Fentanyl transdermal administration

Opioids are generally well absorbed enterally (Reisine and Pasternak 1996). However, blood levels of morphine only reach half of those reached by injection. The more lipid soluble opioids are absorbed through the nasal mucosa or transdermally (e.g., fentanyl). Transdermal administration is much slower and more prolonged, avoiding the fluctuating levels produced by injection. 

If disturbances of gastrointestinal function prevent the use of oral sustained-release morphine, the fentanyl transdermal system (fentanyl patch) can be used over long periods. Furthermore, buccal transmucosal fentanyl can be used for short episodes of breakthrough pain (see Alternative Routes of Administration). Administration of strong opioids by nasal insufflation has been shown to be efficacious, and nasal preparations are now available in some countries. Approval of such formulations in the USA is growing. In addition, stimulant drugs such as the amphetamines have been shown to enhance the analgesic actions of the opioids and thus may be very useful adjuncts in the patient with chronic pain. 

Iontophoresis techniques (i.e., the use of electric current to facilitate transdermal delivery) have also been advocated as a way to enhance transdermal opioid delivery to the systemic circulation.11 By varying the amount of electric current, iontophoresis may ultimately allow the patient to control the rate of transdermal administration of the opioid.10,76,78 Finally, certain opioids such as fentanyl can be administered systemically via lozenges or a lollipop that dissolves in the mouth (transmucosal delivery), or via nasal spray (intranasal administration).21,54 It will be interesting to see if these newer methods of administration will gain widespread acceptance in the future. 

Lattin, G.L. Phipps, J.B. Southam, M.A. Klausner, M. Evaluation of fentanyl delivery in humans using E-TRANS technology. In Transdermal Administration, A Case Study, Iontophoresis APGI/CRS European Symposium, Couvreur, P., Duchene, D., Green, P., Junginger, H.E., Eds. 3 March 1997, Paris, France Editions de Sante Paris, 1997 365-368. 

Transdermal administration of fentanyl has been extensively reviewed (44). In systemic availability studies, 92% of the fentanyl dose delivered from the transdermal therapeutic system into the skin reached the systemic circulation as unchanged unmetabolized fentanyl (41). Morphine, codeine, and hydromorphone are not good candidates for transdermal administration. Pethidine has a high transdermal permeability but poor analgesic potency. Besides fentanyl, only sufentanil and buprenor-phine would be suitable opioids for transdermal administration (45). 

There are three techniques used for the transdermal administration of fentanyl. The transdermal therapeutic system (TTS) is a membrane-controlled system designed... 

Klockgether-Radke AP, Gaus P, Neumann P. Opioidintoxikation dutch transdermales Fentanyl. [Opioid intoxication following transdermal administration of fentanyl.] Anaesthesist 2002 51(4) 269-71. 

The availability of new routes of administration have led to increased utility and decreased opioid adverse drug reaction risk. Epidural and intrathecal administration through spinal catheters produces adequate regional analgesia at relatively low total doses compared with intravenous or oral routes. As such, spinal administration can thus minimize somnolence, nausea, vomiting, and respiratory depression associated with these medications. Other alternative routes include intranasal administration of butorphanol, and rectal and transdermal administration of fentanyl [28]. Availability of such options provides not only a decreased risk of adverse reactions, but also more comfortable measures for patients who would otherwise require continued intravenous administration, or for those who are unable to receive oral medication [28,29]. 

Well known as transdermal patches are those containing fentanyl. Fentanyl is used in the treatment of severe chronic pain. Fentanyl is rapidly metabohsed in the hver resulting in low bioavailabihty after oral administration. After apphcation of the patch, 90 % of the released amount reaches the systemic circulation. After first apphcation the plasma concentration increases gradually, stabDises after 12-24 h and is stable up to 72 h [14]. Fentanyl transdermal patches often offer an adequate alternative to parenteral opioid administration in patients who are not able to take their medications orally. 

Fenoterol, safety in severe asthma, 23.182 Fentanyl, buccal and transdermal administration, 20.77 Fertility drugs... 

Opioids maybe administered in a variety of routes including oral (tablet and liquid), sublingual, rectal, transdermal, transmucosal, intravenous, subcutaneous, and intraspinal. While the oral and transdermal routes are most common, the method of administration is based on patient needs (severity of pain) and characteristics (swallowing difficulty and preference). Oral opioids have an onset of effect of 45 minutes, so intravenous or subcutaneous administration maybe preferred if more rapid relief is desired. Intramuscular injections are not recommended because of pain at the injection site and wide fluctuations in drug absorption and peak plasma concentrations achieved. More invasive routes of administration such as PCA and intraspinal (epidural and intrathecal) are primarily used postoperatively, but may also be used in refractory chronic pain situations. PCA delivers a self-administered dose via an infusion pump with a preprogrammed dose, minimum dosing interval, and maximum hourly dose. Morphine, fentanyl, and hydromorphone are commonly administered via PCA pumps by the intravenous route, but less frequently by the subcutaneous or epidural route. 

