The opioid epidemic in the United States does not appear to be dissipating. From 2000 to 2014, the rate of overdose deaths involving opioids (prescription opioid pain relievers and heroin) has tripled.1 Furthermore, data from the U.S. Centers for Disease Control and Prevention show that anyone can be at risk. Opioid dependence does not discriminate based on sex, age, race, or region of the country.2
This newsletter serves as a primer for recognizing the severity of today’s opioid crisis. Gaining a deeper understanding of opioid dependence—including its prevalence, pathophysiology, and effects—is an important step toward recognizing evidence-based approaches to help combat this chronic, relapsing brain disease.
Opioid Dependence vs. Opioid Use Disorder
In this series of newsletters, the term “opioid” refers to opium-like compounds that bind to opioid receptors, such as prescription opioids (natural, semisynthetic, and synthetic) and heroin.1 Opioids prescribed to treat moderate to severe pain include medications such as oxycodone, hydrocodone, codeine, morphine, and fentanyl.1 The Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) updated the diagnostic criteria for opioid use disorders. The diagnostic criterion of “substance dependence” was combined with “substance abuse” to make one diagnostic category of “substance use disorder,” with the specific substance defining each specific disorder (eg, opioid use disorder).3 The manual also includes a specifier for severity based on the number of symptoms.3 This 2013 update is consistent with the previous edition in citing the “clinically significant impairment or distress” that manifests as a result of substance use disorders, including opioid use disorders.3,4 Substance dependence, including opioid dependence, is characterized by a maladaptive pattern of substance use that leads to clinically significant impairment or distress.4 The Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) defined an individual with substance dependence as experiencing at least 3 of the following criteria within a given 12-month period: tolerance; withdrawal; taking the substance in larger amounts or for longer than intended; persistent desire or unsuccessful efforts to curb or control use; excessive time spent obtaining, using, or recovering from use; giving up or reducing important activities because of use; and continued use despite acknowledged physical or psychological problems due to use.4 This comprehensive definition partially served as the basis for the U.S. Food and Drug Administration to approve most available medication-assisted treatments (MATs) for opioid dependence.5-10 In this newsletter, the term “opioid dependence” is used to be consistent with the approved indication for numerous MAT options.
A National Crisis
While the clinical criteria characterizing opioid dependence can help identify an individual affliction, it does not even begin to demonstrate the impact of opioid dependence on the health of Americans.
First and foremost, the opioid epidemic in the U.S. is continuing, and the incidence of opioid-associated overdose deaths is on the rise.11 According to the National Survey on Drug Use and Health, nearly 2 million American adults had an opioid use disorder in 2016, of whom about 625,000 had a heroin use disorder.12 There are many factors that contributed to the development of this epidemic; one factor may be the increased availability of prescription opioids. Sales of prescription opioids in the U.S. nearly quadrupled from 1999 to 2014, and heroin use increased 63% from 2002 to 2013.13,14
Nearly 2 million American adults had an opioid use disorder in 2016, of whom about 625,000 had a heroin use disorder.12
These fatalities do not appear to be associated with a clear set of demographic criteria. From 2014 to 2015, overdose deaths involving heroin and synthetic opioids other than methadone increased in both men and women, people aged ≥15 years, and all racial/ethnic groups, and overdose deaths involving natural/semisynthetic opioids increased among males overall, both sexes aged 25-44 years, and non-Hispanic whites.11
Pathophysiology of Opioid Dependence
Another facet of understanding opioid dependence and its treatment is appreciating its pathophysiology, starting with its effects on the brain. Opioids have many effects on the brain and body; some of the brain regions associated with opioid dependence are the cortex, which is responsible for decision-making, thinking, reasoning, and planning, and the limbic system, which controls basic drives and urges, rewards, and pleasure (Figure 1).15 As shown in Figure 1, different components of treatment target the different affected brain regions.
