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Opioids

Last updated: May 31, 2021

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Opioids, in the broad sense used throughout this article, are a class of natural (endogenous and exogenous), synthetic, and semisynthetic substances that act on μ-, κ-, and δ-opioid receptors, i.e., antagonists as well as agonists. In the more narrow sense, opioids are distinguished from opiates, with the former including only synthetic, semisynthetic, or endogenous substances with opium-like pharmacological effects and the latter strictly referring to exogenous alkaloids derived from opium, the dried latex of the opium poppy (Papavum somniferum). Morphine, the original opiate, was first extracted from opium in 1804 and revolutionized medicine as the first drug to provide effective analgesia. Today, opioids are still most commonly used to treat severe acute or chronic pain. In addition to their analgesic effects, opioids induce sedation, constipation, and respiratory depression, which represent potentially life-threatening adverse effects but also have clinical uses (e.g., as anesthetic, antidiarrheal, or antitussive drugs). Opioid-receptor agonists induce a strong sense of euphoria and their recreational use, both in the form of illicit drugs (e.g., heroin) and prescription drugs (e.g., oxycodone, hydrocodone), is widespread and has severe effects public health and other aspects of society. Continued use of opioids can lead to physical dependence (the physical adaptation to the substance associated with symptoms of tolerance and withdrawal) and psychological dependence (substance-seeking behavior in response to biochemical changes in the brain from continued exposure to the substance; often referred to as “addiction”). Acute opioid intoxication is a life-threatening condition typically characterized by altered mental status, severe respiratory depression, and miosis. Treatment of acute opioid intoxication requires emergency measures and administration of a fast-acting opioid receptor antagonist (e.g., naloxone) to counter the symptoms of acute intoxication. Since the duration of action of naloxone is shorter than that of many opioid receptor agonists, a long-acting opioid receptor antagonist (e.g., naltrexone) should be administered subsequently to detoxification to prevent opioid dependence relapse.

Definition

  • Opioids
    • Classically used to describe only synthetic and semisynthetic substances with opium-like pharmacological properties (e.g., heroin)
    • Today used in the broader sense to describe any (i.e., natural, synthetic, or semisynthetic) substance that binds to opioid receptors (agonists as well as antagonists).
  • Opiates: alkaloids derived from the opium poppy (e.g., morphine)

Classification

According to effect on opioid receptors

According to origin

Endogenous opioids [1][2]

Exogenous opioids

Opioid receptors [1][2][3]

μ (mu), δ (delta), κ (kappa)

Effects

  • Effects of opioids depend on relative binding affinity of different opioid receptors.
  • Mainly used as analgesics, but also used as sedatives, antidiarrheals, and antitussives [4]
  • Pain relief primarily via the two following mechanisms:
    • Raising the pain threshold
    • Change in pain perception
Overview of opioid effects [5][6]
Site of action Clinical uses Side effects
μ-opioid receptor
  • Strong analgesia
  • Slowed gastrointestinal transit
δ-opioid receptor
κ-opioid receptor
  • Analgesia
  • Sedation
  • Slowed gastrointestinal transit
Nonspecific/other sites of action
  • None

At correct dosage, clinically relevant respiratory depression is unlikely in the treatment of chronic pain.

While the sedative, orthostatic, and emetic effects of opioids go down with tolerance, miosis and constipation remain unaffected.

Receptor affinity, intrinsic activity, and ceiling effect [3][7]

Receptor affinity

Receptor affinity describes the extent to which a ligand binds to a target receptor.

Opioids of different potency should not be combined!

Intrinsic activity (efficacy) [8]

Intrinsic activity is defined as the extent to which a drug activates a receptor after binding to it.

Ceiling effect

The ceiling effect describes the pharmacological phenomenon that once the therapeutic limit is reached, an increase in dose will no longer increase the functional response, but only the side effects.

  • Full opioid receptor agonists (e.g., morphine)
    • No ceiling effect
    • Increase in dose always leads to increased functional response and there is no cut-off point.
  • Partial opioid receptor agonists (e.g., buprenorphine)
    • Ceiling effect
    • At a certain point, an increase in dose does not increase the functional response, but only the side effects.

