different domains including selection of study participants, description of measurement, control of confounding variables, statistical methods and conflicts of interest. Criteria for quality assessment are shown in Table 4. For each study a total quality score was obtained by summing the positive score on the item of the quality assessment list. Overall, 43% of the studies scored 7 [27-42], 46% scored between 5 and 6 [31, 43-57] and 11% scored between 2 and 4 [58-61]. Of the 35 studies, 23 (66%) stated inclusion and exclusion criteria for the selection of participants, which generally excluded patients with a history of neurological disease, psychiatric illness or brain injury; 29 (83%) described methods used to identify and assign participants to different groups, based on self-report, clinical records and urine testing; 35 (100%) clearly described outcome measures and 5 (14%) reported significant differences in demographic factors between those taking methadone and healthy control subjects. The demographic features included differences in age [54, 57, 61], employment status [32] and years of education [38]. Statistical techniques were used to control for the confounding variables in question. All but two clearly described the statistical methods used for primary analyses [60, 61]. It is noted that the methodological appraisal reported here does not consider performance bias (i.e., blinding) or attrition bias (i.e., drop-out reporting), since few studies mentioned them. 3.3. Study Characteristics 3.3.1. Participants and Comparison Groups Of the 35 studies, 15 were from the US, 16 were from European countries, 2 were from Australia and 2 were conducted in Iran. The performance of patients undertaking MMT was compared with a variety of control groups including individuals with no history of substance dependence (i.e., healthy controls) and/or drug users who had used a variety of substances, including opiates, amphetamines and alcohol. The age of subjects receiving MMT ranged from 18-55 years. Subjects undertaking MMT and ex-opiate users were generally recruited from outpatient clinics, drug rehabilitation groups or hospitals and were paid

Methadone Maintenance Treatment and Cognitive Function

Table 1.

Study

Gordon, 1970 US

Cross-Sectional Studies of MMT Targeting Cognitive Function

MMT Groups

(1) 18 males; (2) 9 females, MMT for at least 1 year, average dose 100 mg

Comparison Groups

(3) and (4) 2 groups of males heroin abstinent for min of 14 and 4 days respectively; (5) 20 healthy males; (6) 9 females

Gritz et al., 1975 US

(1) 10 males, MMT for a median of 5 months, mean dose 65 (range 35-85) mg

(2) 10 males heroin abstinent

(1) 24 employed males; Appel &Gordon, 1976 US

(2) 24 unemployed males, MMT for mean 2.5 years (range 11 months-8 years), dose 80-120 mg (1) 24 employed males;

Appel, 1982 US

(2) 24 unemployed males, repeat information from Appel and Gordon’s (1976) paper

Darke et al., 2000 Australia

(1) 18 males and 12 females, MMT for median of 60 (5192) months, mean dose 78.6±43.8 mg

Specka et al., 2000 Germany

Kornreich et al., 2003 Belgium

Davis et al., 2002 US


(1) 35 males and 19 females, MMT for mean 18 (range 448) months, median 11 months, mean dose 93 (range 10240) mg

(1) 25 males and 5 females, MMT for maximum of 18 months, dose was not reported

(1) 15 subjects (gender was not reported), MMT for mean 30 (range 8120) weeks, mean dose 32.5±11.4 (range 15-60) mg

(3) 24 heroin abstinent employed; (4) 24 healthy employed subjects

(3) 24 heroin abstinent employed; (4) 24 healthy employed subjects

Cognitive Domains Not Impaired by MMT or Improved by MMT

Cognitive Domains Impaired by MMT

Study Limitations

Faster reaction times in both males and females undertaking MMT than healthy controls during both simple and complex psychomotor tasks

Only the latency to a correct response was recorded; preexisting conditions (e.g., head injury), motivation and time of methadone intake were possible confounding variables

No difference in immediate memory span, object and story recognition, tests of attention and speed; no doserelated effect

