Alfentanil: A Comprehensive Pharmacological and Clinical Monograph

I. Executive Summary

Alfentanil is a potent, synthetic, short-acting opioid analgesic classified as a small-molecule derivative of fentanyl.[1] Its pharmacological profile is distinguished by an exceptionally rapid onset of action and a brief, predictable duration, characteristics that define its specific niche within clinical anesthesiology and critical care.[1] As a selective agonist of the μ-opioid receptor, Alfentanil exerts powerful analgesic and sedative effects by modulating neurotransmission within the central nervous system.[3] These properties are a direct result of its unique physicochemical nature, particularly a low pKa that facilitates rapid transit across the blood-brain barrier.[2]

The primary clinical utility of Alfentanil is centered on scenarios requiring intense, titratable analgesia with a swift recovery profile. It is approved by the U.S. Food and Drug Administration (FDA) as an analgesic adjunct for the induction and maintenance of general anesthesia, as a primary anesthetic agent for certain surgical procedures, and as the analgesic component for monitored anesthesia care (MAC).[1] Its rapid action makes it particularly valuable for blunting the profound hemodynamic stress responses associated with noxious stimuli of short duration, such as endotracheal intubation.[5]

Despite its clinical advantages, Alfentanil is a high-risk medication with a significant potential for harm if not used appropriately. It is classified as a Schedule II controlled substance in the United States due to its high potential for addiction, abuse, and misuse.[2] Its use is governed by several critical FDA Black Box Warnings that highlight the risks of life-threatening respiratory depression, the dangers of co-administration with other central nervous system depressants like benzodiazepines, and the potential for fatal overdose resulting from interactions with inhibitors of the cytochrome P450 3A4 enzyme system.[4] Safe administration demands a controlled clinical environment, continuous patient monitoring, and practitioners expertly trained in its use and in the management of its potent effects.

II. Chemical Identity and Physicochemical Properties

The precise identification of a pharmaceutical agent is foundational to understanding its behavior. Alfentanil is a well-characterized small molecule with a distinct chemical structure and properties that directly influence its clinical pharmacology.

Systematic Identification

Alfentanil is formally identified through a variety of standardized international systems:

• Generic Name: Alfentanil [3]
• DrugBank ID: DB00802 [3]
• Type: Small Molecule [3]
• CAS Number: 71195-58-9 [2]
• IUPAC Name: N-{1-[2-(4-ethyl-5-oxo-4,5-dihydro-1H-1,2,3,4-tetrazol-1-yl)ethyl]-4-(methoxymethyl)piperidin-4-yl}-N-phenylpropanamide [2]

Molecular and Physical Data

The core molecular and physical data for Alfentanil are summarized as follows:

• Chemical Formula: C21​H32​N6​O3​ [2]
• Average Molecular Weight: 416.5172 g·mol⁻¹ [2]
• Monoisotopic Mass: 416.25358892 g·mol⁻¹ [3]
• Melting Point: 140.8 °C (285.4 °F) [2]
• Structural Identifiers:
• Canonical SMILES: COCC1(CCN(CC1)CCn1nnn(c1=O)CC)N(c1ccccc1)C(=O)CC [8]
• InChI: InChI=1S/C21H32N6O3/c1-4-19(28)27(18-9-7-6-8-10-18)21(17-30-3)11-13-24(14-12-21)15-16-26-20(29)25(5-2)22-23-26/h6-10H,4-5,11-17H2,1-3H3 [2]
• InChIKey: IDBPHNDTYPBSNI-UHFFFAOYSA-N [2]

Clinically Relevant Physicochemical Property (pKa)

Perhaps the most clinically significant physicochemical property of Alfentanil is its acid dissociation constant, or pKa, which is approximately 6.5.[2] This value is the primary determinant of the drug's uniquely rapid onset of action. At the physiological pH of blood (approximately 7.4), a substantial proportion of Alfentanil molecules exist in their un-ionized, lipid-soluble state. The Henderson-Hasselbalch equation demonstrates that for a weak base like Alfentanil, a pKa lower than the surrounding pH results in a high fraction of the uncharged form. At a pH of 7.4, it is estimated that about 90% of Alfentanil is un-ionized.

This high degree of non-ionization is critically important for its ability to cross biological membranes. The blood-brain barrier, which separates the systemic circulation from the central nervous system (CNS), is a lipid-rich structure that is highly permeable to lipid-soluble (un-ionized) molecules but largely impermeable to water-soluble (ionized) molecules. Because a large fraction of administered Alfentanil is already in this lipid-soluble form upon injection into the bloodstream, it can diffuse across the blood-brain barrier with exceptional speed and efficiency. This rapid entry into the CNS, where its opioid receptors are located, directly accounts for its remarkably fast onset of action—four times faster than that of its parent compound, fentanyl.[2] This structure-activity relationship is a cornerstone of its clinical utility, allowing anesthesiologists to achieve profound analgesia almost immediately to counteract intense but brief procedural stimuli.[5]

