Continuing Education Activity

Alfentanil is a synthetic, short-acting opioid analgesic classified as a small-molecule derivative of fentanyl. This medication is widely used as an analgesic supplement during various surgical procedures or as a primary anesthetic agent in high doses during cardiac surgery in hospital settings. In comparison to analogous anesthetics such as fentanyl and sufentanil, alfentanil exhibits the least potency, has the fastest onset of action, and features the shortest duration of action. Due to its brief duration of action, alfentanil is generally favored for shorter procedures or situations requiring swift alterations in the level of consciousness. The drug has received approval from the U.S. Food and Drug Administration (FDA) as an anesthetic for adults and children undergoing general anesthesia and monitored anesthesia care, highlighting its clinical significance.

This activity thoroughly covers crucial aspects of alfentanil usage, including its indications, ideal patient profiles, administration protocols, adverse effects, mechanism of action, and vigilant monitoring strategies. This activity also fosters an interprofessional approach to pain management, elucidating the role of alfentanil within this multidisciplinary framework. Furthermore, the activity highlights the importance of meticulous monitoring practices by healthcare professionals during alfentanil usage, thereby promoting informed decision-making and a coordinated interprofessional approach to efficient and safe pain management across diverse clinical scenarios.

Objectives:

• Identify the appropriate indications for alfentanil usage, distinguishing scenarios where its unique pharmacological properties align with patient needs.

• Screen patients for contraindications and risk factors associated with alfentanil use, ensuring safe and tailored administration.

• Assess patients for potential interactions, especially with benzodiazepines or central nervous system depressants, and adjust dosages accordingly to prevent complications.

• Collaborate with other healthcare professionals to coordinate seamless perioperative care, particularly in scenarios involving alfentanil usage.

Indications

Alfentanil is a synthetic, short-acting opioid analgesic classified as a small-molecule derivative of fentanyl. This medication is widely used as an analgesic supplement during various surgical procedures or as a primary anesthetic agent in high doses during cardiac surgery in hospital settings. The drug has received approval from the U.S. Food and Drug Administration (FDA) as an anesthetic for adults and children undergoing general anesthesia and monitored anesthesia care, highlighting its clinical significance.

In comparison to analogous anesthetics such as fentanyl and sufentanil, alfentanil exhibits the least potency, has the fastest onset of action, and features the shortest duration of action.[1][2] Due to its brief duration of action, alfentanil is generally favored for shorter procedures or situations requiring swift alterations in the level of consciousness.[3][4] Such procedures include gynecological procedures, short ambulatory procedures such as colonoscopies, and shorter surgeries such as tonsillectomies, appendectomies, and cholecystectomies.[5][6] Alfentanil has been demonstrated to be effective and safe in both children and adults at appropriate dosing.[7][8]

Barker et al conducted a retrospective observational study to determine any significant differences in patient outcomes associated with the use of alfentanil or fentanyl for sedation during extracorporeal membrane oxygenation. The researchers conducted the study as their institution was transitioning from alfentanil to fentanyl use. A total of 95 patients receiving fentanyl and 69 patients receiving alfentanil were included in the study. Barker et al observed no disparities in patient outcomes when comparing sedation with alfentanil or fentanyl for extracorporeal membrane oxygenation. However, the researchers highlighted that alfentanil-treated patients received higher doses of the adjuvant sedatives quetiapine and midazolam.[9]

Eberl et al conducted a randomized controlled trial to assess the effectiveness of alfentanil versus esketamine as adjunct medications for propofol-mediated deep sedation during endoscopic retrograde cholangiopancreatography. Propofol was administered as a target-controlled infusion. A total of 162 patients (N=162) were enrolled in the study. The researchers noted that esketamine-treated patients (N=83) required less propofol compared to alfentanil-treated patients (N=79).[10]

FDA-Approved Indications

FDA-approved indications for alfentanil include its use in general anesthesia via continuous infusion, as a general anesthesia adjunct with barbiturate or nitrous oxide or oxygen, as a primary anesthetic agent for patients undergoing general surgery with endotracheal intubation and mechanical ventilation, and as an analgesic adjunct in monitored anesthesia care.

