Introduction
Sleep disorders were frequently reported by opioid-dependent patients during methadone maintenance therapy (MMT) [
1‐
6]. Patients on MMT demonstrated disrupted sleep including increased stage 2 sleep and decreased REM sleep and stage 1 sleep compared to age, sex, and body mass index (BMI) matched normal subjects [
7]. In addition, they reported significantly worse daytime function, were more depressed, and had increased daytime sleepiness when compared to the control subjects [
8]. The sleep disturbances among opioid-dependent patients on MMT contributed to premature exit from treatment [
9‐
11], increased use of medications (prescribed or “over the counter”) to help with sleep [
1‐
3], and increase in chronic depressive symptoms [
8,
12]. The sleep disturbances also impacted on quality of life and could impair engagement with treatment leading to continued drug use [
1,
5,
12].
Previous studies showed that opioids affected sleep by acting on both sleep- and wake-promoting systems at the pontine reticular formation (PRF) and the substantia innominata within the basal forebrain (BF) [
13]. In the PRF, the administration of opioids decreased adenosine levels and this was dependent upon opioid receptor, mu 1 gene (OPRM1) agonism, and subsequently resulted in sleep disturbance-related side effects of opioids [
14].
Opioid drugs, including morphine, fentanyl, and methadone, are agonists of the μ-opioid receptor which is encoded by the OPRM1 gene. It has been suggested that the efficacy and side effects of commonly used opioids are associated with their affinity for μ-opioid receptor. Some of the
OPRM1 polymorphisms that affect the density and function and consequently the signaling efficacy of μ-opioid receptors may contribute to interindividual variations in the response to opioids [
15‐
17]. 118A>G (dbSNP rs1799971, Asn40Asp) polymorphism is one of the most frequently studied polymorphisms of
OPRM1. It is found in exon 1 and may greatly affect the μ-opioid receptor
N-glycosylation and reduced stability of the receptor in cell cultures [
18].
N-Glycosylation plays a part in many cellular processes like receptor folding, sorting, expression, and ligand binding. IVS2 + 691G>C (dbSNP rs2075572) polymorphism at 691 bp downstream of exon 2 is located within intron 2 [
19‐
21]. The polymorphism might change the regulation of the expression of OPRM1 gene and might also cause formation of different isoforms of human μ-opioid receptor [
20,
22].
A few studies have reported on the association between methadone treatment and
OPRM1 polymorphisms [
23‐
27]. Thus far, one study explored if the
OPRM1 polymorphisms could provide a possible explanation for the noted sleep problems of opioid-addicted individuals [
24]; unfortunately the role of the
OPRM1 individual’s pair of haplotypes (diplotype) remains uncertain because they did not consider analysis of
OPRM1 diplotype.
Recently, we published our data on the more clinically important aspects of pain sensitivity [
28]. We felt that it is also necessary to report our findings on the relationship between sleep quality and opioid genetic polymorphisms. Thus, in the present paper, our aim was to investigate sleep quality as sleep disorders were frequently reported by opioid-dependent patients during MMT. A better understanding of the role of
OPRM1 polymorphisms in sleep disturbance-related side effects of opioids has implications for the treatment of sleep and addictive disease, and clinical management of each in the presence of the other. To help resolve this we aimed to investigate the influence of
OPRM1 polymorphisms on sleep quality among opioid-dependent patients on MMT.
Discussion
Previous association studies have produced mixed results regarding
OPRM1 polymorphisms and methadone treatment efficacy, and side effects included changes in libido and insomnia [
24], in MMT response status in terms of illicit opioid use detection in random urinalysis [
25], in apparent susceptibility to methadone poisoning [
26,
27], and in both pain responses and opioid addiction [
23]. Among studies that focused on genetic polymorphisms related to pharmacodynamics of methadone, only one study investigated the association between the noted sleep problems of opioid-addicted individuals and polymorphisms in gene coding for the OPRM1 [
24]; unfortunately the role of the
OPRM1 individual’s pair of haplotypes (diplotype) remains uncertain because they did not consider analysis of
OPRM1 diplotypes.
