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The chapter presents one of the most discussed synthetic anesthetics—fentanyl. The possibilities of its use, the effect on the health of users, pharmacological and chemical findings, the issue of human and veterinary use of these substances, and the comparison of the effects of its derivatives are described. It discusses the issue of the abuse of these psychoactive substances and their seizures by members of the rescue system and the necessity of legislative control. Some methods of detecting fentanyl-type substances are listed, both by simple orientation methods and by more sophisticated techniques of infrared spectroscopy and liquid and gas chromatography. Finally, fentanyl is discussed as an incapacitating agent in the protection of the population.
NBC Defence Institute Vyskov, University of Defence, Brno, Czech Republic
*Address all correspondence to: romana.jelinkova@unob.cz
1. Introduction
The existence of pain-relieving substances has been known since ancient times. The first opioid analgesics were probably natural alkaloids found in the poppy. Morphine was isolated from poppy opium, which was successfully used as a powerful analgesic and sedative. At the end of the nineteenth century, pharmaceutical companies began to focus on the synthesis of new effective drugs.
The story of the most popular opioid analgesic, fentanyl, dates back to 1959, when Dr. Paul Janssen, pharmacologist, physician, and founder of Janssen Pharmaceutica, sought an adequate substitute for the opioid pethidine (also called meperidine, trade name Demerol). The pethidine used at the time showed weak analgesic effects compared to morphine. Due to its simple molecule structure Dr. Janssen assumed that by changing the pethidine structure and achieving better solubility in fats, the newly synthesized substance would have a stronger effect on the organism. Selected opioids have previously been used in anesthetic care for premedication, as intraoperative adjuncts to general anesthesia, and for postoperative pain management.
From a number of newly synthesized molecular entities that showed significant analgesic activity, a substance called fentanyl appeared to be the most advantageous, the effects of which being about 80–100 times stronger than those of morphine. Subsequently, numerous experiments were carried out on animals, first in combination with other inhaled drugs and later as a pure narcotic anesthetic.
Based on the positive results, studies were started in Europe, and fentanyl was approved for regular use in medical practice in the mid-1860s. It was usually used to put people to sleep in combination with some intravenously administered hypnotics, such as droperidol. This technique of “neurolept anesthesia” soon gained considerable popularity. The states of analgesia, apathy, and deep sedation—the neuroleptanalgesia, when the patient can be awakened and when the patient can speak, and neuroleptanesthesia, in which the patient is unconscious, are procedures that allow short and medium-term surgical and diagnostic procedures in patients with cardiovascular diseases with minimal load on the heart and circulatory system. Later, the combination of fentanyl with droperidol was replaced by a combination of fentanyl or alfentanil with a benzodiazepine due to differences in the pharmacokinetics of these substances [1].
The effect of fentanyl is qualitatively similar to morphine. Cortical depression has been shown to be minimal, and respiratory changes may outlast its analgesic effect. However, no significant cardiovascular effects were observed at usual therapeutic doses [2]. The advantage is a lower emetic effect compared to morphine [3].
After its introduction as an intravenous analgesic, it was used in a number of Western European countries in combination with other sedatives or hypnotics in an attempt to create a unique general intravenous anesthesia. Due to its high efficiency, it was possible to use only a minimal amount of the substance [4]. Throughout Europe, “neurolept anesthesia” was subsequently studied for more than a quarter of a century as an alternative to the strong inhalation anesthetics of the time. At the turn of the 1960s and 1970s, the so-called “stress-free anesthesia” came to the fore in Belgium thanks to the anesthesiologist Gorge de Castro and the Janssen team. Stress-free anesthesia refers to the use of a drug or combination of drugs that can provide deep anesthesia with minimal or no change in cardiovascular dynamics and block the increase in stress-responsive hormones that normally occur with surgical stimulation. Animal and patient studies were successful, and the technique called analgesic-anesthesia was reported at the World Congress of Anesthesiology in Mexico City in 1976.
The offer to use fentanyl in the healthcare system of the United States of America was initially not met with the expected response due to concerns about the possible abuse of the substance in the drug scene. It was not until 1968 that fentanyl mixed with droperidol in a ratio of 50:1 droperidol to fentanyl was approved by the U.S. Food and Drug Administration (FDA) for use in clinical anesthesiology under the name Innovar. In other countries, it was used under the name Thalamonal. Six years later, fentanyl was also used alone, in 1 mL ampoules containing 50 μg of the active substance [4].
Today, it is widely used for preoperative analgesia, general anesthesia, anesthesia adjunct, regional anesthesia adjunct, postoperative pain control, and moderate to severe acute pain (off-label). Fentanyl must be titrated with increased caution and care for patients with lung disease, impaired liver or kidney function, alcohol dependence, or hypothyroidism [5].
Fentanyl is rapidly distributed with sequestration in fat and binds to human plasma proteins. It is metabolized mainly in the liver and is excreted by the kidneys. The elimination half-life ranges from 6 to 32 h. With intravenous administration, it works almost immediately, with intramuscular administration it takes about 7–8 min. The maximum effect that the drug achieves is observed in 5–15 min after intravenous injection. Analgesic effect with intramuscular administration is 1–2 h. It has a faster onset and shorter duration of action than morphine. The pharmacokinetics of fentanyl is described as a three-compartment model with a distribution time of 1.7 min, a redistribution of 13 min, and a terminal elimination half-life of 219 min. The volume of distribution is 4 L/kg.
Fentanyl belongs to the strong opioids; it is an agonist of μ-opioid receptors. Fentanyl acts preferentially on μ receptors. All fentanyl-type compounds (a series of 4-anilidopiperidines) are highly μ-selective but could also form affinity for δ- and κ-opiate receptors.
It is highly lipophilic, undergoes first-pass metabolism by the liver, is absorbed very quickly through the oral mucosa, and more slowly through the classic gastrointestinal route. Its administration in oral dosage forms is practically impossible. For this reason, it is only available for parenteral application in anesthesiology and intensive care. Transdermal fentanyl systems have been successfully used in algesiology to address chronic pain in oncology patients.
Among physicians and other professionals, the use of fentanyl opioids for pain relief is highly preferred mainly due to their favorable pharmacochemical properties. Fentanyl maintains cardiac stability and, in certain doses, reduces stress-related hormonal changes. From a number of fentanyl derivatives, it is fentanyl, alfentanil, remifentanil, and sufentanil in the form of salts (fentanyl dihydrogen citrate, alfentanil hydrochloride, remifentanil hydrochloride, and sufentanil dihydrogen citrate) that are allowed to be used in human medicine.
Pain treatment is always started with the lowest possible dose of opioid, taking into account the adverse effects of the substance and the patient’s health. The value of the therapeutic index, which provides information on the relative safety of the drug, is essential for the choice of opioids in the treatment of pain. It is given by the ratio between the dose that is toxic for the 50% of the population and effective for the 50% of the population. TI = TD50/ED50. The higher the TI, the greater the relative safety of the drug [6].
