Meperidine (Pethidine): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Meperidine, also known by its international nonproprietary name pethidine and the brand name Demerol®, is a fully synthetic opioid analgesic of the phenylpiperidine class.[1] First synthesized in the 1930s, it occupied a prominent position in clinical practice for much of the 20th century, often preferred by physicians for the management of moderate-to-severe acute pain under the now-disproven belief that it carried a lower risk of addiction and was superior to morphine for certain types of pain.[1] However, a contemporary, evidence-based understanding of its complex pharmacology and significant risk profile has led to a dramatic re-evaluation of its clinical utility. Today, its use is highly restricted and relegated to a few niche, short-term applications.

The central thesis of this monograph is that meperidine's clinical value is severely constrained by an unfavorable risk-benefit profile. This profile is dominated by two key factors: the central nervous system (CNS) neurotoxicity of its active metabolite, normeperidine, and a high potential for severe, often fatal, drug interactions. The pharmacokinetic mismatch between the short-acting parent drug and its long-acting toxic metabolite creates a predictable pathway to accumulation and toxicity, particularly with repeated dosing or in patients with compromised renal function. Normeperidine-induced neurotoxicity manifests as a spectrum of CNS hyperexcitability, including tremors, myoclonus, and grand mal seizures, which are not reversible with the opioid antagonist naloxone.[3]

Furthermore, meperidine is implicated in a number of high-risk drug interactions. It is absolutely contraindicated with monoamine oxidase inhibitors (MAOIs) due to the risk of fatal reactions resembling either severe opioid overdose or serotonin syndrome.[2] Its inherent serotonin reuptake inhibiting properties also create a significant risk of serotonin syndrome when combined with other serotonergic agents, such as selective serotonin reuptake inhibitors (SSRIs).[6] Compounding these risks are its potentiation of CNS depression when used with benzodiazepines or alcohol and its metabolism via the cytochrome P450 3A4 pathway, making it vulnerable to pharmacokinetic interactions.[2]

Consequently, meperidine is no longer considered a first-line agent for analgesia and is explicitly not recommended for the management of chronic pain, for use in elderly patients, or for individuals with renal impairment.[2] Current clinical guidelines recommend its use be limited to a duration of less than 48 hours and a total daily dose not exceeding 600 mg.[2] Safer and more effective opioids, such as morphine, hydromorphone, and fentanyl, are preferred for nearly all clinical scenarios requiring potent analgesia. Meperidine's remaining role in medicine is largely confined to the short-term management of postanesthetic shivering and drug-induced rigors, non-analgesic applications that leverage its unique pharmacological properties.[10] This report provides a detailed analysis of the chemical, pharmacological, and clinical data that substantiates this conclusion.

Chemical Identity and Physicochemical Properties

Precise identification of a pharmaceutical agent is fundamental to its safe and effective use, ensuring accuracy in prescribing, dispensing, and research. This section details the nomenclature, identifiers, and core physicochemical properties of meperidine.

Nomenclature and Synonyms

Meperidine is known by several names globally, reflecting its history and chemical classification. Its United States Adopted Name (USAN) is Meperidine, while its International Nonproprietary Name (INN) is Pethidine.[1] It is a synthetic opioid belonging to the

phenylpiperidine class and is chemically described as a piperidinecarboxylate ester.[2]

The most widely recognized brand name for meperidine is Demerol®.[13] A comprehensive list of its synonyms includes Isonipecaïne, Meperidina, Pethidinum, Petidina, Petydyna, Centralgin, Dolcontral, Dolosal, Dolsin, Lidol, Lydol, Operidine, Petantin, Pethanol, Pethidineter, Phetidine, Piperosal, and Piridosal.[13] In illicit use, it may be referred to by street names such as "Demmies" or simply "Pain Killer".[18]

Key Identifiers

Meperidine is cataloged across numerous chemical and drug databases, which facilitates cross-referencing and regulatory tracking.

• DrugBank ID: DB00454 [11]
• CAS Number: The Chemical Abstracts Service (CAS) has assigned two primary numbers. The number 57-42-1 refers to the meperidine base molecule.[12] The number 50-13-5 refers to the meperidine hydrochloride salt, which is the form used in clinical formulations to improve solubility and stability.[2] This distinction is critical for researchers and pharmaceutical chemists, as the properties of the salt are most relevant to its behavior in medicinal products.
• DEA Schedule: In the United States, meperidine is classified as a DEA Schedule II controlled substance under the DEA Code Number 9230.[12] This scheduling indicates that the drug has a high potential for abuse, which may lead to severe psychological or physical dependence.[8]
• Other Identifiers: For comprehensive database integration, other identifiers include:
• UNII: 9E338QE28F [12]
• ChEBI ID: CHEBI:6754 [12]
• ChEMBL ID: CHEMBL607 [11]
• RXCUI: 6754 [12]

Chemical Structure and Formula

The molecular structure of meperidine defines its pharmacological activity.

• IUPAC Name: ethyl 1-methyl-4-phenylpiperidine-4-carboxylate [11]
• Chemical Formula: C15​H21​NO2​ [13]
• Molecular Weight: The average molecular weight is 247.3327 g/mol, with a monoisotopic mass of 247.157228921 g/mol.[13]
• Structural Representations: For computational chemistry and database searches, its structure can be represented by:
• SMILES: CCOC(=O)C1(CCN(CC1)C)C2=CC=CC=C2 [12]
• InChIKey: XADCESSVHJOZHK-UHFFFAOYSA-N [11]

Physical and Chemical Properties

The physicochemical properties of meperidine influence its absorption, distribution, and formulation characteristics.

