Alfentanil is a synthetic opioid analgesic and a derivative of fentanyl. It is widely used for analgesia to supplement general anesthesia for various surgical procedures or as a primary anesthetic agent in very high doses during cardiac surgery.
Compared to similar anesthetics, including fentanyl and sufentanil, alfentanil is the least potent, has the fastest onset of action, and has the shortest duration of action. Because of alfentanil’s short duration of action, it is typically preferred for shorter procedures or when rapid changes in the level of consciousness are necessary. Such procedures include gynecological procedures, short ambulatory procedures such as colonoscopies, and shorter surgeries such as tonsillectomies, appendectomies, and cholecystectomies, to list a few. Alfentanil has been demonstrated to be effective and safe in both children and adults at appropriate dosing.
Barker M. et al. conducted a retrospective observational study to determine any significant differences in patient outcomes when using alfentanil or fentanyl for extracorporeal membrane oxygenation sedation. The researcher’s institution was switching from alfentanil to fentanyl use. Ninety-five patients on fentanyl and 69 patients on alfentanil were studied. Barker M. et al. found no differences in patient outcomes when comparing sedation with alfentanil or fentanyl for extracorporeal membrane oxygenation. However, the researchers noted that higher doses of the adjuvant sedatives quetiapine and midazolam were used with alfentanil-treated patients.
Eberl S. et al. conducted a randomized controlled trial on the effectiveness of alfentanil vs. esketamine as adjunct medications for propofol-mediated deep sedation for endoscopic retrograde cholangiopancreatography (ERCP). Propofol was administered as a target-controlled infusion (TCI). One hundred and sixty-two patients (N = 162) were enrolled in the study. The researchers observed that less propofol was needed in the esketamine treated patients (N = 83) vs. the alfentanil-treated patients (N = 79).
Mechanism of Action
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Alfentanil is of the opioid class of medications and thus acts by stimulation of the opioid receptors, of which there are three main subtypes: mu (m), kappa (k), and delta (d). The receptor primarily involved in pain transmission is the m-opioid receptor. The opioid receptors are predominately present in the central nervous system, brain, spinal column, and peripheral nervous system but are also present in vascular, cardiac, lung, gut, 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.
Opioids have various clinical effects but are predominately known and used for their profound pain-relieving effects. Their pain-relieving effects are from binding the m-opioid receptor, which is coupled with G1 proteins, resulting in the closure of N-type voltage-operated calcium channels and opening of calcium-dependent inwardly-rectifying potassium channels. The result is intracellular hyperkalemia and a decrease in the neurotransmission of pain signals resulting in increased tolerability of pain. Opioid receptor binding also decreases intracellular cyclic-adenosine-monophosphate (cAMP), which modulates the release of nociceptive (relating to the perception of pain) neurotransmitters (e.g., substance P).
There have not been acute changes to intracellular sodium noted to occur with opioid-receptor binding; however, intracellular sodium may hypothetically have involvement in opioid-receptor affinity to both endogenous and exogenous opioid-receptor binders. Researchers have observed that opioid-receptor binders seem to bind with a higher affinity in the presence of lower intracellular sodium concentrations and higher intracellular potassium concentrations. Of note, there was no observed change in the total number of binding sites of the opioid receptors during these observations. This phenomenon was observed specifically in cells known to have the m- and d-type opioid receptors.
Opioids are also known for their euphoric effects. Euphoria is a feeling or state of intense excitement and happiness. These effects are usually due to the binding of endorphins to opioid receptors in the central and peripheral nervous systems. Endorphins are primarily synthesized and stored in the anterior pituitary gland from their precursor protein proopiomelanocortin (POMC). POMC is a large protein cleaved into smaller proteins such as beta-endorphin, alpha-melanocyte-stimulating hormone (MSH), adrenocorticotropin (ACTH), and others. Interestingly enough, studies have suggested that cells of the immune system are also capable of beta-endorphin synthesis because immune cells possess mRNA transcripts for POMC and T-lymphocytes, B-lymphocytes, monocytes, and macrophages have shown to contain endorphins during inflammation.
Usually, euphoric effects are primarily due to endorphin binding at opioid receptors in the peripheral nervous system. However, in opioid administration, it is directly due to opioid drugs binding the opioid receptors at both the pre- and postsynaptic junctional in the peripheral nervous system and at the pre-synaptic junction in the central nervous system. The analgesia produced by endorphins in the peripheral nervous system mainly stems from a decreased synthesis of substance P. In the central nervous system, there is also a degree of analgesic effects from endorphins binding opioid receptors, but it is from inhibiting the release of GABA, resulting in excess production of dopamine. Upon opioid administration, the opioid drug takes on this role.
