Cognitive functioning in opioid-dependent patients treated with buprenorphine, methadone, and other psychoactive medications: stability and correlates.

BACKGROUND: In many but not in all neuropsychological studies buprenorphine-treated opioid-dependent patients have shown fewer cognitive deficits than patients treated with methadone. In order to examine if hypothesized cognitive advantage of buprenorphine in relation to methadone is seen in clinical patients we did a neuropsychological follow-up study in unselected sample of buprenorphine- vs. methadone-treated patients. METHODS: In part I of the study fourteen buprenorphine-treated and 12 methadone-treated patients were tested by cognitive tests within two months (T1), 6-9 months (T2), and 12-17 months (T3) from the start of opioid substitution treatment. Fourteen healthy controls were examined at similar intervals. Benzodiazepine and other psychoactive comedications were common among the patients. Test results were analyzed with repeated measures analysis of variance and planned contrasts. In part II of the study the patient sample was extended to include 36 patients at T2 and T3. Correlations between cognitive functioning and medication, substance abuse, or demographic variables were then analyzed. RESULTS: In part I methadone patients were inferior to healthy controls tests in all tests measuring attention, working memory, or verbal memory. Buprenorphine patients were inferior to healthy controls in the first working memory task, the Paced Auditory Serial Addition Task and verbal memory. In the second working memory task, the Letter-Number Sequencing, their performance improved between T2 and T3. In part II only group membership (buprenorphine vs. methadone) correlated significantly with attention performance and improvement in the Letter-Number Sequencing. High frequency of substance abuse in the past month was associated with poor performance in the Letter-Number Sequencing. CONCLUSIONS: The results underline the differences between non-randomized and randomized studies comparing cognitive performance in opioid substitution treated patients (fewer deficits in buprenorphine patients vs. no difference between buprenorphine and methadone patients, respectively). Possible reasons for this are discussed.

Impaired pre-attentive auditory processing in opioid dependence with and without benzodiazepine co-dependence revealed by combined magnetoencephalography and electroencephalography.

Cognitive dysfunctions may be a significant factor in drug-seeking behavior, reducing the efficiency of rehabilitation in opioid dependence. Neurophysiological basis of these dysfunctions is poorly understood. 21 opioid-dependent patients and 15 healthy controls with no experience of illicit drugs were studied with simultaneous electroencephalography (EEG) and magnetoencephalography (MEG). Among opioid dependents 15 were benzodiazepine co-dependent. In a passive oddball paradigm, a train of 700-Hz standard tones (80%), presented to the left ear, was occasionally interrupted by infrequent deviants, which were either 600-Hz or 400-Hz pure tones or complex novel sounds. The auditory evoked potentials (AEP) and fields (AEF) were analyzed. The strength of the N1m dipoles was enhanced in patients with benzodiazepine co-dependence, but the latency of the response or the source location was not changed. A delay of mismatch negativity (MMN) response of novel tones in EEG, and delay of P3am response on the contralateral hemisphere to stimulated ear in MEG in opioid-dependent patients were observed. There were no differences in source locations or strengths of the dipoles for P1m, MMNm, and P3am determined using equivalent current dipoles. There were no group differences in EEG amplitude measures. In conclusion, our results suggest delayed pre-attentive auditory processing of novel information in opioid dependence. Benzodiazepine co-dependence modulated N1m response.

Methadone vs. buprenorphine/naloxone during early opioid substitution treatment: a naturalistic comparison of cognitive performance relative to healthy controls.

BACKGROUND: Both methadone- and buprenorphine-treated opioid-dependent patients frequently show cognitive deficits in attention, working memory, and verbal memory. However, no study has compared these patient groups with each other during early opioid substitution treatment (OST). Therefore, we investigated attention, working memory, and verbal memory of opioid-dependent patients within six weeks after the introduction of OST in a naturalistic setting and compared to those of healthy controls. METHODS: The sample included 16 methadone-, 17 buprenorphine/naloxone-treated patients, and 17 healthy controls matched for sex and age. In both groups buprenorphine was the main opioid of abuse during the recent month. Benzodiazepine codependence, recent use, and comedication were also common in both patient groups. Analysis of variance was used to study the overall group effect in each cognitive test. Pair-wise group comparisons were made, when appropriate RESULTS: Methadone-treated patients, as a group, had significantly slower simple reaction time (RT) compared to buprenorphine/naloxone-treated patients. In Go/NoGo RT methadone patients were significantly slower than controls. Both patient groups were significantly debilitated compared to controls in working memory and verbal list learning. Only methadone patients were inferior to controls in story recall. In simple RT and delayed story recall buprenorphine/naloxone patients with current benzodiazepine medication (n = 13) were superior to methadone patients with current benzodiazepine medication (n = 13). When methadone patients were divided into two groups according to their mean dose, the patient group with a low dose (mean 40 mg, n = 8) showed significantly faster simple RT than the high dose group (mean 67 mg, n = 8). CONCLUSION: Deficits in attention may only be present in methadone-treated early phase OST patients and may be dose-dependent. Working memory deficit is common in both patient groups. Verbal memory deficit may be more pronounced in methadone-treated patients than in buprenorphine/naloxone-treated patients. In sum, to preserve cognitive function in early OST, the use of buprenorphine/naloxone may be more preferable to methadone use of, at least if buprenorphine has been recently abused and when benzodiazepine comedication is used. Longitudinal studies are needed to investigate if the better performance of buprenorphine/naloxone-treated patients is a relatively permanent effect or reflects "only" transient opioid switching effect.