Relative analgesic potency [9]

Pain management

Acute pain management

Chronic pain management [11][12][13]

Pain management outside emergency medicine or anesthesiology should follow the WHO analgesic ladder algorithm.

  • General approach
    • Only consider opioids if other pharmacologic and nonpharmacologic measures have not achieved sufficient pain relief.
    • Evaluate patients for risk factors of opioid dependency (e.g., history of substance use).
    • Initiate treatment on a trial basis with regular monitoring and adjustments
    • Opioid-naive patients should receive immediate-release/short-acting formulations.
    • Avoid concomitant use of benzodiazepines.
  • Common uses

Avoid long-term IV opioid administration, since this can rapidly lead to opioid tolerance and, ultimately, dependence.

Opioids for pain management

Overview of opioids used for pain management [14][15][16][17]
Route of administration and corresponding analgesic potency Duration of analgesic action Receptor interaction Indications Side effects and other features
Morphine
  • Oral: 1
  • Parenteral: 3
  • 3–6 hours
  • 3–6 hours
  • Severe acute and chronic pain
  • Morphine is the standard to which other opioids are compared to in terms of potency
Hydromorphone
  • Parenteral: 10
  • 3–5 hours
  • Moderate to severe acute and chronic pain
  • Not metabolized via CYP450 enzymes [18]

Butorphanol

  • Parenteral: 5
  • 3–4 hours
  • ↓ Risk of respiratory depression compared to full agonists
  • Co-administration with full agonist may induce withdrawal
  • Effects are difficult to reverse with naloxone
Oxycodone
  • Oral: 1.5–2
  • 3–6 hours
  • Moderate to severe acute and chronic pain
Codeine
  • Oral: 0.15
  • Parenteral: 0.08–0.1
  • 4–6 hours
  • Mild to moderate pain
Tramadol
  • Oral: 0.25
  • 4–6 hours
  • Drug of choice for treatment of moderate chronic pain [20]

Meperidine

  • Oral: 0.1
  • Parenteral: 0.13
  • 2–4 hours
Pentazocine
  • Parenteral: 0.2–0.33
  • 3–4 hours
  • Moderate to severe pain
Methadone
  • Oral: 7.75
  • 4–8 hours
Buprenorphine [22]
  • Parenteral: 33
  • Sublingual: 40
  • Topical (transdermal): 100–115
  • 4–8 hours
Fentanyl
  • Parenteral: 85
  • 1–1.5 hours
  • Strong lipophilia
    • Rapid onset and CNS penetration
    • Continuous administration leads to significant accumulation

Nalbuphine

  • Parenteral (intramuscular): 0.7–0.8 [23]
  • 3–6 hours
  • Moderate to severe pain

Antagonization of buprenorphine requires high doses of naloxone or naltrexone due to its very high receptor affinity.

Cough management

Diarrhea management

  • Loperamide: μ-receptor agonist
    • Can not pass the blood-brain barrier (low abuse potential due to lack of central opioid effects)
    • Inhibits propulsive peristalsis, increases sphincter tone, and inhibits intestinal fluid secretion
    • Adverse effects include constipation, vomiting, and nausea.
  • Diphenoxylate
    • Inhibits propulsive peristalsis
    • Only available as a combination drug with atropine to prevent misuse
    • May produce central effects and toxicity at high doses.

Treatment of opioid use disorder

Opioid receptor antagonists bind to opioid receptors without activating them. Antagonists with high affinity to the opioid receptors can be used as antidotes in acute opioid intoxication due to their ability to displace opioids from the receptors.

Centrally acting opioid-receptor antagonists

Overview of centrally acting opioid-receptor antagonists
Naloxone Naltrexone
Routes of administration
  • PO, IM, IV, SC, IO
  • Intranasally (in form of a spray)
  • PO, IM
Pharmacology
  • Rapid action
  • Short half-life (60 minutes on average; ranges from 30 to 90 minutes) [25]
  • Long half-life (4–10 hours) [26]
  • Long, dose-dependent duration of action: 24–72 hours
Indication
  • Prevention of opioid relapse after acute detoxification
  • Alcohol use disorder
  • Smoking cessation
  • Weight management (in combination with bupropion)

“Use nalTRACKsone to get back on TRACK:” Naltrexone is used to prevent opioid relapse.

