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This article has been written for us by:
Mr Andrew Dickman (MSc MRPharmS) - Specialist Principal Pharmacist, Palliative Care Team, Whiston Hospital, Merseyside. Mr Dikman is co-author of the Palliative Care Formulary book (PCF2).
Mr Dickman was sponsored by an unrestricted educational grant from Janssen-Cilag Ltd in the production of this article.
Opioids are a diverse class of drugs that include natural, semi-synthetic and synthetic agents. Their effects are mediated through opioid receptors, with m (mu), k (kappa) and d (delta) being the more important for analgesia. The ability of an opioid to bind to a receptor is termed its affinity; the intrinsic efficacy of an opioid determines the ability to elicit a response. Fentanyl is a synthetic phenylpiperidine opioid with a high affinity for the m-receptor. Its intrinsic efficacy is also high, meaning that it stimulates the receptor maximally. Fentanyl is considered to be between 75 to 100 times more potent than morphine in the clinical setting (for example, 60mg daily of oral morphine is equivalent to 600 micrograms of fentanyl, or a 25microgram/hour patch).(1) However, unlike morphine, fentanyl is highly lipophilic, which facilitates its rapid penetration of the blood brain barrier. This property, in combination with its small molecular size and high potency, make fentanyl an excellent choice for transdermal delivery.
Advantages and Disadvantages of Transdermal Drug Delivery
Transdermal drug delivery presents important advantages when compared with more traditional dosage forms. The steady transfer of drug across the skin allows for more consistent serum drug levels, often leading to reduced adverse effects associated with high peak levels of drug (e.g. nausea and vomiting in the case of opioids). A further advantage is convenience, with the fentanyl TTS being changed once every 72 hours. Such a simple dosing regimen can aid patient adherence to therapy.
One of the greatest disadvantages to transdermal drug delivery is the possibility that a local irritation will develop at the site of application. Erythema, itching, and local oedema can be caused by the drug, the adhesive, or other excipients in the patch formulation. For most patients, site rotation can minimise irritation, although for some, discontinuation is the only course of action.
In order to maintain consistent release rates, transdermal patches contain a surplus of active molecule. A stable concentration gradient is the mechanism used to maintain consistent release rates and constant serum drug levels. Most transdermal patches contain greater amounts of drug that will be absorbed during the time of application. Therefore, patients must be careful when disposing of patches. Each patch should be folded in half and the adhesive sides should be stuck together.
Damage to a transdermal patch, particularly a membrane or reservoir patch, can result in poor control over the release rate. The release rate from a damaged patch would more likely be controlled by the skin, rather than the patch, resulting in a higher, perhaps toxic, rate of drug delivery. Patients should be advised to discard a patch if the outer packaging or the patch itself appears damaged or altered in any way.
History of Transdermal Fentanyl
Transdermal fentanyl (Durogesic®) was first licensed in the UK in 1994. The transdermal therapeutic system (TTS) for Durogesic® incorporates reservoir technology, where a membrane sits between the drug and the skin to control the rate of release from a drug reservoir. The membrane helps to reduce inter-patient variation in skin permeability and ethanol within the reservoir (serving as an absorption enhancer) increases the rate of transfer of fentanyl across the skin.(2) The amount of fentanyl released is dependent upon the surface area of the patch. There are four sizes available, designed to release fentanyl at rates of 25, 50, 75 and 100 micrograms per hour.
Transdermal fentanyl is effective and well tolerated and has been successfully used for the treatment of chronic pain caused by malignancy and non-malignant conditions. Compared with oral opioids, transdermal fentanyl offers advantages which include a lower incidence and impact of adverse effects (such as constipation, nausea and vomiting), improved patient satisfaction, enhanced quality of life, improved convenience and compliance resulting from administration every 72 hours.(3 - 7) Transdermal fentanyl is a particularly useful method of analgesia administration for cancer patients with dysphagia, or gastrointestinal problems such as diarrhoea or obstruction. Transdermal fentanyl forms a depot within the upper skin layers before entering the microcirculation. Therapeutic blood levels are attained 12-16 hours after patch application and decrease slowly, with a half-life of 16-22 hours following removal; steady state is achieved within 36-48 hours after the first application. Under normal physiological conditions, neither skin temperature nor blood flow have any significant effect on absorption of fentanyl from the reservoir system, although absorption may increase as body temperature rises above 37ºC.(8)
From 31st January 2005 Durogesic® D-Trans®, a new fentanyl TTS, will be available that is cost neutral and offers several advantages over the current reservoir system, whilst maintaining all the benefits. This new TTS is based upon matrix technology and has been designed to carefully mimic the established pharmacokinetic profile of the reservoir system. As with the reservoir patch, steady state is achieved by the second application. Thus, the established efficacy and tolerability of Durogesic® can be transposed to Durogesic® D-Trans®. The active drug in Durogesic® D-Trans® is contained in a polymer matrix, rather than a gel reservoir. The drug is released at a rate governed by the components in the matrix; the amount delivered is proportional to the surface area of the patch, exactly the same as the reservoir patch. During the production process, a large sheet of matrix is manufactured in which the drug is evenly distributed. All four strengths of patch are effectively cut from this large sheet, the dose simply being dependent upon size.
