A Comprehensive Pharmacological and Clinical Monograph on Oxymorphone (DB01192)

Executive Summary

Oxymorphone is a potent, semi-synthetic morphinane alkaloid and opioid analgesic first developed in Germany in 1914.[1] As a small molecule drug, it exerts its primary therapeutic and adverse effects through potent agonist activity at the µ-opioid receptor, making it an effective agent for the management of moderate-to-severe pain.[3] Clinically, it has been available in immediate-release (IR) formulations for acute pain and extended-release (ER) formulations for chronic pain requiring around-the-clock therapy.[5]

Its pharmacokinetic profile is distinguished by two key features: a very low oral bioavailability of approximately 10% due to extensive first-pass metabolism, and a metabolic pathway that proceeds primarily through glucuronidation, notably independent of the cytochrome P450 (CYP) enzyme system.[3] This latter characteristic theoretically positions it as a favorable option in patients on complex medication regimens to avoid CYP-mediated drug-drug interactions.

However, the clinical history and utility of oxymorphone are inextricably linked to the trajectory of the U.S. opioid crisis and are defined by the regulatory history of its most prominent brand name product, Opana ER. An attempt by the manufacturer to curb abuse via a crush-resistant reformulation in 2012 failed to achieve its goal. Instead, post-marketing surveillance revealed a perilous shift in the route of abuse from nasal insufflation to injection, which was linked to serious public health consequences, including outbreaks of HIV and hepatitis C.[7] This led to a landmark 2017 U.S. Food and Drug Administration (FDA) request for the product's market withdrawal, concluding that its risks no longer outweighed its benefits.[7] Consequently, oxymorphone serves as a powerful and cautionary case study in the complexities of opioid pharmacology, the limitations of technological solutions like abuse-deterrent formulations in addressing the socio-behavioral problem of addiction, and the evolution of regulatory risk-benefit assessment in the context of a public health emergency.

Chemical Identity and Physicochemical Properties

Systematic Identification and Nomenclature

The unambiguous identification of a pharmaceutical agent is foundational to its study and regulation. Oxymorphone is known by a variety of systematic names and commercial identifiers.

• Primary Identifiers: The compound is most commonly identified as Oxymorphone. Its Chemical Abstracts Service (CAS) Registry Number is 76-41-5, and its DrugBank Accession Number is DB01192.[9]
• Chemical Names: The International Union of Pure and Applied Chemistry (IUPAC) name for the molecule is (4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one, with a more common systematic name being 4,5α-Epoxy-3,14-dihydroxy-17-methylmorphinan-6-one.[9] Its formal chemical name is (5α)-4,5-epoxy-3,14-dihydroxy-17-methyl-morphinan-6-one.[13]
• Synonyms and Brand Names: The drug is also known by several synonyms, including 14-Hydroxydihydromorphinone and Oximorfone.[9] It has been marketed under various brand names, most notably Opana, Opana ER, and Numorphan.[12]

Molecular and Physicochemical Characteristics

Oxymorphone is a semi-synthetic opioid derived from thebaine, a minor alkaloid constituent of the opium poppy (Papaver somniferum).[2] Its molecular structure is closely related to that of morphine but with key modifications that significantly alter its properties. It differs from morphine by a ketone substitution at the C6 position and the saturation of the C7–C8 double bond.[16]

• Molecular Formula and Mass: The chemical formula for oxymorphone is C17​H19​NO4​, and it has a molar mass of 301.342 g·mol−1.[12]
• Physical Description: In its pure form, oxymorphone hydrochloride is an odorless, white to off-white crystalline powder.[12] It is known to darken with prolonged exposure to light, indicating a degree of photosensitivity that necessitates storage in light-resistant containers.[12]
• Solubility and Partition Coefficient: The hydrochloride salt is freely soluble in water but only sparingly soluble in alcohol and ether.[12] The structural modifications relative to morphine render oxymorphone more lipid-soluble.[1] This increased lipophilicity, reflected in an octanol/aqueous partition coefficient of 0.98 at physiological temperature and pH, facilitates more rapid diffusion across the blood-brain barrier, a key factor in its pharmacological profile.[16]

The seemingly minor structural alterations from morphine—the ketone and saturated bond—have profound pharmacological consequences. This increased lipophilicity allows for faster penetration into the central nervous system, which is directly linked to a more rapid onset of action and greater analgesic potency compared to its parent compounds.[1] This illustrates a fundamental principle of medicinal chemistry: subtle changes at the molecular level can create a distinctly different clinical entity. In the case of oxymorphone, these changes contributed not only to its efficacy but also to its high abuse liability, a characteristic that would ultimately define its controversial history.

Regulatory Classification

Reflecting its high potential for abuse and dependence, oxymorphone is subject to stringent regulatory controls globally.

