Fentanyl: General Properties and Therapeutic Uses

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Chapter 9

Sang Ryong Jeon,1, Jin Hoon Park2 and Yongchel Ahn3 1Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea 2Department of Neurosurgery, GangneungAsan Medical Center, University of Ulsan College of Medicine, Gangneung, Korea 3Department of Hemato-oncology, GangneungAsan Medical Center, University of Ulsan College of Medicine, Gangneung, Korea

Abstract

Fentanyl [N- (1- phenethyl - 4-piperidyl) propionanilide] was synthesized by Paul Janssen in 1960 and was first introduced to replace morphine and other opioids for analgesic use in cardiac surgery. This compound is a lipophilic, short-acting synthetic opioid with a piperidine ring structure. It is highly lipophilic thus having high protein- solubility and low water-solubility. The piperidine ring facilitates docking with the opioid receptors and substitutions on the ring influence of its receptor binding thus affecting clinical efficacy. Fentanyl is a highly selective opioid agonist mainly at μ-opioid receptor with less affinity at the δ and κ receptors. It may also interact with serotonin receptors. Though oral administration is not available due to high first-pass metabolism, its high potency and lipophilicity have enabled multiple routes of administration like transdermal, subcutaneous, transmucosal, sublingual, intrathecal, intranasal and transpulmonary as well as intravenous. The major metabolic process of fentanyl occurs in the liver by cytochrome P450 (CYP) 3A4 and most of its metabolites are non-toxic and inactive, which makes this opioid a preferred drug of choice in clinical practice. Fentanyl has a 75 to 100 fold greater potency than that of morphine. Initial limitations to its clinical applications was exclusively due to its rapid onset and short duration of action. These conditions have now been overcome through alternative modes of sustained delivery like

 Corresponding author: Sang Ryong Jeon, M.D., Ph.D. Department of Neurological Surgery, Asan Medical Center, University of Ulsan, College of Medicine,388-1 Pungnap-2dong, Songpa-gu, Seoul 138-736, Korea, Tel: (+)82-2-3010-3550; Fax: (+)82-2-476-6738; E-mail: [email protected]. 170 Sang Ryong Jeon, Jin Hoon Park and Yongchel Ahn

transdermal and transmucosal. Wide spread use of fentanyl from acute postoperative pain control, to chronic pain including cancer-related or noncancerous pain, is attributable to its own potent analgesic efficacy and lipophilicity which enables various routes of administration.

I. Chemistry

1) Introduction of Fentanyl

Using meperidine (C15H21NO2, 1 - Methyl – 4 – phenyl – 4–piperidinecarboxylic acid ethyl ester, Pethidine®) (Figure 1) as a backbone, Janssen and his coworkers synthesized substituted 4-phenylpiperidine derivatives since 1959 [30, 31, 32]. Six compounds such as R951, phenoperidine, pheneridine, anileridine, piminodine, and etoxeridine were found to be clinically useful and the additional compound ‘R4263’ seemed to be highly narcotic in its potency. This R4263 compound ([N-(1-phenethyl-4-piperidyl)-propionanilide], Figure 2), in addition to having a substitution on the piperidine nitrogen, is an aniline derivative. Today, this is called fentanyl [29, 60]. Janssen et al. observed that fentanyl was about 400 times more potent than morphine through a withdrawal reaction test (also known as warm-water induced tail-withdrawal reflex test) in rats. And fentanyl was also fast in onset and short in duration of action compared with those of morphine or meperidine [33]. Other researchers conducted pharmacologic experiments (in mice, dogs and cats) and concluded that intravenous fentanyl, compared to morphine, had higher potency, more rapid onset and shorter duration with no emetogenicity and little cardiovascular toxicities. Narcotic effects were readily antagonized by the antagonist such as nalorphine and the bradycardia could be reversed by atropine [18].

Figure 1. Meperidine (C15H21NO2, 1-Methyl–4–phenyl–4–piperidinecarboxylic acid ethyl ester).

Figure 2. Fentanyl (N-(1-phenethyl-4-piperidyl)propionanilide). Fentanyl: General Properties and Therapeutic Uses 171

Figure 3. Crystal structure conformations of of fentanyl.

