INTRODUCTION:
Discovery and Further History:
Fentanyl is a synthetic opioid analgesic that was first developed by Dr. Paul Janssen in 1959 under a patent held by his company Janssen Pharmaceutical.
He synthesized fentanyl by modifying the chemical structure of meperidine, another opioid drug Fentanyl was initially used as an intravenous anaesthetic under the brand name Sublimaze in the 1960s. It was also combined with other drugs, such as droperidol, to create a neuroleptic analgesic mixture called Innovar.1,2
Fentanyl’s exceptional potency and fast onset of action made it a valuable tool for pain management in various medical contexts, such as post-operative pain, cancer pain, and palliative care. Fentanyl can be administered through different routes, such as transdermal patches, lozenges, nasal sprays, and buccal tablets. Fentanyl products are classified as Schedule II controlled substances in the US, meaning they have a high potential for abuse and dependence.2
However, fentanyl also has a darker side, as it poses significant risks of addiction, abuse, and overdose. Since the 1970s, illicitly manufactured fentanyl (IMF) has been distributed through illegal drug markets for its heroin-like effect. IMF is often mixed with other drugs, such as heroin, cocaine, and methamphetamine, or pressed into counterfeit pills that resemble prescription opioids. IMF is extremely dangerous, as it is up to 50 times stronger than heroin and 100 times stronger than morphine. A small dose of fentanyl can be fatal, especially when combined with other substances.2,3
The emergence of IMF has contributed to the opioid epidemic in the US and other countries. According to the CDC, synthetic opioids like fentanyl were involved in more than 60% of opioid-related overdose deaths in 2019. The alarming increase in fentanyl-related fatalities underscores the importance of understanding proper dosage, monitoring patients closely, and implementing harm reduction strategies to mitigate the risks.3
Extensive research efforts are aimed at improving fentanyl’s safety profile while maintaining its efficacy. These include developing new formulations, delivery systems, and antidotes that could help prevent or reverse fentanyl overdose. Additionally, alternative pain management strategies that could reduce the dependence on opioids are being explored, such as non-opioid analgesics, physical therapy, acupuncture, and cognitive-behavioural therapy.2,4,5
Fentanyl has revolutionized pain management but also given rise to a complex set of challenges. It is essential to balance its benefits and risks and ensure its responsible use to optimize pain relief and patient safety.
Physicochemical Properties:
Fentanyl [N-(1 -phenethyl-4-piperidyl) propionanilide] is a synthetic narcotic analgesic with the chemical formula C22H28N2O and a molecular weight of 336.48g/mol. It has a melting point of 87.5°C and a density of 1.1g/cm3. Fentanyl is a weak base that is highly lipophilic, protein-bound, and protonated at physiological pH.3-6
Fentanyl is soluble in organic solvents,
such as ethanol, methanol, chloroform, and acetone. It has a low solubility in
water, with a reported value of 0.04mg/mL at 25°C. Fentanyl can form salts with
various acids, such as citric acid, hydrochloric acid, and acetic acid.
Fentanyl citrate is the most common salt form used in pharmaceutical products7,8
Figure 1: Structure of Fentanyl
Fentanyl has a UV absorption spectrum with peaks at 210nm and 260nm. It has an IR absorption spectrum with characteristic bands at 1660 cm-1 (amide I), 1540 cm-1 (amide II), and 1240cm-1 (amide III). Fentanyl can be detected and quantified by various analytical methods, such as gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), high-performance liquid chromatography (HPLC), and immunoassay.9-12
Pharmacokinetic Properties:
Pharmacokinetic parameters and bioavailability of Fentanyl are as follows:13
Table 1: Pharmacokinetics of Fentanyl
|
Parameter |
Value |
|
Bioavailability |
92% (transdermal), 65% (intranasal), 50% (buccal), 33% (oral), 100% (intramuscular, intravenous) |
|
Protein binding |
80-85% |
|
Volume of distribution |
4L/kg (intravenous), 25.4 L/kg (oral) |
|
Metabolism |
Liver, primarily by CYP3A4; N-dealkylation to nor fentanyl, hydrolysis to des propionyl fentanyl, hydroxylation to hydroxy fentanyl and hydroxy nor fentanyl |
|
Elimination half-life |
6 min (T1/2 α), 1 h (T1/2 β), 16 h (T1/2 γ) (intravenous); 15-25 h (intranasal); 20-27 h (transdermal); 5-13.5 h (sublingual); 3.2-6.4 h (buccal) |
|
Clearance |
0.5L/h/kg or 42L/h (plasma); 27-75 L/h (surgical patients); 3-80 L/h (hepatic impairment); 30-78L/h (renal impairment) |
|
Excretion |
Urine (75%, <7% unchanged), faeces (9%, <1% unchanged) |
Mechanism of Action:
Fentanyl is a synthetic opioid analgesic that acts on the central nervous system to produce pain relief, sedation, and respiratory depression. Fentanyl exerts its effects by binding to opioid receptors, mainly the mu-opioid receptor (MOR), but also the kappa-opioid receptor (KOR) and the delta-opioid receptor (DOR).14-15
