Levorphanol (Monograph)

Drug class: Opiate Agonists
VA class: CN101
CAS number: 5985-38-6

Medically reviewed by Drugs.com on Apr 19, 2023. Written by ASHP.

Introduction

Opiate agonist; phenanthrene derivative.

Uses for Levorphanol

Pain

Relief of moderate to severe pain.

Usually, temporary relief of moderate to severe pain such as that associated with acute and some chronic medical disorders including renal or biliary colic, acute trauma, postoperative pain, and cancer.

In symptomatic treatment of acute pain, reserve opiate analgesics for pain resulting from severe injuries, severe medical conditions, or surgical procedures, or when nonopiate alternatives for relieving pain and restoring function are expected to be ineffective or are contraindicated. Use smallest effective dosage for shortest possible duration since long-term opiate use often begins with treatment of acute pain. Optimize concomitant use of other appropriate therapies. (See Managing Opiate Therapy for Acute Pain under Dosage and Administration.)

In the management of chronic pain associated with a terminal illness such as cancer, the principal goal of analgesic therapy is to make the patient relatively pain-free while maintaining as good a quality of life as possible.

Generally use opiates for management of chronic pain (i.e., pain lasting >3 months or past the time of normal tissue healing ) that is not associated with active cancer treatment, palliative care, or end-of-life care only if other appropriate nonpharmacologic and nonopiate pharmacologic strategies have been ineffective and expected benefits for both pain relief and functional improvement are anticipated to outweigh risks.

If used for chronic pain, opiate analgesics should be part of an integrated approach that also includes appropriate nonpharmacologic modalities (e.g., cognitive-behavioral therapy, relaxation techniques, biofeedback, functional restoration, exercise therapy, certain interventional procedures) and other appropriate pharmacologic therapies (e.g., nonopiate analgesics, analgesic adjuncts such as selected anticonvulsants and antidepressants for certain neuropathic pain conditions).

Available evidence insufficient to determine whether long-term opiate therapy for chronic pain results in sustained pain relief or improvements in function and quality of life or is superior to other pharmacologic or nonpharmacologic treatments. Use is associated with serious risks (e.g., opiate use disorder [OUD], overdose). (See Managing Opiate Therapy for Chronic Noncancer Pain under Dosage and Administration.)

Related/similar drugs

acetaminophen, cyclobenzaprine, tramadol, naproxen, oxycodone, Tylenol, diazepam

Levorphanol Dosage and Administration

General

Managing Opiate Therapy for Acute Pain

• Optimize concomitant use of other appropriate therapies.

• When opiate analgesia required, use conventional (immediate-release) opiates in smallest effective dosage and for shortest possible duration, since long-term opiate use often begins with treatment of acute pain.

• Consider prescribing naloxone concomitantly for patients who are at increased risk of opiate overdosage or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage. (See Respiratory Depression under Cautions.)

• When sufficient for pain management, use lower-potency opiate analgesics given in conjunction with acetaminophen or an NSAIA on as-needed (“prn”) basis.

• For acute pain not related to trauma or surgery, limit prescribed quantity to amount needed for expected duration of pain severe enough to require opiate analgesia (generally ≤3 days and rarely >7 days). Do not prescribe larger quantities for use in case pain continues longer than expected; instead, reevaluate patient if severe acute pain does not remit.

• For moderate to severe postoperative pain, provide opiate analgesic as part of a multimodal regimen that also includes acetaminophen and/or NSAIAs and other pharmacologic (e.g., certain anticonvulsants, regional local anesthetic techniques) and nonpharmacologic therapy as appropriate.

• Oral administration of conventional opiate analgesics generally preferred over IV administration in postoperative patients who can tolerate oral therapy.

• Scheduled (around-the-clock) dosing frequently is required during immediate postoperative period or following major surgery. When repeated parenteral administration is required, IV patient-controlled analgesia (PCA) generally is recommended.

Managing Opiate Therapy for Chronic Noncancer Pain

• Although specific recommendations may vary, common elements in clinical guideline recommendations include risk mitigation strategies, upper dosage thresholds, careful dosage titration, and consideration of risks associated with particular opiates and formulations, coexisting diseases, and concomitant drug therapy.

• Prior to initiating therapy, thoroughly evaluate patient; assess risk factors for misuse, abuse, and addiction; establish treatment goals (including realistic goals for pain and function); and consider how therapy will be discontinued if benefits do not outweigh risks.

• Regard initial opiate therapy for chronic noncancer pain as a therapeutic trial that will be continued only if there are clinically meaningful improvements in pain and function that outweigh treatment risks.

• Prior to and periodically during therapy, discuss with patients known risks and realistic benefits and patient and clinician responsibilities for managing therapy.

