Fentanyl
Fentanyl is a highly potent synthetic opioid of the piperidine family, used primarily as pain medication. It is 50 to 100 times more potent than morphine. Its primary clinical use is in pain management for cancer patients and those recovering from surgery. Fentanyl is also used as a sedative for intubated patients. Fentanyl has a short duration of action. Fentanyl works by activating μ-opioid receptors. Brand names include Actiq, Duragesic, and Sublimaze, among others.
Fentanyl was first synthesized by Paul Janssen in 1960 and was approved for medical use in the United States in 1968. In 2015, were used in healthcare globally., fentanyl was the most widely used synthetic opioid in medicine; in 2019, it was the 278th most commonly prescribed medication in the United States, with more than a million prescriptions. It is on the World Health Organization's List of Essential Medicines.
The effects of fentanyl are similar to those of other opioids, causing sedation and analgesia at clinical doses. The most common adverse effects are respiratory depression, emesis, and asthenia. Bradycardia and apnoea are uncommon side effects but are serious and can lead to death outside of clinical settings. Fentanyl exerts its actions as an agonist of the μ-opioid receptor and κ-opioid receptor. The μ-receptor agonism is responsible for the respiratory depression and generalised analgesia whilst the κ-receptor agonism is responsbile for sedation and spinal analgesia. Fentanyl is a potent μ-receptor agonist but has less affinity for the κ-receptor.
Fentanyl is contributing to an epidemic of synthetic opioid drug overdose deaths in the United States. From 2011 to 2021, deaths from prescription opioid per year remained stable, while synthetic opioid deaths per year increased from 2,600 overdoses to 70,601. Since 2018, fentanyl and its analogues have been responsible for most drug overdose deaths in the United States, causing over 71,238 deaths in 2021. Fentanyl constitutes the majority of all drug overdose deaths in the United States since it overtook heroin in 2018. The United States National Forensic Laboratory estimates fentanyl reports by federal, state, and local forensic laboratories increased from 4,697 reports in 2014 to 117,045 reports in 2020. Fentanyl is often mixed, cut, or ingested alongside other drugs, including cocaine and heroin. Fentanyl has been reported in pill form, including pills mimicking pharmaceutical drugs such as oxycodone. Mixing with other drugs or disguising as a pharmaceutical makes it difficult to determine the correct treatment in the case of an overdose, resulting in more deaths. In an attempt to reduce the number of overdoses from taking other drugs mixed with fentanyl, drug testing kits, strips, and labs are available.
Medical uses
Anesthesia
Intravenous fentanyl is often used for anesthesia and as an analgesic. To induce anesthesia, it is given with a sedative like propofol or thiopental. To maintain anesthesia, inhaled anesthetics and additional fentanyl may be used. These are often given in 15–30minute intervals throughout procedures such as endoscopy and surgeries and in emergency rooms.For pain relief after surgery, using fentanyl can decrease the amount of inhalational anesthetic needed for emergence from anesthesia. Balancing this medication and titrating the drug based on expected stimuli and the person's responses can result in stable blood pressure and heart rate throughout a procedure and a faster emergence from anesthesia with minimal pain.
Regional anesthesia
Fentanyl is the most commonly used intrathecal opioid because its lipophilic profile allows a quick onset of action and intermediate duration of action. Spinal administration of hyperbaric bupivacaine with fentanyl may be the optimal combination. The almost immediate onset of fentanyl reduces visceral discomfort and even nausea during the procedure.Obstetrics
Fentanyl is sometimes given intrathecally as part of spinal anesthesia or epidurally for epidural anesthesia and analgesia. Because of fentanyl's high lipid solubility, its effects are more localized than morphine, and some clinicians prefer to use morphine to get a wider spread of analgesia. It is widely used in obstetrical anesthesia because of its short time to action peak, the rapid termination of its effect after a single dose, and the occurrence of relative cardiovascular stability. In obstetrics, the dose must be closely regulated to prevent large amounts of transfer from mother to fetus. At high doses, the drug may act on the fetus to cause neonatal withdrawal. For this reason, shorter-acting agents such as alfentanyl or remifentanil may be more suitable in the context of inducing general anesthesia.Pain management
The bioavailability of intranasal fentanyl is about 70–90% but with some imprecision due to clotted nostrils, pharyngeal swallow, and incorrect administration. For both emergency and palliative use, intranasal fentanyl is available in doses of 50, 100, 200, 400μg. In emergency medicine, safe administration of intranasal fentanyl with a low rate of side effects and a promising pain-reducing effect was demonstrated in a prospective observational study in about 900out-of-hospital patients.In children, intranasal fentanyl is useful for the treatment of moderate and severe pain and is well tolerated. Furthermore, a 2017 study suggested the efficacy of fentanyl lozenges in children as young as five, weighing as little as 13kg. Lozenges are more inclined to be used as the child is in control of sufficient dosage, in contrast to buccal tablets.