• DEA Schedule: In the United States, oxymorphone is classified as a DEA Schedule II controlled substance. This classification is reserved for drugs with a high potential for abuse that may lead to severe psychological or physical dependence, but which also have a currently accepted medical use.[9] This status imposes strict regulations on its prescribing, dispensing, and storage.
• International Classification: Other nations have similarly classified oxymorphone under their highest tiers of control for prescription narcotics, such as Schedule I in Canada and Class A in the United Kingdom.[12]

Table 1: Key Chemical and Regulatory Identifiers
Identifier Type	Value	Source(s)
Common Name	Oxymorphone	User Query
CAS Number	76-41-5	User Query, 9
DrugBank ID	DB01192	User Query, 4
IUPAC Name	4,5α-Epoxy-3,14-dihydroxy-17-methylmorphinan-6-one	12
Molecular Formula	C17​H19​NO4​	11
Molar Mass	301.342 g·mol−1	12
DEA Schedule (U.S.)	Schedule II	9
Brand Names	Opana, Opana ER, Numorphan	14

Pharmacology

Pharmacodynamics: Mechanism of Action and Effects

The pharmacological effects of oxymorphone are characteristic of a potent opioid agonist, mediated primarily through its interactions with the endogenous opioid receptor system.

• Receptor Interactions: Oxymorphone is a potent agonist with a high affinity for the µ-opioid receptor (MOR), which is the primary target responsible for its analgesic, euphoric, sedative, and respiratory depressant effects.[1] It also exhibits some activity at the δ-opioid receptor (DOR), which may augment its MOR-mediated analgesia, but has little to no clinically relevant activity at the κ-opioid receptor (KOR).[3]
• Cellular Mechanism: Upon binding to these G-protein coupled receptors located throughout the central nervous system, oxymorphone initiates a signaling cascade. This involves the inhibition of adenylate cyclase, leading to a decrease in intracellular cyclic adenosine monophosphate (cAMP) levels. It also modulates ion channels, increasing potassium conductance and decreasing calcium influx, which hyperpolarizes neuronal membranes. The net effect is a reduction in neuronal excitability and the inhibition of the release of nociceptive neurotransmitters, such as glutamate and substance P, from the presynaptic terminals of primary afferent neurons in the spinal cord.[4] Furthermore, it inhibits GABAergic interneurons in the brainstem, which disinhibits descending pain-modulating pathways, further contributing to its analgesic effect.[4]
• Comparative Potency: Oxymorphone is significantly more potent than morphine. When administered parenterally, it is estimated to be approximately 10 times more potent.[1] However, due to its very low oral bioavailability, the equianalgesic ratio for oral administration is closer to 3:1 (oral morphine to oral oxymorphone).[3] It is also considered to be roughly twice as potent as oral oxycodone.[3]
• Physiological Effects:
• Central Nervous System: The principal therapeutic actions are analgesia and sedation. However, it also produces dose-dependent respiratory depression by directly reducing the responsiveness of brain stem respiratory centers to carbon dioxide.[4] Other CNS effects include euphoria, anxiolysis, and miosis (pupil constriction).
• Gastrointestinal Tract: Oxymorphone significantly impacts the GI system by reducing motility and propulsive contractions while increasing smooth muscle tone in the stomach and intestines. It also decreases gastric, biliary, and pancreatic secretions. These combined effects lead to delayed gastric emptying and constipation, a hallmark side effect of opioid therapy.[4]
• Other Systems: Unlike morphine, animal and in vitro studies have shown that oxymorphone has a lower propensity to cause histamine release from mast cells, potentially resulting in a lower incidence of associated pruritus (itching) and hypotension.[1] It can also influence the endocrine system, inhibiting the secretion of hormones such as ACTH, cortisol, and luteinizing hormone (LH).[18]

Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The disposition of oxymorphone in the body is characterized by several clinically important features that differentiate it from other opioids and influence its dosing, safety profile, and potential for drug interactions.