2) Structure of Fentanyl

The molecular weight of fentanyl is 336.471 g/mol in a free base and the empirical formula is C22H28N2O. It is a prototype of the 4-anilidopiperidine class of synthetic opioid analgesics and consists of crystal structure conformation. (Figure 3) Concerning structural difference from meperidine, the distance between the piperidine nitrogen and the benzene ring is reduced from 3 to 2 carbon atoms, the ester on the right side of the molecule is reversed, and one of its oxygen molecules is replaced with a nitrogen [8]. Compared to morphine, the substituted piperidines are structurally simple and possess much more conformational freedom. In-depth studies of the structure-activity relationship of 4-anilidopiperidine derivatives have described those structural features which are compatible with high morphino-mimetic potency [38, 39, 68]. Substitutions on the 3- or 4-position of the piperidine ring exhibits variable analgesic potencies, up to several thousand times that of morphine [35, 76, 77, 78].

3) Synthesis of Fentanyl Analgesics

The synthesis of substituted piperidines is known to be relatively easy because of conformational flexibility. Substituted piperidine can be divided into four classes of analgesics: meperidine family, ketobemidone family, prodine family and fentanyl family [39]. Of these four classes, the fentanyl class seems to be the most potent analgesic and is now widely used in clinical practice. There are variable synthetic methods to yield fentanyl as the final product [6, 37, 57, 58] but the original synthesis of fentanyl has been described by Janssen and his colleagues, which starts from converting commercially available 1-benzyl-4-piperidone to N-(1-benzyl-4- piperidyl)-N-phenylpropanamide. Subsequent hydrogenolysis yields a versatile intermediate product named N-(4-piperidyl)-N-phenylpropanamide. This intermediate product can be 172 Sang Ryong Jeon, Jin Hoon Park and Yongchel Ahn utilized as a raw material for fentanyl analogues having different substituents on the piperidine ring. Finally, further alkylation with β-phenethyl bromide enables variation of the aniline, acyl and alkylating groups including fentanyl analogues [28, 34, 39]. Commercial fentanyl is made water soluble through conjugate acid formation with citric acid, called fentanyl citrate.

II. Pharmacology

1) Clinical Pharmacology

Fentanyl is a full μ–agonist, its selectivity for the μ site with respect to the δ site in the homogenized rat brain is found to be approximately 80% [82]. It binds μ-opioid G-protein- coupled receptors, which inhibit pain neurotransmitter release by decreasing intracellular Ca2+ levels. Fentanyl shows dose-related analgesic effects. Small doses of 0.5-3.0pg/kg may be applied as a supplementary in spontaneous breathing anesthetized patients [19]. A dose of 5.0μg/kg suppresses somatic and autonomic responses to surgical stimuli in ventilated patients [16]. Combined with muscle relaxants, a dose of 50μg/kg can induce and maintain anesthesia [73]. Fentanyl has typical opioid actions of analgesia and respiratory depression and its effect can be seen within one circulation time, peaks at 5 minutes and lasts for 30 minutes at an anesthetic dose of 0.5-3μg/kg [13]. Thus it reduces brain stem responsiveness to carbon dioxide and peripheral chemoreceptor input during hypoxemia resulting in the CO2 response curve shift-to-right [24, 72]. With high doses of fentanyl, awareness seems to be less frequent. Even without prophylactic use of drugs with amnesic characteristics (such as diazepam and scopolamine), half of patients were amnesic to visual stimulations [41]. High-dose fentanyl produces an EEG response which is characterized by high voltage, slow delta waves like high-dose meperidine [13, 67] but the EEG pattern is not altered by nitrous oxide or surgical stimulation [67]. In addition, a ceiling effect can be observed with high doses of 50 to 150μg/kg without altering the EEG pattern [80]. The cardiovascular effects of opioid administration reflect complex interactions between the heart, blood vessels, CNS and other organs. Different opioids affect the central and peripheral vasculature in different mechanisms. Fentanyl is known to have minimal effects on the cardiovascular system. [8, 24] Fentanyl stimulates the central vagal nucleus and depresses the sinoatrial and atrioventricular nodes, but may decrease central sympathetic tone to the heart [50, 51, 71]. Fentanyl-induced bradycardia can be prevented by premedication with atropine. Unlike meperidine, cardiac output in humans or animals is minimally affected by fentanyl when given slowly [11, 17, 56]. Also, clinical experiences suggests that fentanyl rarely causes hypotension or hypertension which occurs often and is sometimes severe with morphine [4]. The mechanism of skeletal muscle rigidity and clonic movements during and after anesthesia remains obscure, but it can be managed by naloxone or neuromuscular-blocking drugs [5]. Fentanyl blunts the metabolic and hormonal response to surgery, or surgical stress responses. Reports suggest that high dose fentanyl induced abolishment of ACTH and β- dendorphine responses as well as catecholamine response [23, 40, 47]. Fentanyl: General Properties and Therapeutic Uses 173