The answer is c. (Hardman, pp 543—544. Katzang, p 2533) Fentanyl is a chemical relative of meperidine that is nearly 100 times more potent than morphine. The duration of action, usually between 30 and 60 min after parenteral administration, is shorter than that of meperidine. Fentanyl citrate is only available for parenteral administration intramuscularly and intravenously. Tran sbuc cal ( lollipop ) and transdermal patches avoid first-pass metabolism of fentanyl. 

Dosages and routes of administration For acute (postoperative) pain and for anesthesia, fentanyl is given by the intravenous route. For pre-medication in anesthesia and for break-through pain the compound can also been given as an oral-transmucosal formulation (Ashburn and Streisand, 1994). A transdermal patch has been developed for chronic pain treatment (Jeal and Benfield, 1997 O Siordin, 1998). The intravenous doses for premedication are 50-100 pg, oral-transmucosal systems contain 200-400 pg and patch formulations have a delivery rate of 25-100 pg/h. 

A quantum leap in pain therapy with distinct advantages in the form of reduced side-effects and application frequency was achieved with transdermal opioid administration. Transdermal application requires a number of characteristics on the part of the active substance (Fig. 7), the most restrictive being the daily dose, and only very potent opioids which are effective in very low doses, such as fentanyl and buprenorphine, are an option (Sittl and Likar, 2001). 

Buprenorphine, the other option for transdermal application on account of its potency, is more difficult to apply dermally in therapeutic doses (Roy et al., 1994 Grond et al., 2000). A surrogate parameter for skin penetration, provided the other prerequisites are fulfilled (Fig. 7), is the melting point of the active substance. With buprenorphine base this is 209°C and about 260°C for buprenorphine hydrochloride, compared with, for example, 83°C for fentanyl base and 150°C for fentanyl dihydrogen citrate. The DDS developer LTS devised a technical solution for reliable transdermal buprenorphine administration in the form of a matrix patch (Fig. 9). 

Transdermal systems with electrophoretic release of the active substance are under development, e.g. ETRANS by ALZA with fentanyl for postoperative pain in clinical phase III. By virtue of the electrical field administration of the active substance is faster and on demand, e.g. similar to PCA therapy. 

Fentanyl is also available in a patch form (much like a nicotine patch used for smoking cessation) that can also be used for long-term treatment. This form of administration is referred to as transdermal fentanyl and is sold under the trade name Duregasic. The fentanyl is absorbed directly into the skin from the patch and enters the bloodstream, which carries it to the mu receptors. This form of administration appears much easier than it... 

The same technology has been utilized in the development of the following 1) the Estraderm system, which administers a controlled dose of estradiol transdermally over 3 days for the relief of postmenopausal syndrome and osteoporosis 2) the Duragesic system, which provides a transdermal-controlled administration of fentanyl, a potent narcotic analgesic, for 72-h relief of chronic pain and 3) the Androderm system, which provides a transdermal-controlled delivery of... 

A 57-year-old woman using transdermal fentanyl (75 pg/ hour) developed a reduced respiratory rate and bilateral pinpoint pupils when an upper body warming blanket was used as a normal postoperative procedure (24). The resultant increase in skin temperature significantly enhanced skin perfusion, and increased the systemic absorption of fentanyl from the intracutaneous fentanyl depot, leading to sjmptoms of opioid overdose. She recovered after removal of the fentanyl patch and the intravenous administration of naloxone 60 pg. 

Transdermal fentanyl has an adverse effects profile similar to that associated with parenteral administration (SEDA-20, 77). Local erythema and rash have been reported (43), as well as the usual opioid adverse effects. However, an unusual reaction, with progressive agitation to acute delirium, has occurred (SEDA-20, 79). 

The more novel routes of administration of opioids, including oral, nasal, rectal, transdermal, spinal, and by patient-controlled methods, have been outlined (SEDA-17, 78). Oral transmucosal fentanyl administration, avoiding first-pass metabolism, produces analgesia and sedation in both adults and children undergoing short, painful outpatient procedures. The quality of analgesia is good, and the adverse effects are those typical of the opioids. 

Christensen ML, Wang WC, Harris S, et al. Transdermal fentanyl administration in children and adolescents with sickle cell pain crisis. J Pediatr Hematol Oncol 1996 18 372-376. 

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