Etiology

Initiation of opioid use disorder is related to familial and environmental influences such as peer pressure, disrupted family dynamics, and history of availability of opioids in the family.[15][16] Other vulnerable populations include people experiencing homelessness and those recently released from prison.[6]

Comorbid psychiatric disorders such as bipolar disorder, ADHD, major depression, anxiety disorders, personality disorders, PTSD, and psychosis increase the risk of substance abuse, including opioid abuse.[17][18][19][20][21] Possible reasons for the association include substance use causing psychiatric disorders, people with psychiatric disorders using substances to treat symptoms, and shared risk factors for both conditions.[22]

Chronic noncancer pain syndromes that are treated with long-term opioid therapy have also been linked to an increase in opioid use disorders in the US.[6][12]

Genetic influences contribute to about 50% of the risk of addiction to a substance, and it is very likely that multiple genes are involved. Heritability estimates range from 23% to 54% for opioid use disorder.[23] Variants in genes including those encoding the mu opioid receptor, the delta opioid receptor, the dopamine D2 receptor, and brain-derived neurotrophic factor have been associated with small but reproducible effects on risk of opioid use disorder.[23]

Pathophysiology

The dopaminergic mesolimbic system, which originates in the ventral tegmental nucleus with a projection to the nucleus accumbens, plays a critical role in mediating opioid effects. The opioid receptor system includes mu, kappa, sigma, delta, and epsilon receptor subtypes. Opioid-induced activation of mu and sigma receptors increases the activity of the dopaminergic mesolimbic system, thereby releasing dopamine into the nucleus accumbens, which produces feelings of euphoria and well-being. Stimulation of the kappa receptors decreases activity of the mesolimbic system, which results in dysphoria.

Opioid tolerance occurs when there is a decreased response by the opioid receptors in the brain to previous doses of an opioid. A higher dose of opioid is then needed to stimulate the mesolimbic system and achieve the same release of dopamine in the nucleus accumbens.

Enzymatic inhibition occurs at the mu receptors in the locus ceruleus (an area at the base of the brain producing norepinephrine, maintaining normal wakefulness, alertness, and hemodynamic stability) in the presence of opioids initially, and norepinephrine production decreases. However, chronic use of opioids leads to increased enzymatic activity at the mu receptors, thereby resulting in normal or higher levels of norepinephrine. Following opioid deprivation, such as during withdrawal, there is loss of inhibitory effect on enzyme activity leading to an excess release of norepinephrine from these neurons, resulting in symptoms such as muscle cramps, diarrhea, anxiety, and tremors.[24][25]

Physiologic dependence on opioids and their continued use is often reinforced by the euphoric effects (positive cravings) mediated through the mesolimbic dopamine system, and relief of withdrawal symptoms (negative cravings) mediated through the norepinephrine pathways.[26] Dysfunction in other brain areas (such as the prefrontal cortex) and neurochemicals (such as cortisol) also appear to play a role.[24]

Classification

Therapeutic opioids are prescribed for a range of indications and are essential for pain management in cancer pain and palliative care, although they are also used for nontherapeutic reasons. The diagnosis of a disorder due to the use of opioids is characterized by the pattern of use and the consequences of use. Diagnosis can be subdivided into harmful use, dependence, intoxication, withdrawal, and also into disorders induced by psychoactive substances such as opioid-induced delirium.[2]

Use of opioids tips into a disorder when the pattern of use causes harm to the person's physical or mental health or has resulted in behavior leading to the harm of others.[2] Both the Diagnostic and statistical manual of mental disorders, 5th edition, text revision (DSM-5-TR) and the World Health Organization's International statistical classification of diseases and health related problems, 11th revision (ICD-11) classify opioid use disorder when a harmful pattern of use is evident over a 12-month period or at least 1 month if use is continuous.[1][2]

Severity of the disorder can be further classified into mild (presence of 2 to 3 symptoms), moderate (4 to 5 symptoms), or severe (6 or more symptoms).[1] This topic focuses on opioid use disorder; more information on opioid overdose can be found in Opioid overdose.

For information on complications of opioid therapy see Palliative care.

Types of opioids

Opioids can be taken orally, injected, snorted, or smoked.[3] National Institute on Drug Abuse: commonly used drugs chart Opens in new window Types include:

  • Naturally occurring opium derivatives (opiates): morphine

  • Partially synthetic: heroin, oxycodone, oxymorphone

  • Synthetic: fentanyl, alfentanil, levorphanol, meperidine, methadone, codeine, propoxyphene, buprenorphine, tramadol.

Opioids may be either short-acting or long-acting, which depends on the way they are formulated. Examples include:

  • Short-acting opioids: morphine, hydromorphone, oxycodone

  • Long-acting opioids: sustained-release formulations of morphine or oxycodone, transdermal fentanyl.

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