• Absorption:
• Bioavailability: Following oral administration, oxymorphone undergoes extensive first-pass metabolism in the liver, resulting in a very low absolute bioavailability of approximately 10%.[3]
• Time to Peak Concentration (Tmax​): The rate of absorption differs significantly between formulations. The immediate-release (IR) tablet reaches peak plasma concentrations rapidly, at approximately 0.5 hours, contributing to a quick onset of action. The extended-release (ER) formulation is designed for prolonged absorption, with a Tmax​ of 2 to 3 hours.[3]
• Food and Alcohol Effects: The absorption of oral oxymorphone is highly sensitive to external factors. Co-administration with food can increase the peak plasma concentration (Cmax​) by as much as 50%, which can lead to unexpected toxicity. For this reason, it must be administered on an empty stomach (at least 1 hour before or 2 hours after a meal).[3] The interaction with alcohol is even more severe. Co-ingestion of alcohol can disrupt the extended-release mechanism, causing rapid release and absorption of the drug—a phenomenon known as "dose dumping." This can lead to a dramatic and unpredictable increase in Cmax​ (up to 270% in some individuals), resulting in a potentially fatal overdose. This critical interaction is the subject of a black box warning.[3]
• Distribution:
• Volume of Distribution (Vd​): Oxymorphone has a mean volume of distribution of approximately 3 L/kg, indicating that it distributes extensively into body tissues beyond the central circulation.[24]
• Protein Binding: A key distinguishing feature of oxymorphone is its low plasma protein binding of only 10-12%.[24] This is substantially lower than that of other commonly used opioids, such as morphine (~35%), oxycodone (~45%), and fentanyl (80-90%).[21] This property has important clinical implications. In patients with conditions that cause low plasma protein levels (hypoalbuminemia), such as critical illness, malnutrition, or severe liver disease, the unbound (active) fraction of highly protein-bound drugs can increase unpredictably, leading to exaggerated effects and toxicity. Because oxymorphone is not extensively protein-bound, its pharmacokinetics are less affected by changes in plasma protein concentrations, making its effects potentially more predictable in these vulnerable patient populations.
• Metabolism:
• Primary Pathway: Oxymorphone is extensively metabolized, principally in the liver. The primary metabolic pathway is phase II conjugation with glucuronic acid (glucuronidation) to form oxymorphone-3-glucuronide.[3] A smaller portion undergoes reduction of the 6-keto group to form 6-OH-oxymorphone, which possesses some analgesic activity.[1]
• CYP450 System Independence: The most significant aspect of oxymorphone's metabolism is its lack of significant involvement with the cytochrome P450 (CYP) enzyme system.[1] This is a stark contrast to many other opioids, including oxycodone, hydrocodone, fentanyl, and methadone, which are substrates for CYP3A4 and/or CYP2D6.[6] This independence from the CYP system means that oxymorphone is not susceptible to the numerous and often clinically dangerous drug-drug interactions that occur when co-administered with CYP inhibitors or inducers. This theoretically "clean" metabolic profile was promoted by its manufacturer as a key clinical advantage, particularly for patients on polypharmacy.[6] However, this theoretical safety benefit was ultimately rendered irrelevant by the drug's overwhelming real-world abuse liability. This creates a compelling paradox: a drug that is "pharmacokinetically clean" can still be "clinically dirty," demonstrating that a single favorable metabolic property cannot be assessed in isolation from the drug's overall pharmacodynamic and societal risk profile.
• Excretion:
• The metabolites of oxymorphone are primarily eliminated from the body via the kidneys and excreted in the urine.[1] Due to its extensive metabolism, less than 1-2% of an administered dose is excreted as unchanged parent drug.[4] Following a 10 mg oral dose, approximately 49% of the dose is recovered in the urine as drug-related products over a five-day period.[4]
• Half-Life: Reports on the elimination half-life (t1/2​) vary. Some data suggest a very short terminal half-life of approximately 1.3 hours after IV administration.[4] However, for oral formulations, the apparent half-life is much longer, as it is limited by the rate of absorption. The apparent half-life is approximately 8 hours for the IR formulation and ranges from 9 to 12 hours for the ER formulation, which supports the q12h dosing interval.[3]

Table 2: Summary of Pharmacokinetic Parameters for Oral Formulations
Parameter	Immediate-Release (IR)	Extended-Release (ER)	Source(s)
Absolute Bioavailability	~10%	~10%	3
Time to Peak (Tmax​)	~0.5 hours	2–3 hours	3
Apparent Half-life (t1/2​)	~8 hours	9–12 hours	3
Effect of Food	Cmax​ increased up to 50%	Cmax​ increased up to 50%	3
Effect of Alcohol	Not applicable	Cmax​ increased up to 270%	3
Protein Binding	10–12%	10–12%	24

Clinical Efficacy and Therapeutic Applications

Approved Indications

The clinical use of oxymorphone is restricted to specific pain scenarios where its potency is required and alternative analgesics are inadequate, with distinct roles for its different formulations.

• General Indication: Oxymorphone is indicated for the management of pain severe enough to require opioid treatment and for which other pain medicines (e.g., non-opioid analgesics or immediate-release opioids) did not work well enough or cannot be tolerated.[23]
• Immediate-Release (IR) Formulation: The IR tablets are specifically used for the relief of severe, acute pain, such as post-surgical pain, in patients expected to require an opioid analgesic.[5]
• Extended-Release (ER) Formulation: The ER tablets were indicated for the management of severe and persistent chronic pain in patients requiring daily, around-the-clock, long-term opioid treatment. It is crucial to note that the ER formulation is not intended for "as-needed" (PRN) pain relief.[5]
• Other Uses: Beyond general pain management, oxymorphone has also been used in specialized settings, including for the management of labor pain, as an adjunct to anesthesia, and for obstetrical analgesia.[1]

