Opioids

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).

Opioids

• Definition: opioids are substances that act on opioid receptors
• Classification:
  • Endogenous opioids: produced by the body itself (beta-endorphin, enkephalin, dynorphin)
  • Exogenous opioids
    • Natural opioids : e.g., morphine, codeine
    • Semisynthetic opioids: e.g., diamorphine (heroin), buprenorphine
    • Synthetic opioids: e.g., methadone, fentanyl

Production of endogenous opioids

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

• ACTH: cleaved in the corticotroph cells of the anterior pituitary → stimulates adrenal glands
• β-Endorphin and met-enkephalin: cleaved in the hypothalamus → bind to opioid receptors
• α-MSH: cleaved in the arcuate nucleus → promotes satiety
• β-MSH

Opioid receptors

• mu (μ), delta (δ), kappa (κ) (see “Effects” below)
  • Heptahelical transmembrane G-protein-coupled receptors (GPCRs) → binding of opioid receptor agonists causes reduction of synaptic transmission
    • Closing of presynaptic Ca²⁺ channels → hyperpolarization → reduced release of acetylcholine, noradrenaline, serotonin, glutamate, nitric oxide, and substance P (presynaptic inhibition)
    • Opening of postsynaptic K⁺ channels → hyperpolarization (postsynaptic inhibition)
• Spinal analgesia is mediated by all major receptor classes, supraspinal analgesia is mediated mainly by μ-receptors
• Opioids relieve pain by two major mechanisms
  • Raising of pain threshold
  • Change in pain perception

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

• The potency of morphine is the reference (relative potency: 1) for comparing the analgesic potency of opioids→ a higher relative potency allows a lower dose for the same analgesic effect
• Values for relative potency differ between the forms of application (parenteral, oral)

References:^[1][2]

Pain management

Acute pain and sedation

• General approach: lowest effective dose should be prescribed/administered for the shortest duration possible
• Common uses
  • Sudden pain (e.g., ureteric colic, fractures): e.g., PO meperidine or tramadol, IV morphine
  • Emergency medicine (e.g., acute coronary syndrome, pulmonary edema): e.g., IV morphine
  • Analgosedation during surgery: e.g., IV fentanyl

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

• Cough: codeine, dextromethorphan
• Diarrhea: loperamide, diphenoxylate

Avoid long-term IV opioid administration since this can lead to rapidly acquired opioid tolerance and, ultimately, dependence!
References:^{[3][4][5][6][7]}

Opioid intoxication

• Clinical features
  • Altered mental status
  • Bilateral miosis (pinpoint pupils)
  • Respiratory depression (decreased respiratory rate and tidal volume) and hemorrhagic lung edema
  • Seizures
  • Decreased bowel sounds
  • Decreased heart rate and blood pressure, hypothermia
  • Rhabdomyolysis
• 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

• Etiology: sudden reduction or termination of opioid intake in physiologically dependent individuals
• Clinical features
  • Flu-like symptoms: rhinorrhea, chills, piloerection, myalgia, arthralgia, leg cramps
  • Gastrointestinal complaints: nausea, vomiting, abdominal pain, diarrhea, hyperactive bowel sounds
  • Features of sympathetic hyperactivity: mydriasis, tachycardia, hypertension, hyperreflexia
  • Features of CNS stimulation: insomnia, yawning, irritability, anxiety, agitation, aggression
• Treatment: buprenorphine/naloxone or methadone administration

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

Neonatal abstinence syndrome

• Etiology: : maternal drug abuse during pregnancy with subsequent withdrawal reaction in the infant
• Clinical features
  • High-pitched cry, irritability
  • Disturbance of sleep-wake rhythm
  • Muscle tone and movement disorders
  • Seizures
  • Poor feeding, vomiting, diarrhea, failure to thrive
  • Tachypnea, apnea, sneezing
  • Fever and sweating
  • Hypertension, tachycardia
• Treatment
  • Supportive
    • Swaddling
    • Fluid resuscitation
    • Reduced sensory stimulation (e.g., quiet room, no sudden movements)
  • Pharmacological: given in severe cases to avoid withdrawal symptoms and allow for normal growth and interaction
    • First-line: PO morphine
    • Second-line; : phenobarbital, clonidine

References:^{[8][9][10][11][12][13][14][15][16][17][18][19]}

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

• Hypersensitivity to the opioid or any of the other components of the formulation
• Lung disease: acute or severe bronchial asthma, chronic bronchitis, emphysema
• Intoxications: alcohol, sedatives
• Gastrointestinal: paralytic ileus, inflammatory bowel disease
• To be used with caution in cases of
  • Traumatic brain injury
  • Pregnancy and breastfeeding
  • Concurrent SSRI use: dextromethorphan may increase risk of serotonin syndrome
  • Biliary tract impairment or acute pancreatitis: may cause constriction/spasms of the sphincter of Oddi

References:^[20][21]

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

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	κ-receptor agonist μ-receptor partial agonist Lower risk of respiratory depression compared to full agonists
Tramadol	< 1	4–6 hours	Also inhibits serotonin and noradrenaline reuptake Increases risk of serotonin syndrome and of seizures
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	κ-receptor agonist μ-receptor partial agonist
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	Partial μ-agonist with extremely high receptor affinity Can displace other opioids High doses of naloxone or naltrexone are necessary to antagonize buprenorphine effects
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

• Loperamide: μ-receptor agonist that does not accumulate in the CNS → inhibition of propulsive peristalsis, increase in sphincter tone, and inhibition of intestinal fluid secretion → use for treatment of diarrhea
• Diphenoxylate: similar to loperamide
• Dextromethorphan: : weak opioid receptor agonist and NMDA receptor antagonist; also inhibits serotonin and noradrenaline reuptake; used for cough suppression

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:^{[22][23][24][25][26][27][28][29][30][31][32]}

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	Analgesia	Respiratory depression Tolerance Strong addictive potential
κ-opioid receptor agonism	Analgesia Sedation Slowed gastrointestinal transit	Dysphoria Sedation Constipation
Nonspecific/other		Nausea Pruritus Reduced seizure threshold

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:^{[33][34][35][9][10][32]}