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Transdermally administered fentanyl for postoperative pain: a randomized, double-blind, placebo controlled trial
In den 5oer Jahren wurde recht eingehend die Struktur-Wirkungs- Beziehung von synthetischen Opioiden erforscht. Auf der Basis dieser Arbeiten wurden mehrere neue Phenylpiperidine mit deutlich erhöhter Wirkstärke und Sicherheit synthetisiert und schlißlich auf den Markt gebracht. Die erste dieser Verbindungen war Fentanyl. Bald darauf wur- den auch Alfentanil und Sufentanil zur klinischen Anwendung in den USA freigegeben. Inzwischen wurden weitere neue Piperidinderivate synthetisiert, die sich von den bisherigen Opioiden unterscheiden. Sie werden derzeit klinisch geprüft.
The development of Transdermal Therapeutic System (Fentanyl) (TTS fentanyl) has combined fentanyl, an opioid that has been used for over 20 years, with a transdermal drug delivery system [Alza Corporation, Palo Alto, CA]. The system controls release of fentanyl to maintain a continuous and steady supply of drug through the skin. Application of a new TTS fentanyl every 72 h can provide the sustained and relatively constant serum fentanyl concentrations associated with continuous intravenous or subcutaneous opioid delivery but without invasive procedures or special equipment.
In the 1950s considerable work was done on the structure-activity relationship of synthetic opioids. Resulting from this work, several new phenylpiperidines with markedly increased potency and increased safety (over the classical opioids morphine and meperidine) were synthesized and eventually commercialized. The first of these compounds was fentanyl. Following on its heels, alfentanil and sufentanil were also ultimately released for clinical use. All of these compounds have now been available in the U.S. for several years and numerous reviews of their pharmacology have been published. Recently several newer piperidine derivatives have been synthesized that are uniquely different to presently available opioids. These are now undergoing clinical evaluation.
Current investigation is evaluating several novel techniques of opioid administration for acute (postoperative) analgesia. The underlying concept is to mimic a continuous intravenous infusion and provide stable, nontoxic, therapeutic plasma concentrations for prolonged periods in a simple, easy-to-use fashion. The promising techniques that are currently or likely to be widely available in the near future include buccal and sublingual opioids (morphine, buprenorphine), rectal hydrogel suppositories (morphine), and transdermal opioids (fentanyl, sufentanyl).
The transdermal therapeutic system (TTS) is a novel technique of drug administration that can mimic long-term continuous intravenous infusions in maintaining stable drug plasma concentrations. Fentanyl, a potent lipid-soluble synthetic opioid, has been incorporated into such a system and has undergone preliminary clinical trials in postoperative patient populations to assess analgesic efficacy and incidence of undesirable side effects (pruritus, nausea and vomiting, urinary retention, respiratory depression). In general, when applied 2 hr preoperatively, a TTS (fentanyl) patch (in different doses) provides moderate-to-good analgesia for a variety of surgical procedures for periods of up to 3 days. Most patients will require small amounts of systemically administered opioids for supplementary analgesia, especially in the first 24 postoperative hr. The incidence of side effects such as nausea and vomiting varies between studies but can be as high as 70%. Clinically significant respiratory depression is rare but was reported in several of the studies. TTS (fentanyl) is a simple and useful technique for the control of postoperative pain.
A new transdermal drug-delivery system that administers the synthetic opioid fentanyl through intact skin was evaluated for 24 hours postoperatively in eight patients who had undergone orthopedic surgery. Plasma samples were obtained over a 72-hour period for pharmacokinetic analysis in five patients. The patients were also evaluated intensively for adequacy of analgesia, frequency of nausea and sedation, and occurrence of ventilatory depression. A median lag time of 2.25 hours after application of the transdermal system was observed before the appearance of fentanyl in the blood. Median peak concentration and time to peak were 1.0 ng/ml and 22 hours, respectively. The apparent elimination of fentanyl after transdermal administration is prolonged relative to previously reported values. Absorption analysis indicates zero-order fentanyl administration, and in addition, suggests deposition of drug in an epidermal site, with the resultant prolonged absorption process giving the appearance of slow elimination. No significant toxicities were observed. Four patients required no additional analgesia. No consistent correlations among fentanyl concentration and any clinical values were observed. Transdermal administration of fentanyl appears to be a viable alternative to conventional routes of narcotic administration and warrants further study.
The transdermal route of drug delivery has been used for the effective administration of therapeutic agents for more than a decade. The most important consideration in selecting a drug for transdermal delivery is the potential for improving therapeutic efficacy. The development of a transdermal fentanyl system provided an opportunity to add fentanyl to the armamentarium of strong opioids available for the treatment of cancer pain. The transdermal route of administration has advantages over both the oral and parenteral routes. In addition, patient and caregiver factors allow improved acceptance of and compliance to strong opioids and therefore improved analgesic outcome. Four transdermal fentanyl systems are available, providing delivery rates ranging from 25-100 micrograms/h; higher rates can be achieved by multiple system application. The system releases fentanyl continuously for 3 days when applied to the skin. Concentrations of fentanyl in the blood are measurable within a few hours of system application. Fentanyl serum concentrations increase gradually, generally levelling off after 12-24 h and remaining relatively constant for the remainder of the 3-day period. Steady state serum concentrations are reached by the second application. Clinical trials have established the efficacy and safety of transdermal fentanyl for the treatment of cancer pain. Transdermal fentanyl is not licensed for the treatment of acute pain, e.g. postoperative pain, and should not be prescribed for this purpose.
