Opioids

Opioids are a class of natural (endogenous and exogenous), synthetic, and semisynthetic substances that act on μ-, κ-, and δ-opioid receptors as antagonists or agonists. They are distinct from opiates, which refer to exogenous alkaloids derived from opium, the dried latex of the opium poppy (Papavum somniferum). Opioids are commonly used to treat moderate to severe acute pain, and chronic pain refractory to non-opioid analgesics. 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).

When prescribing opioids, risk factors for opioid-related harm and risk mitigation strategies for opioid prescribing should be considered. 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). 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 after 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

According to onset and duration of action

Different routes and formulations (e.g., modified release, extended release) affect the onset and duration of action (e.g., fentanyl has a rapid onset and short duration of action when used intravenously but is long acting when used transdermally).

Rapid-onset opioids ^[3]

• Onset within 5–15 minutes; duration of analgesia < 60 minutes ^[4]
• Uses ^[5]
  • Breakthrough cancer pain in opioid-tolerant patients ^[6][7]
  • Procedural analgesia or supplementation to general anesthesia ^[5]
• Examples ^[8]
  • Transmucosal immediate-release fentanyl ^[3][9]
  • Sublingual sufentanil
  • Intravenous alfentanil

Outpatient use of rapid-onset opioids is limited to management of breakthrough cancer pain because of the risk of developing opioid use disorder. ^[7]

Short-acting opioids

• Onset within 30–60 minutes; duration of analgesia 2–6 hours ^[7][10]
• Use: acute pain, breakthrough pain, palliative pharmacotherapy for dyspnea ^[7][11]
• Examples ^[7]
  • Morphine
  • Codeine
  • Hydromorphone
  • Oxymorphone
  • Hydrocodone
  • Oxycodone
  • Tramadol

Long-acting opioids

• Onset between 20 minutes and 4 hours; duration of analgesia 6–15 hours ^[7][10][12]
• Use: palliative pain management, opioid use disorder
• Examples ^[7]
  • Methadone
  • Levorphanol
  • Extended, controlled, or sustained release preparations of short-acting opioids, which behave as long-acting opioids, e.g.: ^[7]
    • Morphine ^[7]
    • Tramadol ^[7]

Improper administration of opioids may lead to rapid absorption and risk of opioid overdose. Extended-release and long-acting opioid capsules or tablets should be taken whole (without crushing or breaking). Transdermal patches should be used intact and protected from external heat.

Opioid receptors ^[1][2][13]

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 ^[14]
• 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 ^[13][17]

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) ^[18]

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 ^[19]

• 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 ^[20]

• Opioids should only be prescribed if the benefits outweigh the risks and additional precautions are taken to minimize the associated harms (see “Risk mitigation for opioid prescribing”).
• The WHO analgesic ladder can guide the selection of the most appropriate pain management strategy.
• When appropriate, nonpharmacological analgesia and nonopioid analgesics are preferred for pain management.
• Dosages are detailed under “Analgesics” in “Principles of pain management.”

Acute pain ^[20]

• General approach: The lowest effective dose should be prescribed and/or 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) ^[21]
  • Analgosedation during surgery
• See also “Acute pain management.”

Chronic pain and palliation

• General approach ^[20]
  • Nonpharmacologic analgesia and nonopioid analgesics should be maximized as appropriate for the condition.
  • For chronic noncancer pain, opioids should only be initiated if the improvement in pain and function is anticipated to outweigh the risks to the patient.
• Uses
  • Commonly used in pain management in palliative care
  • Limited role in the management of chronic noncancer pain ^[20][22]
• See “Chronic noncancer pain management” and “Palliative pain management.”

Overview of opioids used 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

Dyspnea in palliative care

See “Palliative pharmacotherapy for breathlessness.”

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

Sedation and anesthesia

See “Procedural sedation and analgesia.”

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

• Significant respiratory depression (e.g., due to intoxication with alcohol or sedatives; moderate or severe sleep-disordered breathing)
• Acute or severe bronchial asthma (unless in a monitored setting with access to resuscitative equipment)
• Bowel obstruction (including paralytic ileus)
• Lack of preexisting opioid tolerance (if relevant to specific opioid type and formulation)
• Hypersensitivity: true allergic reaction to opioids and/or compounds
• Patients with multiple risk factors for opioid-related harm ^[20]

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

There is an increased risk of adverse effects with opioid use in individuals with any of the following. Consider alternative analgesia, prescribing emergency naloxone (for overdose reversal), and/or additional monitoring. See also “Prevention of opioid overdose.”

Risk factors for opioid overdose ^[20][38][39]

• Opioid-specific factors
  • High dose
  • High potency (e.g., fentanyl)
  • Long-acting opioids (e.g., methadone)
• Patient-specific factors
  • Age ≥ 65 years ^[20]
  • Concurrent use of sedative-hypnotics
  • Prior opioid overdose
  • Prescriptions from multiple providers and/or pharmacies ^[38][40]
  • Release from incarceration in the past few weeks ^[39]
  • Recent cessation of medications for opioid use disorder ^[39]
  • Comorbidities
    • Renal insufficiency
    • Hepatic insufficiency
    • Chronic obstructive pulmonary disease, sleep-related breathing disorders
    • Mental health conditions (e.g., suicidality, depression, anxiety)
    • History of opioid use disorder and/or other substance use disorders

Opioid-induced CNS depression is intensified when combined with other sedative-hypnotics (e.g., alcohol, benzodiazepines).

Risk factors for other harms ^[20][41]

The following circumstances, when combined with opioid use, can lead to harm.

• Pregnancy ^[20]
• Breastfeeding ^[20][42]
• Biliary tract disease (including biliary pancreatitis) ^[43][44]
• Seizure disorders ^[29][45]
• Age ≥ 65 years ^[20]
• Concomitant medication use that could lead to life-threatening drug interactions (e.g., the increased risk of serotonin syndrome when certain opioids are used concurrently with SSRIs) ^[46][47]
• Safety-critical jobs ^[20]

Older adults are at increased risk of opioid-related harm due to decreased renal clearance (even in the absence of renal disease), increased risk of medication error (e.g., due to polypharmacy and/or dementia), and increased drug interactions. ^[20]

If opioids are prescribed in older adults, take care to mitigate common risks of opioid therapy (e.g., medication review, bowel regimens to prevent constipation, risk assessment for falls, and frequent patient monitoring for cognitive impairment). ^[20]