Opioids

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, with severe effects on 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

• Full agonists
  • Morphine, heroin
  • Methadone
  • Meperidine
  • Codeine
  • Fentanyl
• Partial agonist: buprenorphine
• Mixed agonist/antagonists
  • Butorphanol
  • Nalbuphine
  • Pentazocine
• Full antagonists
  • Naloxone
  • Naltrexone
  • Methylnaltrexone

According to origin

Endogenous opioids ^[1][2]

• β-Endorphin
• Enkephalin
• Dynorphin

Exogenous opioids

• Opiates
  • Morphine
  • Codeine
• Semisynthetic opioids
  • Diamorphine (heroin)
  • Buprenorphine
  • Oxycodone
• Synthetic opioids
  • Fentanyl
  • Methadone
  • Hydromorphone

Opioid receptors ^[1][2][3]

μ (mu), δ (delta), κ (kappa)

• Heptahelical transmembrane G-protein-coupled receptors (GPCRs)
• Binding agonists causes reduction of synaptic transmission through the following mechanisms:
  • Presynaptic inhibition: closing of presynaptic Ca²⁺ channels → hyperpolarization→ ↓ release of acetylcholine, noradrenaline, serotonin, glutamate, nitric oxide, and substance P
  • Postsynaptic inhibition: opening of postsynaptic K⁺ channels → hyperpolarization

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

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.

• 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) ^[8]

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.

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]

• The analgesic potency of opioids is described in relation to morphine, which, accordingly, has the analgesic potency of 1.
• Higher relative analgesic potency allows for lower doses achieving the same analgesic effect.
• Values for relative potency differ depending on route of administration.

Pain management

Acute pain management ^[10]

• General approach: lowest effective dose should be prescribed/administered for the shortest duration possible
• Common uses
  • Acute severe pain (e.g., ureteric colic, fractures)
  • Emergency pain management and sedation (e.g., acute coronary syndrome, pulmonary edema) ^[11]
  • Analgosedation during surgery

Chronic pain management

See “Chronic noncancer pain management.”

Opioids for pain management

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

Cough management

• Dextromethorphan (DXM): synthetic codeine analog used for cough suppression
  • Weak opioid receptor agonist and NMDA receptor antagonist
    • Opioid effects are weak and mostly seen with overdose (can be treated with naloxone).
    • Addictive potential is low.
  • Inhibition of serotonin and noradrenaline reuptake increases the risk of serotonin syndrome when used with other serotonergic drugs.
• Codeine: taken PO

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

• Morphine: used in opioid substitution therapy
• Methadone
  • Treatment of acute opioid withdrawal
  • Long-term maintenance therapy
• Buprenorphine: used for relapse prevention

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

“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
• Substances
  • Methylnaltrexone: quaternary ammonium derivative of naltrexone with limited ability to penetrate the blood-brain barrier
  • Naloxegol
  • Alvimopan
  • Naldemedine

Absolute contraindications ^[25]

• Lung disease
  • Acute or severe bronchial asthma
  • Chronic bronchitis
  • Emphysema
• Intoxications
  • Alcohol
  • Sedatives
• Gastrointestinal conditions
  • Paralytic ileus
  • Inflammatory bowel disease
• Psychiatric conditions
  • Suicidality
  • Concomitant substance use that could lead to life-threatening drug interactions
• Hypersensitivity: true allergic reaction to opioids and/or compounds

Relative contraindications ^[25]

• Pregnancy and breastfeeding
• Renal failure
• Liver failure
• Concurrent SSRI use
• Acute pancreatitis, biliary tract impairment

Risk factors for opioid-related harm ^[10]

There is an increased risk of adverse effects with opioid use in patients with any of the following; consider alternative analgesia and/or additional monitoring:

• Age ≥ 65 years
• Hepatic or renal insufficiency
• History of opioid use disorder and/or other substance use disorders
• Preexisting mental health conditions (e.g., depression, anxiety)
• Prior overdose
• Sleep-related breathing disorders
• Pregnancy
• Polypharmacy

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