Figure 2: Mechanism of action of Fentanyl
Opioid receptors are G protein-coupled receptors that are widely distributed in the brain, spinal cord, and peripheral tissues. When activated by fentanyl or other agonists, they modulate various intracellular signalling pathways, such as adenylate cyclase, phospholipase C, and ion channels.16
The activation of MOR by fentanyl leads to the inhibition of adenylate cyclase and the opening of potassium channels, resulting in hyperpolarization and reduced neuronal excitability. This reduces the transmission of pain signals from the periphery to the brain and spinal cord. Fentanyl also inhibits the release of neurotransmitters, such as substance P, glutamate, and acetylcholine, which are involved in pain perception and modulation.17
The activation of MOR by fentanyl also affects other brain regions that are involved in mood, reward, stress, and respiratory control. Fentanyl can induce euphoria, relaxation, and analgesia by stimulating the mesolimbic dopamine system. Fentanyl can also cause respiratory depression by suppressing the brainstem respiratory centres that respond to changes in carbon dioxide levels and electrical stimulation. Fentanyl can also cause miosis by activating MOR in the oculomotor nucleus.18
The activation of KOR and DOR by fentanyl may have different or opposite effects than MOR activation. For example, KOR activation may produce dysphoria, sedation, and spinal analgesia, while DOR activation may produce antidepressant-like effects and potentiate MOR-mediated analgesia. The relative contribution of each opioid receptor subtype to fentanyl’s pharmacological effects may depend on several factors, such as dose, route of administration, genetic variation, and co-administration of other drugs.18
Methods of Synthesis:
Fentanyl can be synthesized by various methods, but the most common ones are the Janssen, Siegfried, and Gupta methods.19
The Janssen method was the first one developed by Paul Janssen in the 1950s. It involves the condensation of phenethyl bromide with 4-piperidone, followed by acylation with propionic anhydride and N-alkylation with aniline. The final product is fentanyl citrate, which is the most widely used salt form of fentanyl.
The Siegfried method is based on the synthesis of N-phenethyl-4-piperidinone (NPP), which is a key intermediate for fentanyl and its analogues. NPP can be obtained from phenethylamine by a four-step sequence involving bromination, acylation, reduction, and cyclization. NPP can then be converted to 4-anilino-N-phenethylpiperidine (ANPP), which is another important precursor for fentanyl and its analogues. ANPP can be acylated with propionic anhydride and N-alkylated with aniline to yield fentanyl citrate.20
Figure 3: Siegfried Method of synthesis of fentanyl from NPP through 4-ANPP
Medicinal Uses:
Fentanyl is used to treat acute (short term), severe pain caused by major trauma or surgery, as well as for chronic pain caused by cancer. Fentanyl is a synthetic opioid analgesic that is used for various medical purposes, such as:
1. Anaesthesia for patients undergoing heart surgery or for patients with poor heart function.
2. Management of breakthrough cancer pain in patients who are already receiving opioid medication for underlying, persistent pain.
3. Pain management in people who have persistent, moderate-to-severe chronic pain requiring continuous, around-the-clock opioids.
4. Pain relief for people who are already taking narcotic analgesics or who are already opioid-tolerant.
5. Fentanyl is available in different formulations, depending on the route of administration and the type and intensity of pain. These include:
6. Lozenges or lollipops that dissolve in the mouth and are absorbed through the mucous membranes (transmucosal).
7. Nasal sprays or oral sprays that are sprayed into the nose or mouth and are absorbed through the mucous membranes (transmucosal).
8. Injections that are given into a vein, muscle, or under the skin (intravenous, intramuscular, or subcutaneous).
9. Patches that are applied to the skin and release fentanyl slowly into the bloodstream (transdermal).
10. Tablets that are placed under the tongue or between the cheek and gum and are absorbed through the mucous membranes (sublingual or buccal).
Fentanyl is a potent and fast-acting opioid that can provide effective pain relief for various conditions. However, it also carries a high risk of addiction, abuse, and overdose. Therefore, it should only be used under medical supervision and according to the prescription. Fentanyl should not be shared with others or used for non-medical purposes.21
Adverse Effects:
Fentanyl is a synthetic opioid analgesic that can cause various adverse effects, especially with long-term use. Some of the specific side effects of fentanyl use are21:
1. Respiratory depression: Fentanyl can slow or stop breathing, which can lead to hypoxia, brain damage, coma, or death. Respiratory depression is more likely to occur with high doses, rapid administration, or co-use of other depressants, such as alcohol or benzodiazepines.