Cognitive function during early abstinence from opioid dependence: a comparison to age, gender, and verbal intelligence matched controls.

BACKGROUND: Individuals with opioid dependence have cognitive deficits during abuse period in attention, working memory, episodic memory, and executive function. After protracted abstinence consistent cognitive deficit has been found only in executive function. However, few studies have explored cognitive function during first weeks of abstinence. The purpose of this study was to study cognitive function of individuals with opioid dependence during early abstinence. It was hypothesized that cognitive deficits are pronounced immediately after peak withdrawal symptoms have passed and then partially recover. METHODS: Fifteen patients with opioid dependence and fifteen controls matched for, age, gender, and verbal intelligence were tested with a cognitive test battery When patients performed worse than controls correlations between cognitive performance and days of withdrawal, duration of opioid abuse, duration of any substance abuse, or opioid withdrawal symptom inventory score (Short Opiate Withdrawal Scale) were analyzed. RESULTS: Early abstinent opioid dependent patients performed statistically significantly worse than controls in tests measuring complex working memory, executive function, and fluid intelligence. Their complex working memory and fluid intelligence performances correlated statistically significantly with days of withdrawal. CONCLUSION: The results indicate a rather general neurocognitive deficit in higher order cognition. It is suggested that cognitive deficit during early abstinence from opioid dependence is related to withdrawal induced neural dysregulation in the prefrontal cortex and is partly transient.

Magnetic resonance imaging of severe, long-term, opiate-abuse patients without neurologic symptoms may show enlarged cerebrospinal spaces but no signs of brain pathology of vascular origin.

BACKGROUND: Recreational drug abuse is one of the most important risk factors for stroke in young adults. Abuse of opiates may lead to severe acute neurologic problems due to ischemia or hemorrhage. In contrast, their minor effects on brain structures are not well established. We evaluated brain magnetic resonance images (MRI) of opiate-dependent subjects who had no major neurologic symptoms or psychiatric disorder. METHODS: Seventeen opiate-dependent patients and 17 controls underwent 1.5 T MRI. Any abnormalities in signal intensity of the brain were recorded. Areas of vermis, corpus callosum, and midline internal skull surface (MISS) were measured from midline sagittal slice. To evaluate size of cortical sulci, sylvian fissures, and ventricles, axial images were compared with standard sets of reference images. In addition, bifrontal and sylvian-fissure ratios were measured. RESULTS: Only one patient had a small subcortical post-traumatic lesion; otherwise, gray and white matter showed normal signal intensities. Opiate-dependent subjects had significantly wider sylvian fissures (p=0.008, Mann-Whitney U) and larger ventricles (p=0.04) than controls. Bifrontal and sylvian-fissure ratios were significantly higher in patient group than in controls (p=0.013 and p=0.005, respectively). CONCLUSIONS: No signs of brain pathology of vascular origin were found. From the clinical point of view, we want to emphasize that in the first acute neurologic attack of opiate-dependent patients, any abnormal signal intensity in MRI is most probably associated with the patient's current situation. Sylvian fissures and ventricles were wider in opiate-dependent subjects than in controls, which may be related to brain atrophy located especially in frontal and temporal lobes.

Do drug treatment variables predict cognitive performance in multidrug-treated opioid-dependent patients? A regression analysis study.

BACKGROUND: Cognitive deficits and multiple psychoactive drug regimens are both common in patients treated for opioid-dependence. Therefore, we examined whether the cognitive performance of patients in opioid-substitution treatment (OST) is associated with their drug treatment variables. METHODS: Opioid-dependent patients (N = 104) who were treated either with buprenorphine or methadone (n = 52 in both groups) were given attention, working memory, verbal, and visual memory tests after they had been a minimum of six months in treatment. Group-wise results were analysed by analysis of variance. Predictors of cognitive performance were examined by hierarchical regression analysis. RESULTS: Buprenorphine-treated patients performed statistically significantly better in a simple reaction time test than methadone-treated ones. No other significant differences between groups in cognitive performance were found. In each OST drug group, approximately 10% of the attention performance could be predicted by drug treatment variables. Use of benzodiazepine medication predicted about 10% of performance variance in working memory. Treatment with more than one other psychoactive drug (than opioid or BZD) and frequent substance abuse during the past month predicted about 20% of verbal memory performance. CONCLUSIONS: Although this study does not prove a causal relationship between multiple prescription drug use and poor cognitive functioning, the results are relevant for psychosocial recovery, vocational rehabilitation, and psychological treatment of OST patients. Especially for patients with BZD treatment, other treatment options should be actively sought.