• Physical Description: Meperidine hydrochloride is a white crystalline solid.[2]
• Solubility: It has a reported water solubility of 3220 mg/L at 30 °C.[12]
• Partition Coefficient (LogP): The octanol-water partition coefficient (LogP) is approximately 2.72.[12] This value indicates significant lipid solubility (lipophilicity). This property is not merely a chemical statistic; it provides a direct quantitative explanation for a key clinical characteristic of meperidine. Its higher lipophilicity compared to morphine allows it to penetrate the blood-brain barrier more rapidly, resulting in a faster onset of analgesic action, a feature that historically contributed to its clinical appeal.[1]

Table 1: Meperidine Identification and Key Properties

Property	Value/Description
Common Names	Meperidine, Pethidine, Demerol®
Chemical Class	Synthetic Opioid, Phenylpiperidine
DrugBank ID	DB00454
CAS Number	57-42-1 (Base); 50-13-5 (HCl Salt)
DEA Schedule	Schedule II
IUPAC Name	ethyl 1-methyl-4-phenylpiperidine-4-carboxylate
Chemical Formula	C15​H21​NO2​
Molecular Weight	247.33 g/mol
LogP	2.72

Pharmacology: Mechanism of Action and Pharmacodynamic Effects

Meperidine exhibits a complex pharmacological profile that extends beyond simple opioid agonism. Its unique combination of activities at multiple receptor systems accounts for both its therapeutic effects and its distinct and problematic side-effect profile. Understanding these multiple mechanisms is essential to appreciating its clinical behavior and associated risks.

Primary Opioid Receptor Agonism

The principal analgesic and sedative properties of meperidine are mediated through its interaction with endogenous opioid receptors, which are G-protein coupled receptors (GPCRs) that regulate synaptic transmission.[5]

• μ-Opioid Receptor Agonism: Like morphine, meperidine's primary mechanism for analgesia is its action as an agonist at the μ-opioid receptor (mu-opioid receptor).[1] Binding to these receptors, located predominantly in the brainstem and medial thalamus, initiates a signaling cascade. This involves the inhibition of the enzyme adenylate cyclase, which leads to a decrease in intracellular cyclic adenosine monophosphate (cAMP). The downstream effects include the closure of N-type voltage-operated calcium channels and the opening of calcium-dependent inwardly rectifying potassium channels. This results in hyperpolarization of the neuronal membrane, reducing its excitability and inhibiting the release of nociceptive (pain-signaling) neurotransmitters such as Substance P, GABA, dopamine, and norepinephrine.[13] This action effectively dampens the transmission of pain signals to the brain, producing analgesia, euphoria, and sedation.[15]
• κ-Opioid Receptor Agonism: Meperidine also demonstrates significant agonist activity at the κ-opioid receptor (kappa-opioid receptor).[2] This interaction is believed to be the primary mechanism underlying its unique and clinically useful ability to interrupt postanesthetic shivering and treat the severe rigors (shaking chills) induced by certain medications like amphotericin B.[2] This effect is not as prominent with other common opioids like morphine.

Secondary Pharmacological Actions

In addition to its opioid receptor activity, meperidine possesses several other pharmacological properties that contribute to its unique clinical profile and are the source of many of its atypical side effects and risks.

• Local Anesthetic Properties: The chemical structure of meperidine bears a resemblance to local anesthetics.[13] It exhibits local anesthetic activity by blocking voltage-gated sodium ion channels, a mechanism similar to that of drugs like lidocaine.[1] While this action contributes to its observed antispasmodic effects in laboratory settings, these effects are not considered to be clinically significant in vivo.[1]
• Anticholinergic (Atropine-like) Effects: Unlike most other opioids, meperidine possesses notable anticholinergic properties.[1] This atropine-like activity is responsible for a constellation of side effects that are unusual for an opioid, including dry mouth (xerostomia), an increase in heart rate (tachycardia), and, most critically from a diagnostic standpoint, pupillary dilatation (mydriasis).[1] This stands in stark contrast to the classic pupillary constriction (miosis) seen with morphine and other opioids.
• Monoamine Reuptake Inhibition: Meperidine exerts mild stimulant effects by inhibiting the reuptake of several key neurotransmitters. It inhibits the dopamine transporter (DAT) and the norepinephrine transporter (NET), which can contribute to feelings of restlessness rather than pure sedation.[1] Crucially, it also acts as a weak serotonin reuptake inhibitor (SRI).[6] This action on the serotonin transporter (SERT) is the mechanistic basis for its potential to cause or contribute to the life-threatening condition known as serotonin syndrome, especially when combined with other serotonergic drugs.[6]

Pharmacodynamic Consequences

The convergence of these multiple pharmacological actions results in a clinical profile that is both complex and unpredictable. Meperidine functions as a pharmacological paradox: it is simultaneously a CNS depressant via its opioid agonism and a CNS stimulant via its anticholinergic and monoamine reuptake inhibiting properties. This internal contradiction explains why its clinical presentation can be so variable. While it can produce the expected opioid effects of analgesia, drowsiness, and a calm feeling [25], it can also induce agitation, confusion, delirium, and restlessness, effects that are atypical for a pure opioid agonist like morphine.[1]

This dual nature is fundamental to understanding its risks. A particularly dangerous pharmacodynamic consequence arises from its anticholinergic effect on the pupils. In a patient presenting with altered mental status, miosis (pinpoint pupils) is a hallmark sign of an opioid toxidrome.[27] The absence of miosis—or the presence of frank mydriasis—in a patient with meperidine toxicity could mislead a clinician, causing them to incorrectly rule out an opioid overdose and thereby delay the administration of the life-saving antagonist naloxone.[1] This potential for diagnostic confusion, born directly from meperidine's unique pharmacology, represents a significant patient safety hazard.

Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion

The pharmacokinetic profile of meperidine is central to its clinical limitations. The disposition of the drug in the body, particularly its metabolic conversion to the toxic metabolite normeperidine, is the single most important factor dictating its unfavorable safety profile and restricting its therapeutic use.

Absorption and Bioavailability

The route of administration significantly impacts meperidine's systemic availability and onset of action.

• Oral Administration: When taken orally, meperidine has a relatively low and variable bioavailability, estimated to be between 50% and 60%.[13] This is due to extensive first-pass metabolism in the liver, where a significant portion of the absorbed drug is metabolized before it can reach systemic circulation.[9] This poor bioavailability is a major clinical drawback, as it necessitates higher oral doses to achieve a therapeutic effect comparable to parenteral administration. This, in turn, increases the metabolic burden and the production of its toxic metabolite, normeperidine.[9]
• Parenteral Administration: When administered by intravenous (IV), intramuscular (IM), or subcutaneous (SC) injection, meperidine bypasses first-pass metabolism, leading to more predictable bioavailability. The onset of action is rapid, occurring within approximately 5 minutes following IV injection and 10 to 15 minutes after IM or SC injection.[1] However, absorption from IM sites can be erratic and highly variable between patients.[29]

Distribution, Protein Binding, and Passage Across Biological Barriers

Once in the bloodstream, meperidine is widely distributed throughout the body.

• Protein Binding: Approximately 60% to 80% of meperidine in the plasma is bound to proteins, primarily albumin and α1-acid glycoprotein.[13]
• Distribution: As indicated by its LogP value of 2.72, meperidine is lipid-soluble, which facilitates its passage across biological membranes.[1] It readily crosses the blood-brain barrier to exert its effects on the CNS. It also crosses the placenta, exposing the fetus to the drug, and is distributed into breast milk, which has implications for nursing infants.[13]

Hepatic Metabolism: The Critical Pathway to Normeperidine

Meperidine is extensively metabolized in the liver via two primary enzymatic pathways.[9]

1. Hydrolysis: One pathway involves hydrolysis of the ester linkage to form meperidinic acid, which is an inactive metabolite. This acid is then partially conjugated with glucuronic acid for excretion.[13]
2. N-demethylation: The second, and clinically most critical, pathway is N-demethylation. This reaction, mediated by cytochrome P450 (CYP) enzymes, including CYP3A4, removes a methyl group from the piperidine nitrogen to form normeperidine.[2] Normeperidine is not an inactive byproduct; it is an active and highly toxic metabolite that is the primary cause of meperidine-associated neurotoxicity.

The Pharmacokinetic Profile of Normeperidine

The pharmacokinetic properties of normeperidine stand in dangerous contrast to those of its parent compound.

• Pharmacological Activity: Normeperidine possesses approximately half the analgesic potency of meperidine but has at least twice the CNS stimulant and neurotoxic potential.[3]
• Elimination Half-Life: The most critical pharmacokinetic mismatch lies in its elimination half-life. While meperidine has a relatively short half-life of 3 to 5 hours in adults, the half-life of normeperidine is significantly longer, ranging from 14 to 21 hours, and can extend up to 48 hours or longer, especially in patients with renal dysfunction.[3]
• Elimination Route: Normeperidine is primarily eliminated from the body via renal excretion.[3] This makes its clearance highly dependent on kidney function.

Excretion

The metabolites of meperidine, including normeperidine and the conjugated forms of meperidinic and normeperidinic acids, are excreted in the urine. The proportion of unchanged meperidine excreted is dependent on urinary pH; more is excreted unchanged in acidic urine.[13]

This profound pharmacokinetic mismatch creates a clinical "accumulation trap." A patient's pain returns as the short-acting meperidine is cleared within a few hours, prompting the administration of another dose as prescribed (typically every 3 to 4 hours).[25] However, the long-acting, toxic normeperidine from all previous doses has not been cleared and continues to accumulate in the body. This cycle of repeated dosing, driven by the short duration of the desired analgesic effect, inevitably leads to the build-up of the toxic metabolite, creating a predictable and dangerous path toward CNS toxicity. This dynamic is the core reason why meperidine use is restricted to very short durations.

Table 2: Comparative Pharmacokinetic Parameters of Meperidine and Normeperidine

Parameter	Meperidine	Normeperidine
Oral Bioavailability	~50-60% (extensive first-pass)	Not Applicable
Onset of Action (IM)	10–15 minutes	Delayed
Elimination Half-life	3–5 hours	14–48 hours (or longer)
Primary Elimination Route	Hepatic Metabolism	Renal Excretion
Primary Clinical Effect	Analgesia, Sedation	CNS Excitation, Seizures

Clinical Efficacy and Therapeutic Applications

Meperidine's role in modern clinical practice has been significantly curtailed as a comprehensive understanding of its risks has replaced historical perceptions of its utility. While it was once a mainstay of pain management, its use is now confined to specific, limited scenarios where its benefits are thought to outweigh its substantial risks.