2) Pharmacokinetics

Fentanyl has a lipophilic tertiary amine chemical structure with an octanol water partition coefficient at pH 7.4 of 955 compared to 1.4 for morphine [25]. Fentanyl has three distinct structural features. A large hydrocarbon mass enables its high lipophilicity, an amide functional group giving a ready metabolic site and a piperidine ring tertiary amine functional group (pKa=8.43) as another ready metabolic site [63]. Due to the amine group, fentanyl remains mostly in an ionized state at all values of physiological pH. Small modifications in pH can result in relatively large differences to the fraction ionized and to the lipid solubility of fentanyl. Hence distribution of drug and even pharmacological efficacy can be influenced by them [55]. Pharmacokinetic data are calculated from coefficients and exponents of poly-exponential decay equations fitted to fentanyl concentrations in body fluids like plasma or serum from a peripheral artery or vein. From these, the mean total body clearance (TBCl), initial (V) and total (Vss) volumes of distribution and half-lives (T½, range 1-6 hours, mean 3.7 hours) can be calculated. Because of a short duration of drug effect, it was initially assumed to result from rapid drug clearance but it is more attributable to extensive extravascular distribution. (Total volume of distribution, Vss = 300-400 L/kg). After intravenous administration, there is a rapid distribution to the central compartment within 2 minutes, after that peripheral redistribution [13, 55]. The lipophillic nature of fentanyl is not the only major explanation of its rapid onset of drug action. The rate of drug onset depends on two major properties: drug concentration in blood and blood-tissue partition coefficients [27]. Rapid receptor association and dissociation of fentanyl in vitro has been observed and this, when coupled with the high lipophilicity, seems to be a necessary condition for blood concentrations to reflect receptor concentrations, and therefore a pharmacological effect [3, 55]. Fentanyl has a high clearance rate but after single or infrequent doses, its duration of action is terminated by redistribution and repeated doses can cause drug accumulation and prolonged duration of action [25, 26]. Duration of drug action is determined by redistribution with uptake (t½ π) and distribution (t½ β) half-lives of 1.7 hours and 13.4 hours each. And there is a high apparent volume of distribution following intravenous bolus injection (Vd= 3.99 L/kg) and a high apparent volume of distribution for the central compartment. (Vc= 0.356 L/kg) Many proteins in plasma are involved with fentanyl binding (protein binding up to 80%), predominantly with albumin and lipoproteins, and highest affinity can be seen with α1-acid glycoprotein. The remaining free fractions are largely ionized since the pKa of fentanyl is 8.43 [13]. Fentanyl is metabolized mainly in the liver (CYP 3A4 as key enzyme). Its main route of excretion is in the urine as a form of inactive metabolites (more than 60% in 72 hours), with only 7% unchanged in times of excretion [61]. Fentanyl undergoes phase I metabolism, predominantly by oxidative N-dealkylation (Figure 4). The large volume of distribution reflects serum drug concentration is low and the absolute amount of metabolized drug is relatively small [13].

174 Sang Ryong Jeon, Jin Hoon Park and Yongchel Ahn

III. The Therapeutic Use of Fentanyl for Pain Control

1) Introduction

Fentanyl was initially developed as a highly potent opioid analgesic to be used as the analgesic component of balanced anesthesia. It is a highly potent synthetic opioid with a rapid onset and short duration of action; the lipophilic nature of fentanyl permits its rapid transfer across the blood-brain barrier. Fentanyl has an analgesic potency that is 100–300 times greater than that of morphine [36, 69]. The mechanisms of opioid-induced analgesia are incompletely understood. However, fentanyl is known to primarily interact with μ-opioid receptors and is a pure agonist at these receptors. It interacts to a lesser extent with δ- and κ-opioid receptors [59]. While the initial usage was exclusively parenteral and the oral route is not an option due to a high first-pass effect, multiple new routes of administration have been reported to control pain. Fentanyl is most commonly administered transdermally, but can be administered intravenously, subcutaneously, transmucosally and sublingually. In addition, fentanyl has been administered by intrathecal and intranasal routes with aerosols [70].

