The COMT rs4680 Met Allele Is Associated with High Impulsivity, Hyperactivity and Inattention in Patients with Opioid Use Disorder

Abstract

Background: Previous research has linked opioid use disorder (OUD) to neuronal reward systems and impulsivity. The aim of this study was to examine the influence of COMT rs4680 Val158Met polymorphism on impulsivity, hyperactivity and inattention (IHI) in patients with OUD. Methods: Open-label, cross-sectional cohort study was conducted involving individuals, 18 to 65 years, with OUD who either were included in opioid agonist treatment (OAT)—or same group of individuals who were awaiting induction on extended-release naltrexone (XR-NTX). Adult ADHD Self-Report Scale 18-item version was used to score IHI, and saliva samples were collected for genotyping (TaqMan assays). Logistic regression models were used to analyze the data. Results: The data of the entire cohort (n = 206) showed that carriers of one or two Val alleles had a negative association with IHI compared to Met/Met carriers (Val/Met OR = 0.43, p-value = 0.017, and Val/Val OR = 0.29, p-value = 0.005). Individuals included in OAT not waiting for XR-NTX (n = 120) exhibited the same pattern as observed in the entire cohort (Val/Met OR = 0.33, p-value = 0.019, and Val/Val OR = 0.18, p-value = 0.004), but not those who chose XR-NTX (Val/Met OR = 0.60, p-value = 0.353, and Val/Val OR = 0.47, p-value = 2.779). Conclusions: The present study revealed that individuals with OUD carrying the COMT rs4680 Val allele had lower IHI scores than Met/Met carriers. Hence, in individuals with OUD, the COMT rs4680 Met allele is associated with higher IHI symptom burden.

1. Introduction

Earlier data show that opioid use disorder (OUD) may be associated with high impulsivity, cognitive impairment and neuropsychological deficits [1,2]. The association between OUD and impulsivity may be linked to dopaminergic and opioid-activated reward mechanisms in the prefrontal cortex (PFC) and in the striatum [3]. In particular, the transmitter dopamine (DA) plays an important role in impulsivity driven by reward [4], with previous data showing that D2/D3 receptor availability may be associated with both impulsivity, but also hyperactivity and inattention; for review, see [5]. Dysfunction or unbalance of DA levels or receptor affinity may be associated with addiction [4], as well as attention-deficit/hyperactivity disorder (ADHD) [6].

Impulsive behaviour frequently observed in OUD demonstrates substantial interindividual variability, which may be partially attributed to environmental factors. In addition, interindividual biological differences related to reward and impulsivity may play a role as well [3]. Several recent studies suggest that impulsivity may be affected by genetic factors related to the dopaminergic function [7,8,9]. Thus, as described below, we think the function of the dopaminergic system may exhibit alterations in symptom burden among opioid users as well. In individuals with OUD, genetic factors related to dopamine may also influence pain perception [10].

Activation of the opioid systems widely affects the brain areas with high concentrations of DA receptors, such as the PFC, amygdala and hippocampus, which are areas involved in reward and impulsivity [3]; see review [11]. This supports the hypothesis that impulsivity may be a precursor for, or potentially increase the risk of, substance use disorder (SUD) [12]. However, there might be a bidirectional relationship in this process. As one of the most commonly used medications to reduce pain [13], opioids have been suggested to promote impulsivity [6]. In addition, individual factors such as genetic variability may influence such neuronal behavioural processes. Of particular importance is the catechol-O-methyltransferase (COMT) enzyme that breaks down catecholamines such as dopamine (DA) in the PFC [14,15].

In the PFC and striatum, the COMT enzyme accounts for approximately 60 and 15% of the DA degradation, respectively [16]. Since individuals carrying two copies of the single nucleotide polymorphism (SNP) COMT rs4680 Met have approximately 40% lower enzyme activity than those with two copies of COMT rs4680 Val [17], people with COMT rs4680 Met/Met have increased DA levels in the PFC. It has therefore been suggested that Met carriers have a higher dopamine tone, reward sensitivity and dopaminergic brain activity subsequent to rewarding cues; see review [5]. Disruption of DA signalling is also a core feature of neuropsychiatric conditions like ADHD, which is characterized by cognitive symptoms [18].

Previous findings suggest that COMT rs4680 may influence the response to opioid antagonists in certain SUDs such as alcohol use disorder [1]. In addition, the effect of opioids could be associated with other factors such as age, gender and OPRM1 rs1799971 SNP [19]. However, the early literature did not provide conclusive evidence regarding the association between the COMT rs4680 polymorphism, specifically the effect of the Val versus Met alleles, and impulsivity, hyperactivity and inattention (IHT). Some studies showed lower IHI scores for Val carriers and higher IHT scores for those with two copies of Met [20], whereas others showed no such clear associations [4]. Also, the effect of the COMT genotype was not addressed in the OUD population.