Peripherally acting μ-opioid receptor antagonists

Opioid intoxication [27][28]

Opioid intoxication is the main cause of death due to drug overdose.

Altered mental status, respiratory depression, and miosis are the classic triad of opioid intoxication. However, the absence of miosis does not rule out opioid intoxication.

Acute management

  1. Airway management: head-tilt/chin-lift maneuver and assisted breathing to improve oxygenation)
  2. Naloxone
    • Slow administration to prevent acute withdrawal syndrome
    • Neutralization of opioid effects → restoration of ventilation and counteraction of CNS depression
  3. Management of complications (e.g., diazepam for seizures)
  4. Naltrexone: after detoxification to prevent relapse


Naloxone has a dose-dependent duration of action that is shorter than most opioids. Its quick metabolization can, therefore, lead to a renewal of opioid effects. This is the reason why naltrexone, which has a long duration of action, must be administered after detoxification.

Opioid withdrawal

Opioid withdrawal is caused by sudden reduction or termination of opioid intake in physically dependent individuals.

Clinical features

Treatment

Opioid withdrawal causes severe discomfort, but is not life-threatening.

Special patient groups: neonatal abstinence syndrome [30][31][32]

Neonatal abstinence syndrome is caused by maternal drug use during pregnancy (typically opioids) that subsequently leads to a withdrawal reaction in the infant.

Clinical features

Treatment [32][33]

Absolute contraindications [34]

Relative contraindications [34]

We list the most important contraindications. The selection is not exhaustive.

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  8. Smith H, Passik S. Pain and Chemical Dependency. Oxford University Press ; 2008 : p. 195
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  10. Lasheen W, Walsh D, Mahmoud F, et al. The intravenous to oral relative milligram potency ratio of morphine during chronic dosing in cancer pain. Palliat Med. 2009; 24 (1): p.9-16. doi: 10.1177/0269216309346595 . | Open in Read by QxMD
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  12. Brennan MJ. The Effect of Opioid Therapy on Endocrine Function. Am J Med. 2013; 126 (3): p.S12-S18. doi: 10.1016/j.amjmed.2012.12.001 . | Open in Read by QxMD
  13. Besic N, Smrekar J, Strazisar B. Acute pain and side effects after tramadol in breast cancer patients: results of a prospective double-blind randomized study. Scientific Reports. 2020; 10 (1). doi: 10.1038/s41598-020-75961-2 . | Open in Read by QxMD
  14. Bricker L, Lavender T. Parenteral opioids for labor pain relief: A systematic review. Am J Obstet Gynecol. 2002; 186 (5): p.S94-S109. doi: 10.1016/s0002-9378(02)70185-3 . | Open in Read by QxMD
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  16. Beaver WT, Feise GA. A comparison of the analgesic effect of intramuscular nalbuphine and morphine in patients with postoperative pain.. J Pharmacol Exp Ther. 1978; 204 (2): p.487-96.
  17. Zheng Zeng, Jianhua Lu, Chang Shu, Yuanli Chen, Tong Guo, Qing-ping Wu, Shang-long Yao, Ping Yin. A Comparision of Nalbuphine with Morphine for Analgesic Effects and Safety : Meta-Analysis of Randomized Controlled Trials. Scientific Reports. 2015; 5 (1). doi: 10.1038/srep10927 . | Open in Read by QxMD
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  21. Katzung B,Trevor A. Basic and Clinical Pharmacology. McGraw-Hill Education ; 2014
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  33. Hudak ML, Tan RC. Neonatal Drug Withdrawal. Pediatrics. 2012; 129 (2): p.e540-e560. doi: 10.1542/peds.2011-3212 . | Open in Read by QxMD
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