Opioid Substitution Therapy: Measuring Impairment in a Clinically Relevant Population
J. Cameron Davis and Howard Wetsman MD FASAM
Background: The CDC has labeled opioid overdoses an epidemic while treatment is readily available to those suffering. Current research indicates that the best treatment outcomes are in opioid maintenance therapies, yet such therapies carry a significant stigma; opioid maintenance therapy is impairing to patients. Methods: Measures of cognitive ability, the Iowa Gambling task (IGT) and the continuous performance task (CPT), were used to determine cognitive impairment in opioid maintenance patients before and after prescription buprenorphine use. Data was collected from a retrospective chart review of patients enrolled in a medically managed intensive outpatient program that uses frequent neurocognitive testing. Participants were 38 sequential opioid dependent admissions from August to December 2012 who both received buprenorphine and had both before and after testing. Results: A significant difference in IGT scores between the pre and posttest conditions was found with buprenorphine medicated patients having higher average scores than in the pre medication condition, F (74) = 10.74, p=.0016. Target accuracy on the CPT did not differ significantly in any of the time blocks between pre and posttests. A significant difference in foil accuracy was found between the pre and posttests in both the two second block, F (74) = 10.81, p=.0015, and the four second block, F (74) = 5.41, p=.0228 with medicated patients showing improvement over their pre-medicated condition. Conclusion: Evidence from this study does not support the currently prevalent idea that introduction of buprenorphine opioid maintenance treatment will impair patients. This has tremendous implications for buprenorphine maintenance therapy demonstrating that reward overvaluation and impulsivity both decreased after the introduction of prescription buprenorphine in a clinically relevant population. The research also supports the subjective report of opioid dependent maintenance patients that they actually function better when prescribed buprenorphine.
Opioid substitution therapy: Impairment
Opioid dependence is a fast rising cause of death, with opioid overdoses reaching epidemic status(1). In spite of this, treatment is readily available and can help opioid dependent individuals. Risk of relapse following opioid withdrawal is common, and “detox” alone does not count as satisfactory treatment for opioid dependence(2). Best treatment outcomes are in opioid maintenance therapies(3). Unfortunately opioid substitute therapy still carries a significant stigma.
Opioid maintenance therapy in the form of methadone has been available since the 1960’s, but requires a large infrastructure under current law. Recently, maintenance has also become available in the forms of buprenorphine, which specially licensed physicians can prescribe in an office based setting. While this increase in treatment options is welcomed, buprenorphine is a largely underutilized treatment. In contrast, there has been an overall increase in full opioid agonist pain treatment. This has been accompanied by a 63 percent increase in opioid deaths from 1999 to 2004 according to a 2007 national survey on drug use and health(4). This calls for a reevaluation of the stigma surrounding opioid maintenance therapy and a need to use the best therapy available.
In spite of its good record as treatment, there are other problems with methadone. Pud et al. (2012) reported that methadone maintenance patients experience pain, depression, and sleep disorders, which disrupts their general state of health and well-being(5). Methadone has also been found to be impairing. Mintzer et al. (2002) researched psychomotor and cognitive performance among methadone maintenance patients(6). Assessed on a broad range of performance tasks; methadone patients exhibited impairment relative to controls in five out of eight tasks. Methadone maintenance patients are also significantly more likely to make risky decisions when they had been unsuccessful on the previous trial(7). Such disruptions further hinder the success of rehabilitation.
Buprenorphine has been approved because of the need for a new maintenance treatment with fewer drawbacks. Buprenorphine is a semi-synthetic opioid approved by the Food & Drug Administration in 2002 in the forms of ‘Subutex’ and ‘Suboxone’ for treatment of opioid addiction. Buprenorphine is a partial mu opioid agonist and kappa antagonist utilized as an effective treatment of opioid dependence (8,9,10,11,12,13). There are many additional benefits such as effectiveness in treating neuropathic pain, having a ceiling effect on respiratory depression, mild withdrawal symptoms, less physical dependence, and less cognitive impairment compared to other forms of treatment(14). Buprenorphine has been increasingly replacing methadone maintenance because of its lower risk of abuse, side effects, and its ceiling effects for respiratory depression.
While numerous studies have compared the impairment of buprenorphine to methadone, with most research finding buprenorphine less impairing than methadone (15-25) there is an ongoing perception among those who treat addiction that buprenorphine is an impairing opioid. Soyka et al. (2005) compared both treatments in a randomized study of drug dependent patients and found that buprenorphine was less impairing on cognitive functions than methadone in a driving-related battery(26).