• Some experts recommend initiating opiate therapy for chronic noncancer pain with conventional (immediate-release) opiate analgesics prescribed at lowest effective dosage. Individualize opiate selection, initial dosage, and dosage titration based on patient’s health status, prior opiate use, attainment of therapeutic goals, and predicted or observed harms.

• Evaluate benefits and harms within 1–4 weeks following initiation of therapy or dosage increase and reevaluate on ongoing basis (e.g., at least every 3 months ) throughout therapy. Document pain intensity and level of functioning and assess progress toward therapeutic goals, presence of adverse effects, and adherence to prescribed therapies. Anticipate and manage common adverse effects (e.g., constipation, nausea and vomiting, cognitive and psychomotor impairment). If benefits do not outweigh harms, optimize other therapies and taper opiate to lower dosage or taper and discontinue opiate.

• When repeated dosage increases required, evaluate potential causes and reassess relative benefits and risks. Although evidence is limited, some experts state that opiate rotation may be considered in patients with intolerable adverse effects or inadequate benefit despite dosage increases.

• Higher dosages require particular caution, including more frequent and intensive monitoring or referral to specialist. Greater benefits of high-dose opiates for chronic pain not established in controlled clinical studies; higher dosages associated with increased risks (motor vehicle accidents, overdosage, OUD).

• CDC states that primary care clinicians should carefully reassess individual benefits and risks before prescribing dosages equivalent to ≥50 mg of morphine sulfate daily for chronic pain and should avoid dosages equivalent to ≥90 mg of morphine sulfate daily or carefully justify decision to prescribe such dosages. Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80–120 mg of morphine sulfate daily. Some states have established opiate dosage thresholds (e.g., maximum daily dosages that can be prescribed, dosage thresholds at which consultation with specialist is mandated or recommended) or have mandated risk-management strategies (e.g., review of state prescription drug monitoring program [PDMP] data prior to prescribing).

• Recommended strategies for managing risks include written treatment agreements or plans (e.g., “contracts”), urine drug testing, review of state PDMP data, and risk assessment and monitoring tools.

• Taper and discontinue opiate therapy if patient engages in serious or repeated aberrant drug-related behaviors or drug abuse or diversion. Offer or arrange treatment for patients with OUD.

• Consider prescribing naloxone concomitantly for patients who are at increased risk of opiate overdosage or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage. (See Respiratory Depression under Cautions.)

Administration

Administer orally.

Dosage

Available as levorphanol tartrate; dosage expressed in terms of the salt.

Use lowest effective dosage and shortest duration of therapy consistent with treatment goals of the patient.

Individualize dosage according to clinical status of the patient, desired therapeutic effect, degree of existing opiate tolerance, and age and weight; assess dosage at periodic intervals.

Reduce dosage in poor-risk patients and in geriatric patients.

When switching patients receiving chronic opiate therapy from one opiate analgesic to another, generally reduce the calculated equianalgesic dosage of the new opiate agonist by about 25–50% to avoid inadvertent overdosage. This calculation does not apply when switching to methadone; consult specific recommendations for methadone dosage.

When used concomitantly with other CNS depressants, use lowest effective dosages and shortest possible duration of concomitant therapy. (See Specific Drugs under Interactions.)

Reduce initial dose by ≥50% in patients with compromised respiratory function and in those receiving other drugs that depress respiration. (See Specific Drugs under Interactions.)

Reduce initial dose in patients with hypothyroidism, Addison’s disease, toxic psychosis, prostatic hypertrophy, urethral strictures, acute alcoholism, or delirium tremens.

In patients who are tolerant to opiate agonists and who require high dosages (e.g., patients with severe chronic pain associated with cancer), individualize dosage of highly potent preparations based on response and tolerance.

Avoid abrupt withdrawal from relatively high dosages (e.g., in chronic pain patients) since precipitation of severe abstinence syndrome is likely.

Assess patients for signs of hypoventilation or excessive sedation during therapy.

Adults

Pain

Oral

Usually, initiate with 2 mg every 6–8 hours as needed. May increase to 3 mg every 6–8 hours. Adjust according to response and tolerance.

Initial dosages >6–12 mg in 24 hours not recommended in non-opiate-tolerant patients; lower dosages may be appropriate.

If a patient is placed on an “around-the-clock” dosing regimen, allow at least 72 hours to elapse between dosage adjustments; this is needed to avoid excessive sedation. (See Half-life under Pharmacokinetics.)

Switching from Morphine to Levorphanol

Oral

The manufacturer states that the initial total daily dose of oral levorphanol should be 1/15 to 1/12 of the total daily dose of oral morphine; adjust subsequent dosage based on clinical response.

Prescribing Limits

Adults

Pain

Oral

Maximum initial daily dose in non-opiate-tolerant patients: 6–12 mg in 24 hours.