Cerebral measurements and their correlation with the onset age and the duration of opioid abuse.

BACKGROUND: Opioid-dependent patients have been shown to have structural brain alterations. This study focuses on magnetic resonance imaging (MRI) measurements of brain and their correlation with the onset age and the duration of opioid abuse. METHODS: Brain MRI was obtained from 17 opioid-dependent patients (mean age 34 years, SD 7 years) and 17 controls. Compulsive opioid use had begun between ages 15 and 31 (mean 20) and had continued from 5 to 26 years. All patients were tobacco smokers, six had also abused amphetamines and 11 benzodiazepines. Relative volumes of cerebral white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF) spaces were measured. In addition, Sylvian fissure ratio (SFR), bifrontal ratio, and midsagittal cerebellar vermian area were correlated with the onset age and the duration of opioid abuse. RESULTS: The total volume (GM + WM + CSF) of the cerebrum was significantly smaller in patients than in controls (Mann-Whitney U-test, p = 0.026) as well as the absolute volumes of GM and WM (p = 0.014 and p = 0.007, respectively). There was no significant difference in GM and WM volumes normalized with total cerebral volume. In contrast, the absolute volume of CSF did not significantly differ between the groups, but the relative volume of CSF was significantly higher in opioid dependents (p = 0.029). SFR and bifrontal ratio were larger in opioid dependents than in controls (p = 0.005 and p = 0.013). The SFR correlated negatively (p = 0.017, r = - 0.569) and the area of vermis cerebelli correlated positively (p = 0.043, r = 0.496) with the onset age of opioid abuse. The length of opioid abuse and the area of vermis cerebellum had a negative correlation (p = 0.038, r = - 0.523) even though the areas of cerebellar vermis did not significantly differ between opioid dependents and controls. The authors speculate that the onset of substance abuse in adolescence or early adulthood may have in part disturbed the late brain maturation process, as in normal development, the dorsolateral frontal cortex and superior parts of the temporal lobes are the last to maturate. Also, the cerebellar vermis may be affected by early onset substance abuse. It is possible that the brain is more vulnerable to substance abuse at a young age than later in life.

Memory function in opioid-dependent patients treated with methadone or buprenorphine along with benzodiazepine: longitudinal change in comparison to healthy individuals.

BACKGROUND: Opioid-substitution treatment (OST) for opioid dependence (OD) has proven effective in retaining patients in treatment and reducing illegal opiate abuse and crime. Consequently, the World Health Organization (WHO) has listed the opioid agonists methadone and buprenorphine as essential drugs for OD that should be available worldwide. In many areas of the world, OD is often associated with concomitant benzodiazepine (BZD) dependence and abuse, which complicates treatment. However, possible changes in the cognitive functioning of these patients are not well-known. The present study is the first to examine longitudinal stability of memory function in OST patients with BZD use, thus providing a new tool for health policy authorities in evaluating the usefulness of OST. METHODS: Within the first two months (T1) and between 6-9 months (T2) after OST admission, we followed the working memory, immediate verbal memory, and memory consolidation of 13 methadone- and 15 buprenorphine- or buprenorphine/naloxone-treated patients with BZD dependence or abuse disorder. The results were compared to those of fifteen normal comparison participants. All participants also completed a self-reported memory complaint questionnaire on both occasions. RESULTS: Both patient groups performed statistically significantly worse than normal comparison participants in working memory at time points T1 and T2. In immediate verbal memory, as measured by list learning at T1, patients scored lower than normal comparison participants. Both patient groups reported significantly more subjective memory problems than normal comparison participants. Patients with more memory complaints recalled fewer items at T2 from the verbal list they had learned at T1 than those patients with fewer memory complaints. The significance of the main analyses remained nearly the same when the statistical tests were performed without buprenorphine-only patients leaving 12 patients to buprenorphine/naloxone group. CONCLUSION: Working memory may be persistently affected in OST patients with BZD use. A high number of memory complaints among OST patients with BZD use may indicate memory consolidation impairment. These findings show that recovery of memory function in OD patients treated along with BZDs takes time, and their memory complaints may have practical relevance.

Do individuals with former amphetamine dependence have cognitive deficits?

The association between former amphetamine dependence and cognitive performance was studied in a sample of 12 individuals with former amphetamine dependence who had been abstinent for at least 1 year and in 12 age-, gender- and verbal IQ-matched controls. The groups were compared by cognitive tests on attention, memory, executive function and fluid intelligence. Individuals with former amphetamine dependence performed significantly poorer than controls in memory domain. Follow-up analysis of variance showed minor deficits in tests of delayed verbal memory. The results remained essentially the same when participants with current DSM-IV axis I diagnosis were excluded from the analysis. It is concluded that individuals with former amphetamine dependence have normal cognitive function with the possible exception of verbal memory. Thus, if widespread cognitive deficits are found in individuals with former amphetamine dependence, etiologies other than amphetamine abuse as such should be carefully investigated.