DrugClassOverview
Opioid Agonists
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Opioid agonists bind to the mu-opioid receptors within and outside the central nervous system. Opioid analgesia is mediated through changes in the perception of pain at the spinal cord and higher levels in the central nervous system. Opioid analgesics also alter the emotional response to pain. The stimulatory effects of opioids are the result of disinhibition as the release of inhibitory neurotransmitters such as gamma-aminobutyric acid (GABA) and acetylcholine are blocked.[40951][46350] [50846][56303] Some opioids also inhibit norepinephrine (NE) and serotonin (5-HT) reuptake suppressing the transmission of pain.[62532] The effects of opioid agonists depend on the varying degrees of affinity for receptors and the genetic differences in opioid receptor sensitivity.[50846] Oliceridine is a mu-opioid receptor ligand that preferentially engages the G protein pathway and has minimal to no recruitment of beta-arrestin signaling compared to conventional opioids, which is believed to reduce its opioid-related adverse event profile.[65809][65818]
Classification and Receptor Activity of Opioid Agonists [50846]
Subclass | Opioid Agonista | Receptor Activityb |
| Phenanthrenes | Codeine | Mu (weak); Delta (weak) |
| Hydrocodone | Mu | |
| Hydromorphone | Mu | |
| Levorphanol | Mu; Delta; Kappa; NMDA antagonist | |
| Morphine | Mu; Kappa (weak) | |
| Oxycodone | Mu; Kappa | |
| Oxymorphone | Mu; Delta | |
| Phenylpiperidines | Fentanyl | Mu |
| Meperidine | Mu; Delta | |
| Diphenylheptanes | Methadone | Mu; NMDA antagonist |
| Phenylpropylamines | Tapentadol | Mu (weak); NE reuptake inhibitor |
| Tramadol | Mu; NE and 5-HT reuptake inhibitor |
aOliceridine is a mu-receptor agonist that is not structurally related to other opioid agonists.[65809]bOpioids are agonists at the listed receptor unless otherwise specified.
Opioid Equianalgesic Doses and Duration of Action Comparisons (Adults and Children weighing 50 kg or more)
| Drug | Approximate Equianalgesic Dosee | |
Oral | Parenteral | |
| Codeinea | 200 mg | NA |
| Fentanyl | -- | 100 mcg |
| Hydrocodone | 30 mg | NA |
| Hydromorphone | 7.5 mg | 1.5 mg |
| Levorphanol | 2 mg | NA |
| Meperidine | 300 mg | 100 mg |
| Methadoneb | -- | -- |
| Morphinec | 30 mg | 10 mg |
| Oxycodone | 20 mg | NA |
| Oxymorphone | 10 mg | 1 mg |
| Tapentadold | 75 mg | NA |
| Tramadol | -- | NA |
[50850][62531][62533][62599][62600]
NA = Not available in the US
aCodeine doses above 60 mg do not result in increased analgesia but are associated with a higher incidence of side effects (Max recommended dose: 360 mg/24 hours).[33654]bRefer to conversion table below; methadone has incomplete cross-tolerance with other opioids and even when started at low doses, the long half-life of methadone may be underestimated while dosing is titrated. Analgesia can occur at 10% of the calculated equianalgesic doses of conventional opioids.[50846]cDosing conversion is for patients taking around-the-clock morphine (not single or intermittent doses). dSome literature suggests a conversion ratio of 1:2.5 to 3.3 (morphine equivalents: tapentadol).[62538][62539][62540]e Certain long-acting products have product specific recommendations.[29623][39635][51201][56303][58531] | ||