Interestingly, several recent studies continue to suggest that impulsivity may be influenced by genetic factors, such as the COMT rs4680 polymorphism [7,8,9]. Thus, the aim of the present study was to investigate the influence of the COMT rs4680 genotype on the IHI score in patients with OUD. Due to the low number of individuals carrying the rare alle of the OPRM1 rs1799971 SNP, OPRM1 rs1799971 was included as a covariate. We demonstrate that individuals with OUD who carry the COMT rs4680 Met allele may exhibit higher IHI scores compared to those with the Val allele.

2. Methods

2.1. Design

This exploratory study was part of a larger clinical cohort study where the patients with OUD were offered monthly injections of intramuscular XR-NTX (NaltRec study) or continued already ongoing opioid agonist treatment [21]. The patients were recruited between September 2018 and September 2020. The final patient visit at week 24 was in March 2021.

2.2. Ethical Approval and Informed Consent

Ethical approval for the NaltRec trial, including the present study, was granted by the Norwegian Regional Committee for Medical and Health Research Ethics of South East Norway (#2018/132) by the Personal Data Protection Representative for each of the sites and by the Norwegian Medicine Agency [22]. The trial is registered at ClinicalTrials.gov (#NCT03647774), the European Union Clinical Trials Register (#2017-004706-18), and complies with the Declaration of Helsinki. All participants provided written informed consent for their participation including genotyping. The study treatment was provided free of charge, and participants received no payment or economic compensation for their participation, except for reimbursement of travel expenses if public transportation was used.

2.3. Participants and Setting

Participants were recruited between September 2018 and September 2020 from addiction clinics in five urban hospitals in Norway (both in- and outpatient). Eligible participants were men and women aged 18–65 years with OUD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria [22]. Exclusion criteria were alcohol use disorder or serious somatic (e.g., liver failure) or psychiatric illness (e.g., psychosis) or the need for intensive medical treatment that would clearly interfere with study participation. Women of childbearing potential could not be pregnant or lactating and were required to agree to use effective birth control if receiving study medication.

2.4. Screening and Study Interventions

Screening was typically conducted in an outpatient setting. The process began with obtaining written informed consent, ensuring that inclusion criteria were met and exclusion criteria were not present. Screened eligible participants who wanted to end the use of opioids with support from treatment with XR-NTX were referred to an inpatient unit for a medically managed withdrawal and induction procedure for XR-NTX [22,23]. The majority of participants in the XR-NTX group (64%) were recruited from OAT clinics, while 36% were recruited from other settings (e.g., inpatient clinics and primary care).

Participants already in the Norwegian OAT programme continued their usual treatment with either buprenorphine or methadone. Detailed information on study induction and procedure has previously been described [22]. Briefly, participants were interviewed using the European version of the Addiction Severity Index (EuropASI). The outcome variables were retention in treatment and days of overall opioid use, including buprenorphine, methadone and other illicit opioids. Data regarding substance use were collected through an interview using the timeline follow-back technique, whereby participants reported the number of days of use within the last 4 weeks. Participant-reported data regarding the use of opioids were also corroborated by a urine sample. Craving for heroin, treatment satisfaction, and willingness to recommend XR-NTX to others were measured as well.

2.5. Instruments

To assess IHI, the self-administered Adult ADHD Self-Report Scale 18-item version (ASRS-18) was completed at screening [24]. The questions assessed a combination of impulsivity, hyperactivity and inattention with the response to each question graded from 0 to 4 (“never”, “rarely”, “sometimes”, “often” and “very often”). Dichotomization was conducted for all questions in line with previous research [24,25]. A final outcome score was then calculated (range 0–18), which was dichotomised where ≥9 indicated an overall clinical symptom level [25].

2.6. Genotyping

The participants consented to provide a saliva sample for genotyping. To extract genomic DNA from the saliva samples, OrageneRNA sample collection kit (DNA Genotech Inc. Kanata, Ontario, Canada) was used. Predesigned TaqMan Single SNP assays (Applied Biosystems, Foster City, CA, USA) were used for genotyping. Approximately 10 ng of genomic DNA was amplified in a 5 µL reaction mixture in a 384-well plate containing 1× TaqMan genotyping master mix (Applied Biosystems) and 1× assay mix, the latter containing the respective primers and probes. The probes were labelled with the reporter dye FAM or VIC to distinguish between the two alleles. In accordance with the procedure in earlier studies [10], an ABI 79000HT sequence detection system was used. Negative controls were included in every run. Approximately 10% of the samples were re-genotyped, and the concordance rate was 100%.