Tests of learning and immediate recall

Small sample size; male only; lack of healthy control group; MMT group had much longer history of heroin addiction than the comparison group

No difference in psychomotor reaction times between employed patients undertaking MMT, heroin abstinent and healthy controls

slower reaction times in the unemployed MMT group, but it was within the normal range

Males only; brief speed test; preexisting conditions (e.g., head injury) and motivation were possible confounding variables Males only; preexisting conditions (e.g., head injury), education and motivation were possible confounding variables

No difference in response latencies, overall accuracy or commission errors on sustained attention tasks

(2) 30 healthy subjects, matched for age, gender and education

Information processing, visual memory, verbal memory and problem solving; alcohol dependence and drug overdose explained some of the variability in cognitive function

Poly-drug use in the MMT group and recreational drug use in the control group were possible confounding variables

(2) 54 healthy subjects, matched for age, gender and education

Attention, visual perception, visual orientation and complexchoice reaction tasks—may be better explained by age, gender and educational attainment than MMT

Poly-drug use and pre-existing conditions (e.g., head injury) were possible confounding variables

Emotional facial expression recognition; effects could be due to toxic effect of chronic opiate use or pre-existing emotional intelligence deficit

Age, gender and education were possible confounding variables

Word fluency; 9/15 (60%) of the MMT group having a score of two or more standard deviations below the published norm range on two or more measures

Age, gender and education were possible confounding variables; uncorrected for multiple comparisons

No difference in visual structuring and reaction time; tracking tests were more accurate but slower

(2) 22 males and 8 females opiate abstinent; (3) 18 males and 12 females alcohol abstinent; (4) 26 males and 4 females opiate and alcohol abstinent; (5)16 males and 14 females healthy volunteers

(2) 16 opiate abstinent; (3) 14 controls via psychological service for pain management

No difference in sustained attention, spatial learning, verbal learning, spatial and verbal recall, verbal fluency, IQ and flexibility of thinking

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Wang et al.

(Table 1) contd…..

Study

Mintzer et al., 2002 US

Schindler et al., 2004 Austria

MMT Groups

Comparison Groups



Study Limitations

(1) 7 males and 11 females, MMT for 45.4±9.5 months, mean dose 67.2±24.2 mg

(2) 21 healthy subjects, matched for age, gender, education, race, employment and IQ

No difference in time estimation, conceptual flexibility and long-term memory

Psychomotor speed, working memory, decision-making, metamemory and inhibitory attention

Poly-drug use and head injury were possible confounding variables; uncorrected for multiple comparisons


(2) 15 patients undertaking buprenorphine treatment; (3) a sample of 14,5000 people who previously completed the test for the Austria Road Safety Board, matched for age, gender and IQ

No difference in scanning, visuospatital abilities and attention under monotonous circumstances; faster reaction and higher percentage of incorrect reactions.

Slower decision and reaction time when driving in a dynamic environment

Specific traffic psychology test; poly-drug use was a possible confounding variable

No difference in overall decision-making

More risky decision making when failed in the previous trials

Poly-drug use was a possible confounding variable

(2) 26 exopiate/amphetamine users; Ersche et al., 2005 UK

Mintzer et al., 2005 US

Verdejo et al., 2005 Spain

Pirastu et al., 2006 Italy

Prosser et al., 2006 US

Rapeli et al., 2007 Finland

Loeber et al., 2008 Germany

(1) 20 males and 7 females, duration of MMT was not reported, mean dose 45±17.8 (range 20-80) mg

(3) 12 current heroin users; (4) 24 current amphetamine users; (5) 27 healthy subjects, matched for age, gender and IQ

(1) 18 subjects repeat information from Mintzer et al. (2002)

(2) 20 opiate abstinent; (3) 21 healthy subjects from Mintzer et al. (2002)

Opiate abstinent group performed better than the MMT group

Poly-drug use and head injury were possible confounding variables; uncorrected for multiple comparisons