Unfortunately, a cursory perusal of the literature tends to confirm the perception of buprenorphine as impairing, because most confirming studies used strictly healthy volunteers. MacDonald et al. (1989) examined the psychomotor effects of buprenorphine in 12 healthy male volunteers and found it caused significant psychomotor impairment on seven out of eight psychomotor tests(27). Effects peaked at four hours post-dose and were still apparent eight hours later. Similarly, Zacny et al. (1997) cited buprenorphine as increasing impairment on subjective and psychomotor performance measures compared to equianalgesic morphine. The impairment was found in a study examining 16 subjects without history of opiate dependence(28). This evidence supports what is known about the opiate buprenorphine. As opioid dependent persons generally find opioids stimulating rather than sedating, these two studies are not applicable to a clinical population.
To further the understanding of buprenorphine impairment Mintzer et al. (2004) evaluated dose-related effects of repeated administration of buprenorphine/naloxone sublingual tablets in opioid dependent patients. Results revealed minimal impairment in performance as dosage increased. The only significant effect was impairment in episodic/long-term memory at the highest level of buprenorphine (32/8mg) (29).
Additionally, research indicates that long term buprenorphine maintenance does not cause impairment to those undergoing treatment. Shmygalev et al. (2011) studied the impact of long-term maintenance treatment by comparing 30 patients utilizing sublingual buprenorphine treatment with 90 matched controls. Three control subjects were used on each buprenorphine patient with subjects matched for age and sex. They were tested for driving ability using the Vienna Test System and showed no significant cognitive deterioration. Patients receiving a stable dose of sublingual buprenorphine showed no significant impairment of complex psychomotor or cognitive performance compared to healthy controls (30).
Stable doses are only present in laboratory studies, whereas in a clinical atmosphere a patients prescription will change or they may forget to medicate. Singhal et al. (2008) cited that buprenorphine maintenance patients often abuse the drug by taking additional doses over and above the maintenance dose. To examine the impact this might have on psychomotor performance, they studied 19 subjects maintained on buprenorphine and administered the maintenance dose followed by three additional doses at two-hour intervals. Subjects completed a psychomotor performance battery following each administration. Performance on Digit Symbol Substitution Test and Trail Making Test-A and B improved significantly with each assessment, while other tests remained unaffected (31). Buprenorphine dose increase has no effect on impairment. Other possibilities could explain the presumption of buprenorphine “abuse.” For example, patients could be under-dosed because of the sedating stereotype of the opiate and therefore perform better once closer to their effect dosage.
Another popular treatment method for opioid dependence is naltrexone maintenance; approved by the Food and Drug Administration in 1984. Naltrexone, unlike methadone and buprenorphine, is an opioid antagonist or blocker and cannot induce any euphoric drug-like effects. Messinis et al (2009) compared the neurophyshological functioning of 18 buprenorphine maintenance patients, 32 naltrexone maintenance patients, and 34 healthy controls. The results indicate that there were no significant difference in any of the cognitive measures between the buprenorphine and naltrexone groups or between the naltrexone group and controls. Yet, the study cites buprenorphine to have performed more poorly than controls on conceptual flexibility, executive functions, encoding and delayed recall of verbal and visual information(32). This study’s conclusions are questionable because the authors find no difference in impairment between buprenorphine maintenance and naltrexone, while they also claim that naltrexone is less impairing. Moreover, Minozzi et al. (2011) reviewed 13 studies of naltrexone versus placebo or other treatments. The analysis inferred the studies conducted have not been all-encompassing enough to adequately evaluate naltrexone for treatment of opioid dependence (33). In spite of the lack of evidence there are still advocates for naltrexone maintenance therapy as a less impairing alternative to buprenorphine.
Missing from the literature is a clinically relevant comparison of buprenorphine maintenance patients versus those treated with naltrexone or with those not treated at all. Extended evaluation of this comparison may indicate which treatment leads to lesser degree of impairing effects. Choosing a treatment plan that is both effective and does not sacrifice cognitive abilities could lead to more people completing treatment and more people seeking treatment because of a higher success rate. Many clinical and laboratory observations have hypothesized that the primary neural substrates of persistent compulsive drug use are long-term associative memory processes involving multiple neural circuits that receive input from midbrain dopamine (34). In a naturalistic clinical setting, we examined the outcomes from two common cognitive testing measures associated with dopamine tone yet to be used to measure function of buprenorphine maintenance, the continuous performance task (CPT) and the Iowa Gambling task (IGT). If the common presumption of buprenorphine as impairing is correct, this should be evident in before and after measures of these tests.
Data was collected from a retrospective chart review of patients enrolled in a medically managed intensive outpatient program that uses frequent neurocognitive testing. As an anonymous retrospective chart review, the research was granted exempted status by Crescent city IRB. The participants were 38 sequential opioid dependent admissions from August to December 2012 who both received buprenorphine and had both before and after testing. There were 21 males and 17 females. To evaluate the effects of buprenorphine and not other medications or other aspects of the program, only the tests directly before and after being prescribed buprenorphine were examined.
Cog Testing: Iowa Gambling Task & Continuous Performance Task
Measures of cognitive ability: the Iowa Gambling task (IGT) and the continuous performance task (CPT) were used to determine cognitive impairment. The testing occurred on a desktop computer in an undisturbed room at the treatment center using the freeware PEBL.