Off-Label Uses

Off-label use of alfentanil includes its application for acute pain in children through nasal administration.[11]

Mechanism of Action

Alfentanil belongs to the opioid class of medications and operates through the stimulation of opioid receptors, which consist of 3 main subtypes—mu (m), kappa (k), and delta (d). The m-opioid receptor is primarily involved in pain transmission. Although opioid receptors are predominantly distributed in the central nervous system (CNS), including the brain, spinal column, and peripheral nervous system, they are also present in vascular, cardiac, pulmonary, gastrointestinal, and even peripheral blood mononuclear cells. The natural ligands for the opioid receptors are called the "endogenous opioid peptides" and include enkephalins, endorphins, and endomorphins.[12]

Although opioids exhibit various clinical effects, they are primarily recognized and utilized for their potent pain-relieving effects. This pain relief is achieved by binding with the m-opioid receptor, leading to the coupling with G1 proteins. This interaction results in the closure of N-type voltage-operated calcium channels and the opening of calcium-dependent inwardly rectifying potassium channels. This leads to intracellular hyperkalemia and a reduction in the neurotransmission of pain signals, contributing to increased pain tolerability. Opioid receptor binding also reduces intracellular cyclic adenosine monophosphate (cAMP), modulating the release of nociceptive (related to pain perception) neurotransmitters, such as substance P.[13]

No acute changes to intracellular sodium have been noted to occur with opioid-receptor binding. However, there is a hypothetical consideration that intracellular sodium levels may play a role in opioid receptor affinity for endogenous and exogenous opioid receptor binders. Researchers have observed that opioid receptor binders exhibit higher affinity in the presence of lower intracellular sodium concentrations and elevated intracellular potassium concentrations. Notably, there was no change in the total number of binding sites for opioid receptors during these observations. This phenomenon was observed in cells with m- and d-type opioid receptors.[14]

Opioids are recognized for their euphoric effects and are characterized by intense excitement and happiness. Typically, these effects result from the binding of endorphins to opioid receptors in both the CNS and peripheral nervous systems. Endorphins, the primary contributors to this euphoria, are synthesized and stored in the anterior pituitary gland from their precursor protein, proopiomelanocortin (POMC). POMC is a large protein that undergoes cleavage into smaller proteins, including beta-endorphin, alpha-melanocyte-stimulating hormone, and adrenocorticotropin. Interestingly, studies suggest that cells of the immune system can synthesize beta-endorphin, as immune cells possess mRNA transcripts for POMC. T- and B lymphocytes, monocytes, and macrophages have been demonstrated to contain endorphins during inflammation.[15]

Usually, euphoric effects occur primarily due to endorphin binding at opioid receptors in the peripheral nervous system. During opioid administration, euphoria results from opioid drugs binding to receptors at both the pre- and postsynaptic junctions in the peripheral nervous system, as well as at the presynaptic junction in the CNS. Analgesia induced by endorphins in the peripheral nervous system primarily arises from reduced synthesis of substance P. In the CNS, the analgesic effects of endorphins binding to opioid receptors also occur through the inhibition of GABA release, resulting in an elevation of dopamine production. In the context of opioid administration, the opioid drug takes on this role.[16]

Notably, the administration of opioid analgesic drugs to patients leads to a decrease in the synthesis and secretion of endogenous endorphins and opioid peptides. This effect is attributed to negative feedback on the endogenous endorphin and opioid systems.[17]  Additional effects of opioid medications include alterations in mood, drowsiness, and mental clouding. However, the distinctive feature of opioid-induced analgesia is the preservation of consciousness. Although the patient still perceives pain, it is often described as less intense. Therefore, opioids do not diminish or address the root cause of a painful stimulus; instead, they reduce its perception.[18]

Wang et al conducted an analytical chemistry study on the impurities and degradation products of alfentanil hydrochloride using liquid chromatography/quadrupole time-of-flight high-resolution mass spectrometry (LC/QTOF-MS/MS). The research can aid in detecting counterfeit alfentanil, illegal alfentanil, and related analogs. In addition, it provides a means for monitoring wastewater to identify potential drug diversion and ensures quality control in the manufacturing and storage of alfentanil hydrochloride. The researchers identified 17 substances, with 8 of them being degradation products resulting from researcher-induced acidic, alkaline, or oxidative conditions, and the remaining 9 being manufacturing-related. Wang et al noted that the N-phenylpropanamide and piperidine functional groups of alfentanil hydrochloride were particularly susceptible to degradation.[19]

Pharmacokinetics

Absorption: Alfentanil is absorbed in the body completely, and the onset of anesthetic action is immediately after intravenous (IV) administration.

Distribution: Alfentanil has a volume of distribution ranging from 0.4 to 1 L/kg. The drug is bound to proteins to the extent of 92%.