(1) 18 males, MMT for 38.66±41.64 months, mean dose 83.82±29.61 mg

(2) 23 heroin abstinent, matched for age, education, employment status and IQ

Processing speed, visuospatial attention, cognitive flexibility, working memory and analogical reasoning

Absence of healthy comparison group; uncorrected for multiple comparison

(1) 29 males and 1 females, MMT for at least 1 year, mean dose 66±7.45 mg

(2) 18 patients undertaking buprenorphine treatment; (3) 21 healthy subjects, matched for age and gender

Decision making, visual memory and cognitive flexibility

Uncorrected for multiple comparison; IQ was a possible confounding variable

Verbal intelligence, perception, memory and divided attention with response inhibition. Similar to ex-MMT, apart from better visuospatial memory; outcome was not dose or year of opiate userelated

Brief paper and pencil test battery; age was a possible confounding variable

Working memory, verbal memory and attention; impairment may be related to high dose ( 67 mg)

Use of psychoactive medication and length of MMT were possible confounding variables

Vigilance and sustained attention, selecting and focusing of sensory stimuli, response selection and control, psychomotor speed and memory; impairment was doserelated (+)

Head injury was a possible confounding variable

(1) 23 males and 6 females, MMT for 6.44±7.1 years, mean dose 73.39±23.1 mg

(1) 7 males and 9 females, MMT for 14.3±7.4 days, mean dose 53.4±18.6 mg

(1) 23 males and 7 females, MMT for 4.3±4.1 years, mean dose 74.3±30.9 mg

(2) 27 ex-MMT patients, undergone methadone detoxification; (3) 29 healthy subjects matched for gender and ethnicity

(2) 17 patients undertaking buprenorphine treatment; (3) 17 healthy subjects matched for age and gender

(2) 24 patients undertaking buprenorphine; (3) normative control samples



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(Table 1) contd…..

Study

Clair et al., 2009 UK

Prosser et al., 2009 US

Soyka et al., 2009 Germany

Fadardi & Ziaee, 2010 Iran


MMT Groups

Comparison Groups

(1) 21 males, MMT for at least 1 year, mean dose 64 mL

(2) 21 heroin abstinent; (3) 22 healthy unemployed controls matched for age, IQ and employment status

(1) 9 males and 1 females, MMT for 4.72±5.09 years, mean dose 76±20.11mg

(2) 13 opiate abstinent; (3) 14 healthy subjects matched for gender and ethnicity

(1) 26 males and 9 females, MMT for at least 30 days, dose 62.8±38.8 mg;

(1) 8 males and 16 females, duration was not reported, mean dose 56 (range 18-120) mg


Aggressive interpretative bias; bias was dose and duration-related (+)

Sustained attention

(2) 71 healthy subjects (54% males)

(2) 22 patients undertaking buprenorphine treatment; (3) 20 heroin users; (4) 25 healthy subjects matched for age and gender

No difference in visual perception, divided attention, selective attention, reactivity and stress tolerance

for their participation. It is noted that 9 studies included comparison groups treated with buprenorphine for opiate addiction [31, 34, 38, 42, 43, 52, 53, 55, 62] and one include people treated with levo-alpha-acetylmehtadol (LAAM) [59], which have been introduced into clinical practice as alternatives to methadone. 3.3.2. Measures of Cognitive Function A broad range of tests were used to explore the function of cognitive domains, including psychomotor processing speed, memory, attention and verbal learning. The effects of dosage, length of treatment and variation in methadone plasma concentration on cognitive performance were also explored. 3.3.3. Methodologies employed Of the 35 studies, 22 (63%) employed a cross-sectional design, which measures patients at a single time-point [28, 29, 31-36, 40, 41, 44, 47, 50, 52, 54, 55, 57, 58, 60-63] (Table 1); 5 (15%) employed longitudinal designs [38, 43, 48, 56, 59] (Table 3), where patients were followed up at multiple time points and 8 (22%) used an experimental design [27, 39, 42, 45, 46, 49, 51, 53] (Table 2). For example, Rothenberg et al. [39] investigated acute methadone-induced effects on visual reaction time and attention span, where up to 10 mg of methadone was given