The recommended serum concentration for analgesia is 1–2 ng/mL and for anesthesia 10–20 ng/mL. Blood concentrations of approximately 7 ng/mL or higher have been associated with fatal outcomes when multiple agents are involved. During the past decades, a number of studies have been conducted comparing doses for anesthesia of patients, for example, anesthesia was maintained with infusions of propofol (50–100 μg/kg/min) and either remifentanil (0.2 μg/kg/min), alfentanil (20 μg/kg/h), or fentanyl (2 μg/kg/h) [7].
When comparing the effects of alfentanil and remifentanil, it was found that both drugs are pharmacokinetically similar, but the central clearance of remifentanil is significantly higher. Population pharmacokinetic parameters of remifentanil include CLc of 2.9 L/min, corresponding parameters for alfentanil are 0.36 L/min. Pharmacodynamically, the drugs are similar, but remifentanil is 19 times more potent than alfentanil, with an effective concentration for 50% maximal effect of 19.9 ng/mL versus 375.9 ng/mL for alfentanil [8, 9].
In pediatric patients, fentanyl and remifentanil were experimentally administered intraoperatively in doses of 0.2 μg/kg/min remifentanil and 2 μg/kg during induction of anesthesia [10, 11].
Like other opioids, fentanyl and its derivatives are characterized by adverse effects, including nausea and vomiting, fatigue, headache, dizziness, constipation, miosis, anemia, bradycardia, and respiratory depression. After stopping use, withdrawal symptoms characteristic of opioids (sweating, anxiety, diarrhea, bone pain, abdominal cramps, and chills) may appear. Serious health problems are reported when fentanyl is mixed with heroin, cocaine, alcohol, and other central nervous system depressants, such as benzodiazepines. Based on pooled safety data from these clinical trials, the most commonly reported adverse reactions were nausea (35.7%), vomiting (23.2%), constipation (23.1%), somnolence (15.0%), dizziness (13, 1%), and headache (11.8%). All opioids of the fentanyl series can only be administered under conditions where monitoring and support of respiratory and cardiovascular functions is fully ensured [12, 13].
Many experiments on animals are continuously carried out to help explain the effects of fentanyl on the human body. For instance, it was found that in mice the onset of respiratory depression occurs 70 times faster after the administration of fentanyl compared to morphine [14].
In human medicine, fentanyl is administered to patients in several forms, taking into account whether the parenteral route is useful for the patient—penetration of the active substance through the skin, transmucosal and nasal (mucosal) route (transmucosal and nasal administration), and intravenous administration or sublingual administration.
A common application form before performing a surgical procedure is the intravenous administration of a drug solution. Fentanyl Dihydrogen citrate 0.0785 mg/ml, which corresponds to Fentanyl 0.050 mg/ml, is usually administered. The dose of fentanyl is determined individually according to age, body weight, physical condition, pathological conditions, and current treatment, as well as the type of surgery and the type of anesthesia. The dosage regimens listed below are recommended. For neuroleptic analgesia in adults, the usual starting dose is 50–100 μg (0.7–1.4 μg/kg) fentanyl, administered slowly intravenously in combination with neuroleptics (preferably with droperidol). If a second dose of 50–100 μg (0.7–1.4 μg/kg) is required, fentanyl can be administered 30–45 min after the initial dose.
For neuroleptic anesthesia under conditions of controlled pulmonary ventilation in adults, an initial dose of 200–600 μg (2.8–8.4 μg/kg) of fentanyl is generally administered, slowly intravenously in combination with neuroleptics (preferably with droperidol). The dose depends on the duration and severity of the surgical procedure and on the treatment used for general anesthesia. To prolong anesthesia, additional doses of 50–100 μg (0.7–1.4 μg/kg) of fentanyl can be given every 30–45 min. The time intervals and size of further doses are adjusted depending on the course of the medical procedure. For pediatric patients, doses are adapted to the age and condition of the child. In children from 2 to 12 years of age, a single analgesic dose of 1–3 μg of fentanyl/kg of body weight is administered, for example., in combination with inhalation anesthetics. 1.25 μg/kg fentanyl may be administered to maintain analgesia during general anesthesia, depending on the course of the operation. Higher doses of fentanyl are required in patients chronically treated with opioids or with a known history of opioid overdose [15].
Fentanyl is usually administered in preoperative analgesia in a dose of 50–100 μg intravenously 30–60 min before surgery, in general anesthesia 20–50 μg/kg intravenously, and in supplementary anesthesia 2–50 μg per dose intravenously. For elderly patients, 65 years and older, a lower dose is recommended. In high-risk patients undergoing a demanding surgical procedure, it is advisable to supplement the anesthesia with oxygen and increase the dose of fentanyl to 150 μg/kg. For postoperative pain control, administration of 50–100 μg every 1–2 h as needed is recommended [16].
One form of fentanyl use through the skin is transdermal application.
The transdermal therapeutic system (TTS) was developed as an adequate substitute for oral or parenteral drug administration. It is therapeutically usable in case of need for a longer duration of effect of the substance for patients with chronic pain and to prevent possible adverse consequences of treatment occurring in the case of other forms of administration. The advantage is the possibility of setting a balanced level of the opioid acting on the organism, without exposing the patient’s gastrointestinal tract to discomfort [17, 18]. Transdermal fentanyl patches are manufactured, containing a reservoir with the active substance, adjusted to deliver the required amount of substance over the course of 3 days. A base dose is incorporated into the adhesive layer to saturate certain binding sites in the skin and to accelerate the achievement of steady-state blood levels. Fentanyl patches are typically designed by the manufacturer to release approximately 12.5, 25, 50, 75 and 100 μg of fentanyl per hour into the systemic circulation, depending on the patient’s medical condition. After 72 h, the patch should be removed and a new one applied to a different location. TTS has an important place in therapy, especially to prevent repeated oral doses, or when oral therapy is evaluated as ineffective or intolerable. The predecessor of fentanyl patches was the successful and verified administration of the substance scopolamine during the 1980s [19].
Subsequently, a patch containing fentanyl (called Duragesic) was created, for which FDA and European regulatory approval was later obtained (Figure 1) [20].
Figure 1.
Diagram of a transdermal patch with an active substance.
Studies were conducted in patients with acute postoperative pain, previously untreated with opioids, but it caused too much respiratory depression. When it was later evaluated in opioid-tolerant patients with chronic cancer-induced pain in the late 1980s and early 1990s, the patch was shown to be useful for the ability to maintain a steady blood level of fentanyl for 2–3 days and was approved by the FDA and European regulatory authorities [21]. Despite the initial doubts of Dr. Janssen, the transdermal opioid was recognized as a successful drug for chronic pain in cancer patients [4]. Fentanyl Orion, for example, is available on the market to manage severe chronic pain, the properties of which are listed in Table 1.
Designation of patch type
12.5
25
50
75
100
Active substance content (mg)
2.55
5.1
10.2
15.3
20.4
Patch area (cm2)
4.25
8.5
17.0
25.5
34.0
Fentanyl release rate (μg/h)
12.5
25.0
50.0
75.0
100.0
Table 1.
Patch properties.