For acute pain not related to trauma or surgery, limit prescribed quantity to amount needed for the expected duration of pain severe enough to require opiate analgesia (generally ≤3 days and rarely >7 days).

CDC recommends that primary care clinicians carefully reassess individual benefits and risks before prescribing dosages equivalent to ≥50 mg of morphine sulfate daily for chronic pain and avoid dosages equivalent to ≥90 mg of morphine sulfate daily or carefully justify their decision to prescribe such dosages. Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80–120 mg of morphine sulfate daily.

Some states have set prescribing limits (e.g., maximum daily dosages that can be prescribed, dosage thresholds at which consultation with a specialist is mandated or recommended).

Special Populations

Hepatic Impairment

Reduce initial dose in patients with severe hepatic impairment.

Renal Impairment

Reduce initial dose in patients with severe renal impairment.

Geriatric Patients

Reduce initial dose by ≥50% in debilitated geriatric patients.

Respiratory Impairment

Reduce initial dose by ≥50% in patients with any condition affecting respiratory reserve. Titrate subsequent doses according to patient’s response.

Cautions for Levorphanol

Contraindications

• Known hypersensitivity to levorphanol or any ingredient in the formulation.

Warnings/Precautions

Warnings

Respiratory Depression

Causes dose-related respiratory depression.

Occurs most frequently in debilitated patients and following large and/or frequent doses.

Use with extreme caution in patients with impaired respiratory reserve or respiratory depression (e.g., individuals with uremia, severe infection, obstructive respiratory conditions, restrictive respiratory diseases, intrapulmonary shunting, or chronic asthma).

Use not recommended in patients with acute or severe asthma.

Routinely discuss availability of the opiate antagonist naloxone with all patients receiving new or reauthorized prescriptions for opiate analgesics, including levorphanol.

Consider prescribing naloxone for patients receiving opiate analgesics who are at increased risk of opiate overdosage (e.g., those receiving concomitant therapy with benzodiazepines or other CNS depressants, those with history of opiate or substance use disorder, those with medical conditions that could increase sensitivity to opiate effects, those who have experienced a prior opiate overdose) or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage. Even if patients are not receiving an opiate analgesic, consider prescribing naloxone if the patient is at increased risk of opiate overdosage (e.g., those with current or past diagnosis of OUD, those who have experienced a prior opiate overdose).

Dependence and Abuse

Physical and psychologic dependence and tolerance may develop with repeated administration; abuse potential exists. Use with caution.

Use with careful surveillance in patients with a history of drug or alcohol dependence or abuse.

Abrupt cessation of therapy or sudden reduction in dosage after prolonged use may result in withdrawal symptoms. After prolonged exposure to opiate analgesics, if withdrawal is necessary, it must be undertaken gradually.

Concomitant Use with Benzodiazepines or Other CNS Depressants

Concomitant use of opiates, including levorphanol, and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiate agonists, alcohol) may result in profound sedation, respiratory depression, coma, and death. Substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use.

Reserve concomitant use of levorphanol and other CNS depressants for patients in whom alternative treatment options are inadequate. (See Specific Drugs under Interactions.)

Adrenal Insufficiency

Adrenal insufficiency reported in patients receiving opiate agonists or opiate partial agonists. Manifestations are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.

If adrenal insufficiency is suspected, perform appropriate laboratory testing promptly and provide physiologic (replacement) dosages of corticosteroids; taper and discontinue the opiate agonist or partial agonist to allow recovery of adrenal function. If the opiate agonist or partial agonist can be discontinued, perform follow-up assessment of adrenal function to determine if corticosteroid replacement therapy can be discontinued. In some patients, switching to a different opiate improved symptoms.

Head Injury and Increased Intracranial Pressure

Respiratory depressant effects of levorphanol (with CO₂ retention and secondary elevation of CSF pressure) may be markedly exaggerated in the presence of head injury, other intracranial lesions, or preexisting increase in intracranial pressure.

Adverse effects of opiates may obscure the existence, extent, or course of intracranial pathology.

Hypotensive Effects

Possible severe hypotension in individuals whose ability to maintain their BP is compromised by depleted blood volume or concomitant drugs that compromise vasculature tone (e.g., phenothiazines, general anesthetics).

May produce orthostatic hypotension in ambulatory patients.

Cardiovascular Effects

Limit use in patients with acute MI, myocardial dysfunction, or coronary insufficiency. Manufacturer states effect of levorphanol on the cardiac function unknown.

Biliary Tract Surgery

Moderate to marked increases in biliary tract pressure reported. Use not recommended in patients undergoing biliary tract surgery.

General Precautions

Acute Abdominal Conditions

May obscure diagnosis or clinical course of patients with acute abdominal conditions.

Debilitated and Special-Risk Patients.

Use with caution in debilitated patients or in patients with hypothyroidism, Addison’s disease, prostatic hypertrophy, urethral stricture, toxic psychosis, acute alcoholism, or delirium tremens.