Study Limitations Uncorrected for multiple comparisons; polydrug use and education were possible confounding variables

Small sample size

Lack of healthy comparison group; uncorrected for multiple comparisons; training effect was a possible confounding variable

Improved executive function and visuo-construction; no difference in immediate and delay recall, recognition, verbal learning, attention and reaction time

(2) 28 males and 14 females, MMT for at least 6 months, dose 69.3±42 mg

(1) 53 males, MMT for 48±1.86 months, dose 75±27.81 mg


Attention bias

Pre-existing conditions (e.g., history of drug use, head injury and current health status) were not reported.

Attention under monotony and decision making; no dose-related effect

Poly-drug use and psychiatric morbidity were possible confounding variables

to patients receiving MMT and healthy control subjects. Whereas, studies by Curran et al. [46] investigated doserelated cognitive deficits by manipulating the dose of methadone given to ‘patients’ in different conditions, i.e., either 50 mg or 80 mg. RCTs are considered the “gold standard” for determining the clinical effectiveness of drug treatments, yet only small number of the studies in this review used this method (Table 2). 3.4. Association Between Cognitive Function and MMT Overall, 85% of studies showed impaired cognitive function in patients undergoing MMT, with the majority receiving an average dose > 60 mg/day (Tables 1-3). Major differences between individuals undergoing MMT and healthy controls were observed in the domains of memory [33-35, 37, 38, 41, 42, 47]; attention [35, 37, 40-42, 57]; psychomotor speed [28, 33, 41, 53]; decision making [33, 34]; emotional interpretation [44, 50]; and verbal function [35, 61]. However, it should be acknowledged that several studies found either no difference [29, 59] or very minor differences [30, 55, 61] between patients undergoing MMT and control group subjects. Perhaps surprisingly two studies showed that patients undergoing MMT demonstrated superior performance during tasks assessing reaction time [39, 60], suggesting possible increased levels of arousal associated with a long-term history of substance abuse.

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Table 2.

Randomised Controlled Trials of MMT Targeting Cognitive Function

Study

Lombardo et al., 1976 US

Rothenberg et al., 1977 US

Kelly et al., 1978 US

Curran et al., 1999 UK

Curran et al., 2001 US

Lyvers & Yakimoff., 2003 Australia


Rapeli et al., 2011 Finland

Wang et al.

MMT Groups

Comparison

(1) 28 males, stablised on dose 50 mg at least 1 month (10 dropped out at the 2nd test);

(a) High dose vs low dose

In addition to the normal daily dose of methadone, all subjects received 0, 5 or 10 mg of methadone on each of 3 test days

No difference in psychomotor speed

Low dose range used

(a) 1 hour vs 25 hours after receiving methadone

Test was administered at 1-2 hours and 25-26 hours post-ingestion of methadone and of placebo

No difference in auditory threshold, reaction time, time perception, attention and memory

(a) Pre-drug vs postdrug with additional 33% dose

Tests were administered when subjects received additional 33% of their individual prescribed daily dose and matched quantity of placebo

No difference in psychomotor speed, memory and attention

(a) 100% daily dose vs 50% daily dose vs placebo

Tests were administered when subjects received 100%, 50% or 0% of their individual dose

Improved psychomotor speed; no difference in immediate recall, attention and procedural learning

(a) 1.5 hours vs 24 hours after receiving methadone

Tests were administered at 1.5 hours and 24 hours after receiving methadone

(1) 7 males and 5 females, stabilized on dose 20-70 mg at least 1 month

(1) 18 males and 21 females, stablised on 25 mg or more methadone for at least 1 month, mean dose 66.9 mg