Table 1: Physicochemical and Structural Identifiers of Alfentanil

Property	Value	Source(s)
Generic Name	Alfentanil	3
DrugBank ID	DB00802	3
CAS Number	71195-58-9	2
IUPAC Name	N-{1-[2-(4-ethyl-5-oxo-4,5-dihydro-1H-1,2,3,4-tetrazol-1-yl)ethyl]-4-(methoxymethyl)piperidin-4-yl}-N-phenylpropanamide	2
Chemical Formula	C21​H32​N6​O3​	2
Average Molar Mass	416.526 g·mol⁻¹	2
Melting Point	140.8 °C (285.4 °F)	2
pKa	~6.5	2
Canonical SMILES	COCC1(CCN(CC1)CCn1nnn(c1=O)CC)N(c1ccccc1)C(=O)CC	8
InChIKey	IDBPHNDTYPBSNI-UHFFFAOYSA-N	2

III. Clinical Pharmacology

A. Mechanism of Action

Alfentanil is a synthetic opioid analgesic that exerts its effects as a potent and selective agonist at the μ-opioid receptor.[1] These receptors are members of the G-protein coupled receptor (GPCR) superfamily and are widely distributed throughout the central and peripheral nervous systems, with high concentrations in areas of the brain and spinal cord that are critical for pain transmission and modulation, such as the periaqueductal gray matter, thalamus, and substantia gelatinosa of the spinal cord.[3]

Upon binding to the μ-opioid receptor, Alfentanil initiates a cascade of intracellular signaling events. The receptor-agonist complex promotes the exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP) on the α-subunit of the associated inhibitory G-protein (Gi​/Go​).[3] The activated G-protein complex then dissociates, and its subunits modulate downstream effector systems. The primary effect is the inhibition of the enzyme adenylate cyclase, which leads to a decrease in the intracellular concentration of the second messenger cyclic adenosine monophosphate (cAMP).[3]

This reduction in cAMP levels has several crucial downstream consequences for neuronal function. It leads to the inhibition of the release of numerous excitatory and nociceptive neurotransmitters from presynaptic nerve terminals, including Substance P, gamma-aminobutyric acid (GABA), dopamine, acetylcholine, and noradrenaline.[3] Concurrently, activation of the μ-opioid receptor also directly modulates ion channel activity. It promotes the opening of G-protein-coupled inwardly rectifying potassium (

K+) channels, leading to an efflux of potassium and hyperpolarization of the postsynaptic neuronal membrane.[3] It also causes the closing of N-type voltage-gated calcium (

Ca2+) channels on the presynaptic terminal, which further prevents neurotransmitter release.[3] The combined effect of neurotransmitter inhibition and neuronal hyperpolarization is a profound reduction in synaptic transmission and a dampening of neuronal excitability in pain pathways, resulting in the powerful analgesic effect characteristic of Alfentanil.

B. Pharmacodynamics (Physiological Effects)

The principal pharmacologic effects of Alfentanil are mediated through its actions on the central nervous system, but it also produces significant effects on other organ systems.[3]

• Central Nervous System: The primary therapeutic effects are analgesia and sedation.[3] Alfentanil increases the patient's tolerance for painful stimuli and diminishes the emotional perception of suffering.[3] It also produces dose-dependent sedation, ranging from mild drowsiness to unconsciousness at anesthetic doses. Other common CNS effects include alterations in mood, which may manifest as either euphoria or dysphoria.[3]
• Respiratory System: Alfentanil is a potent respiratory depressant. It directly inhibits the respiratory centers located in the brainstem, reducing their responsiveness to carbon dioxide and hypoxic stimuli. This leads to a decrease in respiratory rate, tidal volume, and minute ventilation.[4] This effect is dose-dependent and represents the most significant acute risk associated with its use, potentially leading to severe, life-threatening, or fatal respiratory depression and apnea.[1] The cough reflex is also potently suppressed.[3]
• Cardiovascular System: The cardiovascular effects of Alfentanil can be variable. It frequently causes bradycardia (a slowing of the heart rate) and can produce hypotension, particularly when administered as a rapid intravenous bolus or in high doses.[11] Paradoxically, hypertension and tachycardia have also been reported.[5] Compared to some other opioids, it is often considered to have a relatively stable cardiovascular profile, though this must be balanced against its more pronounced respiratory depressant effects.[2]
• Musculoskeletal System: A well-known adverse effect, especially with rapid administration of high induction doses, is skeletal muscle rigidity.[4] This can affect the muscles of the limbs, neck, and trunk. When it involves the thoracic and abdominal muscles, it is often referred to as "wooden chest syndrome" and can severely impede or prevent mechanical ventilation, creating a medical emergency.[5]
• Gastrointestinal System: Like other opioids, Alfentanil decreases gastrointestinal motility and delays gastric emptying, which can lead to constipation with prolonged use.[11] It also stimulates the chemoreceptor trigger zone in the brainstem, which is a common cause of postoperative nausea and vomiting.[5]
• Ocular System: Alfentanil causes constriction of the pupils (miosis), a characteristic sign of opioid effect mediated through the Edinger-Westphal nucleus.[3]

The pharmacodynamic profile of Alfentanil illustrates the classic challenge of opioid therapy: the same receptor-mediated actions that produce desired therapeutic effects are also responsible for the most dangerous adverse effects. The μ-receptor agonism that provides profound analgesia simultaneously causes dose-dependent respiratory depression. The rapid onset of Alfentanil means that both the desired anesthetic state and the risk of apnea occur almost immediately upon administration. This narrow therapeutic window necessitates that the drug only be administered by practitioners skilled in advanced airway management and in a setting where continuous monitoring and immediate resuscitative support are available.[4] This intrinsic link between benefit and risk is the fundamental reason Alfentanil is restricted to the highly controlled environments of the operating room and intensive care unit.