Previously, Wang et al. [
24] found that the insomnia side effect was significantly higher in patients with IVS2 + 691 CC genotype than those without the genotype (IVS2 + 691 GG/GC genotype). Their results suggested that IVS2 + 691G>C polymorphism may participate in the regulation of the function of the OPRM1. Interestingly, in the current study, PSQI scores were 16.3% higher in patients with homozygous IVS2 + 691 CC genotype than those without the genotype (IVS2 + 691 GG/GC genotype); however, our results were statistically insignificant (
p = 0.081). Additionally, when the PSQI scores were compared using the diplotype approach, we found that patients with combined 118 AA genotype and IVS2 + 691 GC genotype (AC/AG diplotype) had 25.2% significantly lower PSQI scores compared to those without the diplotype. To the best of our knowledge, data on the influence of the
OPRM1 diplotype on sleep quality among opioid-dependent patients is not available for reference. However, this finding suggested that opioid-related adverse effects such as sleep problems were less likely to occur in patients with AC/AG diplotype at 118 and IVS2 + 691 in
OPRM1, given that a mechanism of opioid-induced adverse events involves OPRM1. Hence, results of the current study support the suggestion by Wang et al. [
24] that the OPRM1 gene and its transcript isoforms may be involved in the underlying cause of insomnia.
The exact molecular mechanism regarding the effects of AC/AG diplotype on the sleep quality is unclear. However, it is well established that, in general, the function of the OPRM1 is under the influence OPRM1 gene polymorphisms [
19‐
21]. The IVS2 + 691G>C polymorphism is predicted to change the affinity of transcriptional regulatory factors for the intronic DNA sequence and directly alter mRNA levels, and therefore it might change the regulation of OPRM1 gene expression. It was also shown that the DNA intronic sequence can be involved in alternative DNA splicing, resulting in different isoforms of human OPRM1 [
20,
22].
On the basis of our results, we suggest that strong linkage disequilibrium (LD) between these polymorphisms and other unstudied polymorphisms [
42,
43] formed a series of diplotypes which may affect OPRM1 expression or function (or both) at the site of its action in the brain and resulted in altered binding affinity between endogenous (and/or exogenous) opioid agents and the OPRM1, and hence diplotype differences may contribute to interindividual differences in sleep-disrupting effects of opioids.
Available data indicates that opioids affect sleep by acting on both sleep- and wake-promoting systems at the pontine reticular formation (PRF) and the substantia innominata within the basal forebrain (BF) [
13]. Opioids decreased adenosine levels in the PRF and this is dependent upon OPRM1 agonism, and subsequently resulted in sleep disturbance-related side effects of opioids [
14]. Our results support the hypothesis that patients with AC/AG diplotype had a higher ability to prevent opioid-induced decreases in adenosine and therefore resulted in lower susceptibility to sleep disturbances.
Some limitations to this study need to be highlighted. In our current study, we excluded patients with psychiatric illnesses such as schizophrenia, depression, and anxiety that are commonly associated with sleep disorder; the presence of these illnesses would be expected to increase the severity of sleep problems in our study subjects. Interestingly, although known psychiatric illnesses were one of our exclusion criteria, no participants were excluded because of this criterion. Non-genetic sleep-related factors among patients on MMT were not reported because the focus of the current manuscript was to look into pharmacogenetics factors associated with susceptibility to opioid-induced sleep disturbance among opioid-dependent patients on opioid maintenance therapy.
Patients without the AC/AG diplotype (
N = 141, 85.5%) had a mean PSQI score of 5.68 (SD 2.77), slightly above a cutoff score of 5, thus indicating poor overall sleep quality among them [
39]. We suggest that sleep disorders should be evaluated and treated among MMT patients, particularly in those without the AC/AG diplotype. Patients with sleep disorders tend to self-medicate to promote sleep or to stay awake during the day [
44]. Many of these patients may be at risk of significant drug–drug interactions resulting in ineffective treatment and enhanced side effects of the drugs which could have a profound impact on quality of life, health, and even could impair engagement with treatment leading to continued drug use [
1,
5,
12].
Further studies are needed to study other OPRM1 polymorphisms and genetic variations of other sleep-related genes and genes related to pharmacokinetics and pharmacodynamics of methadone, and to obtain data on endogenous adenosine concentration and data on the functional effects of AC/AG diplotype on OPRM1 expression or function in the brain.
Acknowledgments
We wish to thank Prof. Howard McNulty of the Institute of Pharmacy and Bio-medical Sciences University of Strathclyde Glasgow UK for English language editing and proof reading of this article. We are grateful to Nur Amalina Che Rahim and Wan Izzati Mariah Binti Wan Hassan from the Department of Pharmacy, Hospital Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia; Hazwan Bin Mat Din and Wan Nor Arifin Wan Harun, Biostatistics and Research Methodology Unit, School of Medical Sciences, Universiti Sains Malaysia; and all the members of Pharmacogenetics and Novel Therapeutics Cluster, Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia (USM) for their support and valuable suggestions during the study. The study was funded by the Universiti Sains Malaysia (USM) grant under the ‘Research University Cluster (RUC)’ Grant No.1001.PSK.8620014, under the project Application of Personalised Methadone Therapy Methadone Maintenance Therapy (PMT for MMT). All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.