(1) 24 (gender was not reported), on a stable dose of methadone at least 14 days

(1) 6 males and 6 females, MMT for mean 20±14 days, mean dose 71±39 (30-135) mg

Study Limitations

Males only; small dose difference; lack of healthy comparison group; high drop out rate

(a) Pre-drug vs postdrug;

(1) 16 males and 4 females, MMT for 3-5 days, dose 32.65±10.63 mg


No difference in IQ, verbal comprehension, working memory, perceptual organisation and processing speed

(b) 6 months vs 1 month of MMT

(1) 14 males and 4 females, MMT for at least 6 months, on the same dose (20-100) mg at least 4 weeks


Group 1 stayed at 50 mg through the experiment period. Group 2 gradually reduced to 50mg at the second test

(2) 25 males, stablised on dose 80 mg at least 1 month (5 dropped out at the 2nd test)

(1) 21 males and 9 females, MMT for 24874 days, mean 240 days, mean dose 63 (range 20-120) mg

Manipulation

(b) MMT vs 12 healthy

(2) 22 patients undertaking buprenorphine treatment; (3) 24 healthy subjects, matched for age, gender and education (2) 14 patients undertaking buprenorphine treatment; (3) 14 healthy controls matched for age and gender

Tests were administered at 14 days and 8-10 weeks of MMT

Test were administered at 2 months, 6-9 months and 12-17 months of MMT

Poorer distance perception on the 25-hour test

Poly-drug use was a possible confounding variable; small sample size

Delayed recall (episodic memory) only when receiving 100% dose

Withdrawal symptoms at the induction phrase and poly-drug use were possible confounding variables Possible continuation and withdrawal effects of methadone were confounding variables

Better executive cognitive function in those recently taking methadone

Improved concentration and executive function

Possible continuation and withdrawal effects of methadone were confounding variables

Psychomotor speed, selective attention, verbal memory and cognitive flexibility

Poly-drug use was a possible confounding variables

Attention, working memory and verbal memory

Small sample size


Table 3.

7

Longitudinal Studies of MMT Targeting Cognitive Function

Study

Grevert et al., 1977 US

Gruber et al., 2006 US

Baewert et al., 2007 Austria

Rapeli et al., 2009 Finland Nejati et al., 2011



Study Limitations

MMT Groups

Comparison

(1) 42 (23.3% female), mean dose 52 (range 2080) mg, 12 dropped out at the 2nd test

(a) Baseline vs 1 and 3 months of MMT; (b) MMT vs (2) 31 patients undertaking LAAM treatment & (3) 26 healthy subjects, matched for age, gender, education, ethnicity and employment status

No difference in memory

Poly-drug use was a possible confounding variable; possible learning effects

(a) Baseline vs after 2 months of MMT

No difference in verbal learning and memory, visuospatial learning and memory, attention and psychomotor speed

Small sample size; acute effects of methadone and poly-drug use were possible confounding variables

(1) 11 males and 6 females, MMT for average 15.7±13.1 days, mean dose 68±21.7 mg

a) Peak vs trough level ;

Iran



b) MMT group vs (2) 20 patients undertaking buprenorphine treatment & (3) a sample of 14,500 healthy subjects

(1) 7 males and 6 females, MMT for at least 2 months, dose 72.9±35.2 mg at T1, dose 125.7±35.8 mg at T2

b) MMT vs (2) 15 patients undertaking buprenorphine treatment & (3) 15 healthy controls at 2 months and 69 months of MMT