IV. Pharmacokinetics: A Profile Across Patient Populations

The clinical utility of Alfentanil is defined by its pharmacokinetic profile, which describes the movement of the drug into, through, and out of the body. Its rapid onset, short duration, and metabolic pathway distinguish it from other opioids.

A. Absorption

As Alfentanil is intended for use as an anesthetic and analgesic adjunct in controlled settings, it is administered exclusively by the intravenous (IV) route, either as an intermittent bolus or a continuous infusion.[1] Following IV administration, absorption is complete and instantaneous, with the onset of anesthetic action occurring immediately.[1]

B. Distribution

Alfentanil has a relatively small volume of distribution (Vd​), ranging from 0.4 to 1.0 L/kg in healthy adults.[1] This is notably smaller than that of more lipophilic opioids like fentanyl, indicating less extensive distribution into peripheral tissues such as fat and muscle.[11] The drug is highly bound to plasma proteins, with a bound fraction of 88% to 92% in adults.[1] The primary binding protein is alpha-1-acid glycoprotein.[11]

C. Metabolism

Alfentanil undergoes extensive and rapid biotransformation, primarily in the liver.[1] It serves as a substrate for the cytochrome P450 (CYP) enzyme system, with the CYP3A4 isoenzyme being the principal catalyst for its metabolism.[1] The major metabolic pathways involve N-dealkylation and O-demethylation, resulting in the formation of two primary metabolites: noralfentanil and N-phenylpropionamide.[3] These metabolites are considered pharmacologically inactive and do not contribute to the clinical effects of the drug.

D. Excretion

The metabolites of Alfentanil are primarily eliminated from the body via renal excretion into the urine.[3] Very little of the parent drug is excreted unchanged; only about 1% of an administered dose is recovered in the urine as active Alfentanil.[3] The elimination half-life (

t1/2​) of Alfentanil in adults is short, typically ranging from 90 to 111 minutes (approximately 1.5 to 1.8 hours).[3]

E. Pharmacokinetics in Specific Populations

The handling of Alfentanil can vary significantly based on age and physiological status, necessitating careful dose adjustments.

• Pediatric Patients: Children generally exhibit more rapid clearance of Alfentanil compared to adults. They have a smaller volume of distribution (0.163 to 0.4 L/kg) and a markedly shorter elimination half-life of 40 to 63 minutes.[14] In contrast, neonates, especially those born prematurely, demonstrate immature hepatic metabolic pathways. This results in significantly prolonged elimination, with half-lives reported to be between 5.3 and 9 hours.[14] Neonates also have lower levels of alpha-1-acid glycoprotein, leading to lower protein binding (around 67%) and a higher fraction of free, active drug, which increases the risk of toxicity.[14]
• Geriatric Patients: Elderly patients may exhibit reduced hepatic blood flow and decreased activity of metabolic enzymes, leading to slower clearance and a prolonged duration of action. They are generally more sensitive to the analgesic and respiratory depressant effects of opioids, and dose reductions are essential to prevent adverse events.[11]
• Hepatic and Renal Impairment: Since Alfentanil is extensively metabolized by the liver, patients with hepatic impairment are at risk for decreased clearance and prolonged drug effects.[12] While renal failure does not significantly affect the clearance of the parent drug, caution is still warranted as the inactive metabolites are cleared by the kidneys.

The pharmacokinetic profile of Alfentanil reveals two critical aspects that govern its clinical use. First, its short duration of action is a product of both its rapid hepatic clearance and its small volume of distribution. Unlike fentanyl, whose clinical effects after a single dose terminate primarily due to rapid redistribution from the brain into peripheral tissues, Alfentanil's effects are more closely tied to its actual metabolic elimination from the body.[16] This results in a more predictable duration of action and a less pronounced "context-sensitive half-time" effect, where the recovery time after stopping an infusion does not lengthen as dramatically as it does with fentanyl. This makes Alfentanil particularly well-suited for continuous infusions during procedures of short to moderate length.[16]

Second, its near-complete reliance on the CYP3A4 enzyme for metabolism makes it highly susceptible to significant drug-drug interactions. CYP3A4 is a common pathway for the metabolism of many medications, and its activity can be highly variable between individuals. Co-administration of drugs that inhibit this enzyme can block Alfentanil's clearance, leading to a rapid accumulation of the drug to toxic levels.[4] This metabolic vulnerability is so clinically important that it forms the basis of a specific FDA Black Box Warning, underscoring the need for meticulous review of a patient's concurrent medications before Alfentanil administration.[4]

Table 2: Key Pharmacokinetic Parameters of Alfentanil in Diverse Patient Populations

Parameter	Neonates (Premature)	Children	Adults
Volume of Distribution (Vd​)	0.5 - 0.6 L/kg	0.163 - 0.4 L/kg	0.4 - 1.0 L/kg
Plasma Protein Binding	~67%	Not specified	88% - 92%
Elimination Half-Life (t1/2​)	5.3 - 9 hours	40 - 63 minutes	90 - 111 minutes
Primary Clearance Pathway	Hepatic (immature)	Hepatic (mature)	Hepatic (mature)
Source(s)	14	14	1

V. Clinical Efficacy and Therapeutic Applications

Alfentanil's distinct pharmacokinetic and pharmacodynamic properties have established its role as a specialized agent within anesthesiology. Its use is indicated in specific clinical contexts where its rapid onset and short duration offer clear advantages over other opioid analgesics.