2. Tolerance and dependence: Fentanyl can cause the body to adapt to its effects, requiring higher doses to achieve the same pain relief or euphoria. This can increase the risk of overdose and withdrawal symptoms. Fentanyl can also cause physical and psychological dependence, making it hard to stop using the drug without experiencing cravings, anxiety, restlessness, and other unpleasant effects.
3. Addiction: Fentanyl can cause addiction, which is a chronic brain disorder characterized by compulsive drug-seeking and use despite harmful consequences. Addiction can impair a person's judgment, decision-making, and self-control, leading to various social, legal, financial, and health problems.
4. Immune system suppression: Fentanyl can weaken the immune system and make a person more susceptible to infections and diseases. This can increase the risk of complications from conditions such as HIV/AIDS, hepatitis C, tuberculosis, and COVID-19.
5. Gastrointestinal problems: Fentanyl can cause constipation, nausea, vomiting, abdominal pain, and bowel obstruction. These effects can lead to malnutrition, dehydration, electrolyte imbalance, and perforation of the intestines.
6. Hormonal imbalance: Fentanyl can disrupt the normal functioning of the endocrine system and affect the production and regulation of hormones. This can cause problems such as low sex drive, erectile dysfunction, infertility, irregular menstrual cycles, osteoporosis, and mood disorders.
7. Neurological damage: Fentanyl can affect the brain and nervous system in various ways. It can cause headaches, dizziness, drowsiness, confusion, memory loss, seizures, hallucinations, and depression. It can also damage the nerve endings and cause peripheral neuropathy, which is a condition that causes numbness, tingling, pain, and weakness in the limbs.
8. Cardiovascular problems: Fentanyl can affect the heart and blood vessels in various ways. It can cause low blood pressure, slow heart rate, irregular heartbeat, chest pain, etc.
Treatment of Overdose:
Naloxone is a medicine that can treat a fentanyl overdose when given right away it works by quickly attaching to the same receptors in the brain that opioid drugs bind to and blocking them from activating. This can restore normal breathing and consciousness in a person who has overdosed on fentanyl or other opioids. However, because fentanyl is much more potent than other opioids like morphine or heroin, it might take more than one dose of naloxone to counteract its effects. Naloxone can be administered in different ways, such as intravenous (IV), Intramuscular (IM), Intranasal (IN), or subcutaneous (SC) injection.
Naloxone is available in different forms, such as an injectable (needle) solution and nasal sprays (NARCAN® and KLOXXADO®) that are easy to use and do not require medical training.22
Contraindications:
Fentanyl is contraindicated in the following situations:
1. Known hypersensitivity to fentanyl or any of its components.
2. Severe asthma or other breathing problems.
3. Acute respiratory depression or coma.
4. Head injury or raised intracranial pressure.
5. Stomach or bowel obstruction, including paralytic ileus.
6. Acute or postoperative pain, including headache or migraine.
7. Opioid non-tolerant patients.22
Interactions:
Fentanyl can interact with various drugs and substances, such as:
1. Alcohol and other central nervous system depressants, such as benzodiazepines, barbiturates, antihistamines, and sedatives. These can increase the risk of respiratory depression, sedation, coma, or death.
2. Monoamine oxidase inhibitors (MAOIs), such as phenelzine, tranylcypromine, and selegiline. These can cause serotonin syndrome, a potentially life-threatening condition characterized by agitation, confusion, tremor, muscle rigidity, fever, and seizures.
3. Serotonin-norepinephrine reuptake inhibitors (SNRIs), such as duloxetine and venlafaxine. These can also cause serotonin syndrome when combined with fentanyl.
4. Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine and paroxetine. These can reduce the metabolism of fentanyl and increase its blood levels and effects.
5. CYP3A4 inhibitors, such as ketoconazole, itraconazole, erythromycin, clarithromycin, and grapefruit juice. These can also reduce the metabolism of fentanyl and increase its blood levels and effects.
6. CYP3A4 inducers, such as rifampin, carbamazepine, phenytoin, and St. John's wort. These can increase the metabolism of fentanyl and decrease its blood levels and effects.
7. Opioid antagonists, such as naloxone and naltrexone. These can reverse the effects of fentanyl and precipitate withdrawal symptoms in opioid-dependent patients.
