The aim of the study was to examine the predictive power of drug treatment variables on specific cognitive performance measures in multidrug-treated opioid-dependent patients. Also, we were interested in finding out which of the possible significant associations turn out as hypothesized. All patients had been in OST for at least six months, and there were no major changes in their drug regimen within the last week prior to the study. Being on methadone-treatment predicted a rather low, though statistically significant proportion (about 5%) of attention performance as measured by combined reaction times in alertness tests. When opioid drug groups were analyzed separately about 10% of attention performance variance could be explained in both groups, but the predictors were different. Being on BZD drug treatment predicted about 10% of working memory performance. Having more than one other psychoactive drug (than an opioid or BZD drug) was negatively associated with verbal memory performance. Also, recent high-frequency substance abuse was negatively associated with verbal memory performance. Together these factors predicted about 20% of verbal memory performance variance.

Drug treatment variables as predictors of attention performance

In buprenorphine patients co-treatment with a BZD drug was negatively associated with attention performance, but buprenorphine dose had no significant effect. This is in line with an experimental study showing that BZD diazepam in combination with buprenorphine affects negatively on reaction time, and the effect is independent of the buprenorphine dose administered[21]. In methadone patients the interpretation is more complex. The highest predictor of slower reaction time in methadone patients was treatment with more than one other psychoactive drug than methadone or BZD (beta .31). As hypothesized, there was a positive slope between methadone dose and the combined reaction time (.26) among methadone-treated patients. It is known that rapid elevation of methadone dose reduces peripheral blood oxygen saturation even among patients highly tolerant to methadone[43]. Oxygen saturation reduction has been associated with specific reaction time deficit with relative sparing of other cognitive functions[44]. Specific to methadone it has been shown by Lintzeris et al. that when a higher than normal (150%) dose of methadone is given to methadone-treated opioid-dependent patients, reductions in oxygen saturation and reaction time can be detected[21]. In sum, our results give support to our hypotheses that among buprenorphine patients, co-treatment with a BZD drug is associated negatively with attention performance. Methadone treatment, especially when done together with other psychoactive drugs, can be negatively associated with attention performance. Of note here is the timing of the possible opioid agonist effects: the drug plasma concentration peaks between 0.5–4 h after the dose for buprenorphine and 2–6 h for methadone[31, 45–47].

Drug treatment variables as predictors of working memory performance

Our hypothesis of an advantage for buprenorphine in working performance was not supported by the analyses. Instead, treatment with a BZD drug was negatively associated with working memory performance (Table4). When we analyzed the possible associations of BZD drug type or dose, no significant associations were found, and the model had very low predictive power. Thus, we could not link the working performance with BZD parameters. According to the meta-analysis, BZDs in general have small or medium sized negative effects on working memory functioning as measured by Cohen’s d[24]. Although diazepam and oxazepam are probably the most widely used BZDs, few studies have examined their effects on a complex working memory measure like Letter-Number Sequencing. One study found that 5 mg of diazepam did not affect performance in the complex working memory measure, the n-back task, although it reduced frontal brain activation[48]. It is known that high BZD doses have a general sedative effect and thus have the potential to affect cognitive function, but the development of tolerance may outweigh these effects[49]. Notably, we observed that more than one year in OST was positively, although weakly associated with working memory performance (beta = .16). This observation is in line with our previous observation that working memory improves in buprenorphine patients between six and twelve months into OST[22].

Drug treatment variables as predictors of memory performance

The high number of other psychoactive drugs (than opioid and BZD) and recent high- frequency substance abuse together predicted 20% of immediate verbal memory performance variance as measured by a story recall task. There is some evidence that verbal memory is more sensitive than other cognitive domains to the negative effects of multiple psychoactive drugs. This observation, however, may be specific to elderly patients and anticholinergic drugs[50]. Even less is known about the possible memory effects of psychoactive drug burden (as measured by the number of drugs) in combination with opioid agonists. In our recent longitudinal study, both buprenorphine- and methadone-treated patients lagged behind healthy controls in verbal memory performance as measured by story recall[22]. Surprisingly, when we extended the sample in the second part of our earlier study, the difference to healthy controls disappeared. Also, the correlation between the number of psychoactive drugs and verbal memory was positive, not negative, as in the current study. In sum, although our finding of a negative verbal memory effect of more than one psychoactive drug is in concert with our hypothesis, the specificity of this finding cannot be shown with our data. The finding that recent high-frequency substance abuse predicted poor verbal memory is in accordance with studies showing that recent frequent substance abuse impairs verbal memory performance[51, 52].