2.7. Statistical Analyses

To assess the association between COMT Val158Met, treatment group, and IHI, logistic regression analyses were performed. Step 1 assessed the main effects of treatment and genotype on impulsivity. Step 2 assessed the interaction between treatment and the different genotypes. All logistic regression analyses were adjusted for age, gender and OPRM1 rs1799971 SNP. The analyses were performed using STATA/SE 16.0 (StataCorp, College Station, TX, USA). p-value < 0.05 was deemed statistically significant.

3. Results

A total of 312 participants were considered eligible for the study. These were the individuals we wanted to include, follow up with a questionnaire and later with genotyping. However, participants could choose whether to join the study and were also free to leave at any time without providing a reason. Among the 312 who were considered eligible and included in the study, only 210 consented to genotyping and provided saliva samples of sufficient quality. Therefore, the first part of the descriptive data was based on 312 participants, whereas the rest of the study, i.e., the genetic part, was based on 210 participants.

The mean age of the participants were 40.5 years of age, with a majority being male (71%). No significant deviation from the Hardy–Weinberg equilibrium (Chi-square test p > 0.10) was observed. An overview of the baseline characteristics can be seen in

Table 1. Characteristics for included OAT participants (n = 312).

	OAT Group; Not Waiting for XR-NTX	XR-NTX Group; Waiting for XR-NTX	All
ASRS ≥ 9 (%) ASRS mean (SD) missing	60 (41) 2.81 (0.80) 2	65 (40) 2.90 (0.74) 5	125 (41) 2.86 (0.76) 7
Age, mean (SD)	43.7 (9.95)	37 (9.53)	40.5 (10)
Male, n (%) missing	81 (63) 19	113 (78) 19	194 (71) 38
rs4680, n (%) Met/Met Met/Val Val/Val missing	32 (26) 63 (52) 26 (22) 27	25 (28) 44 (49) 20 (22) 75	57 (27) 107 (51) 46 (22) 100
rs1799971, n (%) AA G* missing	106 (87) 16 (13) 26	68 (78) 19 (22) 77	174 (83) 35 (17) 103

ASRS—adult ADHD self-report scale; n—number; OAT—opioid agonist treatment; SD—standard deviation; XR-NTX—extended-release naltrexone.

. ASRS mean and dichotomised score stratified by genotypes can be seen in

Table 2. Frequency of genotype and ASRS score.

	ASRS Dichotomised		ASRS Score, Mean (SD)
Genotype	<9	≥9	Range 0–18
rs4680 (COMT) Met/Met Met/Val Val/Val	25 66 31	32 41 14	2.99 (0.81) 2.83 (0.73) 2.72 (0.80)
rs1799971 (OPRM1) AA G*	100 24	74 11	2.87 (0.77) 2.64 (0.79)

ASRS—adult ADHD self-report scale, COMT—catechol-O-methyltransferase, OPRM1—opioid receptor mu 1, *—AG and GG variant combined, SD—standard deviation.

.

Step 1 of the logistic regression analyses showed a negative association between Met/Val and the Val/Val genotype compared to the patients with the Met/Met genotype on IHI (OR = 0.43, p-value = 0.017 and OR = 0.29, p-value = 0.005, respectively). This indicates that being a carrier of one or two Val alleles is associated with lower IHI. However, in step 2, when including the interaction effect between treatment group and genotype, no statistically significant results presented (

Table 3. Separate logistic regression analyses on the association between group and COMT rs4680 on dichotomised IHI (n = 206); main effects (step 1) and interaction effects (step 2).

Main Effect (Step 1)	OR	p	CI
Group	0.62	0.155	0.32 to 1.19
Genotype (ref Met/Met)
Met/Val Val/Val	0.43 0.29	0.017 0.005	0.22 to 0.86 0.12 to 0.68
Interaction Effect (Step 2)	OR	p	CI
Group × Genotype Met/Val Val/Val	1.92 2.94	0.352 0.220	0.48 to 7.61 0.52 to 16.56

CI—confidence interval; IHI—impulsivity, hyperactivity and inattention; n—number; OR—odds ratio; p—p-value; ref—reference. All analyses are adjusted for OPRM1 rs1799971, age and gender.

).

Further, separate logistic regression analyses were conducted for COMT rs4680 stratified by treatment group. The analysis for the OAT group showed that carriers of the Met/Val and Val/Val variants were negatively associated with IHI compared to Met/Met carriers (OR = 0.33, p-value = 0.019 and OR = 0.18, p-value = 0.004, respectively). Analysis of the XR-NTX group presented no statistically significant results (

Table 4. Separate logistic regression analyses on the association between COMT rs4680 and IHI stratified by treatment group (OAT = 120, XR-NTX = 86).

OAT	OR	p	CI
Genotype Met/Val Val/Val	0.33 0.18	0.019 0.004	0.13 to 0.83 0.05 to 0.59
XR-NTX	OR	p	CI
Genotype Met/Val Val/Val	0.60 0.47	0.353 0.279	0.20 to 1.75 0.12 to 1.81

CI—confidence interval; IHI—impulsivity, hyperactivity and inattention; OAT—opioid agonist treatment; OR—odds ratio; p—p-value; XR-NTX—extended-release naltrexone. All analyses are adjusted for OPRM1 rs1799971, age and gender.

