Towards a Comprehensive Theory of Non-Cancer Acute and Chronic Pain Management: The Critical Role of Reactive Oxygen and Nitrogen Species in Pain, and Opioid Dependence, Addiction, Hyperalgesia, and Tolerance

•The opioid epidemic is considered the most consequential public health crisis in America•Oxidative/Nitroxidative stress plays a critical role in pain, opioid dependence, tolerance, addiction, and hyperalgesia.•Oxidative/Nitroxidative stress modulates pain exacerbating factors.•The best way to treat pain that does not require surgery is an integrated approach aimed at attenuating oxidative/nitroxidative stress. In the past three decades, prescription opioid use has increased dramatically in the United States (US). This has resulted in opioid addiction, increased overdose deaths, and switch to heroin and illicitly manufactured fentanyl use. Although there has been a reduction in opioid prescriptions from peak levels, they remain critical in pain management. The objective of this narrative review is to discuss the complex role of reactive oxygen and nitrogen species in opioid adverse effects, pain, and pain management. PubMed/Medline, PsycINFO, PubMed Central, and EBSCO were accessed for published articles between January 1, 1970, and February 20, 2021. 419 relevant articles including preclinical studies, randomized clinical trials, observational studies, meta-analyses, narrative and systemic reviews were selected. Reactive oxygen and nitrogen species play a critical role in pain, and opioid dependence, tolerance, addiction, and hyperalgesia. Oxidative/Nitroxidative stress modulates the complex relationship between pain, opioids, and pain exacerbating factors. Opioids remain useful in both acute and chronic pain management but should be used cautiously and at specific times aided by tools assessing patient's risk of opioid abuse and pain chronicity. The best way to treat pain that does not require surgery is an integrated approach aimed at attenuating oxidative/nitroxidative stress which includes lifestyle changes, sleep improvement, diet, exercise, stress reduction, patient education, and opioid-free multimodal analgesic (MMA) regimen. For non-emergency treatment/surgeries, moderate and high-risk patients for increased pain chronicity and poor pain treatment outcomes should be recommended to engage in activities that attenuate oxidative/nitroxidative stress 4-8 weeks before treatment/surgery. The same activities should be recommended for such patients in emergency and non-emergency situations 4-8 weeks post-treatment/surgery.