Accepted Manuscript Changes in resting EEG following methadone treatment in opiate addicts Grace Y. Wang, Rob Kydd, Trecia A Wouldes, Maree Jensen, Bruce R. Russell PII: DOI: Reference:
S1388-2457(14)00487-8 http://dx.doi.org/10.1016/j.clinph.2014.08.021 CLINPH 2007233
To appear in:
Clinical Neurophysiology
Accepted Date:
6 August 2014
Please cite this article as: Wang, G.Y., Kydd, R., Wouldes, T.A., Jensen, M., Russell, B.R., Changes in resting EEG following methadone treatment in opiate addicts, Clinical Neurophysiology (2014), doi: http://dx.doi.org/10.1016/ j.clinph.2014.08.021
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Changes in resting EEG following methadone treatment in opiate addicts Grace Y Wang 1, Rob Kydd 2, 3, Trecia A Wouldes 3, Maree Jensen 4, Bruce R Russell 2, 4
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Department of Psychology, Auckland University of Technology, New Zealand
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Centre for Brain Research, 3 Department of Psychological Medicine, 4 School of Pharmacy,
University of Auckland, New Zealand
Corresponding author: Grace Y Wang Tel: +64 9 921 9999 ext 7432 Fax: +64 9 921 9780 E-mail:
[email protected]
Highlights •
There are methadone-related changes on resting EEG.
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The abnormal neural electrical activity present in those still using illicit opiates might be reduced following methadone maintenance treatment (MMT).
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The present findings provide further support for MMT of opiate dependence and demonstrates potentially positive effects of substitution treatment on brain function.
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Abstract Objective This study investigated the electrophysiological activity associated with methadone maintenance treatment (MMT).
Methods The resting EEG spectrum of beta (14.5-30 Hz), alpha (8-13 Hz), theta (4-7.5 Hz) and delta (1.5-3.5 Hz) rhythm were measured in 32 patients undertaking chronic MMT, 17 opiate users and 25 healthy volunteers. Differences in the EEG components of each group were evaluated using a repeated measures Analyses of Variance (ANOVA). Post-hoc comparisons were Bonferroni corrected.
Results Our results show that either patients undertaking MMT or active opiate users exhibited a significant increase in the power of beta and theta bands relative to healthy control subjects. However, the spectral power of patients undertaking MMT fell between that of current opiate users and healthy control subjects on many regional EEG measures. There was an inverse correlation between the power of beta or theta bands and cognitive performance.
Conclusion The abnormal neural electrical activity present in those still using illicit opiates might be reduced following MMT.
Significance The present findings provide further support for MMT of opiate dependence and demonstrates potentially positive effects of substitution treatment on brain function.
Keywords: Methadone, resting EEG, opiate dependence.
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Introduction Electroencephalography (EEG) has been used to examine brain function since the publication of Berger’s seminal paper in 1929. It records the synchronised activity of excitatory (EPSPs) and inhibitory post-synaptic potentials (IPSPs) in the cerebral cortex and displays the activity as voltage amplitude changes over time (Cooper et al. , 2005, Gevins, 1998). Over the last four decades, EEG has been used extensively for addiction research. It is recognised as a sensitive measure of drug effects on the brain and, in particular, of drug effects on the size and time course of post-synaptic potentials (Gevins et al. , 2011, Smith et al. , 2006). It has been shown that the reinforcing effects of many drugs mediated by the mesolimbic dopamine (DA) pathway modify EEG recordings (Knyazev, 2007). Four frequency ranges are usually recognised and investigated – delta (0-4 Hz), theta (4-8 Hz), alpha (8-13 Hz) and beta (15-30 Hz).
Methadone is a synthetic opioid that has been used as a pharmacological substitute for the treatment
of opiate dependence since the mid-1960s.
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 (Garrido and Trocóniz, 1999, Gruber et al. , 2007). Despite methadone’s effective clinical use, many neuropsychological studies suggest that it has negative effects on cognitive function including attention (Prosser et al. , 2006, Verdejo et al. , 2005), memory (Darke et al. , 2000, Mintzer and Stitzer, 2002, Pirastu et al. , 2006, Rapeli et al. , 2009, Verdejo et al., 2005), and information processing (Davis et al. , 2002, Soyka et al. , 2008).