Implications

The results of this study suggest that cognitive impairment in opioid-dependent patients is more common when the patient is prescribed additional psychoactive drugs. It is also likely, although not confirmed by our study, that at least long-term BZD medication independently predicts cognitive impairment among multidrug-treated opioid-dependent patients. Fortunately, during OST many patients become more open to discussion about medication side-effects. Patients may agree that slower reaction times, associated in our study with co-medication differently in buprenorphine- vs. methadone-treated patients, can be disadvantageous in vehicle driving and many sport activities. For instance there is evidence OST patients being disproportionately involved in road traffic crashes accidents[53, 54]. Working memory deficits, associated in our study with BZD co-medication, are known to impair reading comprehension, learning, and reasoning[55]. BZDs interfere with affective learning which is important in therapy[56]. Thus, combining BZD medication with psychological treatment may actually be detrimental to the long-term outcome of the treatment. The finding that one fifth of story recall performance variance was explained by two variables (high number of psychoactive drugs other than opioid or BZD drug; and high-frequency substance abuse in the previous month) is also relevant information. The optimal functioning of verbal memory is a useful resource in everyday life, work, or education[57]. All these facts may give the patient and prescriber a good reason to consider non-pharmacological treatment choices in place of polypharmacy. In some cases a realistic choice, for the time being, is to change cognitively harmful drugs like BZDs and tricyclic antidepressants for ones that are less harmful to cognition[58, 59].

Limitations

The distribution of the drug treatment variables, except opioid drug groups, was unplanned, and turned out to be highly skewed for some variables. As dichotomizations were used for these variables this reduces the statistical power of the analyses[60]. Therefore our findings about drug treatment effects are preliminary. Also, data about opioid and BZD doses may not be fully accurate, because drug screens do not detect extra doses of prescription drugs. Thus, our results do not confirm a causal association between drug treatment variables and cognitive performance. Patients with a higher number of prescribed drugs may have premorbid cognitive deficits that explain the associations found. On the other hand, longitudinal studies of patient groups other than OST patients have shown that discontinuation of a BZD drug regimen is followed by slow improvement in cognitive function and quality of life but no negative effects on sleep[61–64]. Our results support the idea that this could also be possible in opioid-dependent patients as well. There has been progress in the classification of psychoactive drugs by their interaction potential with buprenorphine or methadone[5, 58] Alternatively, the recently formed drug burden index could be a promising tool for reducing the number of drug treatment variables in clinical studies[65]. These tools were found, however, to be unsuitable for our purposes. Negative cognitive effects of psychoactive drugs usually diminish during long-term use, and there may be differences in this between attention and memory effects[22, 59, 66, 67]. If we had had data on length of drug use this would have been an important variable in analysing drug treatment effects. Our regression analyses were restricted only to the main effects of variables. Perhaps interactions between the variables could have explained more of the variation in cognitive performance. This was not considered appropriate given the high number of variables. Repeated testing of a third of patients is a potential confounder in the results, although after an interval of six months between testing times, as was the case in our study, the effects of repeated testing are trivial or non-existent for most measures[68, 69]. In our study the verbal memory test, the Logical Memory test, was an exception, and this was taken into account in the analyses. Inclusion of psychiatric control variables, as used by Loeber et al. or Prosser et al. when studying cognitive performance in opioid-dependent patients, would probably have raised the predictive power of the analyses[70, 71], and consequently the specificity of the findings.