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.
Pharmacology of 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 (antagonists as well as antagonists).
- Opiates: alkaloids derived from the opium poppy (e.g., morphine)
According to effect on opioid receptors
- Full agonists
- Partial agonist: buprenorphine
- Mixed agonist/antagonists
- Full antagonists
According to origin
Endogenous opioids 
- Semisynthetic opioids
- Synthetic opioids
Opioid receptors 
μ (mu), δ (delta), κ (kappa)
- Heptahelical transmembrane -coupled receptors ()
- Binding agonists causes reduction of synaptic transmission through the following mechanisms:
- Effects of opioids depend on relative binding affinity of different opioid receptors.
- Mainly used as analgesics, but also used as sedatives, antidiarrheals, and antitussives 
- Pain relief primarily via the two following mechanisms:
|Overview of opioid effects |
|Site of action||Clinical uses||Side effects|
|μ-opioid receptor|| || |
|κ-opioid receptor|| |
|Nonspecific/other sites of action|| |
At correct dosage, clinically relevant respiratory depression is unlikely in the treatment of chronic pain.
Receptor affinity, intrinsic activity, and ceiling effect 
- Receptor affinity does not always correspond to potency.
- In some cases, less potent opioids with higher receptor affinity inhibit more potent opioids with lower receptor affinity competitively, rendering them ineffective.
Opioids of different potency should not be combined!
Intrinsic activity (efficacy) 
Intrinsic activity is defined as the extent to which a drug activates a receptor after binding to it.
- Governs the potency of the functional response (e.g., analgesic effect)
- If substances with no intrinsic activity have higher receptor affinity than agonists, they may act antagonistically.
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 
Acute pain management
- General approach: lowest effective dose should be prescribed/administered for the shortest duration possible
- Common uses
Chronic pain management 
- 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 |
|Route of administration and corresponding analgesic potency||Duration of analgesic action||Receptor interaction||Side effects and other features|
|Morphine|| || || || |
|Hydromorphone|| || || || |
| || || |
|Oxycodone|| || || || |
|Codeine|| || || || |
|Tramadol|| || || |
| || || |
|Pentazocine|| || || || |
|Methadone|| || || || || |
|Buprenorphine || || || || |
|Fentanyl|| || || || |
| || || |
- Dextromethorphan (DXM): synthetic codeine analog used for cough suppression
- Codeine: taken PO
- Inhibits propulsive
- 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
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|
|Routes of administration|| || |
|Pharmacology|| || |
“Use nalTRACKsone to get back on TRACK:” Naltrexone is used to prevent opioid relapse.
Peripherally acting μ-opioid receptor antagonists
- Mechanism of action: antagonization of μ-opioid receptors outside the CNS (e.g., in the gastrointestinal tract)
- Indication: reversal of opioid side effects, such as opioid-induced constipation or pruritus
Opioid intoxication 
- Epidemiology: most common cause of death due to drug overdose 
- Altered mental status, euphoria, CNS depression (intensifies in combination with other CNS-depressing substances, such as alcohol, benzodiazepines)
- Bilateral (pinpoint pupils)
- Respiratory depression (↓ respiratory rate and ↓ tidal volume), hemorrhagic lung edema
- Myoclonic jerks; , seizures
- ↓ Gag reflex
- ↓ Bowel sounds
- ↓ Heart rate and ↓ blood pressure, hypothermia
- Differential diagnoses: See “ .”
- Airway management: head-tilt/chin-lift maneuver and assisted breathing to improve oxygenation)
- Slow administration to prevent acute withdrawal syndrome
- Neutralization of opioid effects → restoration of ventilation and counteraction of CNS depression
- Management of complications (e.g., diazepam for seizures)
- 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 is caused by sudden reduction or termination of opioid intake in physically dependent individuals.
- Flu-like symptoms
- Gastrointestinal symptoms
- Sympathetic hyperactivity
- CNS stimulation
Opioid withdrawal causes severe discomfort, but is not life-threatening.
Special patient groups: neonatal abstinence syndrome 
- Flu-like symptoms: fever and sweating
- Gastrointestinal symptoms
- Respiratory symptoms
- Sympathetic hyperactivity: hypertension, tachycardia
- CNS stimulation
Absolute contraindications 
- Lung disease
- Gastrointestinal conditions
- Psychiatric conditions
- Hypersensitivity: true allergic reaction to opioids and/or compounds
Relative contraindications 
- Pregnancy and breastfeeding
- Renal failure
- Liver failure
- Concurrent SSRI use
- Acute pancreatitis, biliary tract impairment
We list the most important contraindications. The selection is not exhaustive.