The IGT is a card task that measures reward overvaluation (35). The goal of the task is to win as much money as possible in 100 trials picking from four possible decks. Each participant starts with a $2000 loan. After each card selection, a reward and a penalty are given to the participant. The reward depends on the deck you choose, while the penalty is different for different cards in the deck. Graphics at the bottom of the screen display the earnings or losses acquired. The IGT is a measure of reward overvaluation, a hardwired symptom of low dopamine tone (36). Those with reward overvaluation also initially sample all of the decks, but then go on to lose money. Reward overvaluation caused by low midbrain dopamine tone occurs when rewards are overvalued and risks unrecognized.
The CPT is a go/no-go task measure of attention and impulsivity. Using the letter “X” as the non-target stimuli and all other letters as target stimuli; responses were recorded using the spacebar. Over a 14 minute period the letters cycle through three distinct intervals between letters: one, two, and four seconds. The goal of the test is for the participant to respond as quickly and accurately to target stimuli, while not responding to non-target stimuli. The major variables the CPT produces are target accuracy, foil accuracy, and reaction time means for correct & error responses. Target accuracy accounts for the rate at which the participant correctly responds to the target stimuli. Foil accuracy accounts for the rate at which the participant correctly did not respond to non-target stimuli. Mean reaction time measures the average amount of time between presentation of the stimuli and the participants’ response at that interval. These measures are calculated for each block (1, 2, & 4 seconds) of stimuli.
The IGT and CPT were given together by an administrator. The administrator led each participant into an undisturbed room and seated them at a desk with a computer monitor. The administrator then opened the testing program PEBL, explained the gambling and impulsivity testing about to take place, and exited the room as the participant began. The testing lasted about 25 minutes on average. After each testing session the administrator recorded the results. Participants were tested at the very beginning of the treatment program, after symptom scores stabilize and/or change in medication, and upon discharge from the program.
A one-way within subjects ANOVA was conducted using the software JMP to compare the effects of buprenorphine on IGT and CPT scores. A significant difference in IGT scores between the pre and posttest conditions was found with buprenorphine medicated patients having higher average scores than in the pre medication condition, F (74) = 10.74, p=.0016.
Target accuracy on the CPT did not differ significantly in any of the time blocks between pre- and post-tests.
A significant difference in foil accuracy was found between the pre and posttests in both the two second block, F (74) = 10.81, p=.0015, and the four second block, F (74) = 5.41, p=.0228 with medicated patients showing improvement over their pre-medicated condition. No statistically significant difference was found for the one second block.
Using tests close together allows examination of the impact of the drug while minimizing the benefits of the additional addiction therapy. The practice effect was not a factor because the pre drug test was not the first time all of the participants were tested.
The IGT is a measure of reward overvaluation, a hardwired symptom of low dopamine tone. Reward overvaluation occurs when rewards are overvalued and risks unrecognized. The magnitude of motivation positively correlates with the incentive salience of reward-related cues and the reward itself (37), thus allowing the behavioral mechanisms to be carried out to fruition without regard for any impediments or distractions. If reward overvaluation can be decreased even an impulsive patient will at least not be impulsive with the same dangerous behaviors as before. The data support that buprenorphine maintenance treatment does not worsen reward overvaluation. This has tremendous implications for buprenorphine maintenance therapy demonstrating that buprenorphine in a clinical population does not impair this executive function.
Similarly, low foil accuracy on the CPT is related to decision-making impairments: impulsivity and inattention (38). A normal brain, when given more time, will take more time to notice the “X” and increase accuracy. A brain with low midbrain dopamine will, instead, speed up in an attempt to speed up the computer. The data are supportive of the thesis that impulsivity and attention are not worsened with buprenorphine treatment.
Generally, target accuracy is used as a proxy for attention, but it has been noted by us that only severely impaired patient or patients who do not understand the directions score less than 90% accuracy; rendering this statistic of questionable use to the study question. Target accuracy was examined only to confirm the integrity of the testing.
In summary, reward overvaluation and impulsivity did not worsen after the introduction of prescription buprenorphine in a clinically relevant population. Evidence from the current research does not support the currently prevalent idea that introduction of buprenorphine opioid maintenance treatment will impair patients. The research may also lend support to the subjective report of opioid dependent maintenance patients that they actually function better when prescribed buprenorphine.
Limitations of the current study include the small sample size and the geographical constraints of using an outpatient facility. Both of which are factors that deserve attention in future replication of this research.
Anecdotally other addiction patients, outside of this study, at the same facility indicated feelings of frustration intolerance during the CPT and during the long (4sec.) block. They began to answer rapidly to try and “speed up the test” to no avail. Future research would benefit by looking at the implications the CPT may have on frustration intolerance in clinical populations. Also future studies could further investigate the relationship between genetics, testing, and dopamine and serotonin levels on reward overvaluation to better pinpoint at risk genotypes.
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