FDA-Approved Indication: Management of Moderate-to-Severe Acute Pain

The primary FDA-approved indication for meperidine is for the relief of pain severe enough to require opioid treatment and when alternative pain medications have proven inadequate or cannot be tolerated by the patient.[2] However, this indication comes with critical limitations. Due to the well-documented risk of neurotoxicity from the accumulation of its metabolite, normeperidine, meperidine is explicitly

not recommended for the management of chronic pain.[2] Its use should be restricted to the short-term treatment of acute pain episodes.

Off-Label Uses

Meperidine has a few recognized off-label applications that leverage its unique pharmacological properties, distinct from its primary analgesic function.

• Post-anesthetic Shivering: Meperidine is widely considered to be a highly efficacious agent for the treatment of postanesthetic shivering.[2] This effect is thought to be mediated primarily by its agonist activity at κ-opioid receptors and represents one of the few remaining, well-defended clinical niches for the drug.[2]
• Drug-Induced Rigors: It is also used to manage the severe shaking chills (rigors) that can be induced by the administration of certain medications, most notably the antifungal agent amphotericin B and some monoclonal antibodies used in cancer therapy.[2]

It is noteworthy that meperidine's most defensible modern clinical uses are for non-analgesic effects. This observation underscores the conclusion that for its primary purpose—pain relief—it has been largely rendered obsolete by safer and more effective alternatives. Its persistence in clinical practice is, in many ways, a legacy of these niche applications.

Historical Context and Declining Clinical Utility

For a significant portion of the 20th century, meperidine was one of the most frequently prescribed opioids. It was patented in 1937 and approved for medical use in 1943.[1] Physicians often favored it over morphine, operating under the belief that it was a safer agent with a lower risk of addiction and was superior for treating pain associated with biliary or renal colic due to supposed antispasmodic effects.[1]

Subsequent decades of research and clinical experience have systematically debunked these beliefs. Meperidine's potential for addiction and dependence is now understood to be equivalent to that of other potent opioids.[2] Furthermore, its purported antispasmodic benefits in conditions like biliary spasm have not been substantiated in vivo, and it offers no advantage over other opioids for these conditions.[1] The growing awareness of its metabolite-driven neurotoxicity and its complex, high-risk drug interaction profile has led to a paradigm shift in clinical practice. As a result, many healthcare institutions have severely restricted its use or removed it from their formularies entirely, particularly the oral formulations.[9]

Dosage, Formulations, and Administration Guidelines

Meperidine is available in several formulations to accommodate different clinical needs.[2]

• Formulations:
• Oral Tablets: 50 mg and 100 mg
• Oral Solution: 50 mg/5 mL
• Solution for Injection: Available in multiple concentrations (e.g., 25 mg/mL, 50 mg/mL, 75 mg/mL, 100 mg/mL) for intramuscular, subcutaneous, or intravenous administration.
• Adult Dosing for Acute Pain: The typical adult dose is 50 to 150 mg administered every 3 to 4 hours as needed, via oral, IM, or SC routes. For continuous IV infusion, a rate of 15 to 35 mg/hr is used.[2]
• Strict Limitations on Use: Current clinical practice guidelines emphasize stringent limitations to mitigate the risk of normeperidine toxicity. The use of meperidine should be limited to a duration of no more than 48 hours, and the total cumulative dose should not exceed 600 mg in a 24-hour period.[2] These restrictions are designed to prevent the metabolite from accumulating to toxic levels.

The Toxicity of Normeperidine: A Defining Clinical Challenge

The primary factor limiting the safety and utility of meperidine is the toxicity of its active metabolite, normeperidine. Unlike the parent drug, which is a CNS depressant, normeperidine is a potent CNS stimulant. Its accumulation leads to a predictable and dangerous syndrome of neuroexcitability that is unique among commonly used opioids.

Mechanism of Normeperidine-Induced Neurotoxicity

Normeperidine directly causes neuronal excitation in the central nervous system.[3] While the precise molecular mechanism by which it induces seizures remains unknown, it is clear that this effect is distinct from the pharmacology of opioid receptors.[3] The neuroexcitatory effects are not reversed by opioid antagonists. Some evidence from animal models suggests that the seizures are not dopaminergic or cholinergic in nature, but may involve serotonergic pathways, as meperidine itself can block serotonin reuptake.[3] The clinical presentation of toxicity, particularly tremors, myoclonus, and seizures, correlates directly with plasma concentrations of normeperidine, not meperidine.[3]

Clinical Presentation of Toxicity

Normeperidine toxicity manifests as a spectrum of CNS hyperexcitability, which can be progressive if meperidine administration is continued.[3] The signs and symptoms include:

• Early Signs: Irritability, agitation, anxiety, mood alterations, and a sense of nervousness.[3]
• Neuromuscular Excitation: Fine tremors of the hands, muscle twitches (myoclonus), and hyperactive reflexes are common and often precede more severe symptoms.[2]
• Severe Manifestations: In severe cases, toxicity can progress to delirium, disorientation, and generalized tonic-clonic seizures (grand mal seizures).[3]

A critical patient safety issue arises from the potential for misinterpretation of these symptoms. The early signs of normeperidine toxicity—agitation, restlessness, and tremors—can be tragically mistaken by clinical staff for uncontrolled pain or even opioid withdrawal.[9] This misdiagnosis can lead to the paradoxical and dangerous administration of

more meperidine in an attempt to treat the perceived pain, which directly worsens the underlying toxicity and accelerates the progression to seizures. This creates a perilous iatrogenic feedback loop that can only be broken by recognizing the true cause of the symptoms and immediately discontinuing the drug.

