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
- Definition: opioids are substances that act on opioid receptors
Production of endogenous opioids
- 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
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
- Spinal analgesia is mediated by all major receptor classes, supraspinal analgesia is mediated mainly by μ-receptors
- Opioids relieve pain by two major mechanisms
- 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
- 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)
Acute pain and sedation
- General approach: lowest effective dose should be prescribed/administered for the shortest duration possible
- Common uses
outside of emergency medicine or anesthesiology should generally be approached according to the .
- 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
- Common uses
Avoid long-term IV opioid administration since this can lead to rapidly acquired opioid tolerance and, ultimately, dependence!
- Clinical features
- Differential diagnoses: See .
- Airway management (e.g., head-tilt/chin-lift maneuver and assisted breathing to improve oxygenation)
Administration of opioid receptor antagonists: IV naloxone → neutralization of opioid effects → restoration of ventilation
- Slow administration
- Patient monitoring
- Management of complications (e.g., diazepam for seizures)
Naloxone has a dose-dependent duration of action (shorter than most opioids). Its quick metabolization can, therefore, lead to a renewed effect of opioids!
- Etiology: sudden reduction or termination of opioid intake in physiologically dependent individuals
- 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
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 , ,
- Intoxications: alcohol, sedatives
- Gastrointestinal: ,
- To be used with caution in cases of
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|| |
|Morphine|| || |
| || |
|Tramadol|| || |
| || |
|Codeine|| || || |
|Pentazocine|| || |
|Methadone|| || |
|Buprenorphine|| || |
|Fentanyl|| || |
- 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 antagonist; also inhibits serotonin and noradrenaline reuptake; used for cough suppression
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!
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|| |
|δ-opioid receptor agonism|| |
|κ-opioid receptor agonism|| || |
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.