• Clinical science

Opioids

Summary

Opioids are a group of endogenous and exogenous substances that act on μ-, κ-, and δ-receptors in the CNS and the gastrointestinal tract. All opioids share crucial chemical and pharmacologic properties with morphine. Opioids provide effective analgesia and are used to treat severe acute or chronic pain. They also cause sedation and constipation, which can be used therapeutically. Additionally, opioids reduce coughing. Other effects include strong euphoria (which can quickly lead to addiction) and respiratory depression. Acute opioid intoxication is a potentially life-threatening condition that typically causes altered mental status, severe respiratory depression, and miosis. Treatment of acute opioid intoxication requires emergency measures and administration of an opioid receptor antagonist (e.g., naloxone).

Basic pharmacology of opioids

Opioids

  • Definition: opioids are substances that act on opioid receptors
  • Classification:

Production of endogenous opioids

Proopiomelanocortin (POMC) is the precursor molecule for different peptide hormones, including:

Opioid receptors

Receptor affinity, intrinsic activity, and ceiling effect

  • Receptor ligands have both a receptor affinity and an intrinsic activity
    • Receptor affinity; : certain opioids have a stronger receptor affinity than comparatively stronger opioids → the weaker opioid inhibits the stronger opioid competitively, which then has no effect → opioids of different potencies must not be combined
    • Intrinsic activity; : substances that bind to a receptor but have no intrinsic activity (receptor antagonists; ) can antagonize the effects of agonists
    • Ceiling effect
      • The functional response of full opioid receptor agonists (e.g., morphine); does not reach an upper limit → no ceiling effect
      • The functional response of partial agonists (e.g., buprenorphine); does reach a limit → ceiling effect
    • Partial opioid agonists can cause withdrawal symptoms in patients habituated to full agonists

(Relative) analgesic potency

References:[1][2]

Overview

Opioids for pain management

Opioid Route of application and corresponding analgesic potency Duration of action

Additional characteristics
Morphine
  • Oral: 1
  • Parenteral: 1
  • 3–6 hours
  • 3–6 hours

Butorphanol
  • Parenteral: 5
  • 3–4 hours
Tramadol
  • < 1
  • 4–6 hours

Meperidine
  • Oral: 0.1
  • Parenteral: 0.13
  • 2–4 hours
Codeine
  • Oral: 0.15
  • Parenteral: 0.08–0.1
  • 4–6 hours
  • Also used as an antitussive
Pentazocine
  • Parenteral: 0.2–0.33
  • 3–4 hours
Methadone
  • Oral: variable
  • Parenteral: variable
  • 4-8 hours
  • Primarily used in treating opioid withdrawal
  • Duration of action is shorter than half-life → risk of accumulation with repeated dosing
  • Should not be given to opioid-naive patients and only be prescribed by doctors experienced in opioid administration
Buprenorphine
  • Parenteral: 33
  • 4–8 hours
Fentanyl
  • Parenteral: 100
  • 1-1.5 hours
  • Lead substance for analgesia in anesthesiology
  • Strong lipophilia
    • Rapid onset and penetration into the CNS
    • Continuous administration leads to significant accumulation.
  • Additional form of application: fentanyl patch for the treatment of chronic pain

Other opioids

Antagonists

Opioid receptor antagonists bind to the opioid receptors but do not trigger the molecular effects that opioid receptor agonists do. Antagonists that have a high affinity to the opioid receptors (naloxone, naltrexone) can displace opioids from the receptors and may, therefore, be used as antidotes in acute opioid intoxication.

  • Naloxone: rapid onset, short duration (1–2 hours) → preferred for treatment of acute opioid intoxication
  • Naltrexone: long duration (24–48 hours) → used for withdrawal treatment after acute detoxification

Do not administer mild and strong opioids simultaneously!

Buprenorphine is difficult to antagonize with naloxone or naltrexone due to its extremely high receptor affinity!
References:[3][4][5][6][7][8][9][10][11][12][13]

Effects

The effects and side effects of opioids depend on the relative binding affinity to the different opioid receptors and on their effects on other neurotransmitter systems. Although opioids are mainly administered as analgesics, they are also used as sedatives, antidiarrheals, and antitussives.

Therapeutic effects Side effects
μ-opioid receptor agonism
  • Strong analgesia
  • Slowed gastrointestinal transit
  • Respiratory depression with subsequent rise in CO2 (and possibly ICP)
  • Constipation
  • Miosis
  • Bradycardia
  • Strong addictive potential
  • Euphoria
  • Sphincter of oddi dysfunction
δ-opioid receptor agonism
  • Respiratory depression
  • Tolerance
  • Strong addictive potential
κ-opioid receptor agonism
  • Analgesia
  • Sedation
  • Slowed gastrointestinal transit
Nonspecific/other

Clinically relevant respiratory depression is unlikely in the treatment of chronic pain!

Although the sedative, orthostatic, and emetic side effects diminish with progressing opioid treatment, miosis, and constipation persist!
Peripherally acting μ-opioid receptor antagonists antagonize μ-opioid receptors outside of the CNS (e.g., in the gastrointestinal tract) and are used to treat opioid-induced constipation. Examples include methylnaltrexone, naloxegol, alvimopan, and naldemedine.

References:[14][15][16][17][18][13]

Opioid intoxication and withdrawal

Opioid intoxication

  • Clinical features
  • Differential diagnoses: See differential diagnoses of drug intoxication.
  • Acute management
    1. Airway management (e.g., head-tilt/chin-lift maneuver and assisted breathing to improve oxygenation)
    2. Administration of opioid receptor antagonists: IV naloxone → neutralization of opioid effects → restoration of ventilation
      • Slow administration
      • Patient monitoring
    3. Management of complications (e.g., diazepam for seizures)

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!

Naloxone has a dose-dependent duration of action (shorter than most opioids). Its quick metabolization can, therefore, lead to a renewed effect of opioids!

Opioid withdrawal

General

Opioid withdrawal causes severe discomfort, but is not life threatening!

Neonatal abstinence syndrome

References:[19][17][18][20][21][22][23][24][25][26][27][28]

Indications

Pain management

Acute pain and sedation

Chronic pain

Pain management outside of emergency medicine or anesthesiology should generally be approached according to the WHO analgesic ladder.

  • 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
    • Initiate treatment on a trial basis with regular monitoring and adjustments
    • Opioid-naive patients should receive immediate-release/short-acting formulations
    • Avoid simultaneous prescription of benzodiazepines
  • Common uses
    • Acute exacerbations of chronic pain (e.g., cancer breakthrough pain): e.g., fentanyl sublingual tablets
    • Chronic pain syndromes (e.g., cancer pain, compression fractures of the spine): e.g., fentanyl (also available as a transdermal patch ), morphine (also available as an intrathecal pump system)

Other

Avoid long-term IV opioid administration since this can lead to rapidly acquired opioid tolerance and, ultimately, dependence!
References:[29][30][31][32][33]

Contraindications

Exact contraindications may vary depending on the specific substance, dosage, formulation, and route of application. The contraindications listed below apply to most opioids, however.

References:[34][35]

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