FDA-Approved Indications

The U.S. Food and Drug Administration has approved Alfentanil for intravenous use in both adult and pediatric patients for several perioperative applications [1]:

1. Analgesic Adjunct for General Anesthesia: Alfentanil is used to supplement general anesthesia, providing analgesia during surgical procedures. It can be administered either in intermittent incremental doses for shorter cases or as a continuous infusion for procedures of longer duration, typically in combination with other anesthetic agents such as barbiturates, propofol, and nitrous oxide/oxygen.[1]
2. Primary Anesthetic Agent for Induction: In higher doses, Alfentanil can be used as the primary agent to induce anesthesia, particularly in patients undergoing general surgery that requires endotracheal intubation and mechanical ventilation.[1]
3. Analgesic for Monitored Anesthesia Care (MAC): Alfentanil is frequently used as the analgesic component of MAC. In this setting, it provides profound pain relief and sedation for patients undergoing diagnostic or therapeutic procedures under local or regional anesthesia, allowing them to remain comfortable and cooperative without requiring full general anesthesia.[1]

Specific Clinical Scenarios

The therapeutic utility of Alfentanil is most evident in scenarios that capitalize on its unique kinetic profile:

• Short, Painful Procedures: Its rapid onset and brief duration make it an ideal choice for short but intensely painful procedures, such as orthopedic fracture reductions, dental extractions, or certain diagnostic interventions. It provides effective analgesia for the duration of the stimulus with a quick return to baseline consciousness, facilitating rapid recovery and patient discharge.[1]
• Attenuation of Intubation Response: One of its most common applications is in blunting the potent sympathetic nervous system response to direct laryngoscopy and endotracheal intubation. This stimulus can cause a sharp increase in heart rate, blood pressure, and intracranial pressure. The immediate onset of Alfentanil, when given just before laryngoscopy, effectively suppresses this hemodynamic reflex, which is particularly beneficial in patients with cardiovascular disease or intracranial pathology.[5]
• Analgesia in the Intensive Care Unit (ICU): Alfentanil can be administered by continuous infusion to provide analgesia and sedation for critically ill patients requiring mechanical ventilation.[3] Its short half-life allows for rapid titration to effect and facilitates quick awakening for neurological assessments when the infusion is stopped.
• Epidural Analgesia: Although less common than intravenous administration, Alfentanil can also be used as part of an epidural analgesic regimen to provide regional pain control.[5]

The clinical role of Alfentanil is a direct consequence of its pharmacology. It is not a universally applicable opioid but rather a specialized instrument in the anesthesiologist's toolkit. The decision to use Alfentanil is a deliberate one, based on matching the drug's kinetic properties to the specific demands and timeline of a medical procedure. For a brief but intensely stimulating event like intubation, its immediate action is superior to that of a slower-onset agent. For a 30-minute procedure, its short duration allows for a more rapid and predictable recovery than would be possible with a longer-acting opioid like fentanyl, which could lead to prolonged postoperative sedation and respiratory monitoring. This precise matching of drug profile to clinical need is the essence of its rational therapeutic use.

VI. Dosage, Administration, and Formulation

Formulation

Alfentanil is supplied as a sterile, preservative-free aqueous solution of alfentanil hydrochloride for intravenous administration only.[1] It is available in various concentrations, most commonly 500 mcg/mL. The existence of different strength preparations, such as a high-concentration 5 mg/mL (5000 mcg/mL) formulation, has been identified as a source of significant medication errors, where a tenfold overdose can be inadvertently administered if the preparations are confused.[19]

Administration

The administration of Alfentanil is restricted to highly controlled clinical settings and requires specialized expertise:

• It should only be administered by personnel specifically trained in the use of intravenous anesthetics and in the management of the respiratory effects of potent opioids, such as anesthesiologists or critical care physicians.[4]
• An opioid antagonist (e.g., naloxone), along with equipment for resuscitation, intubation, and oxygenation, must be immediately available whenever Alfentanil is used.[4]
• To minimize the incidence of adverse effects such as hypotension and skeletal muscle rigidity, induction doses should be administered slowly, typically over a period of three minutes.[13]
• Alfentanil injection is compatible with standard intravenous fluids, including Normal Saline (0.9% sodium chloride), 5% Dextrose in Water (D5W), and Lactated Ringer's solution.[13]

Dosage Regimens

Dosage of Alfentanil must be carefully individualized and titrated to the desired clinical effect. The appropriate dose depends on numerous factors, including the patient's age, body weight (lean body weight in obese patients), physical status (e.g., ASA classification), underlying medical conditions, concurrent medications, and the nature and anticipated duration of the surgical or diagnostic procedure.[6]

The following table summarizes typical dosing regimens for adult patients. Doses for elderly, debilitated, or pediatric patients should be appropriately reduced.