The dosage is always individual and is based on the previous administration of opioid analgesics, taking into account the severity of the disease, the patient’s current state of health, the possible development of tolerance, the possibility of a collision due to other administered drugs, or the onset of contraindications [22].
The danger of overdose lies mainly in the difference in the content of the active substance in the patch, and especially in the case of patches already used by the patient, the residual concentration of the extracted fentanyl is completely unknown to the user. In addition to fatal overdose, users are at risk of various ischemic injuries, limb amputation, thrombophlebitis, and severe skin ulcers. Other serious consequences include endocarditis, septic embolism, and osteomyelitis [23].
A suitable method for fast, safe, and easy application of fentanyl is transmucosal administration, whether in oral, buccal, or sublingual form, because lipophilic drugs, such as fentanyl, are easily and quickly absorbed by the mucous membrane [24]. With the development of pain treatment, new routes of fentanyl administration are being developed, which are intended for the treatment of PB: orotransmucosal systems (lollipops, sublingual tablets) and intranasal spray [25, 26], and there are also mentions of the possibility of transpulmonary administration of fentanyl by inhalation [27]. The principle of the new medicinal form of fentanyl intended for buccal application (FBT—fentanyl buccal tablet) is a technology using an effervescent reaction that increases the speed and extent of absorption of the oral mucosa [28].
The first mucosal application method was an OTFC (oral transmucosal fentanyl citrate) lollipop [29] called Oralet. Due to the lack of Oralet’s clinical success, Actic was later produced, intended for patients with oncological diseases already on opioid treatment [4]. It has been used for breakthrough pain for more than a decade and is particularly suitable for pediatric patients. Buccal [30] or sublingual [31] application is made possible by a fast-dissolving tablet, where fentanyl is bound to a carrier that adheres to the mucosa and can act for a sufficiently long time. The onset is very fast, and the maximum effect is achieved within 30 min. The effect lasts up to 240 min. From the point of view of patient comfort (meaning the elimination of fear and anxiety), this form of fentanyl administration appears to be very advantageous. Application by the transmucosal route has its origin in an experiment with the sedation of larger animals in the state of Utah with carfentanil. This form of administration has been found to have the advantage of a simple application that does not stress the patient. Studies on monkeys have shown that it is possible to ensure the comfort of animals by, for instance, giving a sugar cube with a sedative. After a few minutes, the animals were either completely anesthetized or allowed to be handled by the veterinarian, depending on the size of the dose.
With an overdose of fentanyl and its derivatives, respiratory depression is especially dangerous, and respiratory assistance is the priority in such cases. The antidote given in overdose is a strong opioid antagonist—naloxone (also known as naltrexone, nalmefene, and so forth), which blocks μ-receptors and can, therefore, be used both in overdoses with fentanyl, heroin, and other new synthetic opioids [32, 33].
The chemical structure of fentanyl, a substance with the chemical name N-(1-phenethyl-4-piperidyl) propionamide and the formula C22H28N2O, is a monocarboxylic acid amide. It contains a relatively simple skeleton with four important parts, namely the amide group, aniline, piperidine ring, and alkyl chain linked to s tertiary nitrogen (Figure 2).
Figure 2.
Structure of fentanyl.
It was patented in 1965 under the number U.S. Pat. No. 3,164,600 ('600) [34, 35].
The synthesis consisted of several parts, namely:
refluxing mixture of 1-benzyl-4-piperidone, aniline, toluene, and 4 toluenesulfonic acid for 15 h to produce N-(1-benzyl-4-piperydylidene)aniline,
reducing N-(1-benzyl-4-piperydylidene)aniline is obtained using lithium aluminum hydride in anhydrous ether to 1-benzyl-4-anilinopiperidine in nitrogen atmosphere, then
alkalizing by refluxing with propionic anhydride for 7 h to give N-(1-benzyl-4-piperydylidene)propionanilide,
subjecting to debenzylation by employing hydrogenation over palladium on charcoal catalyst in ethanol to get N-(4-piperidyl)propionanilide, and finally
treating a mixture of N-(4-piperidyl)propionanilide, sodium carbonate, and potassium iodide in hexone with the solution of β phenethylchloride in 4-methyl-2-pentanone and refluxed for 27 h to obtain fentanyl.
Due to the time-consuming nature of the synthesis, the relatively low yield, and the current requirements for environmental quality, it underwent several modifications in later years [36, 37]. The basic skeletal structure of fentanyl can be advantageously modified at fourmolecule positions [38, 39].
Some selected properties of fentanyl are listed in Table 2.
Janssen’s first synthesis of fentanyl, which is based on N-benzyl-4-piperidone, has been effectively modified several times over the years. Expansion and contraction of the piperidine ring were performed, and a series of conformationally restricted fentanyl analogs were stereochemically characterized, methyl substituents and others, for example, 4-phenyl group were inserted into various positions of the fentanyl molecule, the phenyl ring was replaced by heteroaromatic thienyls or tetrazolyl rings, and a number of other changes were performed. Thus, hundreds of new fentanyl derivatives were created.
A relationship between the structure of substances and their activity of fentanyl compounds exists. Compounds with a 4-N-anilinopiperidine group (except N-methyl derivatives) are known to show high affinity for μ-receptors. High activity and affinity to μ-receptors are also caused by the methyl substitution at the third position of the piperidine ring and the presence of a 4-carboxymethyl or 4-methoxymethyl substituent. It was also found that methyl substitution at the second position of the piperidine ring does not cause a significant change in activity. However, many questions remain unanswered such as the fact that fentanyl, sufentanil, methylfentanyl, and lofentanil are more effective than could be expected based on the obtained binding values [2, 41].
In addition to fentanyl, its derivatives alfentanil, remifentanil, and sufentanil are permitted for use in the healthcare sector, sufentanil, and carfentanil are used in veterinary practice:
Alfentanil, (C21H32N6O3), a piperidine with a 2-(4-ethyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)ethyl group in position 1, as well as N-phenylpropanamido- and methoxymethyl groups in position 4 [42]. It is suitable for neuroleptanalgesia in ambulatory surgery with shorter medical procedure time. It accumulates in tissues less than fentanyl and has more favorable pharmacokinetic properties. It was synthesized in the laboratories of Janssen Pharmaceutica in 1976, and in the pharmaceutical industry, it is referred to as Alfenta®, Rapifen [43]. Intravenous administration is common. However, other routes of alfentanil administration, including epidural (injection into the epidural space), intrathecal (injection into the spinal canal or subarachnoid space), transdermal (through the skin), and intranasal, have demonstrated the expected and desired efficacy. Potential adverse effects are similar to those of other opioids, but the observed specificity of alfentanil compared to other derivatives is the reduction of pressure and the induction of chest wall stiffness [44, 45]. The risk or severity of adverse effects may increase if alfentanil is combined, for instance, with 1,2-benzodiazepine [46].