Durogesic® D-Trans® is smaller and thinner than the equivalent reservoir patch. It is flexible and has a useful S-cut protective liner (see Figure 1). One of the problems patients often encountered with the reservoir patch was the removal of the patch from the liner. By incorporating the S-cut design, patients will find it easier to remove the protective liner from the matrix patch. Another important difference between the two products is the packaging. The reservoir patch is packaged in a simple pouch; the new matrix patch is packaged in a child resistant pouch. Poor adhesion and skin irritation represent occasional problems encountered with the reservoir patch. Durogesic® D-Trans® has been shown to have better adherence over a 72 hour period and cause less skin sensitisation than Durogesic®.(9)
Durogesic® D-Trans® is governed by the strict controlled-drug legislation as described in the Misuse of Drugs Act 1971 and Medicines Act 1968. Amongst other requirements, the form of the product has to be specified on a prescription. At present, 'transdermal fentanyl matrix patch" or "transdermal fentanyl reservoir patch" would suffice. Although Janssen-Cilag UK plan to cease supplying Durogesic® reservoir patches within the coming months, from June 2005 there remains the possibility of generic matrix and/or reservoir patches becoming available. The bioequivalence of such products cannot be guaranteed. As with other modified release preparations, and until guidance is provided, it is recommended that prescriptions for Durogesic® D-Trans® should include both the brand name and form.
Durogesic® D-Trans® represents an advance in the delivery of transdermal fentanyl. The new matrix patch is cost neutral and has been designed to mimic the pharmacokinetic profile of the reservoir patch, thereby maintaining the recognised benefits of transdermal delivery. Durogesic® D-Trans® offers improved adhesion and it is smaller, thinner, more flexible and easier to apply than the reservoir patch; it is also associated with less skin sensitisation. It will be available from the beginning of February, in child resistant packaging in the same four strengths as the reservoir, namely: 25, 50, 75 and 100 microgram per hour.
1.Zuurmond WW, Meert TF, Noorduin H. Partial versus full agonists for opioid-mediated analgesia focus on fentanyl and buprenorphine. Acta Anaesth Belg 2002; 53:193-201 2.Gupta SK, Southam M, Gale R et al. System functionality and physicochemical model of fentanyl transdermal system. J Pain Symptom Manage 1992; 7(Suppl):S17-26 3.Clark AJ, Ahmedzai SH, Allan LG, Camacho F et al. Efficacy and safety of transdermal fentanyl and sustained-release oral morphine in patients with cancer and chronic non-cancer pain. Curr Med Res Opin. 2004; 20:1419-1428 4.van Seventer R, Smit JM, Schipper RM, Wicks MA, Zuurmond WW. Comparison of TTS-fentanyl with sustained-release oral morphine in the treatment of patients not using opioids for mild-to-moderate pain. Curr Med Res Opin. 2003; 19:457-469 5.Gourlay GK. Treatment of cancer pain with transdermal fentanyl. Lancet Oncol. 2001; 2:165-172 6.Allan L, Hays H, Jensen NH, de Waroux BL et al. Randomised crossover trial of transdermal fentanyl and sustained release oral morphine for treating chronic non-cancer pain. Br Med J. 2001; 322:1154-1158 7.Mystakidou K, Parpa E, Tsilika E, Mavromati A. Long-term management of noncancer pain with transdermal therapeutic system-fentanyl. J Pain. 2003; 4:298-306 8.Jeal W, Benfield P. Transdermal Fentanyl. A Review of its Pharmacological Properties and Therapeutic Efficacy in Pain Control. Drugs. 1997; 53:109-138 9.Data on file. Janssen-Cilag 2005