Opioid Use Disorder Induces Oxidative Stress and Inflammation: The Attenuating Effect of Methadone Maintenance Treatment

Abstract

Objective: Frequent use of opioids produces reactive oxygen species, upregulates inflammatory factors, and contributes to opiate dependence. In this study, we examined perturbations of plasma oxidative and inflammatory markers in patients with opioid use disorder in two phases. In the first phase, we compared the oxidative status in patients with opioid use disorders and in healthy controls; and in the second phase, we examined oxidative changes before and after methadone maintenance treatment. Method: To explore whether oxidative changes were associated with opioid use disorder, we compared plasma oxidative and inflammatory markers in patients with opioid use disorder and in smoking and non-smoking healthy participants. All participants completed measures of catalase (CAT), glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), matrix metalloproteinase (MMP-9), and TNF-α at baseline. Baseline measures were compared using Kruskal-Wallis test. In the second phase, to explore oxidative changes during transition from opium use to methadone, blood and urine samples of patients with opioid use disorder were re-evaluated on Days 3, 7, and 14 after methadone therapy. Repeated measures analysis was used to determine the relative contribution of intervention to changes in CAT, GSH, MDA, SOD, MMP-9, and TNF-α level over time. Results: We observed lower SOD and catalase activities, and higher TNF-α and MMP-9 level in patients compared to the two comparison groups. Opioids exacerbated the oxidative imbalance and superimposed the underlying oxidative injury in smoker comparison group. Methadone therapy was associated with lower MMP-9 and TNF-α level, and higher SOD and catalase activities two weeks after therapy; showing an improvement in oxidative profile. Conclusion: This was an investigation indicating an oxidative imbalance before methadone therapy and during early days of transition from opium use to methadone. Being aware of redox status is crucial for determining an appropriate antioxidant therapy in opioid use disorder.

Keywords: Methadone Maintenance Treatment; Opioid Use Disorder; Oxidative Status.

Figure1

Schematic Representation of Experimental Procedures in Opioid Use Disorder Patients

Figure 2

Comparison of Erythrocyte Superoxide Dismutase (A), Catalase Activity (B), Glutathione (C), Plasma Malondialdehyde, MDA (D), Plasma MMP9 (E), Plasma TNF-α (F) in Non-smokers, Smokers and Patients with Opioids Use Disorder (before MMT). The Data Are Presented as Means ± SD. *P<0.05 Compared to the Non-smoker Comparison Group. †P<0.05 Compared to the Smoker Comparison Group

Figure 3

Comparison of Oxidative and Inflammatory Markers, 3, 7 and 14 Days after Methadone Therapy in Patients with Opioid Use Disorder. The Erythrocyte SOD (A) and Catalase Activity (B) Were Significantly Higher on Day 14 after Methadone Therapy. The Effect of MMT on GSH (C) and MDA (D) levels; as Shown, lower MDA level was Observed on Days 7 and 14 after MMT. The Plasma level of MMP-9 (E) and TNF-α (F) was lower on Days 7 and 14 after MMT. Data Are Expressed as Means ± SD. *P<0.05 Compared with Day-0 (before MMT)