Risk Factors for Accumulation and Toxicity

The risk of developing normeperidine toxicity is not uniform and is significantly elevated in specific patient populations and clinical situations.

• Renal Impairment: This is the single most important risk factor. Because normeperidine is cleared by the kidneys, any degree of renal dysfunction can lead to its rapid accumulation.[3] Meperidine is therefore considered contraindicated in patients with moderate to severe renal impairment.[10]
• Prolonged Use: Administration for periods longer than 48 hours dramatically increases the risk of accumulation, as the metabolite's long half-life allows it to build up with each successive dose.[2]
• High Doses: Cumulative daily doses exceeding 600 mg are strongly associated with an increased risk of toxicity.[2]
• Elderly Patients: Older adults are at heightened risk due to the natural age-related decline in renal function, which can impair normeperidine clearance even in the absence of diagnosed kidney disease.[9]
• Concomitant Medications: The risk of seizures is amplified in patients who are also taking other medications that are known to lower the seizure threshold.[3]

The Role of Naloxone in Meperidine Overdose

The management of meperidine overdose is complicated by the dual pharmacology of the parent drug and its metabolite. This can create a complex clinical picture that is effectively a mixture of two distinct toxidromes: an opioid toxidrome (from meperidine) and a stimulant toxidrome (from normeperidine).

• Efficacy for Opioid Effects: Naloxone, a pure opioid antagonist, is highly effective at reversing the opioid-mediated effects of meperidine itself. It will successfully reverse respiratory depression, sedation, and hypotension.[3]
• Inefficacy for Neurotoxicity: Critically, naloxone does not reverse the CNS excitatory effects—such as myoclonus and seizures—that are caused by normeperidine.[4] These symptoms require different management, typically with benzodiazepines and other supportive care.[4]
• The Naloxone Paradox: A significant clinical concern exists regarding the use of naloxone in patients with mixed meperidine/normeperidine toxicity. By rapidly blocking the sedative, CNS-depressant effects of the parent drug meperidine, naloxone may "unmask" or precipitate the underlying neuroexcitatory effects of the accumulated normeperidine. This can potentially trigger the onset of seizures in a patient who was previously only sedated.[4] Therefore, while naloxone is essential for treating life-threatening respiratory depression, it must be administered with caution, and clinicians must be prepared to manage emergent seizures with benzodiazepines.

High-Risk Drug Interactions: Mechanisms and Management

Meperidine is notable for its involvement in several severe and potentially fatal drug interactions. Its complex pharmacology, involving multiple receptor systems and metabolic pathways, creates a "perfect storm" of interaction potential. This multifaceted risk profile makes it particularly hazardous in the context of polypharmacy and is a primary reason for its declining use.

The MAOI Interaction: An Absolute Contraindication

The interaction between meperidine and Monoamine Oxidase Inhibitors (MAOIs) is the most notorious and dangerous. Concomitant use is absolutely contraindicated and can lead to unpredictable, severe, and often fatal reactions.[2] This includes traditional MAOIs (e.g., phenelzine, tranylcypromine), selective MAO-B inhibitors (selegiline), and other drugs with MAOI activity, such as the antibiotic linezolid.[10] A washout period of at least 14 days is required between the use of an MAOI and the administration of meperidine.[5]

• Mechanism: The exact mechanism is not fully elucidated but is thought to involve a massive potentiation of serotonergic effects, as MAOIs prevent the breakdown of serotonin while meperidine inhibits its reuptake.[5]
• Clinical Presentation: The reaction can manifest in two distinct forms:

1. Excitatory (Serotonin Syndrome): This is the more common presentation, characterized by agitation, delirium, hyperthermia, headache, hyperreflexia, muscle rigidity, convulsions, tachycardia, and severe hypertension, which can progress to coma.[1]
2. Depressive (Opioid Overdose-like): A less common presentation that mimics an acute narcotic overdose, with severe respiratory depression, cyanosis, hypotension, and coma.[2]

Serotonin Syndrome with Other Serotonergic Agents

Beyond MAOIs, meperidine's weak serotonin reuptake inhibiting (SRI) properties create a risk of serotonin syndrome when it is co-administered with other serotonergic drugs.[6]

• Interacting Agents: These include Selective Serotonin Reuptake Inhibitors (SSRIs) like fluoxetine and sertraline, Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), tricyclic antidepressants, triptans, and other opioids with serotonergic activity like tramadol.[6]
• Mechanism: The combination of two or more drugs that increase synaptic serotonin levels through different mechanisms (e.g., inhibiting reuptake, increasing release, inhibiting metabolism) can lead to serotonergic overstimulation.[6]
• Symptoms: The classic triad of serotonin syndrome includes:
• Mental Status Changes: Agitation, confusion, restlessness, hallucinations.[36]
• Autonomic Hyperactivity: Tachycardia, hypertension, fever, sweating (diaphoresis), diarrhea.[23]
• Neuromuscular Abnormalities: Tremor, hyperreflexia, myoclonus (muscle jerks), ataxia (loss of coordination).[36]
• Management: Treatment involves immediate discontinuation of all serotonergic agents and provision of supportive care. In moderate to severe cases, benzodiazepines may be used for agitation and muscle stiffness, and the serotonin antagonist cyproheptadine may be administered.[36]

Potentiation of CNS and Respiratory Depression

As an opioid, meperidine causes CNS and respiratory depression. This effect is additive with other depressant drugs, leading to a boxed warning about the risks of this combination.[2]

• Interacting Agents: Benzodiazepines, alcohol, general anesthetics, phenothiazines, barbiturates, sedatives, hypnotics, and other opioids.[2]
• Mechanism: Additive pharmacodynamic depression of the central nervous system.
• Outcome: The combination can result in profound sedation, life-threatening respiratory depression, hypotension, coma, and death.[2] Concomitant prescribing should be reserved only for patients for whom alternative treatment options are inadequate.