A small number of studies, conducted mostly during the 70’s, examined EEG changes in patients undertaking methadone maintenance treatment (MMT) during resting states. Resting state EEG is thought to provide a measure of the brain’s ability to allocate resources and prepare for changes in the internal and external environment, which also provides a measure of cognitive capability (Canuet et al. , 2011). Gritz et al. (1975) recorded EEG from 10 patients undertaking MMT for a median of 5 months; 10 ex-opiate users who were abstinent for a median of 2 months; and 5 healthy volunteers. The investigation found that 3
the location of peak alpha activity was shifted to a lower frequency in MMT subjects, compared to abstinent subjects and healthy controls. Lenn et al. (1976) assessed the resting EEG difference between patients undergoing MMT and ex-opiate users who had been abstinent from opiates for at least one year prior to the study. They compared group EEG recordings using a scale of normal, mildly abnormal, and severely abnormal, and found no significant group differences. Unfortunately, there is no description of the scale used to assess the EEG recordings so it is difficult to interpret their results within context. Nevertheless, the authors described two abnormal recordings in the methadone group, one with “a waking resting occipital frequency of 6 to 8 cycles per second and irregular low amplitude delta slowing during drowsiness” and the other “showing increased beta activity in waking and asymmetrical right temporal predominant delta activity in drowsiness and hyperventilation” (Lenn et al., 1976). A more recent study by Fingelkurts et al. (2007) demonstrated lower levels of alpha and beta activity and increased delta and theta activity in patients undertaking MMT compared to healthy volunteers, although the patients undertaking MMT showed EEG oscillations more comparable to the healthy control subjects than participants with either opiate dependence or withdrawal. Subjects with past major head trauma and neurological illness were excluded in the study of Fingelkurts et al. (2007), these factors were not addressed in previous studies, e.g., those by Gritz et al. (1975) and Lenn et al. (1976).
Several studies have investigated EEG changes in the patients during different stages of MMT. In the study by Martin and colleagues (1973), EEG recordings were conducted two weeks prior to MMT, during the administration of methadone, then after stabilisation on 100 mg/day of methadone, and following 6 weeks abstinence from MMT. The study found reduced alpha activity and increased delta and theta activity during the induction and stabilisation periods of MMT compared to the period before MMT. During the period of withdrawal from MMT, delta activity was significantly less than the periods either before MMT was initiated or after they were stabilised on 100 mg/day of methadone. Feistein and Hanley (1975), Kay (1975) and Martin et al. (1973) adopted a similar approach in their studies of EEG changes amongst patients undertaking MMT and reported similar findings.
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Although the majority of studies have found methadone-related EEG changes, there are inconsistent findings about the effects of MMT on neurophysiological function, as measured by EEG. Some may have arisen because of variation in the study design, sample size and/or the inclusion criteria of participants. The aim of the current study was to extend the previous findings by investigating the effect of MMT on electrophysiological activity during resting states.
Methods Participants Inclusion criteria. All participants recruited were between 18-45 years of age, had basic English literacy skills and were able to provide written informed consent. Inclusion criteria for the MMT group included undertaking MMT for a minimum of six months and stabilised on their current dose for at least 2 weeks. Participants in the opiate user group were required to meet the DSM-IV criteria for opiate dependence which was diagnosed using the Composite International Diagnostic Interview (CIDI) (Kessler and Ustün, 2004). This requires participants to be physically dependent on opiates as evidenced by a history of withdrawal symptoms and to have been actively using opiates for a minimum of one year prior to the study date.
Participants in the opiate user group were not allowed to be currently
undertaking MMT. The inclusion criteria for healthy control subjects were no current or lifetime history of drug or alcohol abuse other than nicotine dependence.
Exclusion criteria. Exclusion criteria were based on the results of the CIDI, which was administered to all participants, and included a history of psychotic disorder, depression, cardiac disease, endocrine disorder, head trauma, neurological disease and self-reported current pregnancy or breastfeeding. The CIDI is a well validated clinical assessment tool that has been used extensively for clinical and research purposes (Wittchen, 1994). It provides detailed information based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (American Psychiatric Association, 2000) and includes 22 diagnostic sections that assess mood disorders, anxiety disorders, substance-use disorder, childhood disorder and other disorders. There are additional sections screening for the presence of cognitive 5
impairments, such as memory, speech and learning, and current physical status (i.e. headache, speech and sensor perception). At the time of testing, none of the participants were experiencing symptoms that could be attributed to acute drug intoxication or withdrawal.
MMT group. The group undertaking MMT were recruited following recommendations from the case managers of Auckland Community Alcohol and Drug Services (CADS), New Zealand. The MMT group consisted of 18 males and 14 females, with a mean age of 39.36 (SD=5.14) years. Their mean duration of education was 12.06 (SD=2.00) years; mean duration of opiate use was 10.03 (SD=6.08) years; mean duration of MMT 7.29 (SD=6.39) years; and current methadone dose 70.86 (SD=40.61; range 8−180) mg/day.