Guidelines for Morphine PO to Methadone Conversion (Chronic Administration)
Total Daily Oral Morphine Dose | Estimated Daily Oral Methadone Requirement as a % of Total Daily Morphine Dose* | Estimated Daily IV Methadone Requirement as a % of Total Daily Morphine Dose* |
less than 100 mg | 20% to 30% | 10% to 15% |
100 to 300 mg | 10% to 20% | 5% to 10% |
300 to 600 mg | 8% to 12% | 4% to 6% |
600 mg to 1,000 mg | 5% to 10% | 3% to 5% |
more than 1,000 mg | less than 5% | less than 3% |
| *Divide the total daily methadone dose by the dosing interval (i.e., for administration every 8 hours, divide total daily dose by 3).[33136][51312] | ||
Opioid Duration of Action Comparisons
Drug | Duration (hours) | |
Short-acting (immediate-release) | Long-acting (controlled-, extended-, sustained-release) | |
| Codeine PO | 4 to 6 | -- |
| Fentanyl IV | 1 to 2 | -- |
| Fentanyl patch | -- | 48 to 72 |
| Hydrocodone PO | 4 to 8 | 12 to 24 |
| Hydromorphone IV | 3 to 4 | -- |
| Hydromorphone PO | 3 to 6 | 24 |
| Levorphanol PO | 6 to 15 | -- |
| Meperidine PO/IV | 2 to 4 | -- |
| Methadone PO/IV | 6 to 8 | -- |
| Morphine IV | 3 to 4 | -- |
| Morphine PO | 3 to 6 | 8 to 24 |
| Oxycodone PO | 3 to 6 | 8 to 12 |
| Oxymorphone IV | 3 to 6 | -- |
| Oxymorphone PO | 4 to 6 | 12 |
| Tapentadol PO | 4 to 6 | 12 |
| Tramadol PO | 4 to 6 | 24 |
Opioid Comparative Efficacy Trials
Citation | Design | Results | Conclusion |
APOLLO-2 Singla NK, et al. Pain Pract. 2019;19:715-731.[65818] | Randomized, placebo- and active-controlled trial (n = 401) comparing oliceridine (1.5 mg IV loading dose then demand doses of 0.1, 0.35, or 0.5 mg IV) vs. morphine (4 mg IV loading dose then demand doses of 1 mg IV) vs. placebo for moderate to severe acute pain after abdominoplasty. Demand doses were delivered by a patient-controlled analgesia (PCA) device; PCA doses were allowed 10 minutes after the loading dose and limited by a 6-minute lockout interval. Clinician-administered, blinded supplemental doses of oliceridine 0.75 mg and morphine 2 mg were allowed as often as hourly. | Responder rate at 24 hours Oliceridine 0.1 mg: 61% Oliceridine 0.35 mg: 76.3% Oliceridine 0.5 mg: 70% Morphine: 78.3% Placebo: 45.7% (p less than 0.05 for all comparisons)
Respiratory safety burden (RSB) Mean hours [SD] Oliceridine 0.1 mg: 0.43 [1.56] Oliceridine 0.35 mg: 1.48 [3.83] (p = 0.27 vs. morphine) Oliceridine 0.5 mg: 1.59 [4.26] (p = 0.54 vs. morphine) Morphine: 1.72 [3.86] (p less than 0.05 vs. placebo) Placebo: 0.6 [2.82] (p more than 0.05 for all oliceridine comparisons)
Gastrointestinal Adverse Events Oliceridine 0.1 mg: 49.4% Oliceridine 0.35 mg: 65.8% Oliceridine 0.5 mg: 78.8% Morphine: 79.3% Placebo: 47%
Rescue antiemetic medication receipt Oliceridine 0.1 mg: 32.5% (p less than 0.05 vs. morphine) Oliceridine 0.35 mg: 55% Oliceridine 0.5 mg: 61.3% Morphine: 65.1% | Oliceridine 0.35 and 0.5 mg regimens were equianalgesic to morphine based on noninferiority analysis.