Cytochrome P450 (CYP3A4) Interactions

Meperidine's metabolism is dependent on the CYP450 enzyme system, making it susceptible to pharmacokinetic interactions. This risk is significant enough to warrant a boxed warning.[2]

• Mechanism: Meperidine is a substrate for the CYP3A4 enzyme.[2]
• CYP3A4 Inhibitors: Drugs that inhibit CYP3A4 (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir) will decrease the metabolism of meperidine. This leads to increased and prolonged plasma concentrations of meperidine, which can cause potentially fatal respiratory depression.[2]
• CYP3A4 Inducers: Drugs that induce CYP3A4 (e.g., carbamazepine, phenytoin, rifampin) will increase the metabolism of meperidine. While this may reduce its analgesic effect, the greater danger lies in the discontinuation of the inducer. If a patient stabilized on meperidine and a CYP3A4 inducer suddenly stops taking the inducer, meperidine metabolism will slow, causing its plasma concentration to rise to potentially toxic levels.[2]

Table 3: Summary of Major Meperidine Drug Interactions

Interacting Agent Class	Mechanism of Interaction	Clinical Consequence	Management
MAOIs	Serotonergic overstimulation	Potentially fatal serotonin syndrome or opioid overdose-like reaction	Contraindicated
SSRIs & Serotonergic Agents	Additive serotonergic effects	Serotonin syndrome	Avoid if possible; monitor closely for symptoms
CNS Depressants	Additive pharmacodynamic depression	Profound sedation, respiratory depression, coma, death	Avoid concomitant use; reserve for when no alternatives exist
CYP3A4 Inhibitors	Decreased meperidine metabolism	Increased meperidine levels, risk of fatal respiratory depression	Avoid concomitant use; monitor closely if unavoidable
CYP3A4 Inducers	Increased meperidine metabolism	Decreased efficacy; risk of toxicity upon inducer discontinuation	Monitor for efficacy and for toxicity if inducer is stopped

Comparative Analysis: Meperidine vs. Morphine and Fentanyl

To fully appreciate meperidine's clinical standing, it is essential to compare it directly with other cornerstone opioids: morphine, the natural phenanthrene prototype, and fentanyl, a potent synthetic phenylpiperidine. This analysis highlights the key differences in potency, pharmacokinetics, and side-effect profiles that define their respective therapeutic roles and solidify the argument for meperidine's limited utility.

Relative Analgesic Potency and Equianalgesic Dosing

Potency is a measure of the dose required to produce a given effect. Opioid potency is typically compared using equianalgesic dose charts, with parenteral morphine serving as the standard reference.

• Meperidine: It is significantly less potent than morphine. The equianalgesic dose ratios indicate that approximately 300 mg of oral meperidine or 75 mg of parenteral meperidine is required to produce the same analgesic effect as 30 mg of oral morphine or 10 mg of parenteral morphine, respectively. This gives it a relative potency of roughly 0.1 that of morphine.[39]
• Morphine: As the prototype, it is the reference standard with a relative potency of 1.[22]
• Fentanyl: It is a high-potency synthetic opioid, estimated to be 50 to 100 times more potent than morphine.[27]

Onset and Duration of Action

The speed of onset and duration of effect are critical determinants of an opioid's clinical application.

• Meperidine: It has a faster onset of action than morphine, with effects beginning within 10-15 minutes of an IM injection. However, its duration of action is shorter, lasting only 2 to 4 hours.[1]
• Morphine: It has a slower onset (15-30 minutes IM) but provides a longer duration of analgesia, typically around 4 hours, making it more suitable for scheduled dosing.[22]
• Fentanyl: It has a very rapid onset, with peak effects occurring within 5 minutes of IV administration, but a short duration of action (30-60 minutes). This profile makes it ideal for managing acute, severe pain in procedural settings, such as anesthesia and surgery, where rapid control and quick recovery are desired.[26]

Comparative Side-Effect Profiles

While all three drugs share the classic opioid side-effect profile, meperidine possesses a unique and more dangerous set of adverse effects that are its key clinical differentiators.

• Common Opioid Effects: All three agents can cause dose-dependent respiratory depression, sedation, nausea, vomiting, and constipation.[22] Some meta-analyses suggest that fentanyl may be associated with a lower incidence of constipation and sedation compared to morphine.[42]
• Meperidine's Unique Adverse Profile: This is where meperidine diverges significantly and unfavorably from morphine and fentanyl.
• Neurotoxicity: The accumulation of the metabolite normeperidine can cause CNS excitation, including tremors, myoclonus, and seizures. This is the single most important differentiating risk and does not occur with morphine or fentanyl.[3]
• Cardiovascular Effects: Due to its anticholinergic properties, meperidine typically causes tachycardia (an increased heart rate).[2] In contrast, morphine and fentanyl are more likely to cause bradycardia (a slowed heart rate).[15]
• Pupillary Effects: Meperidine's anticholinergic action can cause mydriasis (pupil dilation).[1] Morphine and fentanyl characteristically cause miosis (pupil constriction).[27]
• Drug Interactions: Meperidine has a uniquely severe and often fatal interaction profile with MAOIs and a higher risk of serotonin syndrome with other serotonergic agents. While caution is advised with all opioids, the risk with meperidine is substantially greater and more well-documented.[1]