(1) 16 males, dose range 30-40 mg

a) Baseline vs after 45 days MMT

It is also possible that cognitive impairment is associated with a history of substance abuse rather than the use of methadone, because a considerable proportion of patients undergoing MMT also have a history of alcohol abuse, polydrug use and overdose. Specka et al. [40] argued that additional physical and mental disorders, including dependence on or the use of alcohol and other drugs, may be a causative factor associated with the cognitive deficits reported in previous studies. This issue has been addressed in 12 studies comparing patients undergoing MMT with abstinent former opiate users [28-30, 32, 35, 36, 41, 44, 50, 58, 60, 61]. It was assumed that patients currently taking methadone and former opiate users had a similar history of drug use. Therefore, any differences in performance were assumed to be methadone-induced. However, no significant differences were found between patients undertaking MMT and abstinent opiate users, both groups performed significantly worse than subjects with no history of substance dependence. In contrast, five studies have found that abstinent opiate users showed a marginal improvement in cognitive function when compared to patients currently taking MMT [24, 32, 41, 58, 61]. Therefore, it was concluded that methadone may be associated with additional impairment beyond the persisting effects of opiate abuse [32, 41]. 3.5. Other Factors Associated with Cognitive Impairment The evidence surrounding the effects of the daily prescribed dose of methadone on cognitive deficits is often

No difference in orientation and observation capacity, concentration, stress resistance, reaction speed and IQ

Improved selective attention and drugrelated attention bias

More errors and incorrect action at trough levels

Testing was specifically for driving related errors

Working memory, immediate verbal memory and memory consolidation

Small sample size; poly-drug use was a possible confounding variable Small sample size; males only; simple test

contradictory. Some have reported severe impairments associated with higher doses [31, 37, 44, 46], while others have failed to find dose-related deficits [27, 35, 45, 53, 55, 58]. Curran et al. [46] suggested that the effects of methadone may be subtle, in particular with people exposed to much higher doses of opiates over a longer period. In their previous study, patients undergoing MMT did not show any significant difference in cognitive function following an additional daily 33% increase in dose (43.5±16.2 ml) [45]. Pharmacological tolerance may also minimise the acute effects of methadone on cognitive function. A study by Rothenberg et al. [39] tested the acute effects of methadone on cognition, by comparing the cognitive performance of 24 patients undergoing MMT with healthy control subjects before and after receiving a 0-20 mg oral dose of methadone. They found that healthy subjects suffered deficits in visual sensitivity when they were compared to those undergoing MMT who showed no difference. Other investigators have measured differences between recently enrolled and long-term patients. Gruber et al. [48] examined the cognitive function of patients at baseline and after 2 months of MMT. After 2 months of MMT patients showed improvements in verbal learning, memory, visuospatial encoding, recall and psychomotor speed, and a reduced frequency of drug use. Improved cognitive function has also been reported by Soyka et al. [54] and Nejati et al. [56], who assessed the cognitive performance of patients

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Table 4.

Wang et al.

Classification System for the Methodological Quality, Modified After Sanderson et al. [26] Domain

Explanation of the Criteria A. Inclusion and exclusion criteria are clearly described;

Selection of study participants Description of measurement Control for confounding variables Statistical methods Conflict of interest

B. Methods used to identify and assign participant to study (and control, if applicable) group are clearly described; C. Measurement methods for outcomes are clearly described; D. There are differences between study and control groups, other than the factor being investigated, that may affect the outcome of the investigation; E. Statistical methods for primary analysis of effect are described; F. Statistical techniques were used to control for confounding variables; G. Declarations of conflict of interest or identification of funding sources.