Review of Clinical Trial Evidence

The efficacy of oral oxymorphone, particularly the ER formulation, has been established in a clinical trial program involving over 2,000 patients with various chronic pain conditions.[31]

• Efficacy vs. Placebo: Multiple randomized, double-blind, placebo-controlled trials have consistently demonstrated the superiority of oxymorphone ER over placebo for the management of chronic low back pain and pain associated with osteoarthritis.[3] In these studies, patients treated with oxymorphone ER experienced statistically significant reductions in pain intensity scores compared to those receiving placebo. Furthermore, patients in the placebo groups were significantly more likely to discontinue treatment due to a lack of efficacy.[22]
• Efficacy vs. Active Comparators: Head-to-head comparisons have been conducted against other long-acting opioids. These trials found that oxymorphone ER provided comparable analgesic efficacy and had a similar tolerability profile to both controlled-release (CR) morphine and CR oxycodone.[19]
• Long-Term Efficacy: The durability of oxymorphone's analgesic effect has been assessed in open-label studies lasting up to one year. These trials showed that pain control was maintained over time with little need for dose escalation. In patients with osteoarthritis and low back pain, this sustained analgesia was accompanied by improvements in physical function.[30]
• Acute Pain Efficacy: Studies evaluating the IR formulation in the acute post-operative pain setting demonstrated that it provided rapid and effective analgesia and was generally well-tolerated by patients.[3]

A critical analysis of this body of evidence reveals an important conclusion: while oxymorphone is an effective analgesic, it has not been shown to be clinically superior to other potent, long-acting opioids like morphine or oxycodone.[3] The clinical trials established non-inferiority, not superiority. This lack of a distinct clinical advantage in either efficacy or tolerability is a crucial factor in its overall risk-benefit assessment. Without a compelling therapeutic reason to choose it over existing, more familiar, and often less expensive alternatives, its position in the therapeutic armamentarium was inherently precarious. This context helps to explain why, once the profound public health risks associated with its abuse became undeniable, there was little clinical justification to argue for its continued market presence. It offered no unique benefit to outweigh the significant societal harm it was causing.

Formulations, Dosage, and Administration

Available Pharmaceutical Formulations

Oxymorphone has been made available in several formulations to accommodate different clinical needs, from acute inpatient care to chronic outpatient management.

• Oral Tablets (Immediate-Release): Marketed as Opana®, these are available in 5 mg and 10 mg strengths for rapid onset of pain relief.[3]
• Oral Tablets (Extended-Release): Marketed as Opana® ER, these were designed for 12-hour dosing and came in a wider range of strengths: 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, and 40 mg.[1]
• Other Formulations: For institutional use, oxymorphone is also available as an injectable solution (Numorphan®) for intravenous (IV), intramuscular (IM), or subcutaneous (SC) administration, and as a rectal suppository.[1]

Dosing and Titration Guidelines

The safe and effective use of oxymorphone requires strict adherence to dosing guidelines, particularly given its high potency and narrow therapeutic index.

• Administration: A critical administration instruction is that all oral forms of oxymorphone must be taken on an empty stomach—defined as at least one hour before or two hours after a meal—to avoid the significant increase in peak plasma concentrations caused by food.[5] The ER tablets must be swallowed whole. Crushing, chewing, or dissolving them can disrupt the controlled-release mechanism, leading to the rapid absorption of a potentially fatal dose.[18]
• Opioid-Naïve Patients: For patients who are not tolerant to opioids, treatment must be initiated at the lowest possible dose.
• IR: The typical starting dose is 10 to 20 mg every 4 to 6 hours as needed for pain.[23]
• ER: The recommended starting dose is 5 mg every 12 hours.[22]
• Opioid-Tolerant Patients and Conversion: Converting a patient from another opioid to oxymorphone is a high-risk procedure that requires extreme caution.
• Calculations should be based on standard equianalgesic conversion tables. However, due to incomplete cross-tolerance between opioids, it is standard practice to administer an initial dose that is 25% to 50% lower than the calculated equianalgesic dose and then titrate upwards as needed.[34]
• Specific instructions exist for converting from oxymorphone IR to ER, or from other oral opioids like morphine or oxycodone.[23]
• Dose Titration: Once initiated, the dose of oxymorphone ER can be titrated upwards to achieve adequate analgesia. Dose increases should not occur more frequently than every 3 to 7 days to allow the patient to reach steady-state. Typical increments are 5 to 10 mg every 12 hours.[22]

Table 3: Equianalgesic Dosing Conversion to Oral Oxymorphone
Prior Oral Opioid	Approximate Oral Conversion Factor	Example Calculation
Morphine	0.333	A patient on 60 mg/day of oral morphine would convert to approximately 20 mg/day of oral oxymorphone (60 mg * 0.333).
Oxycodone	0.5	A patient on 40 mg/day of oral oxycodone would convert to approximately 20 mg/day of oral oxymorphone (40 mg * 0.5).
Hydrocodone	0.5	A patient on 40 mg/day of oral hydrocodone would convert to approximately 20 mg/day of oral oxymorphone (40 mg * 0.5).
Oxymorphone	1	A patient on 20 mg/day of oral IR oxymorphone would convert to 20 mg/day of oral ER oxymorphone, typically given as 10 mg q12h.
Note: These are approximate conversion factors. The initial dose for conversion should be reduced by 25-50% to account for incomplete cross-tolerance and then titrated to effect. Sources: 22

Special Population Considerations

Dose adjustments and heightened monitoring are required for several patient populations who are at increased risk of adverse effects.

