Pain is a complex phenomenon affected by past experiences and psychological factors. In 2019, it was estimated that one in five Americans suffered from chronic pain, resulting in pain being the most common reason adults seek medical care. The high prevalence of pain highlights the importance of responsible opioid prescribing.
According to the Centers for Disease Control and Prevention (CDC), approximately 107,000 drug overdose deaths involved an opioid in 2021. If unaddressed, this number is projected to increase to over half a million cases in the next decade. Understanding the physiology of opioids, identifying and treating opioid use disorders, and instituting current best practice guidelines are ways physicians can impact the opioid epidemic sweeping through the United States.
Recommended course: Responsible Opioid Prescribing Practices
Physiology of opioids
Endogenous opioids are naturally produced by the body and include enkephalins, endorphins, endomorphins, dynorphins, and nociception/orphanin. Exogenous opioids, such as morphine, fentanyl, and heroin, are substances introduced into the body that have an affinity for the same receptors as endogenous opioids.
Opioid receptors are classified into five different categories: mu, kappa, delta, nociception, and zeta receptors. The variable activation of these receptors results in the differing effects of the synthetic opioids.
Physiologic effects of opioid use
Analgesia
Opioid medications stimulate the mu receptor within the central nervous system which triggers descending inhibitory impulses to reduce nociceptive transmission from the periphery to the thalamus. In addition, exogenous opioids can directly inhibit peripheral nociceptor-afferent neurons.
Stress
Activation of mu receptors reduces the central stress response by inhibiting the secretion of norepinephrine from the locus ceruleus, attenuating the release of corticotropin-releasing hormone involved in high-stress states.
Mood and reward
The presence of mu receptors in the limbic system regulates mood and are targets for the potential treatment of anxiety and depression.
The ventral tegmental area is the reward center of the brain. Mu receptors within this area inhibit GABA secretion by inhibitory nerves that project to the ventral striatum. Inhibition of these neurons results in an increased release of dopamine which provides the rewarding effects of opioid use.
Side effects of opioid use
Respiratory depression
Opioid receptors within the respiratory center in the cerebral cortex, thalamus, and peripheral chemo and baroreceptors in the carotid bodies can lead to slow, irregular breathing resulting in hypoxia and hypercapnia.
Constipation
Stimulation of opioid receptors can affect the GI tract through two main mechanisms. The inhibitory effects on acetylcholine release from myenteric neurons via opioid receptors decrease propulsive motility of the GI tract. Additionally, opioids can inhibit chloride secretion reducing the passive movement of water into the intestinal lumen resulting in harder stools which contribute to constipation.
Orthostatic hypotension and syncope
Opioid receptor stimulation can result in the hyperpolarization of membranes and the activation of the vagus nerve resulting in vasodilation and bradycardia. Couple this with peripheral histamine release, orthostatic hypotension can be a significant concern with opioid administration.
Tolerance and addiction
Chronic administration of exogenous opioids leads to the suppression of endogenous opioid production leading to reliance on exogenous opioids. This can ultimately lead to an increased risk of hyperalgesia, dependence, and addiction.
Tolerance to opioids is a constant concern for prescribers as chronic use will eventually lead to the ineffectiveness of the opioid medication. Researchers once thought that the downregulation of opioid receptors lead to tolerance. However, new research has called this hypothesis into question. Disruptions in intracellular signaling and beta-arrestin-triggered internalization of opioid receptors are currently believed to be the mechanisms leading to tolerance.
What is Opioid Use Disorder?
According to the DSM-V, substance use disorder or opioid use disorder are the preferred terms for individuals with dependence or addiction to opioids. The diagnosis of an opioid use disorder requires at least two of the following to be present within a 12-month period.
- Using opioids in larger amounts or over a longer period than was intended
- A persistent desire or unsuccessful efforts to cut down or control opioid use
- Spend a great deal of time trying to obtain opioids, use opioids, and/or recover from their effects
- Craving or strong urges to use opioids
- Failure to fulfill major role obligations at work, school, or home due to opioid use
- Continued social or interpersonal problems caused or exacerbated by the effects of opioids
- Avoiding or skipping important social, occupational, or recreational activities to use opioids
- Recurrent opioid use despite physically hazardous effects on the body
- Continued opioid use despite knowledge of physical or psychological problems caused or exacerbated by the substance
- Exhibits tolerance
- Exhibits withdrawal
Treatment of opioid abuse disorder
The initiation of treatment for opioid abuse disorders can reduce the risk of overdoses and overall mortality rates. The FDA has approved three medications for the treatment of opioid abuse disorder. These include methadone, buprenorphine, and naltrexone.
Methadone
- Mu receptor agonist
- Reduces carvings and blunts the effects of opioids
- Dispensed from a certified treatment program
Buprenorphine
- Partial mu receptor agonist
- Suppresses cravings and safer treatment options as respiratory depression has a ceiling effect
- Improved safety profile allows prescriptions and avoids daily trips to treatment centers
Naltrexone
- Mu receptor antagonist
- Blocks euphoric and sedative effects of opioids
- Caution can precipitate an acute withdraw
In addition to medication management, physicians should offer and refer patients for psychosocial treatment and behavioral therapy.
It is important to identify co-existing substance use disorders and patients actively using other substances. These patients often require more support.
Clinicians should prescribe all patients naloxone. They should also ensure that friends and family of the patient receive training on the proper administration in suspected overdoses.
Treatment of opioid overdose
Two FDA-approved medications are available for the treatment of acute overdose, naloxone and nalmefene. Administering these medications can reverse respiratory depression and sedation in the setting of an opioid overdose. However, use caution when administering these medications to help reduce the risk of acute withdrawal.
Naloxone is available in an intranasal spray and intramuscular, subcutaneous, and intravenous injections. Because of the relatively short half-life of naloxone, overdoses secondary to long-acting opioids such as methadone may require secondary doses.
Nalmefene is a longer-acting antagonist available in an intranasal spray. The longer half-life of this medication can provide more lasting reversal effects. However, this medication can increase risk of prolonged acute withdrawal.
Physicians have a responsibility to ensure opioids are prescribed for legitimate medical purposes and are actively monitored for abuse and diversion. Maximizing nonpharmacologic and non-narcotic treatments should be the first line in treating pain unrelated to cancer pain and end-of-life treatment. Using the lowest dose possible for the shortest duration needed is important to reducing the risk of developing dependence and addiction.