before and after 45 days of MMT. In contrast, Grevert et al. [59] measured the memory performance of 30 patients receiving MMT at three different time points (prior to treatment, one and three months after treatment) but found no significant change. At both the second and third test sessions, the mean dose of methadone was 52 mg/day (range: 20-80 mg/day). The authors argued that memory deficits reported by others may be due to the comparison of those undergoing MMT with control groups at a single time point, based on the assumption that individuals were equal at baseline [59]. It is well known that an individuals’ methadone plasma concentration varies over time and this may also contribute to differences in cognitive performance. The timing of plasma concentrations in relation to dose has been shown to negatively influence cognitive function [43, 49, 51]. Poorer performance was often observed at the trough plasma level of methadone compared to the peak level. 4. DISCUSSION The objectives of this review were to examine the evidence of a relationship between MMT and cognitive functioning, and to explore the potential mediating effects of treatment factors such as daily dose, duration of treatment and individual plasma levels. The majority of research suggests that MMT is associated with impaired cognitive function and that the deficits extend across a range of domains [33-35, 37, 38, 41, 47]. Cognitive impairment was also more apparent in patients taking higher doses of methadone, i.e., > 60 mg/day. According to World Health Organisation [64], a maintenance dose of at least 60 mg of methadone/day is recommended. In this review, studies reporting impaired cognitive performance in patients were receiving average doses > 60 mg/day (i.e., [28, 35, 38, 41, 47]. Moreover, those patients tended to report a relatively prolonged history of substance abuse (i.e., 14.6 years [61]). Although a growing body of evidence suggests that MMT is associated with impaired cognitive function, there is very little evidence available to suggest what might cause these deficits. Furthermore, methodological differences and study limitations make it difficult to conclusively determine whether prolonged exposure to methadone leads to greater cognitive impairment. The actual mechanisms underlying cognitive deficits have not been clearly identified. Nevertheless, research has shown

differential effects between methadone and opiates on brain function. Methadone is able to substantially desensitize the delta opiate receptor and block the adaptive alterations induced by their continued activation following chronic exposure to morphine [65]. Delta opiate receptors are considered critical in the development of morphine-induced tolerance and dependence [66, 67]. Furthermore, unlike morphine and heroin, methadone does not decrease key parameters of adult hippocampal neurogenesis [68]. It has been suggested that adult hippocampal neurogenesis positively correlates with performance in hippocampal-dependent tasks, such as memory and locomotor activity [69]. While it is acknowledged that some studies demonstrate an improvement following MMT, some of the differing results may have arisen because of variations in sample size and the inclusion criteria of participants. For example the largest study, that of Specka et al. [40] had 54 subjects in each group, while Gritz et al. [58], only included 10. Furthermore, participants differ across studies with respect to age, gender and educational attainment. It has also been argued that differences in some cognitive tests are better explained by socio-demographic features rather than methadone, for example, tasks measuring motor reaction time, concentration and sensorimotor coordination [40]. In addition, potential confounders such as alcohol abuse, polydrug use, brain dysfunction, psychotic disorder and neurological disease are not routinely controlled for, or adjusted. For example, the MMT group recruited by Darke et al. [47] had high rates of alcohol dependence, head injury and heroin overdose in contrast to the healthy control group, all factors which correlated with poor cognitive performance. In general, it is difficult to perform experimental studies in drug-dependent patients due to significant somatic and psychiatric comorbidities, the possible presence of other drugs and a lack of motivation [54]. Therefore, crosssectional and longitudinal studies remain a good way to determine predisposition and are useful for identifying associations that can be rigorously studied. It is also important to take into account potential baseline differences (possibly even in cognitive ability) that may moderate which people become drug users and which do not. Future research combining psychological and physiological measures within well-controlled group comparison studies is needed. This should include the careful examination of factors that might mediate or moderate the relationship between MMT and


cognitive outcomes such as daily dose and duration of treatment and, the use of other drugs. This review is limited by applying English and published academic literature limits to the search. Also, the scope of this review does not cover the effects of hepatitis C, HIV and other pre-existing medical conditions, which may also contribute to cognitive deficits associated with people undergoing MMT [70-72]. To our knowledge, there are no systematic reviews investigating an association between cognitive function and MMT and very few general review papers concerning this topic have been published [1, 73]. It is acknowledged that it is difficult to synthesise knowledge generated by different studies employing diverse measures, populations, control groups and study designs. Nevertheless, this systematic review attempted to address these difficulties by adopting a series of techniques set out by MacDonald [74] that minimises bias and error in the findings of literature reviews, and allows information from diverse research designs to be summarized and conceptualized for clinicians, and to produce further testable hypotheses for researchers engaged in MMT research. In conclusion, the findings to date have been inconsistent, but ample evidence suggests that MMT might induce cognitive impairment. Populations with a history of opiate use and undergoing MMT tend to perform poorly in cognitive tasks compared to those with no history of drug dependence. It is important to emphasize that the studies in


this review are in agreement regarding their need for further investigation of the effects of MMT on cognitive function. Key Learning Objective: •

Thirty-five studies were included in this review, the majority suggest that MMT is associated with impaired cognitive function i.e. deficits in attention, memory, psychomotor speed, verbal function, decision making and emotional interpretation.