).

4. Discussion

The main finding of the study was that the COMT Val allele was associated with a lower odds ratio of IHI in patients with OUD receiving OAT compared to the Met/Met carriers. Hence, our data showed that the Val allele may have a protective effect regarding IHT symptoms in patients receiving OAT. However, there were no statistically significant interaction effects between the COMT genotype and the different treatment groups. Moreover, separate analyses of the data for each treatment group showed that the effect of the COMT genotype was significant only in the OAT group (not waiting for XR-NTX) but not in the XR-NTX group (waiting for monthly XR-NTX injections). Thus, only opioid users carrying the COMT rs4680 Val allele, that did not choose XR-NTX, seemed to have a lower IHI burden than Met/Met carriers.

Importantly, only a few of the XR-NTX patients in the present study had begun contemplating strategies to reduce their opioid use prior to responding to the IHI questionnaire. Therefore, a clear effect in the OAT group, but no effect in the XR-NTX group, was a little surprising as previous data indicate homogenous psychosocial characteristics among patients in both treatment groups [26]. Still, we observed a distinct difference between the groups concerning the influence of the genetic variant. Clearly, individuals who chose to discontinue their opioid use with XR-NTX had no clear protective effect of the COMT Val genotype. This observation prompts speculation that those who chose XR-NTX might differ from other patients in certain respects. For instance, they were willing to commit to a decision that could not be reversed for a period of one month, after every injection. Additionally, they were on average five years younger and might have been more receptive to novel treatments, willing to take the risk of not experiencing the effects of opioids.

Prolonged use of drugs that affect opioid signalling, along with the expectations associated with new treatments, may both influence cognitive function, mental state and optimism. For example, previous data suggest that the use of opioid agonists such as methadone is linked to impaired selective attention and impulsivity [27], whereas use of opioid antagonists like naltrexone can reduce urge-related symptoms, such as impulsivity [28,29]. Hence, in patients with OUD who still use opioid agonists, the unpredictable use of opioid medication may have influenced cognitive performance that, in turn, affected the data collected by the IHI questionnaire. Therefore, we cannot rule out the possibility that individual differences in daily opioid use may have influenced patient performance, which could, in turn, affect our results.

Nevertheless, individuals with SUD, including those with OUD, tend to show a preference for immediate reward over delayed gratification, a behaviour commonly associated with impulsivity. It has been suggested that chronic illicit exposure to, e.g., heroin, i.e., stimulating the opioid system, may exacerbate ADHD-like symptoms such as impulsivity, hyperactivity and inattention [1,30]. Previous research suggests that there might be a reciprocal relationship between SUD and disorders with high IHI [31], which are both related to the reward system. Altered natural DA levels, metabolism and/or receptor availability [32] and inadequate DA activity may increase the risk of risk behaviour such as substance abuse [33].

Hence, one could speculate that SUDs are related to the dopaminergic reward mechanisms that, in turn, may be dependent on genetic factors. Considering the findings in the present paper, it would be of interest for future studies to collect IHI scores after implementing the same detox regime. In doing so, future investigations would also be able to assess for any potential influence of genetic variants on the effect of OAT versus XR-NTX treatment over time as well.

Limitations

First, the candidate gene approach is generally a method that normally requires a higher number of participants than what was included in each subgroup, OAT and XR-NTX, in this study. In particular, the data of the smallest XR-NTX group should be interpreted with caution.

Next, although all OAT and most participants in the XR-NTX patients were recruited from typical OAT clinics, others, i.e., 36% of the XR-NTX patients, were recruited from other settings. Therefore, the XR-NTX group was likely more heterogeneous in terms of opioid use, as some members continued to use illegal opioids.

Finally, we decided to focus on COMT and simply adjust for the OPRM1 genotype in our logistic regression analyses. If the number of individuals was higher, it would have been a strength to include two or more genetic factors as well.

5. Conclusions

The present study revealed that individuals with OUD carrying the COMT rs4680 Val allele had lower IHI scores than Met/Met carriers, indicating that the COMT rs4680 Met allele is associated with a higher IHI symptom burden in these individuals. Thus, our data support the hypothesis that the variability of impulsive behaviour observed in opioid use disorder (OUD) may be associated with the genetic factor COMT rs4680. Consequently, this study demonstrates that this genetic factor, related to the dopaminergic system in the brain, may contribute to explaining interindividual variability in impulsive behaviour among individuals with OUD. Why this effect was not observed in the subgroup of patients seeking opioid abstinence through XR-NTX treatment remains to be investigated.