Remifentanil, methyl 1-(3-methoxy-3-oxopropyl)-4-(N-propanoylanilino)piperidine-4-carboxylate, substance with general formula C20H28N2O5, is a white, water-soluble powder, known in the field of pharmacy under the former name GI-87084B [47]. Due to the absence of a chiral center, it exists in only one form. It contains a piperidinecarboxylate ester in its molecule, which is methylpiperidine-4-carboxylate, in which the hydrogen bound to the nitrogen is substituted by a 3-methoxy-3-oxopropyl group. The hydrogen at position 4 is substituted by the nitrogen of N-propanoylaniline.
It is split by nonspecific esterases in plasma and tissues. In healthcare, it is used in the form of hydrochloride. It is administered to adult patients as an intravenous infusion in doses ranging from 0.1 to 0.5 (μg/kg)/min [48]. In the blood, it is relatively quickly inactivated by esterases into inactive metabolites; therefore, it has a very short effect and good controllability duration of action. The substance is used for short-term analgesia during ambulatory procedures, but it has almost zero use in the treatment of chronic pain. Concomitant medication is carried out with propofol and isoflurane [49, 50].
Sufentanil, an anilide synthesized by formal condensation of the arylamino group of 4-(methoxymethyl)-N-phenyl-1-[2-(2-thienyl)ethyl]piperidin-4-amine with propanoic acid [51], is a white or off-white powder previously also known under the name R 3073, with the general formula C22H30N2O2S. It is practically insoluble in water; however, it is easily soluble in methanol and ethanol (96%). It is known under the brand names Sufenta® and Sufenta Forte. It has up to 10x greater analgesic effect than fentanyl, 30× higher affinity for opioid receptors [52], and is extremely fat soluble, allowing rapid penetration into the central nervous system. The duration of its effect is approximately 10–25 min. In combination with propofol, it creates acceptable conditions for incubating the patient without administering a muscle relaxant. The advantage over fentanyl is a shorter biological half-life. Its high therapeutic index of 25,000 and minimal respiratory depression predetermine this substance for use in the medical environment. Experimental work comparing, for example, sublingual sufentanil in an administered amount of 30 μg and fentanyl in an amount of 50 μg did not confirm a significant difference in analgesic assistance [53, 54, 55].
Carfentanil is the most powerful opioid known. Its systematic name is methyl 1-(2-phenylethyl)-4-[phenyl(propanoyl)amino]piperidine-4-carboxylate), and the general formula is C24H30N2O3. Carfentanil is a monocarboxylic acid amide formed by the formal condensation of the arylamino group methyl-4-anilino-1-(2-phenylethyl) of piperidine-4-carboxylate with propanoic acid [56]. It is an analgesic with an approximately 10,000 times stronger analgesic effect compared to morphine. It was first synthesized in 1974 (trademark Wildnil®) and was approved for use as an intramuscular tranquilizer for large animals (rhinoceros, bears, and elephants) in 1986. However, other methods of application, such as intravenous, oral, and transmucosal, are also approved. The usual dosage for a 6-ton elephant is 10 mg intravenously. For human purposes, the use of carfentanil is not allowed. The estimated threshold dose in humans is 1–2 μg, and the effective dose 8–15 μg/kg administered intramuscularly [57, 58].
Lofentanil, the most effective known fentanyl derivative to date, was created by modifying the central fentanyl piperidine ring (similar to e.g., carfentanil), which induces significant analgesia lasting up to 8–12 h. It has been clinically tested during epidural application, but the disadvantage is the resulting severe respiratory depression and problems in antagonizing its effect with the classic opioid antagonist—naloxone [52]. Due to steric hindrances caused by its structure and extremely high toxicity, it is used only for experimental studies of opiate receptors and is not allowed in human or veterinary practice [59, 60] as it induces anesthesia already at a dose of 0.025 g/kg of body weight, while, for instance, the expected lethal dose of the nerve agent labeled VX, O-ethyl-S-(2-diisopropylaminoethyl)methylphosphonothiolate, is 100 times higher [61].
Acryloylfentanyl, (sometimes written as acrylfentanyl), is a derivative of fentanyl whose detection in forensic analysis is difficult due to the fact that it differs from the fentanyl molecule only by the presence of an extra double bond. Acryloylfentanyl differs from fentanyl in the double bond present in the 2-position of the propane attached to the N-phenyl moiety and is, therefore, an unsaturated analog of fentanyl. Like many other derivatives, it contains one basic nitrogen atom in the piperidine ring, so it can easily form salts with organic or inorganic acids. The synthesis and antinociceptive activity of acryloylfentanyl was first described in 1981. It is also known by the names acryloyl-F, Acr-F, and ACF. It shows about 170 times stronger effect compared to morphine but weaker effect compared to fentanyl [62, 63].
Other synthetic “nonmedical” opioids that were not included among pharmaceutical products are acetylfentanyl, butyrfentanyl, furanylfentanyl, ocfentanil, and other fentanyl derivatives [64].
The abuse of fentanyl and its derivatives by drug addicts is a worldwide problem. Although the amount of new synthetic opioids seized by the police is lower in percentage compared to substances such as cocaine, cannabinoids, cathinones, and others, it is necessary to be aware of their potency. High efficiency significantly increases the level of danger to the health of individuals and society. The substances of the fentanyl series are considered a relatively attractive and profitable commodity for organized crime. They are offered directly via the Internet, the so-called darknet, or as counterfeit drugs or mixtures with other substances. The opioids are administered by known application routes, using tablets, nasal spray, or injection. The danger of the illegal market for users lies primarily in the fact that it is not certain whether the declared content of the active ingredient corresponds to reality, such as in the case of tablets [64], as shown in the picture (Figure 3).
Figure 3.
Different distribution of the active substance in illegally produced tablets [64].
Drug addicts obtain some opioids not only from illegal laboratories but also from legal supplies of medicinal products, such as transdermal patches. The users extract fentanyl from the patches and inject it intravenously without maintaining sterile conditions, chew the patches, apply a large number of patches to the skin, inhale the smoke from a heated patch, and so forth [65].
Opioids continue to lead the way in overdose deaths. There have been over 91,000 overdose deaths in North America, a number greatly increased by fentanyl, with estimates for 2021 of over 107,000 deaths. According to the 2022 data from forensic toxicologists in Canada, up to 86% of deaths are caused by the illegal ingestion of fentanyl or its derivatives. The cause is the high toxicity of illicit drugs, the detected concentrations exceed 50 μg/L. Carfentanil was identified in 126 deaths in 2022 [66, 67]. On the European continent, the situation with opioid consumption is less problematic compared to the United States. Higher consumption and reports of overdose deaths are reported from the United Kingdom and Scotland [68, 69].
On March 31, 1961, the single convention on narcotic drugs was negotiated in New York, which aimed to curb drug abuse through coordinated action at the international level. The convention establishes a system of international control of psychotropic substances based on the likelihood of abuse and on the other hand according to their therapeutic index. All EU member states are parties to the convention on narcotic drugs and the convention on psychotropic substances. There is interagency cooperation and coordination of efforts in addressing and countering the world drug problem. The activities of the United Nations Office on Drugs and Crime (UNODC) are known, whose mission is to contribute to global security by making the world safer from drugs, crime, and terrorism.