This comparative analysis demonstrates that for the primary purpose of analgesia, meperidine offers no therapeutic advantage over safer alternatives. It is less potent than morphine, has a shorter duration of action that is less convenient for managing persistent pain, and carries a far greater burden of unique and severe risks. The risk-benefit calculation for meperidine is therefore overwhelmingly negative for most analgesic indications, cementing the clinical rationale for preferring agents like morphine, hydromorphone, or fentanyl.

Table 4: Comparative Profile of Meperidine, Morphine, and Fentanyl

Characteristic	Meperidine	Morphine	Fentanyl
Relative Potency (vs. IV Morphine)	~0.1x	1x (Reference)	~100x
Onset of Action (IV)	~5 minutes	15–30 minutes	<5 minutes
Duration of Action	2–3 hours	~4 hours	30–60 minutes
Key Metabolite	Normeperidine (Neurotoxic)	Morphine-6-Glucuronide (Active Analgesic)	Inactive Metabolites
Primary Unique Risk	Seizures, Serotonin Syndrome	Respiratory Depression	Respiratory Depression, Chest Wall Rigidity
Cardiovascular Effect	Tachycardia	Bradycardia	Bradycardia
Pupillary Effect	Mydriasis (Dilation)	Miosis (Constriction)	Miosis (Constriction)
Use in Renal Failure	Contraindicated	Use with caution, dose adjust	Safer choice, dose adjust

Use in Special Populations and Specific Conditions

The risks associated with meperidine are not uniform across all patients. Certain populations are at a significantly elevated risk for adverse events, particularly normeperidine-induced neurotoxicity. The contraindications and warnings for these groups are so extensive that they functionally exclude meperidine as a viable analgesic for a large percentage of the complex patient population requiring potent pain relief.

Geriatric Patients

Elderly patients are particularly vulnerable to the adverse effects of meperidine for several reasons.

• Increased Sensitivity: Older adults generally exhibit increased sensitivity to the effects of all opioid analgesics.[25]
• Decline in Renal Function: The natural, age-related decline in glomerular filtration rate impairs the clearance of normeperidine, even in patients without a formal diagnosis of kidney disease. This leads to a high risk of metabolite accumulation and subsequent neurotoxicity.[9]
• Anticholinergic Effects: The anticholinergic properties of meperidine place elderly patients at a high risk for developing confusion and delirium. In fact, meperidine is the narcotic most often associated with delirium in the geriatric surgical population.[2] For these reasons, meperidine is considered a poor choice and should generally be avoided in this population.

Patients with Renal or Hepatic Impairment

Organ dysfunction profoundly alters the pharmacokinetics of meperidine and its metabolite, dramatically increasing the risk of toxicity.

• Renal Impairment: This is a critical contraindication. Because normeperidine is almost exclusively cleared by the kidneys, any degree of renal insufficiency will lead to its accumulation. The half-life of normeperidine can be prolonged to 34 hours or more in patients with renal dysfunction.[10] This dramatically increases the risk of CNS excitation and seizures. Therefore, meperidine should not be used in patients with renal impairment.[3]
• Hepatic Impairment: In patients with liver disease, such as cirrhosis, the metabolism of the parent drug meperidine is impaired. This prolongs its elimination half-life from the normal 3-5 hours to 7-11 hours.[13] This can lead to an accumulation of meperidine itself, increasing the risk of its own side effects, such as sedation and respiratory depression. Use in patients with hepatic impairment requires extreme caution and significant dose reduction with slow titration.[2]

Pregnancy and Lactation

The use of meperidine during pregnancy and lactation poses significant risks to the neonate and infant.

• Pregnancy: Meperidine readily crosses the placenta.[13] Chronic or prolonged use by the mother during pregnancy can lead to the development of Neonatal Opioid Withdrawal Syndrome (NOWS) in the newborn after delivery. NOWS is a serious and potentially life-threatening condition characterized by irritability, high-pitched crying, tremors, vomiting, and poor feeding, which requires specialized management by neonatology experts. This risk is significant enough to be included as a boxed warning by the FDA.[2]
• Lactation: Meperidine and its toxic metabolite normeperidine are both distributed into breast milk.[13] Maternal use can lead to adverse effects in the breastfed infant, including sedation, increased sleepiness, difficulty breastfeeding, breathing difficulties, and limpness (hypotonia). While a single dose for a procedure may not cause issues in an older infant, repeated use is discouraged. Alternative analgesics, such as fentanyl or morphine (with close monitoring), are generally preferred for postpartum pain management, especially when nursing a newborn or preterm infant.[25]

Patients with Pre-existing Conditions

Meperidine can exacerbate several underlying medical conditions, making it a high-risk choice.