Hypogonadism

Hypogonadism or androgen deficiency reported in patients receiving long-term opiate agonist or opiate partial agonist therapy; causality not established. Manifestations may include decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility. Perform appropriate laboratory testing in patients with manifestations of hypogonadism.

Specific Populations

Pregnancy

Category C.

Use not recommended during labor and delivery.

Infants born to women regularly taking opiates during pregnancy may be physically dependent.

Lactation

Not known whether levorphanol is distributed into human milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years age.

Geriatric Use

Use with caution. Dosage adjustment recommended in debilitated geriatric patients. (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use with caution. Extensive liver disease may predispose to excessive sedation, probably due to increased pharmacodynamic sensitivity or decreased hepatic metabolism of the drug. Reduce initial dose in patients with severe hepatic impairment.

Renal Impairment

Use with caution in patients with severe renal impairment; reduce initial dose in these patients.

Common Adverse Effects

Nausea, vomiting, altered mood/mentation, flushing, urinary retention, pruritus, constipation, biliary spasm.

Drug Interactions

Drugs Associated with Serotonin Syndrome

Risk of serotonin syndrome when used with other serotonergic drugs. May occur at usual dosages. Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases. (See Advice to Patients.)

If concomitant use of other serotonergic drugs is warranted, monitor patients for serotonin syndrome, particularly during initiation of therapy and dosage increases.

If serotonin syndrome is suspected, discontinue levorphanol, other opiate therapy, and/or any concurrently administered serotonergic agents.

Specific Drugs

Levorphanol Pharmacokinetics

Absorption

Bioavailability

Well absorbed from the GI tract. Following oral administration, peak plasma concentration achieved in about 1 hour. Steady-state plasma concentrations expected to be achieved by the third day of continuous dosing.

Duration

6–8 hours.

Distribution

Plasma Protein Binding

40%.

Elimination

Metabolism

Extensively metabolized in the liver; undergoes conjugation with glucuronic acid.

Elimination Route

Primarily in urine as the glucuronide conjugate.

Half-life

IV administration: 11–16 hours.

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at 15–30°C.

Actions

• A potent analgesic; shares actions of the opiate agonists.

• Precise mechanism of action has not been fully elucidated; opiate agonists act at several CNS sites, involving several neurotransmitter systems to produce analgesia.

• Pain perception is altered in the spinal cord and higher CNS levels (e.g., substantia gelatinosa, spinal trigeminal nucleus, periaqueductal gray, periventricular gray, medullary raphe nuclei, hypothalamus).

• Opiate agonists do not alter the threshold or responsiveness of afferent nerve endings to noxious stimuli, nor peripheral nerve impulse conduction.

• Opiate agonists act at specific receptor binding sites in the CNS and other tissues; opiate receptors are concentrated in the limbic system, thalamus, striatum, hypothalamus, midbrain, and spinal cord.

• Agonist activity at the opiate μ- or κ-receptor can result in analgesia, miosis, and/or decreased body temperature.

• Agonist activity at the μ-receptor also can result in suppression of opiate withdrawal (and antagonist activity can result in precipitation of withdrawal).

• Respiratory depression may be mediated by μ-receptors, possibly μ₂-receptors (which may be distinct from μ₁-receptors involved in analgesia); κ- and δ-receptors may also be involved in respiratory depression.

Advice to Patients

• Importance of informing patients that levorphanol may impair mental and/or physical ability required for performance of potentially hazardous tasks; avoid driving or operating heavy machinery until effects on individual are known.

• Importance of informing patients that this is a drug of potential abuse and should be protected from theft.

• Risk of respiratory depression following overdosage. Advise patients of the benefits of naloxone following opiate overdose and of their options for obtaining the drug.

• Risk of potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma) if used concomitantly with benzodiazepines or other CNS depressants, including alcohol and other opiates, either therapeutically or illicitly; avoid concomitant use unless such use is supervised by clinician. Importance of informing patients that levorphanol should not be combined with alcohol.

• Risk of hypotension, dizziness, and syncope.

• Potential risk of serotonin syndrome with concurrent use of levorphanol and other serotonergic agents. Importance of immediately contacting clinician if manifestations of serotonin syndrome (e.g., agitation, hallucinations, tachycardia, labile BP, fever, excessive sweating, shivering, shaking, muscle stiffness, twitching, loss of coordination, nausea, vomiting, diarrhea) develop.

• Potential risk of adrenal insufficiency. Importance of contacting clinician if manifestations of adrenal insufficiency (e.g., nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, hypotension) develop.

• Possible risk (although causality not established) of hypogonadism or androgen deficiency with long-term opiate agonist or partial agonist use. Importance of informing clinician if decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility occurs.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule II (C-II) drug.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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