In view of the critical global drug abuse situation, the UNODC early warning board (EWA) was established in 2013 to monitor, analyze, and report on trends in the consumption and abuse of new psychoactive substances. It stores the obtained data and provides technical assistance to member states. EWA is managed by the UNODC global synthetics monitoring: Analyses, Reporting, and Trends (SMART) program.
Dangerous synthetic fentanyl-type psychoactive substances that are frequently reported from forensic laboratories or police seizures include 4-methoxybutyrfentanyl, acryloylfentanyl, butyrfentanyl, despropionylfentanyl, despropionyl-2-fluorofentanyl, furanylfentanyl, para-fluoroisobutyrfentanyl, valerylfentanyl, (iso)butyrfentanyl, (iso)butyr-F-fentanyl N-benzyl analog, acetylfentanyl (controlled under Schedule I of the 1961 Single Convention on Narcotic Drugs), ocfentanil, and beta-hydroxythiofentanyl [70].
Acetylfentanyl, for example, is about 16 times more potent than morphine, and the therapeutic index is relatively low, which increases the risk of fatal overdose. It appears on the illegal market in the USA, Europe, Japan, China, and Australia as a substitute for fentanyl or heroin. Sometimes, he is called sometimes being called the “first apostle of extinction”. Police seizures of this substance are reported from the USA, some European countries, and China [71].
Butyrylfentanyl, such as acetylfentanyl and other fentanyl opioids, poses a potential overdose risk without legitimate clinical use despite being about times less potent than fentanyl. Dozens of deaths linked to butyrylfentanyl abuse have been reported. It is also legislatively controlled [72].
Another fentanyl analog, 4-fluorobutyrylfentanyl, is often available mixed with heroin and is the cause of many deaths [73].
The report of the International Narcotics Control Board (Report of the International Narcotics Control Board) shows that attention must also be paid to the so-called precursors in the synthesis of fentanyl. The substance 4-anilidopiperidine (4-AP) is a substitution chemical for N-phenethyl-4-piperidone (NPP) for the synthesis of 4-anilino-N-phenethylpiperidine (ANPP), which itself was an immediate precursor for the production of fentanyl and some of its analogs. NPP and ANPP were included in Schedule I of the 1988 convention in 2017 [74, 75].
The properties and risks of addictive substances are continuously assessed by the Scientific Committee of the European Monitoring Center for Drugs and Drug Addiction, and many are legislatively controlled at international level under the Single Convention on Narcotic Drugs of 1961 [76].
6. Instrumental methods of detecting the presence of fentanyl
Qualitative and quantitative analyzes of opioids, including fentanyl, are performed in biological materials—urine, blood, plasma, and hair. Postmortem concentrations of fentanyl opioids detected in the blood of victims are extremely low in the range of picograms per milliliter (pg/mL), which in a certain way presents a challenge for forensic laboratories dealing with analyzes of these substances. Both simple orientation methods and sophisticated instrumentation are used to detect their presence. Tests based on the principle of immunochemical methods, often originally developed to control biological samples, are used for rapid field testing. The indicated cut-off concentrations are 200 ng/mL [77, 78].
Indicative information about fentalogs can also be obtained by the proven method of thin-layer chromatography, where the emphasis is primarily on simplicity and financial simplicity while maintaining maximum reproducibility of results. In this method, attention is focused on the choice of suitable chromatographic systems in combination with various detection reagents [79].
A relatively simple, fast, and cheap method, used primarily to determine the amount of the substance of interest, is the analysis of extraction spectrometry in the visible radiation range. The base of the method is that the amine nitrogen present in the fentalogs molecule provides ion pairs with acid dyes, which can then be extracted with nonpolar solvents and subjected to measurements on proven single-beam or double-beam spectrometers [80].
The presence of fentanyl and its derivatives, or other drugs, can also be determined using the electrochemical-surface enhanced Raman spectroscopy (EC-SERS) method. Detection limits for fentanyl compounds were found to be in the low nanogram per milliliter range, with the most sensitive compound detected at 10 ng/mL. This analysis was successful even when the sample contained 5–1% fentanyl [81, 82]. The method is highly selective for the analysis of fentanyl in the presence of some interfering compounds, including cocaine, heroin, and methamphetamine. It represents a powerful application for screening seized drugs in the laboratory and at the crime scene.
Known methods, often used to determine fentanyl and its derivatives, are electroanalytical methods such as voltammetry, potentiometry, and electrochemiluminescence [83].
Accurate identification of opioids can be performed with analytical systems with high separation capability, such as gas or liquid chromatography, which is usually coupled with mass spectrometry [84].
Current modern devices stand out for their high scanning speed, minimal requirements for the amount of the controlled substance, programmable temperature and other technical advantages that enable quick and accurate obtaining of the desired result. Distinction of structural isomers is provided, for instance, by HPLC-DOD, LC-MS/MS, or LC-QToF-MS with quadrupole and others [85, 86].
From this analysis, it emerges that the gold standard for the identification and quantification of 4-anilinopiperidines is LC-MS/MS, coupled with liquid-liquid or solid-phase extraction [87].
A very sensitive LC-MS/MS method for the multiplex detection of analogs and their metabolites in blood, namely for fentanyl, norfentanyl, furanylfentanyl, furanylnorfentanyl, butyrylnorfentanyl, acetylfentanyl, alfentanil, acryloylfentanyl, remifentanil, sufentanil, p-methoxyfentanyl, carfentanil, (±)-cis-3-methylfentanyl, butyrylfentanyl, isobutyrylfentanyl, valerylfentanyl, and others, was successfully applied with results of concentrations in the range of 0.1–0.5 ng/mL [88].
The use of substances that affect the central nervous system was originally intended for the medical field. However, their importance has also extended to the military sphere, where they can be used, for instance, in managing critical situations.
Fentanyl, as an interesting type of opioid, became more widely known to the lay public mainly after the incident in Moscow in 2002 when the army of the Russian federation used a mixture of fentanyl derivatives in the form of an aerosol to rescue hostages in the Dubrovka theater occupied by Chechen separatists as part of an antiterrorist operation. In 2012, Porton Down laboratory workers published information on the composition of the aerosol used in Moscow after analyzing samples of clothing and urine from people in the Moscow theater; it was a mixture of remifentanil and carfentanil, still illegal in human medicine and very potent [89]. As a potential chemical incapacitating agent, fentanyl was already investigated in the 1970s by the Soviet KGB under the name Kolokol-1 [90].
The effects of incapacitating chemical substances raise questions about their legitimate use in armed conflicts, hostage-taking crises, maintaining public order, or peacekeeping missions. Due to the need for new strategies that could help reduce the number of deaths and injuries, this issue has been debated by individual states for decades [91, 92, 93].