• Geriatric Patients: Elderly patients are more likely to experience adverse effects such as confusion, dizziness, and somnolence, and may have age-related declines in renal or hepatic function. Treatment should be initiated at the lowest dose (e.g., 5 mg ER q12h), titrated very slowly, and patients must be carefully monitored for signs of CNS and respiratory depression.[23]
• Renal Impairment: In patients with moderate to severe renal impairment (Creatinine Clearance, CrCl<50 mL/min), the clearance of oxymorphone and its metabolites is reduced. The starting dose should be the lowest available (5 mg) for opioid-naïve patients or reduced by 50% for opioid-tolerant patients, followed by slow titration and careful monitoring.[23]
• Hepatic Impairment:
• Mild: Similar to renal impairment, the starting dose should be reduced by 50% or initiated at the lowest dose, with slow titration.[32]
• Moderate to Severe: Oxymorphone is contraindicated in patients with moderate to severe hepatic impairment due to its extensive hepatic metabolism, which can lead to dangerously elevated and unpredictable drug levels.[18]
• Pregnancy and Lactation: Oxymorphone crosses the placenta and is classified as a high-risk medication in pregnancy. Prolonged maternal use can lead to neonatal opioid withdrawal syndrome, a potentially life-threatening condition for the newborn.[12] The drug is also excreted in breast milk and is not recommended during lactation, as it can cause unusual sleepiness, respiratory difficulties, and limpness in the breastfed infant.[5]
• Pediatric Use: The safety and efficacy of oxymorphone have not been established in children, and its use is not recommended in this population.[3]

Safety Profile and Risk Management

The use of oxymorphone is associated with a significant risk of serious adverse effects, contraindications, and drug interactions, which are reflected in its extensive warnings and regulatory controls.

Adverse Drug Reactions

The adverse effects of oxymorphone are typical of a potent µ-opioid agonist.

• Most Common (≥10% incidence): The most frequently reported adverse reactions in clinical trials include nausea, constipation, dizziness or vertigo, vomiting, pruritus (itching), somnolence (drowsiness), headache, and diaphoresis (increased sweating).[1]
• Less Common (1% to <10% incidence): Other notable side effects include dry mouth, fatigue, anxiety, confusion, insomnia, dyspnea (shortness of breath), flushing, and hypotension.[5]
• Serious Reactions: Severe and potentially life-threatening adverse reactions can occur. These include respiratory depression, severe hypotension leading to circulatory shock, adrenal insufficiency with long-term use, seizures, anaphylactic reactions, and gastrointestinal obstruction, including paralytic ileus.[1]

Black Box Warnings and Contraindications

The FDA has mandated several black box warnings for oxymorphone, highlighting its most critical life-threatening risks.

• FDA Black Box Warnings:
• Addiction, Abuse, and Misuse: Oxymorphone exposes users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. A risk assessment should be performed for every patient prior to prescribing.[18]
• Life-Threatening Respiratory Depression: Serious or fatal respiratory depression can occur, with the greatest risk during treatment initiation and following any dose increase. This is a primary cause of opioid-related mortality.[5]
• Accidental Ingestion: Accidental ingestion of even a single dose of oxymorphone, especially by children, can result in a fatal overdose.[33]
• Neonatal Opioid Withdrawal Syndrome: Prolonged use during pregnancy can result in this life-threatening condition in the newborn, requiring specialized management.[33]
• Interaction with Alcohol: Patients must be instructed not to consume alcohol while taking oxymorphone ER, as co-ingestion can cause rapid drug release and a potentially fatal overdose.[18]
• Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants: The concurrent use of opioids with benzodiazepines, alcohol, or other CNS depressants can result in profound sedation, respiratory depression, coma, and death. Concomitant prescribing should be reserved for patients for whom alternative treatment options are inadequate.[33]
• Contraindications: The use of oxymorphone is absolutely contraindicated in the following situations:
• Patients with significant respiratory depression.[18]
• Patients with acute or severe bronchial asthma or hypercarbia.[18]
• Patients with known or suspected paralytic ileus or other GI obstruction.[18]
• Patients with moderate to severe hepatic impairment.[18]
• Patients with a known hypersensitivity to oxymorphone or other morphine analogs.[18]

Clinically Significant Drug Interactions

The potential for drug-drug interactions with oxymorphone is a major clinical concern, although it is uniquely spared from CYP450-mediated interactions.