Table 3: Recommended Intravenous Dosing Regimens for Alfentanil

Clinical Indication	Dosing Regimen	Details	Source(s)
Anesthesia Induction	130 - 245 mcg/kg	Administered as a single IV bolus over 3 minutes.	1
Anesthesia Maintenance (Continuous Infusion)	0.5 - 1.5 mcg/kg/min	Titrated to clinical response. Infusion should generally be discontinued 10-15 minutes prior to the end of surgery.	6
Anesthesia Maintenance (Incremental Dosing)
Procedures < 30 min	Initial: 8-20 mcg/kg Maintenance: 3-5 mcg/kg	Maintenance doses are given IV every 5-20 minutes as needed. Total dose typically does not exceed 40 mcg/kg.	1
Procedures 30-60 min	Initial: 20-50 mcg/kg Maintenance: 5-15 mcg/kg	Maintenance doses are given IV every 5-20 minutes as needed. Total dose typically up to 75 mcg/kg.	1
Monitored Anesthesia Care (MAC)	Initial: 3-8 mcg/kg Maintenance: 0.25-1 mcg/kg/min or 3-5 mcg/kg increments	Initial bolus followed by either a continuous infusion or intermittent boluses as needed for patient comfort.	21

VII. Safety Profile and Toxicology

Alfentanil is a potent opioid with a narrow therapeutic index and a significant risk profile. Its safe use is contingent upon a thorough understanding of its potential for adverse events, contraindications, and the management of overdose.

A. Black Box Warnings (FDA)

The U.S. Food and Drug Administration mandates that the prescribing information for Alfentanil include boxed warnings—the agency's strongest safety advisory—for the following life-threatening risks [4]:

1. Addiction, Abuse, and Misuse: Alfentanil is a Schedule II controlled substance with a high potential for abuse. Its use exposes patients and healthcare providers to the risks of opioid addiction, misuse, and diversion. These behaviors can lead to overdose and death. A patient's risk for opioid abuse or addiction should be assessed prior to administration, and all patients should be monitored for the development of these conditions.[1]
2. Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression is a primary risk of Alfentanil administration, even at recommended doses. The risk is greatest during the initiation of therapy or following a dosage increase. To mitigate this risk, proper dosing, slow administration, and careful titration are essential.[1]
3. Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants: The concurrent use of Alfentanil with other CNS depressants—including benzodiazepines, alcohol, general anesthetics, and other opioids—may result in profound sedation, respiratory depression, coma, and death. This combination should be avoided unless alternative treatment options are inadequate. If co-administration is necessary, the lowest effective doses should be used, and patients must be monitored closely.[6]
4. Cytochrome P450 3A4 Interaction: Alfentanil is metabolized by CYP3A4. Concomitant use with drugs that inhibit CYP3A4 can cause a significant increase in Alfentanil plasma concentrations, which can increase or prolong adverse reactions, including potentially fatal respiratory depression. Conversely, discontinuation of a CYP3A4 inducer can have the same effect. Close monitoring is required when Alfentanil is used with any CYP3A4 inhibitor or inducer.[4]

B. Adverse Drug Reactions (ADRs)

The adverse effects of Alfentanil are largely extensions of its opioid pharmacology.

• Common (Incidence >1%):
• Gastrointestinal: Nausea (28%), Vomiting (18%) [4]
• Cardiovascular: Bradycardia (14%), Hypertension (18%), Hypotension (10%), Tachycardia (12%) [4]
• Musculoskeletal: Chest wall rigidity (17%) [4]
• Respiratory: Apnea, postoperative respiratory depression [4]
• Central Nervous System: Postoperative sedation, sleepiness, dizziness, blurred vision [4]
• Less Common/Rare:
• Anaphylaxis, laryngospasm, bronchospasm, seizures, itching (pruritus), urticaria, headache, myoclonic movements.[4]
• Postmarketing and Other Serious ADRs:
• Serotonin Syndrome: A potentially life-threatening condition characterized by mental status changes, autonomic instability, and neuromuscular hyperactivity, which can occur with concomitant use of serotonergic agents.[12]
• Opioid-Induced Hyperalgesia (OIH): A paradoxical state where patients receiving opioids become more sensitive to painful stimuli.[12]
• Endocrine Effects: Prolonged opioid use has been associated with adrenal insufficiency and androgen deficiency (hypogonadism).[4]

C. Contraindications and Precautions

• Contraindications: Alfentanil is contraindicated in patients with a known hypersensitivity to Alfentanil or any component of the formulation (e.g., a history of anaphylaxis).[4]
• Precautions: Extreme caution and reduced dosages are required in several patient populations:
• Patients with Respiratory Disease: Individuals with chronic obstructive pulmonary disease (COPD), severe asthma, sleep apnea, or other conditions associated with compromised respiratory drive are at heightened risk of life-threatening respiratory depression.[11]
• Patients with Head Injury or Increased Intracranial Pressure (ICP): Opioid-induced respiratory depression leads to carbon dioxide (CO2​) retention, which causes cerebral vasodilation and can dangerously increase ICP. Furthermore, the sedative effects and miosis can obscure the clinical course and neurological assessment of a patient with a head injury.[5]
• Elderly, Cachectic, or Debilitated Patients: These patients are often more sensitive to the effects of opioids and may have reduced clearance, necessitating significant dose reductions.[6]
• Patients with Hepatic or Renal Impairment: As Alfentanil is cleared by the liver, hepatic dysfunction can prolong its effects. Caution is also advised in severe renal disease.[12]

D. Overdose Management

An overdose of Alfentanil is a medical emergency that manifests as an exaggeration of its pharmacological effects. The clinical triad of opioid overdose consists of coma, pinpoint pupils (miosis), and severe respiratory depression.[3] Skeletal muscle rigidity may also be prominent.