References
1.Lüllmann H, Mohr K, Welhing M. Farmakologie a toxikologie. 2nd ed. Praha: Grada Publishing; 2004. ISBN 80-247-0836-1
2.Vardanyan RS, Hruby VJ. Fentanyl-related compounds and derivatives: Current status and future prospects for pharmaceutical applications. Future Medicinal Chemistry. 2014;6(4):385-412. DOI: 10.4155/fmc.13.215
3.Fentanyl Citrate Injection, USP. Reference ID: 3336008 [Internet]. 2013. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/016619s034lbl.pdf [Accessed: May 19, 2023]
4.Stanley TH. The fentanyl story. The Journal of Pain. 2014;15(12):1215-1226. DOI: 10.1016/j.jpain.2014.08.010
5.Kawanaka R, Sakuma S, Kokubun H, et al. Effects of intraoperative opioid administration on postoperative pain and pain threshold: A randomized controlled study. Journal of Clinical Medicine. 2022;11(19):5587. DOI: 10.3390/jcm11195587
6.Gable R. Comparison of acute lethal toxicity of commonly abused psychoactive substances. Addiction (Abingdon, England). 2004;99:686-696. DOI: 10.1111/j.1360-0443.2004.00744.x
7.Coles PJ et al. Propofol anesthesia for craniotomy: A double-blind comparison of remifentanil, alfentanil, and fentanyl. Journal of Neurosurgical Anesthesiology. 2000;12(1):15-20. DOI: 10.1097/00008506-200001000-00004
8.Egan TD, Minto CF, Hermann DJ, Barr J, Muir KT, Shafer SL. Remifentanil versus alfentanil: Comparative pharmacokinetics and pharmacodynamics in healthy adult male volunteers. Anesthesiology. 1996;84(4):821-833. DOI: 10.1097/00000542-199604000-00009. Erratum in: Anesthesiology 1996;85(3):695
9.Hughes LM, Irwin MG, Nestor CC. Alternatives to remifentanil for the analgesic component of total intravenous anaesthesia: A narrative review. Anaesthesia. 2023;78(5):620-625. DOI: 10.1111/anae.15952
10.Baek J, Park SJ, Kim JO, et al. The effects of remifentanil and fentanyl on emergence agitation in pediatric strabismus surgery. Children (Basel). 2022;24(5):606. DOI: 10.3390/children9050606
11.Choi EK, Lee S, Kim WJ, Park SJ. Effects of remifentanil maintenance during recovery on emergence delirium in children with sevoflurane anesthesia. Paediatric Anaesthesia. 2018;28(8):739-744. DOI: 10.1111/pan.13446
12.Boysen PG, Patel JH, King AN. Brief history of opioids in perioperative and periprocedural medicine to inform the future. Ochsner Journal. 2023;23(1):43-49. DOI: 10.31486/toj.22.0065
13.State Institute for Drug Control [Internet]. 2011. Available from: https://www.sukl.cz/download/spc/SPC31591.pdf [Accessed: May 20, 2021]
14.Hill R, Santhakumar R, Dewey W, Kelly E, Henderson G. Fentanyl depression of respiration: Comparison with heroin and morphine. British Journal of Pharmacology. 2020;177:254-265. DOI: 10.1111/bph.14860
15.FENTANYL TORREX 50 μg/ml [Internet]. 2011. Available from: https://www.sukl.cz/download/pil/PI20569.pdf [Accessed: May 14, 2023]
16.Carlos FR-M, Bistas KG, Lopez-Ojeda W. Fentanyl [Internet]. 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459275/ [Accessed: June 12, 2023]
17.Eissenberg E, McNicol ED, Carr DB. Efficacy of mi-opioi agonist in treatment of evoked neuropathic pain: Systematic review of randomized controlled trials. European Journal of Pain. 2006;10(8):667-676. DOI: 10.1016/j.ejpain.2005.10.007
18.Moore KT et al. Bioequivalence and safety of a novel fentanyl transdermal matrix system compared with a transdermal reservoir system. Journal of Opioid Management. 2011;7(2):99-107. DOI: 10.5055/jom.2011.0052
19.Zohar N, Shupak A, Gordon CR. Transdermal scopolamine for prevention of motion sickness: Clinical pharmacokinetics and therapeutic applications. Clinical Pharmacokinetics. 2006;45(6):543-566. DOI: 10.2165/00003088-200645060-00001
20.Kress HG, Boss H, Delvin T, et al. Transdermal fentanyl matrix patches Matrifen® and Durogesic® DTrans® are bioequivalent. European Journal of Pharmaceutics and Biopharmaceutics. 2010;75(2):225-231. DOI: /10.1016/j.ejpb.2010.02.005
21.Stanley TH. Anesthesia for the 21st century. Proceedings (Baylor University. Medical Center). 2000;13(1):7-10. DOI: 10.1080/08998280.2000.11927635
22.Chen J, Zou X, Hu B, et al. Effect of different doses of esketamine compared with fentanyl combined with propofol on hypotension in patients undergoing painless abortion surgery: A prospective, randomized, double-blind controlled clinical trial. BMC Anesthesiology. 2022;22:305. DOI: 10.1186/s12871-022-01848-6
23.The Dangers of Abusing Fentanyl Patches. Drug & Alcohol Rehab Centers [Internet]. 2019. Available from: https://americanaddictioncenters.org/fentanyl-treatment/dangers-of-abuse [Accessed: March 26, 2020]
24.Payne R, Coluzzi P, Hart L, et al. Longterm safety of oral transmucosal fentanyl citrate for breakthrough cancer pain. Journal of Pain Management. 2001;22:575-583. DOI: 10.1016/s0885-3924(01)00306-2
25.Heshmati F, Noroozinia H, Abbasivash R, et al. Intranasal sufentanil for postoperative pain control in lower abdominal pediatric surgery. IJPT. 2006;5:131-133
26.Corrigan M, Wilson SS, Hampto J. Safety and efficacy of intranasally administered medications in the emergency department and prehospital settings. American Journal of Health-System Pharmacy. 2015;72:1544-1554. DOI: 10.2146/ajhp140630
27.Bevans T, Deering-Rice C, Stockmann C, et al. Inhaled remifentanil in rodents. Anesthesia and Analgesia. 2016;122:1831-1838. DOI: 10.1213/ANE.0000000000001228
28.Nosková V. Fentanyl v bukální formě – nové řešení průlomové bolesti [Internet]. 2010. Available from: https://www.remedia.cz/rubriky/klinicka-farmakologie-a-farmacie/fentanyl-v-bukalni-forme-nove-reseni-prulomove-bolesti-3457/ [Accessed: January 15, 2023]. In Czech Language
29.Singh RB, Choubey S, Mehra R. Efficacy of oral transmucosal fentanyl citrate for premedication in patients for surgery under general anesthesia. Anesthesia, Essays and Researches. 2017;11(4):854-858. DOI: 10.4103/aer.AER_106_17
30.Slatkin NE, Xie F, Messina J, Segal TJ. Fentanyl buccal tablet for relief of breakthrough pain in opioid-tolerant patients with cancer-related chronic pain. The Journal of Supportive Oncology. 2007;5(7):327-334
