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Opioids: Tolerance, Dependency, and Addiction



What Is Tolerance?


According to a journal published by the American Academy of Pediatrics, Tolerance occurs when a person “no longer responds to a drug they did at first; therefore, a high dose of the drug is needed to achieve the same effect when the person first used it.”


The same source states that opioids reduce stress response, pain, anxiety, and agitation in critically ill pediatric patients. The appropriate dosage and use of opioids can reduce stress responses and improve pediatric patients’ clinical outcomes. The opposite happens when these agents’ overuse leads toward consequences such as prolonging their need for a ventilator and staying in the ICU. Also, treating the withdrawal symptoms (because the children become dependent on them) may extend their stay.


Frequent opioids analgesics used in PICU patients are morphine, fentanyl, and methadone. Chart reviews of opioid dosages in neonates (newborns) showed a fivefold increase in fentanyl infusions with increased plasma fentanyl concentrations to maintain the same clinical effect.

Total fentanyl does more than 1.6 mg/kg or infusions that lasted for more than five days resulted in opioid withdrawal in 13 out of 23 infants. Reports suggest that opioid withdrawal occurs in 60% of PICUs and 57% in PICU patients.


Physiological Effects of Opioid Analgesia


The binding of opioid receptors leads to changes in the receptor protein which activates activation of inhibitory G proteins, which lowers neuronal excitability, reduced action-potential duration, and decreases neurotransmitter release., according to the same journal.


Factors That Affect Development of Opioid Tolerance


Duration of therapy: opioid tolerance rarely occurs after therapy for less than 72 hours. In an RCT, continuous infusion of opioids vs. intermittent treatment of opioids showed no significant difference in inducing tolerance in 0 to 3-year-olds.


Gender differences: In a study conducted on rats that were given two weeks of twice-daily morphine, effective analgesic dose for 50% of subjects increased 6.9 fold in male rates and only 3.7 fold in female rates. As a result, male rats experience heavier withdrawal symptoms. In infant rats, however, there was no gender difference in morphine and fentanyl. Gender difference for opioid tolerance in infants has not been studied in humans.


What Is Dependency?


Dependency occurs when a person stops using a drug, and their body goes through “withdrawal”: a group of physical and mental symptoms that can range from mild (ex. caffeine) to life-threatening (ex. Alcohol or opiates) (as per the original journal). To get off a drug, a person must do so gradually to avoid withdrawal discomfort. People who depend on a drug are not necessarily addicted.


Image is courtesy of the American Journal on Addictions.


Image is courtesy of the American Journal on Addictions.


Withdrawal Symptoms


With the abrupt halt to Short-acting opioids (heroin, hydrocodone, oxycodone), withdrawal symptoms begin within 12 hours after a missed dose and peak at 36-72 hours; symptoms taper after 4 - 7 days. Abrupt halts to long-acting opioids like buprenorphine may produce similar symptoms, but the overall withdrawal period would last longer: about two weeks. Though 4-7 days or two weeks seems short, the severity of withdrawal symptoms makes patients unable to get off opioids without adequate treatment (The American Journal on Addictions).


What Is Addiction


According to the previously mentioned journal by the American Academy of Pediatrics, Addiction is a disease and can result from taking drugs or alcohol repeatedly. AKA severe substance use disorder. If a person continues to use a drug despite negative consequences, one can become dependent on a drug, or have a high tolerance and NOT be addicted to a drug.


The opioid crisis in the United States has cost billions of dollars annually -- this is due to medications that can help prevent relapse or remission. Because of the severe withdrawal symptoms, individuals may use opioids again to alleviate those symptoms. When a person abuses opioid use, their opioid receptors become desensitized, resulting in uncontrolled intake.


MOR (μ opioid receptor)is an opioid receptor that can trigger euphoria, essential for brain reward circuits that are highly dynamic, plays an essential role in goal-directed behaviour (ex. Drug-seeking for pleasure). As the severity of opioid addiction increases, this can cause “cognition impairment causes addicted individuals to make poor decisions, shifting goal-directed behaviors to habitual behaviors such as repetitive drug seeking and/or craving”


Homeostasis of the brains’ reward circuit becomes compromised, and the ability to maintain proper social functioning becomes compromised.


KOR (κ opioid receptor) is another opioid receptor that triggers anti-reward effects and produces dysphoria. Drug use can promote KOR function by causing stress in the hypothalamic-pituitary-adrenal axis: this stress response produces relapse. Prolonged exposure to drugs can also cause dysphoric feelings due to the build of these dysphoric feelings and stress; it also enhances the function of KOR.


The issue of opioid addiction has many layers that we must work to conquer and more widely understand if we are to overcome it in the future.



Article Author: Ashley Chen

Article Editors: Stephanie Sahadeo, Olivia Ye