The immediate priority in managing an overdose is the re-establishment of a patent airway and the institution of assisted or controlled ventilation with oxygen. A specific opioid antagonist, such as naloxone, should be administered intravenously to reverse the respiratory depression. Because the duration of action of naloxone may be shorter than that of Alfentanil, repeated doses may be necessary, and the patient must be continuously monitored for the recurrence of respiratory depression. Supportive measures to manage circulatory shock and pulmonary edema should be employed as needed.

The safety profile of Alfentanil is a direct reflection of its potent pharmacology. The Black Box Warnings serve as a clinical guide to its most significant dangers, each of which can be traced back to its mechanism of action, pharmacokinetics, or pharmacodynamics. The risk of respiratory depression is a direct consequence of μ-receptor agonism in the brainstem. The danger of interaction with CYP3A4 inhibitors is a result of its specific metabolic pathway. The synergistic depression with benzodiazepines is a classic pharmacodynamic interaction. This interconnectedness emphasizes that the safe use of Alfentanil requires a holistic understanding of the drug, the patient, and the clinical environment, including systems-level safeguards to prevent errors like strength confusion.[19]

VIII. Clinically Significant Drug Interactions

The potential for drug-drug interactions with Alfentanil is high and clinically significant, stemming from both its pharmacodynamic effects on the CNS and its specific pharmacokinetic reliance on the CYP3A4 metabolic pathway. These interactions can potentiate its toxicity and are a central focus of its safety warnings.

A. Pharmacodynamic Interactions

These interactions occur when co-administered drugs have additive or synergistic effects at the receptor or system level.

• Central Nervous System (CNS) Depressants: This is the most critical pharmacodynamic interaction. Co-administration of Alfentanil with other CNS depressants, including benzodiazepines, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, other opioids, and alcohol, results in additive depressant effects. This synergy significantly increases the risk of profound sedation, hypotension, life-threatening respiratory depression, coma, and death.[3] This interaction is the subject of a major Black Box Warning, and combinations should be avoided or used with extreme caution and reduced dosages of one or both agents.[4]
• Serotonergic Drugs: When Alfentanil is used concurrently with drugs that increase serotonergic activity—such as Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), Tricyclic Antidepressants (TCAs), and Monoamine Oxidase Inhibitors (MAOIs)—there is a risk of precipitating Serotonin Syndrome. This is a potentially fatal condition characterized by a triad of symptoms: autonomic hyperactivity (tachycardia, hypertension, diaphoresis), neuromuscular abnormalities (tremor, rigidity, myoclonus), and mental status changes (agitation, hallucinations, delirium).[12]
• Mixed Agonist/Antagonist Opioids: Drugs such as buprenorphine, nalbuphine, and pentazocine have mixed opioid receptor activity. When given to a patient receiving a pure agonist like Alfentanil, they can compete at the μ-receptor, reducing the analgesic effect of Alfentanil and potentially precipitating an acute opioid withdrawal syndrome in physically dependent individuals. Concomitant use should be avoided.[4]

B. Pharmacokinetic Interactions

These interactions occur when one drug alters the absorption, distribution, metabolism, or excretion of another. For Alfentanil, the most important interactions involve the inhibition or induction of its metabolic pathway.

• CYP3A4 Inhibitors: Alfentanil is extensively metabolized by the CYP3A4 isoenzyme. Co-administration with potent inhibitors of CYP3A4 will significantly decrease Alfentanil's clearance, leading to elevated and prolonged plasma concentrations. This markedly increases the risk of severe and potentially fatal respiratory depression.[4] This interaction is also the subject of a Black Box Warning. Clinically important CYP3A4 inhibitors include:
• Azole Antifungals: Ketoconazole, itraconazole, fluconazole [18]
• Macrolide Antibiotics: Erythromycin, clarithromycin [4]
• Protease Inhibitors: Ritonavir, indinavir, saquinavir [4]
• Other: Amiodarone, diltiazem, verapamil. Grapefruit juice is also a known CYP3A4 inhibitor and should be avoided.[3]
• CYP3A4 Inducers: Conversely, drugs that induce or increase the activity of the CYP3A4 enzyme can accelerate the metabolism of Alfentanil. This can lead to lower-than-expected plasma concentrations, resulting in decreased analgesic efficacy or, in opioid-tolerant patients, the precipitation of withdrawal symptoms. Important CYP3A4 inducers include rifampin, carbamazepine, phenytoin, and St. John's Wort.[4]

Table 4: Major Drug Interactions with Alfentanil and Clinical Management Strategies