31.Hashemi M, Zali A, Golmakani E, et al. Efficacy, safety, and tolerability of sublingual fentanyl orally disintegrating tablet in the treatment of breakthrough cancer pain: A randomized, double-blind, placebo-controlled study. Daru. 2021;29(1):51-59. DOI: 10.1007/s40199-020-00381-6
32.Boyer EW. Management of opioid analgesic overdose. The New England Journal of Medicine. 2012;367:146-155. DOI: 10.1056/NEJMra1202561
33.Mann K, Bladström A, Torup L, et al. Extending the treatment options in alcohol dependence: A randomized controlled study of as-needed nalmefene. Biological Psychiatry. 2013;73(8):706-713. DOI: 10.1016/j.biopsych.2012.10.020
34.PAJ J, Gardocki JF. Method for producing analgesia. US Patent 3141823. 21 Jul 1964. Available from: https://patents.google.com/patent/US3141823A/en [Accessed: May 19, 2023]
35.Braga FC, Ramos TO, Brocksom TJ, de Oliviera KT. Synthesis of fentanyl under continuous photoflow conditions. Organic Letters. 2022;24(45):8331-8336. DOI: 10.1021/acs.orglett.2c03338
36.Zee S-H, Wang W-K. A new process for the synthesis of fentanyl. JCCS. 1980;27(4):147-149. DOI: 10.1002/jccs.198000026
37.Gupta PK, Manral L, Ganesan K, et al. A method for the preparation of fentanyl. European Patent, 2252149A2. 2010. Available from: https://patents.google.com/patent/EP2252149A2/en [Accessed: April 22, 2023]
38.Cayman. Standardized Naming of Substituted Fentanyls [Internet]. 2018. Available from: https://www.caymanchem.com/news/standardized-naming-of-substituted-fentanyls [Accessed: May 10, 2023]
39.Valdez CA, Leif RN, Mayer BP. An efficient, optimized synthesis of fentanyl and related analogs. PLoS One. 2014;9(9):e108250. DOI: 10.1371/journal.pone.0108250
40.National Library of Medicine. Fentanyl [Internet]. 2023. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Fentanyl [Accessed: June 02, 2023]
41.Wilde M, Pichini S, Pacifici R, et al. Metabolic pathways and potencies of new fentanyl analogs. Frontiers in Pharmacology. 2019;5(10):238. DOI: 10.3389/fphar.2019.00238
42.National Library of Medicine. Alfentanil [Internet]. 2023. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Alfentanil [Accessed: June 02, 2023]
43.Lee GM et al. The clinical effective dose of alfentanil for suppressing cough during emergence from desflurane anesthesia. KJA. 2011;61(4):292-296. DOI: 10.4097/kjae.2011.61.4.292
44.Moman RN, Mowery ML, Kelley B. Alfentanil [Internet]. 2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470456/#article-17352.s8 [Accessed: November 13, 2022]
45.Zhao N, Zeng J, Fan L, Zhang C, Wu Y, Wang X, et al. The effect of alfentanil on emergence delirium following general anesthesia in children: A randomized clinical trial. Paediatric Drugs. 2022;24(4):413-421. DOI: 10.1007/s40272-022-00510-5
46.Drugbank Online. Alfentanil [Internet]. 2023. Available from: https://go.drugbank.com/drugs/DB00802 [Accessed: March 28, 2023]
47.Westmoreland LC. Pharmacokinetics of remifentanil (GI87084B) and its metabolite (GI90291) in patients undergoing elective inpatient summery. Anesthesiology. 1993;79(5):893-903. DOI: 10.1097/00000542-199311000-00005
48.National Center for Biotechnology Information. PubChem Compound Summary for CID 60815, Remifentanil [Internet]. 2023. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Remifentanil [Accessed: May 16, 2023]
49.Servin FS, Billard V. Remifentanil and other opioids. Handbook of Experimental Pharmacology. 2008;182:283-311. DOI: 10.1007/978-3-540-74806-9_14
50.Kurzová A, Málek J, Hess L, et al. Non-traditional administration of remifentanil in an experimental setting. Physiology. 2019;68(Suppl. 1):97-103. In Czech Language
51.National Center for Biotechnology Information. PubChem Compound Summary for CID 41693, Sufentanil [Internet]. 2023. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Sufentanil [Accessed: May 16, 2023]
52.Hess L. Nové deriváty fentanylu – carfentanil, lofentanil, sufentanil a alfentanil. Remedia. 1992;2(4-5):263-264. ISSN 0862-8947. In Czech Language
53.Berg A, Habeck J, Strigenz M, et al. Sublingual Sufentanil vs. intravenous fentanyl for the treatment of acute postoperative pain in the ambulatory surgery center: A randomized clinical trial. Anesthesiology Research and Practice. 2022;2022:5237877. DOI: 10.1155/2022/5237877
54.Savoia G, Loreto M, Gravino E. Sufentanil: An overview of its use for acute pain management. Minerva Anesthesiology. 2001;67(9):206-216
55.Zhang C, Huang D, Zeng W, et al. Effect of additional equipotent fentanyl or sufentanil administration on recovery profiles during propofol-remifentanil-based anaesthesia in patients undergoing gynaecologic laparoscopic surgery: A randomized clinical trial. BMC Anesthesiology. 2022;22(1):127. DOI: 10.1186/s12871-022-01671-z
56.National Center for Biotechnology Information. PubChem Compound Summary for CID 62156, Carfentanil. [Internet]. 2023. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Carfentanil [Accessed: May 16, 2023]
57.Hess L. Carfentanil – nejsilnější známý opioid. Remedia. 2017;27(6):582-586. Available from: https://www.medvik.cz/bmc/link.do?id=bmc18000366 Accessed: May 16, 2023
58.Leen JLS, Juurlink DN. Carfentanil: A narrative review of its pharmacology and public health concerns. Canadian Journal of Anesthesia. 2019;66:414-421. DOI: 10.1007/s12630-019-01294-y
59.Bhatt N, Nimavat K. Synthesis, characterization and antimicrobial activity of methyl 1-(−2-amine-alkylcarbonyl) piperidine-4-carboxylate. IJPRS. 2013;2:11-15
60.Bilsback P, Rolly G, Tampubolon O. Efficacy of the extradural administration of Lofentanil, buprenorphine or saline in the management of postoperative pain. British Journal of Anaesthesia. 1985;57:943-948. DOI: 10.1093/bja/57.10.943
61.Středa L, Patočka J. Neletální chemické zbraně a Úmluva o zákazu chemických zbraní. Vojenské zdravotnické listy. 2004;73(5-6):184-193. In Czech Language
62.European Monitoring Centre for Drugs and Drug Addiction and Europol. Acryloylfentanyl: EMCDDA–Europol Joint Report on a New Psychoactive Substance: N-(1-Phenethylpiperidin-4-yl)-N-Phenylacrylamide (Acryloylfentanyl); Lisbon. 2017 [Internet]. 2017. Available from: https://www.emcdda.europa.eu/publications/joint-reports/acryloylfentanyl_en [Accessed: August 23, 2022]