Table 4: Summary of Clinically Significant Drug Interactions
Interacting Drug Class	Specific Examples	Clinical Effect	Management Recommendation	Source(s)
CNS Depressants	Benzodiazepines, alcohol, other opioids, barbiturates, general anesthetics	Additive pharmacodynamic effects leading to profound sedation, respiratory depression, coma, and death.	Avoid concomitant use. If necessary, reduce the dose of one or both agents and monitor patient closely.	23
Monoamine Oxidase Inhibitors (MAOIs)	Phenelzine, isocarboxazid, tranylcypromine, linezolid	Potentiation of opioid effects, leading to unpredictable and severe adverse reactions, including serotonin syndrome or hypertensive crisis.	Use of oxymorphone with or within 14 days of MAOI use is not recommended.	23
Anticholinergics	Ipratropium, diphenhydramine, tricyclic antidepressants	Increased risk of urinary retention and/or severe constipation, which may progress to paralytic ileus.	Use with caution and monitor for signs of urinary retention and decreased bowel motility.	36
Mixed Agonist/Antagonist Opioids	Buprenorphine, pentazocine, nalbuphine, butorphanol	May reduce the analgesic effect of oxymorphone and/or precipitate withdrawal symptoms in physically dependent patients.	Avoid concomitant use.	36
CYP450 Inducers/Inhibitors	Rifampin, ketoconazole, ritonavir	No significant pharmacokinetic interaction.	No dose adjustment needed based on CYP status. This is a key differentiating feature.	6

Overdose and Management

An overdose of oxymorphone is a medical emergency.

• Symptoms: The clinical presentation is characterized by the classic opioid overdose triad: respiratory depression (slowed, shallow, or absent breathing), central nervous system depression (progressing from extreme somnolence to stupor or coma), and miosis (pinpoint pupils). Other signs may include skeletal muscle flaccidity, cold and clammy skin, bradycardia (slowed heart rate), and hypotension. In severe cases, overdose can lead to apnea, circulatory collapse, cardiac arrest, and death.[1]
• Management: Treatment is focused on supportive care, with the immediate priority being the restoration of adequate ventilation. This includes establishing a patent airway and providing assisted or controlled ventilation. Naloxone, a pure opioid antagonist, is the specific antidote for reversing the life-threatening respiratory depression caused by oxymorphone overdose.

Regulatory History and The Opana ER Case Study

The history of oxymorphone is a multi-decade narrative that culminates in a landmark regulatory action, making it a critical case study in the intersection of pharmaceutical development, pain management, and public health policy during the opioid crisis.

Developmental and Approval Timeline

• Early History: Oxymorphone was first synthesized in Germany in 1914.[1] It was later patented in the United States by Endo Pharmaceuticals in 1955 and received its initial FDA approval for medical use in 1959, primarily as a parenteral formulation (Numorphan®) for inpatient use.[1] An immediate-release oral tablet was also marketed but was withdrawn in 1972 for what the company described as commercial reasons.[16]
• Introduction of Opana ER: In the early 2000s, amidst a growing emphasis on long-acting opioids for chronic pain, Endo Pharmaceuticals developed an extended-release formulation. This product, branded Opana ER, utilized the TIMERx® controlled-release delivery system and was approved by the FDA in June 2006 for the management of chronic pain requiring continuous, around-the-clock opioid therapy.[7]

The Rise and Fall of Opana ER: A Case Study in Abuse-Deterrence and Public Health

The story of Opana ER is a quintessential example of the failure of a purely technological solution to address the complex socio-behavioral problem of addiction and drug abuse.

• The Reformulation: The original formulation of Opana ER was susceptible to abuse by crushing the tablets to defeat the time-release mechanism, allowing the powder to be snorted or injected for a rapid, intense high. In response to growing concerns about this abuse, Endo developed a new, crush-resistant formulation intended to be "abuse-deterrent." This reformulated version was approved by the FDA in 2011, and the original formulation was removed from the market.[7]
• FDA's Stance on "Abuse-Deterrent" Labeling: Although the new formulation was approved, the FDA determined that the data submitted by Endo were insufficient to prove that it would meaningfully deter abuse in the real world. Consequently, the agency declined Endo's request to include an "abuse-deterrent" description in the product's official labeling.[7]
• A Perilous Shift in Abuse Patterns: The manufacturer's technological fix had an unintended and devastating consequence. Post-marketing surveillance data quickly revealed that while the reformulation made the tablets more difficult to crush and snort, it did not stop abuse. Instead, determined users discovered methods to dissolve the new formulation for intravenous injection. This led to a significant and dangerous shift in the primary route of abuse from nasal to injection.[8] This shift was directly linked to severe public health crises, including outbreaks of HIV, hepatitis C, and a serious blood disorder (thrombotic microangiopathy) among clusters of individuals injecting the drug.[8]
• The Advisory Committee and FDA Action: In March 2017, the FDA convened an independent advisory committee to review the post-marketing data. After evaluating the evidence of the changing abuse patterns and the associated harms, the committee voted overwhelmingly (18 to 8) that the benefits of the reformulated Opana ER no longer outweighed its risks.[7]
• Unprecedented Market Withdrawal: Based on the committee's recommendation and its own review, the FDA took an unprecedented step in June 2017. For the first time, the agency requested that a manufacturer voluntarily remove an opioid analgesic from the market due to the public health consequences of its abuse. The FDA's rationale was clear: the reformulation had not only failed to curb abuse but had also shifted it to a more dangerous route, thereby worsening the public health impact. Endo Pharmaceuticals complied with the request and announced the voluntary withdrawal of Opana ER from the market in July 2017.[4]