The motivation to seek reward and pleasure is considered a natural component of normal human behavior.16 Reward pathways are necessary, as they serve to promote survival (e.g., seeking food and water, engaging in reproductive activities) and influence beneficial behaviors.16
|Figure 1. Brain Regions Associated With Dependence.15|
The Pleasure Pathway
Problems with opioids, including dependence, can occur when the brain’s natural mechanisms of pleasure and reward are dysfunctional.17,18 When someone takes an opioid drug, that drug binds to and activates the mu opioid receptors in the limbic system.18 This activation turns on the same “pleasure pathway” as the brain’s own natural opioids but releases 2 to 10 times more dopamine than natural (endogenous) opioids (see Figure 2).15 In some cases, this reward response can occur immediately, and the effects can last longer than those produced by natural rewards (i.e., eating, sex).15
|Figure 2. The Brain and Opioid Use: Understanding the Effects of Opioids.15,18,20|
Acute exposure to opioids can have a positive reinforcing effect, where the individual may impulsively seek opioids for the pleasurable effects19 However, prolonged administration of opioids can create neuroadaptations in the dopamine reward system.19 These neuroadaptations are thought to contribute to loss of motivation for natural (non-opioid) stimuli and increased sensitivity to opioid-related stimuli or cues.19 Eventually, opioid addiction can transition to a negative reinforcing effect, where individuals may compulsively begin seeking opioids to avoid the negative effects of withdrawal.19 The negative reinforcing effects may increase the likelihood of relapse.19 Chronic relapse, even after prolonged abstinence, is a hallmark of opioid use disorders.18
The negative reinforcing effects of opioid addiction may increase the likelihood of relapse.19
The opioid epidemic in the U.S. has no single solution. However, understanding the prevalence, pathophysiology, and effects of opioid dependence is an important step in addressing this national crisis. It also is important to be action-oriented and examine evidence-based approaches to treatment and rehabilitation.
- Centers for Disease Control and Prevention (CDC). Opioid overdose: opioid data analysis. https://www.cdc.gov/drugoverdose/data/analysis.html. Revised February 9, 2017. Accessed June 1, 2017.
- Rudd RA, Aleshire N, Zibbell JE, Gladden RM. Increases in drug and opioid overdose deaths—United States, 2000-2014. MMWR Morb Mortal Wkly Rep. 2016;64(50):1378-1382.
- Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013.
- Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Revision. Washington, DC: American Psychiatric Association; 2000.
- Subutex (buprenorphine) [package insert]. Reckitt Benckiser Pharmaceuticals, Inc. Richmond, VA; December 2014.
- Suboxone (buprenorphine and naloxone) [package insert]. Reckitt Benckiser Pharmaceuticals Inc. Richmond, VA; February 2017.
- Probuphine (buprenorphine) [package insert]. Titan Pharmaceuticals, Inc. San Francisco, CA; May 2016.
- Zubsolv (buprenorphine and naloxone) [package insert]. Orexo US, Inc. Morristown, NJ; December 2016.
- Bunavail (buprenorphine and naloxone) [package insert]. BioDelivery Sciences International, Inc. Raleigh, NC; April 2015.
- VIVITROL [prescribing information]. Waltham, MA: Alkermes, Inc; rev September 2019.
- Rudd RA, Seth P, David F, Scholl L. Increases in drug and opioid-involved overdose deaths—United States, 2010-2015. MMWR Morb Mortal Wkly Rep. 2016;65(5051):1445-1452.
- Center for Behavioral Health Statistics and Quality. (2017). 2016 National Survey on Drug Use and Health: Detailed Tables. Substance Abuse and Mental Health Services Administration, Rockville, MD.
- Jones CM, Logan J, Gladden RM, Bohm MK. Vital signs: demographic and substance use trends among heroin users—United States, 2002-2013. MMWR Morb Mortal Wkly Rep. 2015;64(26):719-725.
- Centers for Disease Control and Prevention (CDC). Opioid overdose: prescribing data. https://www.cdc.gov/drugoverdose/data/prescribing.html. Revised December 20, 2016. Accessed June 27, 2017.
- National Institute on Drug Abuse (NIDA). Drugs, Brains, and Behavior: the Science of Addiction. NIH publication 14-5605. https://www.drugabuse.gov/publications/drugs-brains-behavior-science-addiction/preface. Revised July 2014. Accessed July 28, 2017.
- Esch T, Stefano G. The neurobiology of pleasure, reward processes, addiction and their health implications. Neuro Endocrinol Lett. 2004;25(4):235-251.
- Bunch RW. Neuroanatomy and physiology of the “brain reward system” in substance abuse. University of Colorado Health Sciences Center. Center for Antisocial Drug Dependence. http://ibg.colorado.edu/cadd1/a_drug/essays/essay4.htm. Accessed July 28, 2017.
- Kosten TR, George TP. The neurobiology of opioid dependence: implications for treatment. Sci Pract Perspect. 2002;1(1):13-20.
- Koob GF. Focus on: Neuroscience and treatment: the potential of neuroscience to inform treatment. Alcohol Res Health. 2010;33(1-2):144-151.
- Meyer JS, Quenzer LF. The Opioids. In: Psychopharmacology: Drugs, the Brain, and Behavior. 2nd ed. Sunderland, MA: Sinauer Associates, Inc; 2013:305-337.
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