63.Ujváry I, Jorge R, Christie R, et al. Acryloylfentanyl, a recently emerged new psychoactive substance: A comprehensive review. Forensic Toxicology. 2017;35:232-243
64.UNODC. Fentanyl and its Analogues - 50 Years on [Internet]. 2017. Available from: https://www.unodc.org/documents/scientific/Global_SMART_Update_17_web.pdf [Accessed: August 29, 2021]
65.The Dangers of Abusing Fentanyl Patches. Drug & Alcohol Rehab Centers [Internet]. 2019. Available from: https://americanaddictioncenters.org/fentanyl-treatment/dangers-of-abuse [Accessed: April 26, 2021]
66.UNODC. World Drug Report 2022 (United Nations publication, 2022) [Internet]. 2019. Available from: www.unodc.org/unodc/en/data-and-analysis/world-drug-report-2022.html [Accessed: May 26, 2023]
67.Legislative Assembly of British Columbia. Expanding the Response to the Toxic Drug and Overdose Crisis. [Internet]. 2022. Available from: https://www.leg.bc.ca/content/CommitteeDocuments/42nd-parliament/3rd-session/health/report/SSC-Health-Report_42-3_2022-11-01_Final.pdf [Accessed: June 08, 2023]
68.Pierce M, van Amsterdam J, Kalkman GA, et al. Is Europe facing an opioid crisis like the United States? An analysis of opioid use and related adverse effects in 19 European countries between 2010 and 2018. European Psychiatry. 2021;64(1):e47. DOI: 10.1192/j.eurpsy.2021.2219
69.Ellis CR, Kruhlak NL, Kim MT, et al. Predicting opioid receptor binding affinity of pharmacologically unclassified designer substances using molecular docking. PLoS One. 2018;13(5):e0197734. DOI: 10.1371/journal.pone.0197734
70.UNODC: World Drug Report 2022 [Internet]. 2022. Available from: https://www.unodc.org/res/wdr2022/MS/WDR22_Booklet_1.pdf [Accessed: April 25, 2023]
71.US Department of Justice; Drug Enforcement Administration. Schedules of controlled substances: Temporary placement of acetyl fentanyl into schedule I. Federal Register. 2015;80:29227-29230
72.Papsun D, Krywanczyk A, Vose JC, et al. Analysis of MT-45, a novel synthetic opioid, in human whole blood by LC–MS-MS and its identification in a drug-related death. Journal of Analytical Toxicology. 2016;40:313-317. DOI: 10.3390/ijerph16020177
73.Bäckberg M, Beck O, Jönsson KH, Helander A. Opioid intoxications involving butyrfentanyl, 4-fluorobutyrfentanyl, and fentanyl from the Swedish STRIDA project. Clinical Toxicology. 2015;53:609-617. DOI: 10.3109/15563650.2015.1054505
74.Report of the International Narcotics Control Board [Internet]. 2022. Available from: https://www.unodc.org/documents/treaties/COP11/Other_Relevant_Documentation/E_2022_28-E_CN.7_2022_14_E.pdf [Accessed: January 18, 2023]
75.Vandeputte MM et al. Phenethyl-4-ANPP: A marginally active byproduct suggesting a switch in illicit fentanyl synthesis routes. Journal of Analytical Toxicology. 2022;46(4):350-357. DOI: 10.1093/jat/bkab032
76.Lovrecic B, Lovrecic M, Gabrovec B, et al. Non-medical use of novel synthetic opioids: A new challenge to public health. IJRPH. 2019;16(2):177. DOI: 10.3390/ijerph16020177
77.Dynex. Drug test. New: Fentanyl test. NPC Bulletin 2013. p. 3 [Internet]. 2013. Available from: https://www.dynex.cz/data/machines/bulletin-npdc-03_2013.pdf [Accessed: August 18, 2017]
78.Goldman JE, Waye KM, Periera KA, et al. Perspectives on rapid fentanyl test strips as a harm reduction practice among young adults who use drugs: A qualitative study. Harm Reduction Journal. 2019;16:3. DOI: 10.1186/s12954-018-0276-0
79.Jelínková R, Moravcová I, Žuja P. Orientation test for the presence of fentanyl derivatives by thin-layer chromatography. Chemicke Listy. 2023;117(3):155-162. DOI: 10.54779/chl20230155
80.Jelínková R. Extractive spectrophotometry of fentanyl and its derivatives [thesis]. Brno: University of Defence; 2014
81.Ott CE, Perez-Estebanez M, Hernandez S, et al. Forensic identification of fentanyl and its analogs by electrochemical-surface enhanced Raman spectroscopy (EC-SERS) for the screening of seized drugs of abuse. Frontiers in Analytical Science. 2022;2:202. DOI: 10.3389/frans.2022.834820
82.Travon C, Ott CE, Dalzell KA, et al. Screening of seized drugs utilizing portable Raman spectroscopy and direct analysis in real time-mass spectrometry (DART-MS). Forensic Chemistry. 2021;25:1000352. DOI: 10.1016/j.forc.2021.100352
83.Choińska MK, Šestáková I, Hrdlička V, et al. Electroanalysis of fentanyl and its new analogs: A review. Biosensors (Basel). 2022;12(1):26. DOI: 10.3390/bios12010026
84.UNODC – United Nations Office on Drugs and Crime. Recommended Methods for the Identification and Analysis Od Fentanyl and its Analogues in Biological Specimens. The United Nations in Vienna; 2017
85.Maher S, Elliot SP, George S. The analytical challenges of cyklopropylfentanyl and crotonylfentanyl: An approach for toxicological analysis. Drug Testing and Analysis. 2018;10(9):1493-1487. DOI: 10.1002/dta.2417
86.Marchei E, Pacifici R, Mannocchi G, et al. New synthetic opioids in biological and non-biological matrices: A review of current analytical methods. TrAC Trends in Analytical Chemistry. 2018;102:1-15. DOI: 10.1016/j.trac.2018.01.007
87.Roda G, Faggiani F, Bolchi C, et al. Ten years of fentanyl-like drugs: A technical-analytical review. Analytical Sciences. 2019;35:479-491. DOI: 10.2116/analsci.18R004
88.Strayer EK et al. LC-MS/MS-based method for the multiplex detection of 24 fentanyl analogues and metabolites in whole blood at sub ng.mL−1 concentrations. ACS. Omega. 2018;3(1):514-523. DOI: 10.1021/acsomega.7b01536
89.Riches RJ et al. Analysis of clothing and urine from Moscow theatre siege casualties reveals Carfentanil and remifentanil use. Journal of Analytical Toxicology. 2012;36(9):647-656. DOI: 10.1093/jat/bks078
90.Halámek E, Kobliha Z. Potential chemical warfare agents. Chemicke Listy. 2011;105(5):323-333
91.Kobliha Z, Středa L. Neletální chemické zbraně – zbraně pro 21. století? Brno; 2015 ISBN: 978-80-263-0975-8
92.Pearson A. Incapacitating biochemical wapons. Nonprolferation Review. 2006;13(2):151-188. DOI: 10.1080/10736700601012029
93.Pitschmann V, Hon Z. Drugs as chemical weapons: Past and perspectives. Toxics. 2023;11(1):52. DOI: 10.3390/toxics11010052
Written By
Romana Jelínková
Submitted: 19 June 2023Reviewed: 02 August 2023Published: 20 February 2024
Open access peer-reviewed chapter