Metabolism: Alfentanil undergoes extensive hepatic metabolism through the CYP450 enzyme system, where it serves as a substrate for CYP3A4.

Elimination: Approximately 1% of the administered dose is excreted as an unchanged drug, with urine being the primary route of excretion. The half-life of alfentanil ranges from 1.5 to 1.8 hours.

Administration

Available Dosage Forms and Strengths

Alfentanil is usually administered to adults via intravenous (IV) infusion over 3 minutes or continuous IV infusion. For children, the typical administration is IV over 3 to 5 minutes or by continuous IV infusion. However, alternative administration methods for alfentanil, such as epidural (injection into the epidural space), intrathecal (injection into the spinal canal or subarachnoid space), transdermal (via the skin), and intranasal, have also demonstrated efficacy.[1]

Adult Dosage

When determining the appropriate dosage for both pediatric and adult patients, the calculation should be based on the lean body weight.

General anesthesia: For general anesthesia, the recommended alfentanil dosages for adults are provided below.

• Induction: Induction involves 130 to 245 mcg/kg per dose of alfentanil administered IV for a single dose.

• Maintenance: Maintenance involves 0.5 to 1.5 mcg/kg/min of alfentanil administered via IV route.

General anesthesia adjunct: For general anesthesia adjunct, the recommended alfentanil dosages for adults are provided below.

• Incremental dosing is recommended when anesthesia lasts less than 30 minutes. A dosage of 3 to 5 mcg/kg per dose of alfentanil is administered IV every 5 to 20 minutes.

• Incremental dosing is recommended when anesthesia lasts for 30 to 60 minutes. A dosage of 5 to 15 mcg/kg per dose of alfentanil is administered IV every 5 to 20 minutes.

• Continuous infusion is recommended when anesthesia lasts more than 45 minutes. A dosage of 0.5 to 3 mcg/kg per dose of alfentanil is administered via the IV route.

Monitored anesthesia care adjunct: For monitored anesthesia care adjunct, the recommended alfentanil dosage is 3 to 5 mcg/kg/min administered IV every 5 to 20 minutes.

Pediatric Dosage

General anesthesia: For general anesthesia, the recommended alfentanil dosages for pediatric patients are provided below.

• Induction: Induction for individuals aged 12 or older involves 130 to 245 mcg/kg per dose of alfentanil administered IV for a single dose.

• Maintenance: Maintenance for individuals aged 12 or older involves 0.5 to 1.5 mcg/kg/min per dose of alfentanil administered IV.

General anesthesia adjunct: For general anesthesia adjunct, the recommended alfentanil dosages for pediatric patients are provided below.

• Incremental dosing is recommended when anesthesia lasts less than 30 minutes for individuals aged 12 or older. A dosage of 3 to 5 mcg/kg per dose of alfentanil is administered IV every 5 to 20 minutes.

• Incremental dosing is recommended when anesthesia lasts for 30 to 60 minutes for individuals aged 12 or older. A dosage of 5 to 15 mcg/kg per dose of alfentanil is administered IV every 5 to 20 minutes.

• Continuous infusion is recommended when anesthesia lasts more than 45 minutes for individuals aged 12 or older. A dosage of 0.5 to 3 mcg/kg per dose of alfentanil is administered IV.

Monitored anesthesia care adjunct: For monitored anesthesia care adjunct, the recommended alfentanil dosage for individuals aged 12 or older is 0.5 to 3 mcg/kg/min administered IV every 5 to 20 minutes.

Specific Patient Populations

Hepatic impairment: As there is no defined dosing for alfentanil in hepatic impairment, clinicians should exercise caution.

Renal impairment: For patients with renal impairment, it is advisable to consider a reduction in the usual dose.

Pregnant considerations: Clinicians should carefully assess the risks versus benefits for pregnant patients, particularly in the period immediately before and during labor, as alfentanil may pose a risk of fetal harm.

Breastfeeding considerations: Alfentanil use during breastfeeding is permissible, as data from human studies are unavailable, and there is a low risk of CNS depression. However, close monitoring of infants for signs of excess sedation and respiratory distress is recommended.

Pediatric patients: For pediatric patients, it is recommended to refer to the pediatric dosing information provided above. Alfentanil is specifically designated for use in children aged 12 and older.

Older patients: Healthcare providers advise reducing alfentanil dosing in the older population.