Figure 4. Metabolism of fentanyl. Fentanyl: General Properties and Therapeutic Uses 175

2) Intravenous Delivery

The distribution time is 1.7 minutes, redistribution time is 13 minutes, and the terminal elimination half-life is 219 minutes. Fentanyl accumulates in skeletal muscle and fat and is released slowly into the blood. Fentanyl has a high first-pass clearance—75% of an intravenous dose is released in the urine as inactive metabolites, and less than 10% is excreted as the unchanged drug. Metabolites appear in plasma within 2 minutes, and plasma metabolite levels exceed that of the parent drug after 30 minutes. Duration of analgesia after an intravenous bolus is 30 to 60 minutes. The plasma protein–binding capacity of fentanyl is 80% to 85%. The main binding protein is α-1-acid glycoprotein, but albumin and lipoproteins can also be bound. The fraction of free fentanyl increases with acidosis, which may affect its distribution between the plasma and the central nervous system [63].

3) Subcutaneous Delivery

No studies have examined the pharmacokinetic properties of subcutaneously administered fentanyl. This route is believed to be interchangeable with the intravenous route because no differences have been detected in terms of analgesic effectiveness or toxicity. The infusion is well tolerated locally, but volume considerations limit the use of fentanyl in subcutaneous tissues [2, 65].

4) Buccal Tablets

The fentanyl buccal tablet is a novel drug delivery method in which an effervescence reaction is used to enhance fentanyl absorption through the buccal mucosa, thereby facilitating rapid systemic exposure to the analgesic. The bioavailability of fentanyl is approximately 50%. In healthy subjects, the time to maximal serum concentration is 0.75 to 0.99 hours. Mean serum fentanyl concentration shows a bi-exponential decline from peak after 200μg and 500μg doses and a tri-exponential decline after 810μg and 1080μg doses. Median half-life increases with dose and ranges from 2.6 hours for the 100μg dose to 11 hours for the 800μg dose [10, 15, 62].

5) Intranasal Delivery

An advantage of this mode of administration is that the venous outflow of the nasal mucosa bypasses the liver and enters the systemic circulation, thereby avoiding the hepatic first-pass effect. The aqueous formulation approved for intravenous injection has been used for nasal administration. When fentanyl is administered intranasally, the bioavailability is approximately 71%. The Tmax is as short as 5 minutes; pain decreases within 5 minutes, and analgesia lasts for approximately1 hour. One drawback of intranasal administration is that the volume of opioid is limited by the size of the nasal cavity [9, 74]. 176 Sang Ryong Jeon, Jin Hoon Park and Yongchel Ahn

6) Transdermal Delivery

After application of a transdermal fentanyl patch, serum concentrations gradually increase (leveling off between 12 and 24 hours), and they remain relatively constant throughout the 72-hour application period. The time from application to minimal effective concentration and maximal serum concentration (Cmax) is 1.2 to 40 hours and 12 to 48 hours, respectively. The Cmax is dose dependent, and peak serum levels are reached within 8–12 hours [28]. Steady-state is reached on the third day after application, and it can be maintained as long as patches are replaced. Heat shortens the time needed to reach steady-state. When a transdermal therapeutic system (TTS) is removed, fentanyl continues to be absorbed into the systemic circulation from the cutaneous depot. This accounts for the slower disappearance of fentanyl from the serum compared to intravenous infusion. The terminal half-life of fentanyl after removal of the TTS is approximately 13 to 25 hours. The skin does not affect the metabolism of fentanyl. Age seems to influence transdermal fentanyl pharmacokinetics; elderly subjects (67–87 years) have a greater area under curve for plasma fentanyl concentrations than younger patients. A newly designed, 72-hour transdermal fentanyl matrix patch has 35% to 50% lower absolute fentanyl content compared to other currently available transdermal fentanyl patches that do not use matrix technology. In addition, transdermal patch mono-therapy can be also useful in intractable non-cancerous pain [66]. The newer style patch appears to be pharmacokinetically bioequivalent to the marketed fentanyl patch. Another new administration method is iontophoresis through a battery- operated, patient-controlled transdermal system (PTCS); this process drives medication deep into the dermis with a weak electrical current. The pharmacokinetic properties of the PCTS are similar to those of intravenous fentanyl infusion and appear to be unaffected by gender, age, race, or weight. The amount of fentanyl absorbed through the PCTS is linearly dependent on the magnitude of current applied. It is 0.40 and 0.54μg h/L during single- and multiple-day treatment periods. Location of the delivery device on the body may influence pharmacokinetic properties [12, 20, 22, 44].