Oliceridine has a favorable safety and tolerability profile for respiratory and gastrointestinal adverse effects compared to morphine. |
Rarely, adrenocortical insufficiency has been reported in association with opioid use. Patients should seek immediate medical attention if they experience symptoms such as nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or hypotension. If adrenocortical insufficiency is suspected, confirm with diagnostic testing as soon as possible. If diagnosed, the patient should be treated with physiologic replacement doses of corticosteroids, and if appropriate, weaned off of opioid therapy. If the opioid can be discontinued, a follow-up assessment of adrenal function should be performed to determine if corticosteroid treatment can be discontinued. Other opioids may be tried; some cases reported use of a different opioid with no recurrence of adrenocortical insufficiency. It is unclear which, if any, opioids are more likely to cause adrenocortical insufficiency.[40951][46350]
True IgE-mediated opioid hypersensitivity reactions are rare; most reactions are due to histamine release from mast cell degranulation.[62602][62603] If true allergic reaction occurs (e.g., rash, severe hypotension, bronchospasm, angioedema), a nonopioid analgesic or an opioid analgesic from a different subclass, with close monitoring, may be used.[62603][62604] Pruritus, urticaria, flushing, and sneezing suggest pseudoallergy due to histamine release and may be managed by decreasing the opioid dose or concurrent use of an antihistamine.[62604]
Sedation is common with opioid agonists. Counsel patients about transient and lasting cognitive impairment that may affect activities requiring mental alertness as well as the effects and risks of concomitant exposure to other sedating agents.[40951][46350] Opioid agonists, especially in high doses, can precipitate seizures.[28314] [50846][51182] Significant neurotoxicity (e.g., tremors, delirium, seizures) has been reported with meperidine use, primarily due to the accumulation of the normeperidine metabolite. These central nervous system effects may occur with repeat meperidine exposure even in patients with normal renal function. Do not use meperidine for the treatment of chronic pain.[51182]
Nausea, vomiting, and constipation are common with opioid agonist therapy. Constipation does not resolve with continued exposure; hence, routine initiation of a bowel regimen (e.g., increased fluid and fiber intake, stool softeners, laxatives) is advised.[40951][46350][63932]
Cases of opioid-induced hyperalgesia (OIH) have been reported, both with short-term and longer-term use of opioids. OIH occurs when an opioid paradoxically causes an increase in pain or an increase in sensitivity to pain. Symptoms of OIH include increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Data suggests a strong biologic plausibility between opioids and OIH and allodynia. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching to a different opioid).[68838]
QT prolongation and torsade de pointes have been reported with methadone use. Guidelines for methadone safety recommend a baseline electrocardiogram (ECG) for patients with risk factors for QT prolongation, prior QT prolongation on an ECG, or history of ventricular arrhythmia, and follow-up ECGs are recommended based on baseline ECG findings, methadone dose changes, and other risk factors for QTc interval prolongation.[57282] Although the risk of QT prolongation appears to be dose-related, with the greatest incidence occurring in patients receiving large doses for pain management (i.e., more than 200 mg/day in adults), smaller doses have also been implicated. Risk/benefit evaluation and consideration of alternative therapy is prudent in patients with risk factors for QT prolongation.[33136]
Physiological dependence develops as a result of repeated drug use. It manifests with a withdrawal syndrome after abrupt discontinuation or significant dose reduction, or administration of an agent with opioid antagonist activity (e.g., naloxone).[40951][46350] The shorter the onset and duration of action of the opioid agonist, the greater the intensity and rapidity of onset of withdrawal symptoms. Withdrawal is characterized by restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms include irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal. Neonatal opioid withdrawal syndrome may be life-threatening and requires management according to protocols developed by neonatology experts. It presents as irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.[40951][46350]
Serious, life-threatening, or fatal respiratory depression may occur with opioid agonist use. Treat symptomatic respiratory depression with an opioid antagonist such as naloxone. Use extreme caution when administering opioid antagonists to individuals physically dependent on opioids to avoid precipitating acute withdrawal syndrome.[40951][46350]
Serotonin syndrome has been reported in patients taking opioids at recommended doses. Advise patients to seek immediate medical attention if they develop symptoms such as agitation, hallucinations, tachycardia, fever, excessive sweating, shivering or shaking, muscle twitching or stiffness, trouble with coordination, nausea, vomiting, or diarrhea. Symptoms generally present within hours to days of taking an opioid with another serotonergic agent, but may also occur later, particularly after a dosage increase. If serotonin syndrome is suspected, either the opioid and/or the other agent should be discontinued.[40951][46350]