•

Impaired cognitive performance has been observed in patients receiving doses greater than 60 mg/day and reporting an extensive history of substance abuse.

•

In contrast, some demonstrate improved cognitive function during MMT.

•

Methodological differences and limited sample sizes make it difficult to conclusively determine whether prolonged exposure to MMT leads to increased cognitive impairment.

Future Research Question: •

Evidence suggests that MMT has a negative effect on cognition; future research should aim to identify the underlying mechanisms.

•

Cognitive impairment is more apparent in patients taking methadone at doses > 60 mg/day. Future research should aim to determine whether there is a relationship between methadone plasma concentrations and cognitive function.

•

Comorbid drug use is common in patients undertaking MMT. Future research should include a control group of subjects who still use opiates to minimise the confounding effects associated with comorbid drug use.

•

Future research should include a longitudinal study to investigate the degree of changes in cognition following enrolment in MMT.

APPENDIX 1 Search Strings Used when Searching in Different Databases PsycINFO

MEDLINE In-Process

1

methadone maintenance/

methadone/or methadyl acetate/

2

methadone/

methadone.tw.

3 4

methadone.tw 1 or 2 or 3

1 or 2 exp Cognition/

5

cognition

Executive Function/

6

cognitive impairment/

7 8. 9. 10.

cognitive ability/ cognitive neuroscience/ (cognit* adj3 function*).tw. (cognit* adj3 impair*).tw.

11

5 or 6 or 7 or 8 or 9 or 10

12

4 and 11

13

limit 12 to (peer reviewed journals and English language)

14 15 16 17 18

cognition disorders/or auditory perceptual disorders/ exp Memory/ Attention/ (cognit* adj3 impair*).tw (cognit* adj3 function*).tw. (memory or attention or psychomotor speed).tw. 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 3 and 12

limit 13 to English language

9

EMBASE ((cognit* adj3 impair*) or (cognit* adj3 dysfunct*)).ti,ab. ((cognit* adj3 funct*) or (cognit* adj3 perform*)).ti,ab. memory.ti,ab. neuropsychological test/ cognition/or attention/or memory/or mental capacity/or mental performance/or perception/or thinking/

Cochrane Central (methadone and cognit*).mp. methadone.mp. cognit*.mp. 2 and 3 cognitive therapy.mp.

cognitive defect/

4 not 5

or/1-6 *methadone treatment/ *methadone/ (methadone adj3 maint*).ti,ab.

cognitive behav*.mp. 4 not 7 exp cognition/ cognition disorders/

or/8-10

memory disorders/

7 and 11

(cognit* adj5 function*).tw.

limit 12 to english language

memory.tw.

. drug dependence/or cocaine dependence/or multiple drug abuse/or exp narcotic dependence/ addiction/ ((drug* or narcotic*) adj3 depend).ti,ab. 14 or 15 or 16 13 and 17

9 or 10 or 11 or 12 or 13 (cognit* adj3 impair*).tw. 14 or 15 exp methadone/ 16 and 17

10


Wang et al.

CONFLICT OF INTEREST

[21]

The authors confirm that this article content has no conflict of interest.

[22] [23]

ACKNOWLEDGEMENTS Declared none.

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Revised: January 31, 2013

Accepted: May 27, 2013

DISCLAIMER: The above article has been published in Epub (ahead of print) on the basis of the materials provided by the author. The Editorial Department reserves the right to make minor modifications for further improvement of the manuscript.

PMID: 23773088