This series of events marked a paradigm shift in opioid regulation. It established a critical precedent that the FDA would consider a drug's real-world abuse patterns and its total societal impact as part of its ongoing risk-benefit assessment. The withdrawal was not based on a lack of efficacy or a defect in the product itself, but on the conclusion that its net effect on public health had become negative. It demonstrated that a pharmaceutical product's performance in the complex environment of human behavior and addiction, not just in controlled clinical trials, is a key component of its regulatory lifecycle.

Conclusion and Clinical Perspective

Oxymorphone is a pharmacologically potent and clinically effective semi-synthetic opioid analgesic. Its distinct pharmacokinetic profile, characterized by a lack of CYP450-mediated metabolism and low plasma protein binding, offers theoretical advantages for use in specific, complex patient populations, such as those on polypharmacy or those with hypoalbuminemia.

However, any assessment of oxymorphone's place in modern medicine is dominated by the regulatory and public health history of its extended-release formulation, Opana ER. The attempt to mitigate abuse through a crush-resistant reformulation proved to be a stark failure, leading not to a reduction in abuse but to a shift toward more dangerous routes of administration with devastating public health consequences. The subsequent and unprecedented FDA request for its market withdrawal underscores a critical lesson: technological fixes are insufficient to solve the deeply entrenched socio-behavioral problem of addiction.

Ultimately, the story of oxymorphone serves as a profound cautionary tale for the pharmaceutical industry, regulators, and clinicians. It highlights that the risk-benefit analysis for a potent opioid must extend beyond the controlled environment of clinical trials to encompass its real-world impact on society. While generic formulations of oxymorphone remain available, its clinical use is now exceptionally limited and approached with the utmost caution. Its legacy is less that of a therapeutic mainstay and more that of an instructive case study on the intersection of pharmacology, drug formulation, addiction, and the evolution of public health-based regulation in the shadow of the opioid epidemic.