Pharmacological tolerance may develop with the chronic use of opioid agonists. Tolerance is characterized by a reduced response to a drug after repeated administration. Methadone is not fully cross-tolerant with other opioid agonists. Use extreme caution when converting from other opioid agonists to methadone; deaths have been reported.[33136]
Concomitant use of opioid agonists and anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when opioids are used concomitantly with anticholinergic drugs.[40951][46350]
Many opioid agonists are metabolized by CYP3A4 and/or CYP2D6. Concurrent use of an enzyme inhibitor or discontinuation of a concurrently used enzyme inducer may increase plasma opioid concentrations and potentiate the risk of fatal respiratory depression. Methadone plasma concentrations may also be affected by CYP2B6, CYP2C19, and CYP2C9.[33136][40951][46350]
Concomitant use of opioids with other central nervous system depressants, including alcohol and benzodiazepines, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant use of these drugs for patients in whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations possible and monitor patients closely for signs and symptoms of respiratory depression and sedation. Concomitant use of alcohol and some extended-release opioid formulations may result in increased opioid plasma concentrations and potentially fatal overdose.[40951][46350][56303][61143]
Avoid concomitant use of opioid agonists with mixed opioid agonists/antagonists and partial opioid agonists (e.g., buprenorphine, butorphanol, nalbuphine, pentazocine). Concomitant use may reduce the analgesic effect of the opioid agonist and/or precipitate withdrawal symptoms.[40951][46350]
Use of opioid agonists is not recommended for patients taking monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping MAOI therapy. Some opioid agonists contraindicate concomitant use. Coadministration may result in serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).[40951][46350][51182]
Concomitant use of opioid agonists with drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If use together is necessary, carefully observe the patient and discontinue either agent if serotonin syndrome is suspected.[40951][46350]
Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents or drugs capable of inducing electrolyte disturbances; monitor patients closely for cardiac conduction changes during concomitant use.[33136]
Opioid agonists may potentiate the neuromuscular blocking action of skeletal muscle relaxants and increase the risk of respiratory depression. Monitor patients for signs of respiratory depression that may be more than otherwise expected and adjust the dosage of opioid and/or muscle relaxant as necessary.[40951][46350]
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Monitor patients for decreased diuresis and/or effects on blood pressure and increase the diuretic dosage as needed. Diuretics are also capable of inducing electrolyte disturbances, which may potentiate the risk for QT prolongation with methadone use.[33136][40951][46350]
Opioid use exposes patients to the risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk before prescribing opioids and monitor patients closely for the development of these behaviors and conditions.[40951][46350] Query prescription drug monitoring programs (PDMPs) before prescribing and dispensing opioids to determine or verify an individual's history of use of controlled substances.[68447] Consider prescribing a limited duration of opioids for acute pain episodes, particularly upon hospital discharge.[66134] Diversion of controlled substances by health care employees may endanger health care workers, compromise patient safety, cause substandard patient care, and increase costs. Consider implementing a proactive approach within health care organizations to prevent, identify, report, and respond to controlled substance drug diversion according to best safety practices.[69109]
Accidental exposure to opioids can result in respiratory depression and death.[40951] Instruct patients to store their medication securely and provide patients with resources about proper disposal of unused medication, including medication take back locations.[68447]
Discuss the availability of naloxone with all patients and consider prescribing it in patients who are at increased risk of opioid overdose, including those also using other CNS depressants, with a history of opioid use disorder (OUD), who have experienced a previous opioid overdose, or with household members or close contacts at risk for accidental ingestion or overdose.[65733] Instruct patients and their caregivers about proper naloxone use.[68447]
Long-acting opioids should not be used for as-needed analgesia in patients with acute pain. Monitor all patients closely for respiratory depression, especially during initiation and dose escalation.[40951]
Methadone is associated with an increased risk for QT prolongation and torsade de pointes. Although the risk of QT prolongation appears to be dose-related, with greatest incidence occurring in patients receiving large doses for pain management (i.e., more than 200 mg/day in adults), smaller doses have also been implicated. Dose-dependent QT prolongation was observed during dedicated QT/QTc studies with oliceridine; the underlying mechanism and clinical significance of the transient QT changes seen in healthy volunteers are unknown. Do not exceed a cumulative total daily dose of oliceridine 27 mg.[28225][28319][28320][28321][28322][65809]