Interacting Drug/Class	Mechanism	Potential Outcome	Clinical Management	Source(s)
Pharmacodynamic Interactions
Benzodiazepines & other CNS Depressants	Synergistic CNS and respiratory depression	Profound sedation, respiratory depression, hypotension, coma, death	BLACK BOX WARNING: Avoid combination if possible. If necessary, use lowest effective doses of both agents and monitor patient vigilantly.	22
Serotonergic Drugs (SSRIs, SNRIs, MAOIs)	Additive serotonergic effects	Serotonin Syndrome	Monitor closely for signs/symptoms (mental status changes, autonomic instability). Discontinue Alfentanil if syndrome is suspected.	14
Mixed Agonist/Antagonist Opioids	Receptor competition, partial agonism/antagonism	Reduced analgesia, precipitation of opioid withdrawal	Avoid concomitant use.	4
Pharmacokinetic Interactions
CYP3A4 Inhibitors (e.g., ketoconazole, erythromycin, ritonavir)	Inhibition of Alfentanil metabolism	Increased plasma concentration, prolonged opioid effect, potentially fatal respiratory depression	BLACK BOX WARNING: Avoid combination if possible. If necessary, monitor patient closely for adverse effects and consider significant Alfentanil dose reduction.	4
CYP3A4 Inducers (e.g., rifampin, carbamazepine)	Induction of Alfentanil metabolism	Decreased plasma concentration, reduced efficacy, potential for opioid withdrawal	Monitor for inadequate analgesia. Alfentanil dose increase may be required. Monitor for withdrawal if inducer is discontinued.	4

IX. Comparative Analysis: Alfentanil, Fentanyl, and Remifentanil

In modern anesthesia, Alfentanil is part of a triad of commonly used short-acting synthetic opioids, alongside fentanyl and remifentanil. While all are potent μ-receptor agonists derived from the same phenylpiperidine scaffold, their distinct pharmacokinetic and pharmacodynamic profiles create specific clinical niches. A rational selection among these agents requires a nuanced understanding of their comparative properties.

Potency

• Alfentanil: It is the least potent of the three on a weight-for-weight basis. Its potency is estimated to be approximately one-fourth to one-tenth that of fentanyl.[1]
• Fentanyl: Serves as the historical and clinical benchmark for this class. It is a highly potent analgesic, approximately 50 to 100 times more potent than morphine.[27]
• Remifentanil: Its potency is generally considered to be similar to or slightly greater than that of fentanyl.[28]

Onset of Action

• Alfentanil: Possesses the most rapid onset of action. Its peak effect is achieved within 1 to 2 minutes of intravenous administration, a rate that is roughly four times faster than fentanyl's.[1] This is a direct consequence of its low pKa (~6.5), which results in a high fraction of un-ionized, lipid-soluble drug at physiological pH, allowing for extremely rapid equilibration across the blood-brain barrier.[2]
• Fentanyl: Has a rapid onset, but it is noticeably slower than Alfentanil's, with a plasma-effect site equilibration half-time of 5–6 minutes.[16]
• Remifentanil: Also has a very rapid onset of action, comparable to that of Alfentanil, due to its properties as a relatively unbound and un-ionized molecule.[9]

Duration of Action and Metabolism

• Alfentanil: Has a short duration of action, approximately one-third that of fentanyl after a single bolus dose.[2] Its clinical effect is terminated primarily by hepatic metabolism via the CYP3A4 enzyme system. Its small volume of distribution means that redistribution plays a lesser role in terminating its effect compared to fentanyl, making its duration more predictable, especially during infusions for procedures lasting less than 6-8 hours.[1]
• Fentanyl: Has a longer duration of action. The termination of effect after a single dose is largely due to the rapid redistribution of the drug from the central compartment (blood and brain) into peripheral compartments (fat and muscle). During prolonged or high-dose infusions, these peripheral compartments become saturated, and the termination of effect then becomes dependent on the much slower process of hepatic elimination. This leads to a significantly prolonged and less predictable recovery time, a phenomenon known as a long context-sensitive half-time.[16]
• Remifentanil: Is unique among all clinically used opioids due to its ultra-short duration of action. It contains an ester linkage that is rapidly hydrolyzed by non-specific plasma and tissue esterases throughout the body.[17] This metabolic pathway is independent of hepatic or renal function, resulting in an extremely rapid and predictable clearance. Its context-sensitive half-time is very short (approximately 3-5 minutes) and, crucially, does not increase with the duration of the infusion. This means recovery is rapid and predictable even after many hours of continuous administration.[17]

Clinical Applications and Niche

The differences in their pharmacokinetic profiles directly translate into distinct clinical roles:

• Alfentanil: Is the agent of choice for providing profound analgesia for brief but intense stimuli (e.g., intubation) and for short surgical procedures where rapid onset and a reasonably quick, predictable recovery are desired.[1]
• Fentanyl: Is a versatile and widely used opioid for a broad range of surgical procedures of varying lengths. It is effective for induction, maintenance, and postoperative pain control, often administered as intermittent boluses.[27]
• Remifentanil: Is ideally suited for procedures where precise, moment-to-moment control of opioid effect is critical and an extremely rapid offset is beneficial. Examples include neurosurgery (to allow for intraoperative neurological assessment), outpatient surgery, and situations requiring "wake-up tests." Its rapid offset means that a proactive plan for transitioning to a longer-acting analgesic for postoperative pain is essential.[28]

Table 5: Comparative Profile of Short-Acting Synthetic Opioids

Feature	Alfentanil	Fentanyl	Remifentanil
Relative Potency	10-25% of Fentanyl	1 (Benchmark)	~1-2x Fentanyl
Onset of Action	Very Rapid (1-2 min)	Rapid (~5-6 min)	Very Rapid (1-2 min)
Duration (single bolus)	Short (~10 min)	Moderate (~30-60 min)	Ultra-short (~3-5 min)
Primary Metabolic Pathway	Hepatic (CYP3A4)	Hepatic (CYP3A4)	Plasma & Tissue Esterases
Context-Sensitive Half-Time (4-hr infusion)	~60 min	~260 min	~4 min
Primary Clinical Niche	Brief, intense stimuli; short procedures; MAC	Versatile use for various surgical durations	Procedures requiring rapid, predictable offset; neurosurgery
Source(s)	1	16	17