Chronic pain
It is also used in the management of chronic pain. Often, transdermal patches are used. The patches work by slowly releasing fentanyl through the skin into the bloodstream over 48 to 72hours, allowing for long-lasting pain management. Dosage is based on the size of the patch, since, in general, the transdermal absorption rate is constant at a constant skin temperature. Each patch should be changed every 72hours. Rate of absorption is dependent on a number of factors. Body temperature, skin type, amount of body fat, and placement of the patch can have major effects. The different delivery systems used by different makers will also affect individual rates of absorption, and route of administration. Under normal circumstances, the patch will reach its full effect within 12 to 24hours; thus, fentanyl patches are often prescribed with a fast-acting opioid to handle breakthrough pain. It is unclear if fentanyl gives long-term pain relief to people with neuropathic pain.Palliative care
In palliative care, transdermal fentanyl patches have a definitive, but limited role for:- people already stabilized on other opioids who have persistent swallowing problems and cannot tolerate other parenteral routes such as subcutaneous administration.
- people with moderate to severe kidney failure.
- troublesome side effects of oral morphine, hydromorphone, or oxycodone.
Combat medicine
s in Afghanistan used fentanyl lozenges in the form of lollipops on combat casualties from IED blasts and other trauma. The stick is taped to a finger and the lozenge put in the cheek of the person. When enough fentanyl has been absorbed, the person generally lets the lollipop fall from the mouth, indicating sufficient analgesia and somewhat reducing the likelihood of overdose and associated risks.Breathing difficulties
Fentanyl is used to help relieve shortness of breath when patients cannot tolerate morphine, or whose breathlessness is refractory to morphine. Fentanyl is useful for such treatment in palliative care settings where pain and shortness of breath are severe and need to be treated with strong opioids. Nebulized fentanyl citrate is used to relieve end-of-life dyspnea in hospice settings.Other
Some routes of administration such as nasal sprays and inhalers generally result in a faster onset of high blood levels, which can provide more immediate analgesia but also more severe side effects, especially in overdose. The much higher cost of some of these appliances may not be justified by marginal benefit compared with buccal or oral options. Intranasal fentanyl appears to be equally effective as IV morphine and superior to intramuscular morphine for the management of acute hospital pain.A fentanyl patient-controlled transdermal system is under development, which aims to allow patients to control the administration of fentanyl through the skin to treat postoperative pain. The technology consists of a "preprogrammed, self-contained drug-delivery system" that uses electrotransport technology to administer on-demand doses of 40μg of fentanyl hydrochloride over ten minutes. In a 2004 experiment including 189 patients with moderate to severe postoperative pain up to 24hours after major surgery, 25% of patients withdrew due to inadequate analgesia. However, the PCTS method proved superior to the placebo, showing lower mean VAS pain scores and having no significant respiratory depression effects.
Adverse effects
Fentanyl's most common side effects, which affect more than 10% of people, include nausea, vomiting, constipation, dry mouth, somnolence, confusion, and asthenia. Less frequently, in 3–10% of people, fentanyl can cause abdominal pain, headache, fatigue, anorexia and weight loss, dizziness, nervousness, anxiety, depression, flu-like symptoms, dyspepsia, shortness of breath, hypoventilation, apnoea, and urinary retention. Fentanyl use has also been associated with aphasia. Despite being a more potent analgesic, fentanyl tends to induce less nausea, as well as less histamine-mediated itching, than morphine. In rare cases, serotonin syndrome is associated with fentanyl use. Existing studies advise medical practitioners to exercise caution when combining selective serotonin reuptake inhibitor drugs with fentanyl.The duration of action of fentanyl has sometimes been underestimated, leading to harm in a medical context. In 2006, the United States Food and Drug Administration began investigating several respiratory deaths, but doctors in the United Kingdom were not warned of the risks with fentanyl until September 2008. The FDA reported in April 2012 that twelve young children had died and twelve more had become seriously ill from separate accidental exposures to fentanyl skin patches.