The aim of this study was to determine the safety and effectiveness of a transdermal fentanyl delivery system for the relief of pain following abdominal surgery.
In a nonblinded, noncrossover, placebo-controlled study, 40 ASA I and II patients of both sexes, 18-69 years of age, who were scheduled for abdominal surgery under general anesthesia, were randomly divided into two groups of 20 patients each. Patients in group I received a transdermal patch containing 0.16 mg/cm2 of fentanyl, which was applied to the skin over the subclavian area 60 minutes before the induction of anesthesia. For body weight less than 60 kg, a 30 cm2 patch was applied, and for weight greater than 60 kg, a 40 cm2 patch was used. A second group of 20 patients received placebo patches of identical size. Approximately 20 to 30 minutes before the expected end of surgery, 60 mg ketorolac was administered intramuscularly. Patients were observed for 36 hours after placement of the patch. If patients reported their pain at rest as 5 or greater at rest on a 0-10 visual analog scale, they were given 30-mg increments of ketorolac 5 to 7 hours apart. If this regimen did not relieve their pain, they received 1,300 mg acetaminophen between two ketorolac doses. If despite this, they still had pain 30 minutes afterward, intravenous morphine was given, and the patients were excluded from further study. The patch was removed in four patients in the fentanyl group and seven in the placebo group for various reasons, which included, inadequate pain relief requiring additional analgesia postoperatively and more than 1 microgram/kg of sufentanil given intraoperatively or immediately prior to the end of surgery. During the 36-hour observation period, 30 doses of 30 mg ketorolac and 14 doses of 1.3 g acetaminophen were given to 13 patients in the placebo group and 18 doses of ketorolac and 8 doses of acetaminophen were administered to 16 in the fentanyl group.
The differences in postoperative analgesic requirements were significant. Plasma fentanyl concentrations at 12 and 24 hours after the application of the fentanyl patch were 0.98 +/- 0.14 ng/mL and 1.22 +/- 0.17 ng/mL, respectively. At 8, 16, 24, and 36 hours after application of the patch, the pain relief, assessed by a VAS at rest and with movement, was similar in the two groups. In the fentanyl and control groups, 12 and 5 patients, respectively, experienced nausea, and 2 and 3 patients, respectively, vomited.
Similar postoperative analgesia was achieved with less parenteral analgesics in patients who received transdermal fentanyl preoperatively than in control patients. Fentanyl, 50-75 micrograms/h, administered in a transdermal delivery system, did not depress respiratory rate or hemoglobin oxygen saturation. Although the exact role of continuously administered opioids in managing acute postoperative pain has yet to be clearly defined, it is concluded that if properly used, this new transdermal device can be effective in providing a background of analgesia, which may assist in the management of acute postoperative pain as well as some chronic pain states.
Transdermal delivery allows continuous systemic application of opioids through the intact skin. This review analyses the pharmacokinetic properties of transdermal opioid administration in the context of clinical experience, with a focus on fentanyl.
A transdermal therapeutic system (TTS) for fentanyl has been developed. The amount of fentanyl released is proportional to the surface area of the TTS, which is available in different sizes. After the first application of a TTS, a fentanyl depot concentrates in the upper skin layers and it takes several hours until clinical effects are observed. The time from application to minimal effective and maximum serum concentrations is 1.2 to 40 hours and 12 to 48 hours, respectively. Steady state is reached on the third day, and can be maintained as long as patches are renewed. Within each 72-hour period, serum concentrations decrease gradually over the second and third days. When a TTS is removed, fentanyl continues to be absorbed into the systemic circulation from the cutaneous depot. The terminal half-life for TTS fentanyl is approximately 13 to 25 hours. The interindividual variability of serum concentrations, partly caused by different clearance rates, is markedly larger than the intraindividual variability.
The effectiveness of TTS fentanyl was first demonstrated in acute postoperative pain. However, the slow pharmacokinetics and large variability of TTS fentanyl, together with the relatively short duration of postoperative pain, precluded adequate dose finding and led to inadequate pain relief or, especially, a high incidence of respiratory depression; such use is now contraindicated. Conversely, in cancer pain, TTS fentanyl offers an interesting alternative to oral morphine, and its effectiveness and tolerability in this indication has been demonstrated by a number of trials. Its usefulness in chronic pain of nonmalignant origin remains to be confirmed in controlled trials.
In general, TTS fentanyl produces the same adverse effects as other opioids, mainly sedation, nausea, vomiting and constipation. In comparison with oral morphine, TTS fentanyl causes fewer gastrointestinal adverse events. The risk of hypoventilation is comparatively low in cancer patients.
Sufentanil and buprenorphine may also be suitable for transdermal delivery, but clinical results are not yet available. Transdermal morphine is only useful if applied to de-epithelialised skin. However, iontophoresis may allow transdermal administration of opioids, including morphine, with a rapid achievement of steady state concentrations and the ability to adjust delivery rates. This would be beneficial for acute and/or breakthrough pain, and initial clinical trials are in progress.
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