Opioid agonists may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure is compromised (e.g., depleted blood volume, concomitant agents that compromise vasomotor tone). Monitor these patients for signs of hypotension after initiation and dose titration. Avoid opioid use in patients with circulatory shock.[40951][46350]
Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioid agonists can reduce biliary and pancreatic secretions and cause spasm of the sphincter of Oddi.[40951][46350]
Patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive, including apnea, with opioid use, even at recommended dosages. Consider the use of non-opioid analgesics in these patients. Monitor all patients closely for respiratory depression, especially during opioid initiation and dose escalation.[40951][46350]
Opioids are contraindicated in persons with known or suspected gastrointestinal obstruction, including paralytic ileus. Opioids cause a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and in the duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation.[40951][46350]
Use opioid agonists cautiously in patients with hepatic impairment; dosage adjustment may be necessary.[40951][51182][56303][65809] Oxymorphone is contraindicated in patients with moderate to severe hepatic impairment.[32438] The metabolite normeperidine may accumulate in patients with hepatic impairment who receive meperidine and increase the risk of seizures.[51182]
Use opioids cautiously in persons with renal impairment; dosage adjustment may be necessary. Opioids are known to be excreted by the kidney and their clearance may be decreased in persons with renal impairment. Persons with renal impairment may have higher opioid plasma concentrations than those with normal renal function.[40951][51182][56303][61897]
Monitor patients who may be susceptible to the intracranial effect of carbon dioxide retention (e.g., those with evidence of increased intracranial pressure, brain tumor, or intracranial mass) for signs of sedation and respiratory depression, particularly when initiating opioid therapy. Opioids may reduce respiratory drive and resultant carbon dioxide retention can further increase intracranial pressure.[40951][46350]
Instruct patients to avoid exposing the fentanyl transdermal patch application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, sunbathing, hot baths, saunas, hot tubs, and heated water beds, while wearing the patch; exposure to heat may increase fentanyl absorption and there have been reports of overdose and death as a result of exposure to heat.[29623]
Use opioids with caution in older adults, starting at the low end of the dosing range and titrating slowly. Monitor for signs of central nervous system and respiratory depression. Older adults may have increased sensitivity to opioids, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and concomitant disease or other drug therapy.[40951][46350]
Do not use codeine, dihydrocodeine, and tramadol in persons who are CYP2D6 ultrarapid metabolizers. Some individuals may be ultrarapid metabolizers due to a specific CYP2D6 genotype (gene duplications noted as *1/*1xN or *1/*2xN). These individuals convert codeine, dihydrocodeine, and tramadol into their active metabolites more rapidly and completely than other people. This rapid conversion results in higher than expected concentrations of the active metabolites. Even at labeled dosage regimens, individuals who are ultrarapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose. Because some children who are normal metabolizers can covert opioids at similar rates to ultrarapid metabolizers, this concern extends to all pediatric patients. Codeine, dihydrocodeine, and tramadol are contraindicated in children younger than 12 years and for postoperative pain management in pediatric patients younger than 18 years after a tonsillectomy and/or adenoidectomy.[28314][29774][33654][60162][61890]
Prolonged maternal use of opioids during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). Monitor the exposed neonate for withdrawal symptoms, including irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight, and manage accordingly. Onset, duration, and severity of opioid withdrawal may vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination by the newborn.[40951] [46350] Guidelines recommend early universal screening of pregnant patients for opioid use and opioid use disorder at the first prenatal visit. Obtain a thorough history of substance use and review the Prescription Drug Monitoring Program to determine if patients have received prior prescriptions for opioids. Discuss the risks and benefits of opioid use during pregnancy, including the risk of becoming physiologically dependent on opioids, the possibility for NOWS, and how long-term opioid use may affect care during a future pregnancy.[64838][64909]
If an infant is exposed to an opioid through breast milk, monitor for excessive sedation and respiratory depression. Withdrawal symptoms can occur in breast-fed infants when maternal use of an opioid is stopped or when breast-feeding is stopped. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breast-fed infant, advise patients that breast-feeding is not recommended during treatment with codeine, dihydrocodeine, and tramadol as well as long-acting opioids.[28314][29774][33654][40951][51182][56303][61897]
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