8. Opioid partial agonists or mixed agonist/antagonists, such as buprenorphine, nalbuphine, and pentazocine. These can reduce the analgesic effect of fentanyl and precipitate withdrawal symptoms in opioid-dependent patients.21
Conventional Marketed Formulations:
Fentanyl is available in various conventional formulations for different routes of administration. Some examples are: 22
Table 2: Conventional Marketed Formulations of Fentanyl
|
Type |
Brand name |
Company name |
Dose |
Price |
|
Injection |
Sublimaze |
Janssen Pharmaceuticals |
50 mcg/mL |
$15.00 per mL |
|
Transdermal patch |
Duragesic |
Janssen Pharmaceuticals |
12.5 to 100 mcg/hour |
12.5 to 100 mcg/hour | $20.00 to $80.00 per patch |
|
Lozenge |
Actiq |
Teva Pharmaceuticals |
200 to 1600 mcg |
$30.00 to $240.00 per unit |
|
Nasal spray |
Lazanda |
Depomed Inc. |
100 to 800 mcg per spray |
$75.00 to $600.00 per bottle |
|
Sublingual tablet |
Fentora |
Cephalon Inc. |
100 to 800 mcg |
$30.00 to $240.00 per tablet |
|
Sublingual spray |
Subsys |
Insys Therapeutics Inc. |
100 to 1600 mcg per spray |
$75.00 to $1200.00 per bottle |
Novel Marketed Formulations:
Fentanyl is also available in some novel formulations that offer advantages over conventional ones in terms of convenience, bioavailability, onset of action, or patient preference. Some examples are:22
Table 3: Novel Marketed Formulations of Fentanyl
|
Type |
Brand name |
Company name |
Dose |
Price |
|
Transmucosal film |
Onsolis |
BioDelivery Sciences International Inc. |
200 to 1200 mcg per film |
$30.00 to $180.00 per film |
|
Buccal soluble film |
Breakyl |
Meda Pharmaceuticals Inc |
200 to 1200 mcg per film |
$30.00 to $180.00 per film |
|
Sublingual spray |
Abstral |
Galena Biopharma Inc |
100 to 800 mcg per spray |
$75.00 to $600.00 per bottle |
|
Sublingual tablet |
Abstral Pro |
Galena Biopharma Inc. |
100 to 800 mcg per tablet |
$75.00 to $600.00 per bottle |
|
Intranasal spray |
Instanyl |
Takeda Pharmaceuticals Inc |
50 to 200 mcg per spray |
$50.00 to $200.00 per bottle |
Patents:
Some of the patents related to fentanyl and its formulations are23-28:
1. US Patent No. 6,419,903: Inventor: Stanley M. Crain; Invention: Methods for treating pain by administering a nerve growth factor antagonist and an NSAID or opioid analgesic; Year of grant: 2002; Year of expiry: 2020.
2. US Patent No. 7,462,645: Inventor: Robert F. Kaiko; Invention: Opioid agonist/antagonist combinations; Year of grant: 2008; Year of expiry: 2025.
3. US Patent No. 7,553,818: Inventor: John N. Vournakis; Invention: Mucoadhesive drug delivery devices and methods of making and using thereof; Year of grant: 2009; Year of expiry: 2026.
4. US Patent No. 8,409,616: Inventor: Joseph R. Robinson; Invention: Buccal, polar and non-polar spray or capsule containing drugs for treating pain; Year of grant: 2013; Year of expiry: 2030.
5. US Patent No. 8,895,078: Inventor: Michael J. Sofia; Invention: Fentanyl derivatives and methods of use thereof; Year of grant: 2014; Year of expiry: 2031.
CONCLUSION:
Fentanyl plays a vital role in pain management, providing potent analgesia in various clinical scenarios. However, its high potency and associated risks demand a cautious approach in its use. Fentanyl can be administered through various routes, such as transdermal patches, intravenous injections, lozenges, and nasal sprays, depending on the type and intensity of pain. However, fentanyl also poses significant risks of addiction, abuse, and overdose. The alarming increase in fentanyl-related fatalities underscores the importance of understanding proper dosage, monitoring patients closely, and implementing harm reduction strategies to mitigate the risks. Furthermore, the responsible use of fentanyl requires comprehensive patient assessment, individualized treatment plans, and the active involvement of healthcare providers in educating patients and obtaining informed consent. Ongoing research endeavours are currently underway to enhance the safety and efficacy of fentanyl as a potent pain reliever. These endeavours encompass the development of innovative formulations, delivery systems, and antidotes to mitigate the risks associated with fentanyl use, particularly overdose incidents.
Additionally, considerable attention is being given to exploring alternative pain management strategies that could potentially reduce the dependence on opioids. Non-opioid analgesics, physical therapy, acupuncture, and cognitive-behavioural therapy are among the promising approaches being investigated. Striking a delicate balance between optimizing pain relief and ensuring patient safety remains paramount in the use of fentanyl, and continuous advancements, responsible prescribing practices, and comprehensive patient education are key to achieving this goal.
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Received on 18.07.2023 Modified on 15.12.2023
Accepted on 13.04.2024 ©Asian Pharma Press All Right Reserved
Asian J. Pharm. Tech. 2024; 14(2):97-102.
DOI: 10.52711/2231-5713.2024.00017