• Seizure Disorders: Because normeperidine is a proconvulsant that lowers the seizure threshold, meperidine should be avoided in patients with a history of seizure disorders.[3]
• Increased Intracranial Pressure (ICP) or Head Injury: The respiratory depressant effects of meperidine can cause hypercapnia (increased blood CO2), which leads to cerebral vasodilation and can dangerously elevate ICP. This can mask the neurological signs of a head injury. It should be avoided in these patients.[5]
• Supraventricular Tachycardias: In patients with arrhythmias like atrial flutter, meperidine's atropine-like (vagolytic) effects can increase the ventricular response rate, potentially destabilizing the patient's cardiac rhythm.[31]

Regulatory Status, Risk Management, and Clinical Practice Recommendations

The significant risks associated with meperidine have led to stringent regulatory controls, comprehensive risk management strategies, and clear clinical practice guidelines aimed at minimizing patient harm. Its modern use is governed by a framework that emphasizes its dangers and promotes safer alternatives.

DEA Scheduling and FDA Boxed Warnings

Meperidine is subject to strict regulatory oversight due to its potential for harm and abuse.

• DEA Schedule II: The U.S. Drug Enforcement Administration classifies meperidine as a Schedule II controlled substance. This designation signifies that it has a currently accepted medical use but also a high potential for abuse, which can lead to severe psychological or physical dependence.[8]
• FDA Boxed Warnings: The U.S. Food and Drug Administration requires a comprehensive "boxed warning" on meperidine's prescribing information to highlight its most serious and life-threatening risks. These warnings are a cornerstone of risk communication and include [2]:

1. Addiction, Abuse, and Misuse: Risk of opioid addiction, which can lead to overdose and death.
2. Life-Threatening Respiratory Depression: Serious or fatal respiratory depression may occur, especially upon initiation or dose increase.
3. Accidental Ingestion: Accidental ingestion, particularly by children, can result in a fatal overdose.
4. Neonatal Opioid Withdrawal Syndrome (NOWS): Prolonged use during pregnancy can cause life-threatening withdrawal in the newborn.
5. Cytochrome P450 3A4 Interaction: Concomitant use with CYP3A4 inhibitors or discontinuation of CYP3A4 inducers can lead to fatal overdose.
6. Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants: Combination use can result in profound sedation, respiratory depression, coma, and death.
7. Fatal Interaction with Monoamine Oxidase Inhibitors (MAOIs): Concomitant use is contraindicated and can be fatal.
8. Risk of Medication Errors: High potential for dosing errors with the oral solution due to confusion between mg and mL.

Risk Evaluation and Mitigation Strategy (REMS)

As part of a class-wide opioid safety program, meperidine is subject to a Risk Evaluation and Mitigation Strategy (REMS). This FDA-mandated program requires that healthcare providers are educated on the serious risks associated with the drug. Key components include [2]:

• Provider Education: Healthcare professionals are strongly encouraged to complete a REMS-compliant education program on safe opioid prescribing.
• Patient Counseling: Prescribers must counsel patients and their caregivers on the risks, safe use, proper storage, and disposal of meperidine with each prescription. This includes discussing the availability and use of naloxone for reversing an opioid overdose.[30]

Medication Error Prevention

Meperidine has been associated with a high rate of medication errors, some of which have been fatal.[9] Errors often arise from confusion between meperidine and other opioids with similar-sounding names (e.g., morphine, hydromorphone/Dilaudid) or from dosing mistakes with the oral solution.[2] Strategies to prevent these errors include:

• Avoiding verbal orders for meperidine.[9]
• When prescribing the oral solution, including both the total dose in milligrams (mg) and the total volume in milliliters (mL).[30]
• Instructing patients and caregivers to always use a calibrated oral syringe or measuring cup for the liquid formulation, never a household spoon.[25]

Summary of Clinical Practice Guidelines and Recommendations

Synthesizing the evidence from pharmacology, pharmacokinetics, and clinical trials leads to a clear and restrictive set of practice recommendations:

• DO NOT USE meperidine for the management of chronic pain.[31]
• DO NOT USE meperidine in elderly patients or in any patient with known or suspected renal impairment.[9]
• LIMIT USE for acute pain to the shortest possible duration, ideally less than 48 hours, and ensure the cumulative dose does not exceed 600 mg per 24 hours.[2]
• MONITOR all patients closely for signs of normeperidine neurotoxicity (agitation, tremors, myoclonus) and opioid-induced respiratory depression, especially within the first 24 to 72 hours of treatment initiation.[9]
• AVOID concomitant use with all MAOIs (contraindicated) and exercise extreme caution when co-administering with any other serotonergic agent or CNS depressant.[10]
• PREFER alternative opioids such as morphine, hydromorphone, or fentanyl for nearly all clinical indications requiring potent analgesia, as they offer a superior risk-benefit profile.[9]

Concluding Assessment of Meperidine's Role in Contemporary Medicine

In conclusion, meperidine is a legacy drug whose once-prominent role in pain management has been justly and decisively eclipsed by a modern, evidence-based understanding of its significant and unique risks. Its complex pharmacological profile, defined by the dangerous pharmacokinetic mismatch between the parent drug and its long-acting, neurotoxic metabolite normeperidine, creates a clinical scenario where risk frequently and predictably outweighs benefit. The extensive list of contraindications, boxed warnings, and high-risk patient populations functionally removes meperidine as a rational choice for the vast majority of patients. Its continued use should be highly restricted to its few remaining, well-defined, and short-term indications, such as refractory postanesthetic shivering or drug-induced rigors. This use must only occur in carefully selected, healthy individuals with normal renal function, under conditions of meticulous monitoring, and with a full institutional and clinical awareness of its profound potential for harm. For the purpose of analgesia, safer, more effective, and more predictable agents have rendered meperidine largely obsolete.

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