X. Regulatory Status and Developmental History

Development and Approval

Alfentanil was synthesized in 1976 at Janssen Pharmaceutica in Belgium, the same company responsible for the development of fentanyl.[2] Its creation was part of a focused research effort to develop analogues of fentanyl with more favorable pharmacokinetic profiles for anesthetic use, specifically seeking a more rapid onset and shorter duration of action.[30] Following preclinical and clinical evaluation, it was introduced into clinical practice as a valuable addition to the growing armamentarium of potent synthetic opioids, which already included fentanyl and sufentanil.[30]

The initial U.S. Food and Drug Administration (FDA) approval for Alfentanil was granted on December 29, 1986.[20]

Controlled Substance Scheduling

Recognizing its high potential for abuse and dependence, Alfentanil is strictly regulated as a narcotic drug worldwide. Its legal classification varies by country but consistently places it under high levels of control.

• United States: Alfentanil is classified as a Schedule II controlled substance under the Controlled Substances Act (CSA). This schedule is for drugs with a high potential for abuse which may lead to severe psychological or physical dependence, but which also have a currently accepted medical use.[2]
• United Kingdom: It is designated as a Class A drug under the Misuse of Drugs Act 1971 and a Schedule 2 substance under the Misuse of Drugs Regulations 2001, indicating the highest level of control for drugs with therapeutic use.[2]
• Canada: Alfentanil is listed under Schedule I of the Controlled Drugs and Substances Act, the category for the most dangerous drugs, including other opioids like fentanyl and heroin.[2]
• International and Other National Classifications:
• Australia: Schedule 8 (S8), Controlled Drug.[2]
• Brazil: Class A1 (Narcotic drug).[2]
• Germany: Anlage III, requiring a special narcotic prescription form.[2]

Brand Names and Manufacturers

Alfentanil is marketed globally under several brand names, and its generic form is produced by various pharmaceutical companies.

• Common Brand Names: The most widely recognized brand names are Alfenta® (primarily in the United States) and Rapifen® (used in many other countries).[5] Other historical or regional names include Limifen and Fanaxal.[5]
• Manufacturers and Distributors: The original developer was Janssen Pharmaceutica.[39] Over the years, various companies have manufactured and/or distributed Alfentanil injection in the U.S. and abroad, including Pfizer, Hospira (a Pfizer company), Akorn, and Rising Pharmaceuticals.[20]

XI. Conclusion and Clinical Recommendations

Alfentanil is a specialized synthetic opioid whose clinical value is defined by a unique pharmacokinetic profile characterized by an exceptionally rapid onset and a short, predictable duration of action. Its identity as a potent μ-opioid receptor agonist provides powerful analgesia and sedation, but also carries the inherent and significant risks of the opioid class, most notably life-threatening respiratory depression and a high potential for abuse and addiction. Its specific properties—a low pKa facilitating rapid CNS entry and a small volume of distribution coupled with hepatic clearance—distinguish it from its analogues, fentanyl and remifentanil, and establish its firm place in the anesthesiologist's armamentarium. It is not a general-purpose analgesic but a precision tool, best suited for short-duration procedures and for the management of brief, intense noxious stimuli where rapid titration and swift recovery are paramount.

The safe and effective use of Alfentanil is predicated on a comprehensive understanding of its pharmacology, a respect for its narrow therapeutic index, and adherence to strict clinical protocols. Based on the evidence reviewed, the following recommendations are provided to guide its clinical application:

1. Patient and Procedure Selection: The use of Alfentanil should be reserved for clinical scenarios that specifically leverage its rapid onset and short duration. It is an excellent choice for blunting the hemodynamic response to laryngoscopy and intubation, for providing analgesia during brief but painful procedures, and for use in monitored anesthesia care where rapid recovery is a primary goal.
2. Vigilant Monitoring: Alfentanil must only be administered in a controlled environment, such as an operating room or intensive care unit, where continuous monitoring of respiratory status (e.g., pulse oximetry, capnography) and hemodynamics (e.g., blood pressure, heart rate) is possible. Equipment for advanced airway management and resuscitation must be immediately at hand.
3. Thorough Medication Review: A meticulous review of a patient's concurrent medications is critical before administering Alfentanil. Particular attention must be paid to identifying the use of other CNS depressants (especially benzodiazepines) and potent inhibitors of the CYP3A4 enzyme system. Failure to recognize these interactions can lead to catastrophic and fatal adverse events.
4. Dose Individualization and Titration: Dosage must be carefully individualized based on patient factors such as age, weight, and clinical condition. Significant dose reductions are required for geriatric, debilitated, and pediatric patients (especially neonates). Doses should be administered slowly and titrated carefully to the desired clinical effect to minimize the risk of muscle rigidity and hemodynamic instability.
5. Systems-Level Safety: Healthcare institutions should implement systems-level safeguards to prevent medication errors. Given the documented confusion between different available concentrations of Alfentanil, strategies such as segregated storage, clear labeling, and barcode medication administration should be employed to reduce the risk of accidental overdose.

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