7) Adverse Effects

Overall, the adverse effects observed with fentanyl (e.g., nausea, vomiting, constipation, somnolence) are similar to those seen with other potent μ-opioid receptor agonists. Three recent crossover studies have shown a reduced incidence of constipation among patients treated with transdermal fentanyl compared with oral morphine. Intravenous fentanyl may cause chest wall rigidity. This has been observed postoperatively in adult and pediatric patients, as well as in healthy volunteers; Fentanyl-induced rigidity is associated with peak plasma concentrations and the effects are reversible with naloxone. The U.S. Food and Drug Administration guidelines for medications used in pregnancy classify fentanyl as a category C medication (all trimesters). Controlled studies in women or animal models are not available. Although fentanyl does appear in breast milk in very low concentrations, relatively rapid elimination and low oral bioavailability limit the extent of a nursing infant’s exposure, particularly after a single dose. Fentanyl: General Properties and Therapeutic Uses 177

Withdrawal symptoms (e.g., irritability, hyperreflexia, hyperactivity, tremors, diaphoresis, tachypnea) and respiratory depression have been observed in neonates whose mothers were receiving fentanyl during pregnancy or labor (epidural route) [47]. There are insufficient data to establish safety during breastfeeding; thus, caution is advised [1, 14, 46, 64, 75, 79, 81].

8) Several Methods of Fentanyl for Anesthesia

1. Premedication: Fentanyl may be administered as a fentanyl impregnated lollipop, otherwise by intramuscular injection combined with a tranquillizer [42]. 2. To reduce anesthetic needs: Small increments (e.g. 0.5-1μg/kg) are used to supplement intravenous or gaseous anesthetics in spontaneously breathing patients, or in a larger dose (e.g. up to 5μg/kg) to reduce the requirements for volatile anesthetic agents for maintenance of anesthesia. In day case surgery, fentanyl is used to reduce the dose of other anesthetic agents in order to speed recovery, although there may be increased sickness [43]. 3. Intubation and surgery: In ventilated patients, it is used to suppress the somatic and autonomic response to surgery. In elderly patients, 3μg/kg given before induction will suppress the cardiovascular response to intubation. Following induction of anesthesia, fentanyl 5μg/kgobtunds the hemodynamic response to intubation. Fentanyl 6μg/kg prior to anesthesia with thiopentone and suxamethonium ameliorates the hemodynamic response to bronchoscopy. A larger dose (e.g. 50μg/kg) may be used to suppress the hormonal and metabolic response to surgery, such as elevation of catecholamines, ADH, cortisol, etc. [21, 45, 48]. 4. Total intravenous anesthesia: Fentanyl has been used for total intravenous anesthesia when combined with a suitable hypnotic such as etomidate or propofol. A suitable starting rate is 1μg/kg/min for 10 minutes then a maintenance rate of 0.1μg/kg/min [49]. 5. Postoperative analgesia: For postoperative pain relief fentanyl can be administered transdermally at about 100μg/h. Effective plasma concentrations are reached only slowly and a loading dose should be given intravenously during surgery. Plasma levels decay slowly due to a reservoir of fentanyl remaining in the skin. Using an on demand system for postoperative analgesia, the rate of fentanyl use is about 0.8μg/min in adults [52, 53, 54]. 6. Spinal epidural techniques: Fentanyl is active via the spinal and epidural routes and may be given by infusion and bolus techniques, producing analgesia in about 10 minutes. The high lipid solubility of fentanyl (partition coefficient 813 versus 1.42 for morphine) confines the effects of fentanyl to cord level. Good quality pain relief is usually obtained postoperatively, including after caesarian section, and side effects are not usually troublesome. During the labor the use of extradural fentanyl is relatively disappointing, but when added to local anesthetics, it improves the onset and duration of action and provides better quality anesthesia [7].

178 Sang Ryong Jeon, Jin Hoon Park and Yongchel Ahn

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