Opioid misuse has led to an unprecedented crisis, with more than 3 million people in the United States experiencing dependence or addiction (1). Despite the success of in-patient rehabilitation programs, relapse rates are approaching 90%, creating a critical need for effective relapse prevention strategies (2). To address this, researchers from Boston University and Icahn School of Medicine asked whether long-term changes in gene transcription occur after opioid withdrawal. Their analyses identified a novel epigenetic mechanism involved in difficult withdrawal symptoms that could influence dependence and relapse (3).
The Rise of the Opioid Epidemic
Use of opioids has increased dramatically in the United States from 76 million prescriptions in 1991 to more than 250 million in 2012 (4). Aggressive marketing strategies contributed to this increase despite evidence suggesting that opioids are not better at controlling pain than non-opioids like non-steroidal anti-inflammatories (5,6). As rates of use and misuse increased, the number of opioid-related deaths doubled from 2010 to 2017 (1).
In response, medical societies and the US Centers for Disease Control updated their prescribing guidelines to limit opioid prescriptions in favor of non-opioid alternatives (7). As a result, the number of prescriptions decreased to about 140 million by 2020 (8). Even at this lower level, however, the dispensing rate was still 43.3 prescriptions per 100 people in the US, and deaths continued to rise due to misuse (8).
Biological Effects of Opioids
Opioids like oxycodone and fentanyl bind to one of three opioid receptors that are expressed throughout the body. Activation of these receptors in the brain and spinal cord produces potent pain relief and pleasant feelings (9). In addition to their analgesic effects, however, opioids can also induce physical dependence, decreased breathing and heart rate, nausea, and vomiting (9). These secondary effects contribute to the risk of overdose and death.
Use and Misuse Leading to Addiction
Overprescribing and misuse of opioids led to a significant increase in substance use disorders. The addictive properties of opioids are caused by increased excitability of neurons that release dopamine in the reward pathways of the brain (10). Intense feelings of pleasure that are reinforced by dopamine further contribute to physical and psychological dependence. To complicate this issue, tolerance develops as the brain attempts to maintain a typical system, and higher doses are required for an individual to achieve the same feelings. This escalation requirement makes cessation more difficult and increases the risk of addiction (11).
A Better Understanding of Addiction
Inpatient treatment for opioid addiction has a high success rate. However, relapse rates are between 72 and 88% at 12 or more months after treatment, suggesting a long-term mechanism that affects the neurons involved in the reward circuits in the brain (). Researchers, therefore, asked whether there are transcriptional effects induced by opioids that could represent novel targets for helping people who are struggling with addiction.
New Research Addresses Relapse
Researchers were interested in effects that persist after withdrawal from opioids that could be mediated by epigenetic modifications induced by the drugs and chronic neuropathic pain (3). They used a mouse model of nerve pain to examine the effects of opioid withdrawal in regions of the brain relevant to the reward system.
After mice with neuropathic pain received oxycodone for 2 weeks, administration was stopped to induce withdrawal. Three weeks later, researchers tested the animals for depression and anxiety-like behaviors and measured transcriptional changes in their brains.
Similar to humans who have experienced withdrawal from opioids, mice developed painful responses to non-painful stimuli (allodynia). Withdrawal also caused mice to be less social, exhibit anxiety-like symptoms, and be less resilient when faced with stress. These effects occurred regardless of whether the mice had a nerve injury that caused neuropathic pain, making the model relevant to people who misuse oxycodone.
When researchers examined gene transcription in the brains of the mice, they observed transcriptional changes in neurons involved in reward pathways that persisted for weeks after the drug was stopped. Interestingly, a subset of these genes was regulated differently when oxycodone was given to animals with nerve injury. The genes included histone deacetylases (HDACs), epigenetic modifiers that restrict access of transcription factors to DNA.
A Treatment to Address Dependence and Relapse?
To determine whether inhibiting HDACs could represent a potential therapeutic for withdrawal, they administered a novel class I HDAC inhibitor, Regenacy Brain Class I Inhibitor (RBC1H1), to the mice. Mice that received the inhibitor exhibited less hypersensitivity and fewer emotional effects after opioid withdrawal. Effects were most significant in mice with nerve injuries but could be transferrable to settings where neuropathic pain causes high sensitivity to stimuli.
The authors suggest that class I HDAC inhibitors like RBC1H1 could ease allodynia during withdrawal and reduce relapse in people with long-term opioid exposure. Further investigation into the genes that are influenced by RBC1H1 could help identify targets for the prevention of dependence. Importantly, the research represents a new tool for managing the opioid epidemic, especially in individuals seeking help with the difficult withdrawal process.
- National Institute on Drug Abuse. Drug overdose death rates. Updated February 9, 2023. Accessed June 26, 2023.
- Chalana H, Kundal T, Gupta V, et al. Predictors of relapse after inpatient opioid detoxification during 1-year follow-up. J Addict. 2016;2016:7620860. doi: 10.1155/2016/7620860.
- Pryce KD, Serafini RA, Ramakrishnan A, et al. Oxycodone withdrawal induces HDAC1/HDAC2-dependent transcriptional maladaptations in the reward pathway in a mouse model of peripheral nerve injury. Nat Neurosci. 08 June 2023. doi: 10.1038/s41593-023-01350-3.
- Cicero T, Ellis M. The prescription opioid epidemic: a review of qualitative studies on the progression from initial use to abuse. Dialogues Clin Neurosci. 2017 Sep;19(3):259-269. doi: 0.31887/DCNS.2017.19.3/tcicero
- Chaparro LE, Furlan AD, Deshpande A, et al. Opioids compared with placebo or other treatments for chronic low back pain: an update of the Cochrane Review. Spine. 2014;39(7):556-63. doi: 10.1097/BRS.0000000000000249.
- Van Zee A. The promotion and marketing of OxyContin: commercial triumph, public health tragedy. Am J Public Health. 2009 February;99(2):221-227. doi: 10.2105/AJPH.2007.131714
- Dowell D, Ragan KR, Jones CM, et al. Prescribing opioids for pain – the new CDC clinical practice guideline. N Engl J Med. 2002;387:2011-2013. doi: 10.1056/NEJMp2211040.
- Centers for Disease Control and Prevention. US opioid dispensing rate maps. Accessed June 23, 2023.
- Stein, C. Opioid receptors. Ann Rev Medicine. 2016;67:433-451. doi: 10.1146/annurev-med-062613-093100.
- Kosten TR, George TP. The neurobiology of opioid dependence: implications for treatment. Sci Pract Perspect. 2002 Jul;1(1):13-20. doi: 10.1151/spp021113.
- Dumas EO, Pollack GM. Opioid tolerance development: a pharmacokinetic/pharmacodynamic perspective. AAPS J. 2008 Dec;10(4):537. doi: 10.1208/s12248-008-9056-1.