It bears mention that when administering opioid analgesic drugs to patients, there is a decrease in synthesis and secretion of endogenous endorphins and opioid peptides; this is due to negative feedback on the endogenous endorphin and opioid systems.
Other effects of opioid medications include changes in mood, drowsiness, and mental clouding. However, the distinctive feature of the analgesia induced by opioids is the lack of consciousness. The patient still perceives the pain but describes it as less intense. Thus, opioids do not decrease or treat the cause of a painful stimulus but rather decrease its perception.
Wang Y. et al. conducted an analytical chemistry study on alfentanil hydrochloride impurities and degradation products 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, and monitoring wastewater for drug diversion as well as quality control for the manufacturing and storage of alfentanil hydrochloride. The researchers found 17 substances. Eight of the substances were degradation products from researcher-induced acidic, alkaline, or oxidative conditions, and 9 of the substances were manufacturing-related. Wang Y. et al. found that alfentanil hydrochloride’s N-phenylpropanamide and piperidine functional groups were most vulnerable to degradation.
Administration of alfentanil to adults is typically intravenous over three minutes or by continuous intravenous infusion, and administration to children is typically intravenous over three to five minutes or by continuous intravenous infusion. However, other methods of administration of alfentanil have demonstrated efficacy, including epidural (injection into the epidural space), intrathecal (injection into the spinal canal or the subarachnoid space), transdermal (across the skin), and intranasal.
With alfentanil being an opioid-class analgesic, it has adverse effects common to this group of medications, including respiratory depression, decreased gastrointestinal motility, sedation, nausea, vomiting, constipation, and intestinal bloating. An interesting note about alfentanil is that it causes less intense respiratory depression than fentanyl, likely due to its lower total body clearance, smaller volume of distribution, and shorter half-life than other commonly used similar opioid analgesics, such as fentanyl and sufentanil. Additional adverse effects noted to be more specific to alfentanil include hypotension, chest wall rigidity, bradycardia, and tachycardia.
Alfentanil is contraindicated in patients who have a history of hypersensitivity to alfentanil (e.g., anaphylaxis) or any component of the formulation. It is also contraindicated in those who have shown hypersensitivity to other similar opioid-class medications.
There has been evidence that alfentanil can increase the risk of seizures in those with a history of seizures and can increase the duration of seizures. In such patients, electroencephalogram monitoring may be necessary if another analgesic is unable to be used, but a history of seizures is not necessarily a contraindication to alfentanil.
Outside of the United States, specifically in Canada, contraindications to alfentanil include suspected abdomen surgery, mild pain that is manageable with other pain medications, acute/severe bronchial asthma, chronic obstructive airway, acute respiratory depression, status asthmaticus, hypercapnia, cor pulmonale, acute alcoholism, convulsive disorders, delirium tremens, severe CNS depression, increased intracranial or cerebrospinal pressure and head injury, or using monoamine-oxidase inhibitors, e.g., phenelzine concurrently or within 14 days of use, as well as women or who are nursing or pregnant, and during labor/delivery.
Because of the adverse effects of alfentanil highlighted above, the recommendation is that vital signs undergo close monitoring for those receiving alfentanil, including respiratory status, cardiovascular status, blood pressure, and heart rate. These parameters should continue to be monitored closely immediately after surgery as well. Also, electroencephalogram monitoring may be necessary for those with a history of seizure activity. This precaution is due to an observed focal activation of cerebral activity occasionally seen in those with seizure history who have received alfentanil.
Alfentanil toxicity symptoms are similar to that of other opioid-class medication toxicities and include rigidity of the skeletal muscles, cardiac depression, respiratory depression, and narrowing of the pupils.
If signs of toxicity develop, supportive measures should be deployed, including the reestablishment of a patent-protected airway (with ventilation if needed) and oxygen/vasopressors in the case of circulatory shock or pulmonary edema. Naloxone – an opioid receptor antagonist – is typically used for the reversal of alfentanil toxicity. Nalmefene is another antidote commonly used reversal agent in the case of opioid toxicity.
Enhancing Healthcare Team Outcomes
It is a schedule two controlled substance, meaning it has a high potential for misuse, which can ultimately lead to psychosocial and/or physical dependence. Amid the current opioid abuse problem, it is important to implement harm-reducing strategies and technologies in the healthcare field. Interprofessional collaboration between every member of the interprofessional team involved in the care of patients, including all clinicians, nurses, and pharmacists, and utilizing prescription drug monitoring programs is the best way to watch for potential abuse of opioid drugs.
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