Adverse Effects

As an opioid-class analgesic, alfentanil shares common adverse effects with this medication group, including respiratory depression, reduced gastrointestinal motility, sedation, nausea, vomiting, constipation, and intestinal bloating. Notably, alfentanil tends to induce less intense respiratory depression than fentanyl. This is likely attributed to alfentanil's lower total body clearance, smaller volume of distribution, and shorter half-life when compared to other commonly used similar opioid analgesics, such as fentanyl and sufentanil. Additional adverse effects, more specific to alfentanil, include hypotension, chest wall rigidity, bradycardia, and tachycardia.[13][4][7]

Drug-Drug Interactions

Alfentanil is contraindicated with drugs such as isocarboxazid, potassium chloride, potassium citrate, safinamide, and samidorphan.

The extensive list of agents requiring caution and close monitoring include benzodiazepines, CNS depressant medications, CYP3A4 and CYP2D6 inhibitors (including macrolides such as erythromycin, azole antifungals such as ketoconazole, and protease inhibitors such as ritonavir), potentially leading to increased plasma concentrations of alfentanil. In addition, CYP3A4 inducers (including rifampin, carbamazepine, and phenytoin) may cause decreased alfentanil levels, resulting in therapeutic failure.

Contraindications

Alfentanil is contraindicated in patients with a history of hypersensitivity to alfentanil, such as anaphylaxis, or any component of the formulation. In addition, alfentanil is also contraindicated in individuals who have shown hypersensitivity to other similar opioid-class medications.

There is evidence suggesting that alfentanil may elevate the risk of seizures in individuals with a history of seizures and increase the duration of seizures. In such cases, electroencephalogram monitoring may be warranted if an alternative analgesic is not feasible. Notably, a history of seizures is not an absolute contraindication to alfentanil.

In locations outside the United States, particularly in Canada, contraindications to alfentanil include suspected abdominal surgery, mild pain manageable with alternative pain medications, acute or severe bronchial asthma, chronic obstructive airway disease, acute respiratory depression, status asthmaticus, hypercapnia, cor pulmonale, acute alcoholism, convulsive disorders, delirium tremens, severe CNS depression, increased intracranial or cerebrospinal pressure, head injury, or concurrent use of monoamine oxidase inhibitors (such as phenelzine) or within 14 days of their use. In addition, contraindications include pregnant women, nursing, or during labor or delivery.[20][21]

Box Warnings

Alfentanil has an FDA box warning for the following:

• Alfentanil exposes users to risks of opioid addiction, abuse, and misuse, which can lead to overdose and death.

• Severe or life-threatening respiratory depression can occur while using alfentanil.

• The concurrent use of alfentanil with benzodiazepines or other CNS depressant drugs, including alcohol, may result in profound sedation, respiratory depression, coma, or death.

• The concurrent use of alfentanil with CYP3A4 inhibitors can result in increased alfentanil serum levels, potentially leading to prolonged adverse reactions and, in severe cases, fatal respiratory depression.

Monitoring

Due to the highlighted adverse effects of alfentanil, it is recommended that individuals receiving alfentanil closely monitor vital signs, including respiratory status, continuous oxygen saturation, cardiovascular status, blood pressure, and heart rate. These parameters should be closely monitored immediately after surgery as well. In addition, individuals with a history of seizure activity may require electroencephalogram monitoring. This precaution is prompted by the occasional observed focal activation of cerebral activity in individuals with a seizure history who have been administered alfentanil.

Toxicity

Symptoms of alfentanil toxicity are similar to those of other opioid-class medications and include skeletal muscle rigidity, cardiac depression, respiratory depression, and constriction of the pupils.

If signs of toxicity develop, healthcare providers should initiate supportive measures, including re-establishing a patent airway (with ventilation if necessary) and providing oxygen or vasopressors in circulatory shock or pulmonary edema cases. The typical choice for reversing alfentanil toxicity is naloxone—an opioid receptor antagonist. Another antidote commonly used for opioid toxicity reversal is nalmefene.[22]

Enhancing Healthcare Team Outcomes

Alfentanil is classified as a Schedule II controlled substance due to its high potential for misuse, with the potential for psychosocial and/or physical dependence. Given the ongoing opioid abuse issue, it is crucial to adopt harm-reducing strategies and technologies in the healthcare field. Interprofessional collaboration involving all members of the healthcare team, including physicians, advanced practice practitioners, nurses, and pharmacists, and the use of prescription drug monitoring programs, is the most effective approach for monitoring and identifying potential abuse of opioid drugs.[23][24][25]