Works cited

1. Oxymorphone: Mechanisms of Action, Clinical Uses and Adverse Effects, accessed September 5, 2025, https://radiusga.com/oxymorphone-mechanisms-of-action-clinical-uses-and-adverse-effects/
2. Clinical applications of oxymorphone | Journal of Opioid Management, accessed September 5, 2025, https://wmpllc.org/ojs/index.php/jom/article/view/676
3. Oral Oxymorphone | Palliative Care Network of Wisconsin, accessed September 5, 2025, https://www.mypcnow.org/fast-fact/oral-oxymorphone/
4. Oxymorphone: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 5, 2025, https://go.drugbank.com/drugs/DB01192
5. Oxymorphone: MedlinePlus Drug Information, accessed September 5, 2025, https://medlineplus.gov/druginfo/meds/a610022.html
6. Concomitant Filled Prescriptions of Oxymorphone or Oxycodone with CYP3A Inhibitors and Inducers - PMC, accessed September 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10391052/
7. Oxymorphone (marketed as Opana ER) Information - FDA, accessed September 5, 2025, https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/oxymorphone-marketed-opana-er-information
8. FDA Calls for Manufacturer to Pull Opioid from the Market | ASH Clinical News, accessed September 5, 2025, https://ashpublications.org/ashclinicalnews/news/3238/FDA-Calls-for-Manufacturer-to-Pull-Opioid-from-the
9. Oxymorphone | C17H19NO4 | CID 5284604 - PubChem, accessed September 5, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Oxymorphone
10. Oxymorphone - Drugs and Lactation Database (LactMed®) - NCBI Bookshelf, accessed September 5, 2025, https://www.ncbi.nlm.nih.gov/books/NBK500661/
11. [Oxymorphone CII (300 mg)] - CAS [76-41-5] - USP Store, accessed September 5, 2025, https://store.usp.org/product/1488000
12. Oxymorphone - Wikipedia, accessed September 5, 2025, https://en.wikipedia.org/wiki/Oxymorphone
13. Oxymorphone (CAS 76-41-5) - Cayman Chemical, accessed September 5, 2025, https://www.caymanchem.com/product/15911/oxymorphone
14. Oxymorphone - brand name list from Drugs.com, accessed September 5, 2025, https://www.drugs.com/ingredient/oxymorphone.html
15. Definition of oxymorphone hydrochloride - NCI Drug Dictionary, accessed September 5, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/oxymorphone-hydrochloride
16. Oxymorphone extended-release (Chapter 25) - The Essence of Analgesia and Analgesics, accessed September 5, 2025, https://www.cambridge.org/core/books/essence-of-analgesia-and-analgesics/oxymorphone-extendedrelease/530124F1C31123CE7094D8501A25306C
17. Oxymorphone USP Reference Standard CAS 76-41-5 Sigma-Aldrich, accessed September 5, 2025, https://www.sigmaaldrich.com/US/en/product/usp/1488000
18. OPANA® ER (Oxymorphone Hydrochloride) Extended-Release Tablets 5 mg, 10 mg, 20 mg, and 40 mg - accessdata.fda.gov, accessed September 5, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021610s001,021611s001lbl.pdf
19. Review of oral oxymorphone in the management of pain - PMC - PubMed Central, accessed September 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2621383/
20. Drug Scheduling - DEA.gov, accessed September 5, 2025, https://www.dea.gov/drug-information/drug-scheduling
21. Pharmacology of opioids - Deranged Physiology, accessed September 5, 2025, https://derangedphysiology.com/main/cicm-primary-exam/nervous-system/Chapter-334/pharmacology-opioids
22. Opana - Mass.gov, accessed September 5, 2025, https://www.mass.gov/doc/opana-er-drug-monograph-0/download
23. Oxymorphone (oral route) - Side effects & dosage - Mayo Clinic, accessed September 5, 2025, https://www.mayoclinic.org/drugs-supplements/oxymorphone-oral-route/description/drg-20071555
24. Clinical Pharmacology of Oxymorphone | Pain Medicine - Oxford Academic, accessed September 5, 2025, https://academic.oup.com/painmedicine/article/10/suppl_1/S3/1915029
25. 201655Orig1s000 - accessdata.fda.gov, accessed September 5, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201655Orig1s000ClinPharmR.pdf
26. PharmGKB summary: oxycodone pathway, pharmacokinetics - PMC - PubMed Central, accessed September 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6602093/
27. Morphine: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 5, 2025, https://go.drugbank.com/drugs/DB00295
28. Opioid analgesics-related pharmacokinetic drug interactions: from the | JPR, accessed September 5, 2025, https://www.dovepress.com/opioid-analgesics-related-pharmacokinetic-drug-interactions-from-the-p-peer-reviewed-fulltext-article-JPR
29. opana® er - This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed September 5, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021610s027lbl.pdf
30. Oxymorphone and oxymorphone extended release: A pharmacotherapeutic review, accessed September 5, 2025, https://scholars.uky.edu/en/publications/oxymorphone-and-oxymorphone-extended-release-a-pharmacotherapeuti
31. Oxymorphone Extended-Release Tablets (Opana ER) For the Management of Chronic Pain: A Practical Review for Pharmacists - PMC - PubMed Central, accessed September 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2888551/
32. Opana (oxymorphone) dosing, indications, interactions, adverse effects, and more., accessed September 5, 2025, https://reference.medscape.com/drug/opana-oxymorphone-343322
33. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed September 5, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/021610s031lbl.pdf
34. Oxymorphone and Opioid Rotation | Pain Medicine - Oxford Academic, accessed September 5, 2025, https://academic.oup.com/painmedicine/article/10/suppl_1/S39/1915574
35. HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use OXYMORPHONE HYDROCHLORID - Mallinckrodt Pharmaceuticals, accessed September 5, 2025, https://www.mallinckrodt.com/globalassets/documents/products/generic-products/oxymorphone/oxymorphone-hcl-tabs-x30000145-in-052017-2.pdf
36. Opana ER (oxymorphone hydrochloride) tablets label - accessdata.fda.gov, accessed September 5, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/201655s004lbl.pdf
37. Determination That OPANA ER (Oxymorphone Hydrochloride) Extended-Release Tablets, 7.5 Milligrams and 15 Milligrams, Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness - Federal Register, accessed September 5, 2025, https://www.federalregister.gov/documents/2011/08/30/2011-22143/determination-that-opana-er-oxymorphone-hydrochloride-extended-release-tablets-75-milligrams-and-15
38. Oxymorphone (Opana): Uses & Side Effects - Cleveland Clinic, accessed September 5, 2025, https://my.clevelandclinic.org/health/drugs/20829-oxymorphone-tablets
39. OPANA® ER (oxymorphone hydrochloride) Extended-Release tablets, CII - accessdata.fda.gov, accessed September 5, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021610s009lbl.pdf