Opiate user group. Opiate users were recruited from the Auckland Drug Information Outreach (ADIO) Trust Needle Exchange Services by advertisement (notices put up in services and handouts given to people coming in) or by word of mouth. They were not required to abstain from opioids before testing. The group included 11 males and 6 females, with a mean age of 37.38 (SD=7.44) years; a mean duration of education 12.47 (SD=1.46) years; and a mean duration of opiate use of 11.41 (SD=8.60) years.
Healthy control group. A group of 25 healthy control subjects was recruited by advertisements (notices posted on notice boards) distributed in a range of local communities, such as the public library, shopping mall, cafés, or by word of mouth. This group included 14 males and 11 females, with a mean age of 36.12 (SD=6.61) years and a mean duration of education 13.71 (SD=1.73) years.
Materials
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Drug test. Drug use was detected using a NZDDA6 Panel Cup with adulterants for the drugs listed in the AS/NZS4308:2008 Amphetamines, Benzodiazepines, Marijuana (THC), Cocaine, Methamphetamine and Opiates. Concentrations above the cut off level were considered positive and those below the level, negative: 300 µg/L for amphetamines, cocaine, methamphetamine and opiates; 200 µg/L for benzodiazepines and 50 µg/L for marijuana. Participants assigned to the healthy control group were required to produce negative test results and those assigned to the opiate group positive for opiate use. The urine drug screen for opiate does not detect the presence of methadone or its metabolites.
Addiction Severity Index (ASI). History of drug use was assessed using the Addiction Severity Index (ASI) (McLellan et al. , 1980). Questions in this scale refer to the age at onset of drug use, the number of days of heroin or other opiate use in the last month and total years of drug use. Studies have shown that the ASI demonstrates satisfactory concurrent and predictive criterion-related validity across diverse subpopulations (Hendricks et al. , 1989, Leonhard et al. , 2000).
Data recording Prior to commencing this research, ethical approval was granted by the Northern Regional X Ethics Committee of New Zealand and informed consent was given by all participants. All EEG recordings were conducted after the completion of a neuropsychological test battery (Wang et al. , 2014) between 12 pm and 4 pm, apart from three participants (one was from the opiate user group and two were from the healthy control group) who completed EEG recording at 6pm due to their availability.
A QuickCap (Neuroscan 4.3) 40 sensor shielded cap was used to acquire EEG data from the cephalic sites. The 26 cephalic sites included Fp1, Fp2, Fz, F3, F4, F7, F8, Cz, C3, C4, FC3, FCz, FC4, CP3, CPz, CP4, T3, T4, T5, T6, Pz, P3, P4, O1, O2, and Oz electrode sites (10-20 International System). A further 14 channels recorded other data, e.g. VPVA and VPVB vertical electrooculogram (EOG), HPHL and HNHR horizontal EOG, heart rate (HR), muscle
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movements and events, etc. HR is considered as one of the most sensitive measures of withdrawal, which has been shown to be positively correlated with severity of opiate withdrawal (Zilm and Sellers, 1978). EEG was recorded relative to the average of A1 and A2 (mastoid) electrodes sites as commonly used in cognitive neurophysiological studies, e.g. (Clark et al. , 1994, Franken et al. , 2003, Gehring et al. , 2000, Massey et al. , 2004). Horizontal eye movements were recorded with electrodes placed 1.5 cm lateral to the outer canthus of each eye. Vertical eye movements were recorded with electrodes placed 3 mm above the middle of the left eyebrow and 1.5 cm below the middle of the left bottom eyelid. Skin resistance was kept at < 5 kOhms. Scalp and EOG potentials were amplified and digitised continuously by a system (NuAmps, SCAN 4.3) having a frequency response from DC to 100 Hz (above which attenuating by 40 dB per decade), and a sampling rate of 500 Hz. EEG data were screened visually for artefacts, normal variants and changes in alertness (the technician screening these data was blinded to group status). All EEG recordings were conducted on a one-to-one basis in a sound and light attenuated laboratory. Participants were observed by the researcher who operated the stimulus computer to deliver the stimuli (paradigms) in the same room. Recording instructions were delivered with stereo headphones. To reduce muscle artefacts in the EEG signal, the participants were instructed to assume a comfortable seated position and avoid movement during recording. Electrical impedance was always
