Opioid use disorder (OUD) is a condition characterized by the misuse and abuse of opioids, which are drugs that are typically used for pain relief. These drugs include legal, prescribed medications, such as oxycodone and morphine, as well as illegal drugs, such as heroin. Opioids are also used as anesthetics during surgical procedures. In recent years, OUD has become an epidemic in the United States, and in 2017, The Department of Health and Human Services declared the opioid epidemic a public health crisis. The drastic increase in OUD is due in part to a misunderstanding of the addictive properties of opioids and a subsequent increase in the prescription of opioids for pain relief by doctors.1
To improve our understanding of the addictive nature of opioids, researchers are working to discover the mechanisms by which opioids act on the brain. Opioids attach to proteins called receptors, which are located on the surfaces of brain cells. There are three variants of cell-surface opioid receptors, and they differ in the types of opioids that they preferentially bind. Researchers have determined that one particular receptor variant is more likely than the others to be involved in opioid addiction.
Primarily, opioids work by inhibiting the release of chemicals called neurotransmitters, thereby reducing the transmission of signals that cause the sensation of pain.2 Patients with chronic pain as a result of traumatic brain injury (TBI) are often prescribed opioids for pain management. However, recent clinical practice guidelines do not support the use of opioids to treat pain associated with TBI.3 Studies have shown that OUD is more common in patients with mental health disorders, which can be caused or exacerbated by TBI. Moreover, some evidence indicates that opioid use can aggravate inflammation of tissue in the nervous system. Known as neuroinflammation, this symptom is one of the hallmarks of TBI, so further opioid-related tissue inflammation may be harmful to individuals with TBI.
A recent article published in the Journal of the American Medical Association Psychiatry explored the relationship between TBI and OUD.4 The authors of the study sought to understand the relationship between opioids and TBI-related neuroinflammation by studying the analgesic (or pain-relieving) effects of opioids. They approached this question by studying a patient who had experienced mild TBI in the course of military service. The patient was prescribed opioids to manage the symptom and subsequently developed an opioid dependence. This case study allowed researchers to characterize some properties of opioids and their long-term effects. They identified six major principles that help to explain the way opioids work in the human brain:
- Opioids activate receptors that decrease pain AND receptors that increase inflammation. Drugs such as morphine bind to receptors in the brain and produce an analgesic effect. Simultaneously, these drugs bind to receptors on cells in the immune system, which raises a physiological red flag and activates an immune response. Over time, repetitive activation of cells associated with the immune system causes increased pain.
- Multiple cellular pathways can be activated by a single opioid molecule binding to a single receptor. Activation of these pathways ultimately results in the same outcome: reduction in the activity of the nerve cell to which the opioid binds. This increases the analgesic effect of the opioid.
- Multiple receptors can activate a single cellular pathway upon opioid binding. This cellular pathway is also involved in decreasing activity of the nerve cell to which the opioid binds, so the effect of the opioid is amplified.
- Opioid molecules binding to a receptor can increase the number of receptors on the cell surface. Cellular receptors are not fixed in place; rather, they move on and off the cell surface depending on the needs of the cell and the environment around the cell. When a large number of opioid molecules interact with cell surface receptors, the cell sends more receptors to the surface to allow even more opioids to bind. This increases the effect of a given dose of opioids.
- There are genetic variants of opioid receptors that may increase the likelihood of opioid dependence. The patient in this study possessed a variant of the gene that codes for one type of opioid receptor. This gene variant produces a receptor that requires more opioid molecules to bind to have the same effect; this variant has also been shown the be involved in greater withdrawal symptoms, requiring more opioids to relieve the feeling of withdrawal.
- Opioid tolerance develops because receptors become less sensitive to opioid molecules. This requires an increased dosage of opioids to achieve the same pain-relieving effect, which increases opioid dependence.
Taken together, these finding further our understanding opioids and their long-term effects. Efforts to identify risk factors leading to opioid dependence allow physicians to develop treatment plans for patients with TBI that minimize the use of opioids for chronic pain management. Alternative treatments for chronic pain are critical to reducing the burden of the ongoing opioid crisis.
- Al-Hasani, Ream, and Michael R. Bruchas. "Molecular mechanisms of opioid receptor-dependent signaling and behavior." Anesthesiology: The Journal of the American Society of Anesthesiologists 115.6 (2011): 1363-1381.
- Seal, Karen H., et al. "Traumatic brain injury and receipt of prescription opioid therapy for chronic pain in Iraq and Afghanistan veterans: do clinical practice guidelines matter?." The Journal of Pain (2018).
- Kosten, Thomas R., David P. Graham, and David A. Nielsen. "Neurobiology of Opioid Use Disorder and Comorbid Traumatic Brain Injury." JAMA psychiatry (2018).