Transdermal drug delivery: principles and opioid therapy

Lyn Margetts FRCA Richard Sawyer FRCA FIPP

The application of medications to the skin to ease ailments is a practice that has been utilized by humankind over the millennia and has included the application of poultices, gels, ointments, creams, and pastes. These applications were primarily intended for a local topical effect. The use of adhesive skin patches to deliver drugs systemically is a relatively new phenomenon.1 The rst adhesive transdermal delivery system (TDDS) patch was approved by the Food and Drug Administration in 1979 (scopolamine patch for motion sickness). Nitroglycerine patches were approved in 1981. This method of delivery became widely recognized when nicotine patches for smoking cessation were introduced in 1991. TDDS offer pharmacological advantages over the oral route and improved patient acceptability and compliance. As such, they have been an important area of pharmaceutical research and development over the last few decades. Conditions for which TDDS are suitable are detailed in Table 1.

rapid due to the large capillary bed. Removing the stratum corneum speeds the diffusion of small water-soluble molecules into the systemic circulation by up to 1000 times.2 Alternatively, hydrophilic compounds can reach the dermis via shunt pathways such as hair follicles, sweat glands, nerve endings, and blood and lymph vessels. These routes contribute minimally to steady-state drug ux. The dermis is the thickest layer of the skin (3 5 mm) and possesses hair follicles, sweat glands, nerve endings, and blood and lymph vessels. It acts as the systemic absorption site for drugs. There are variations between individuals in the rate at which drugs are absorbed via the skin due to factors such as thickness of the stratum corneum, skin hydration, underlying skin diseases or injuries, ethnic differences, and body temperature.

Key points The transdermal route for drug delivery avoids rst pass metabolism and large variations in plasma drug concentrations. The stratum corneum is the greatest barrier to transdermal transport. Drugs suitable for transdermal administration have a low molecular weight and high lipid solubility. There are two types of patches available: reservoir and matrix systems. Opioid patches are frequently utilized in chronic malignant and nonmalignant pain management.

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Pharmacokinetics of transdermal drug delivery

The drug is stored in the TDDS either in a reservoir or impregnated into the fabric of the patch. On applying the TDDS to the skin, a drug concentration gradient is developed and the drug starts to move down the gradient. A second drug reservoir is established in the stratum corneum. As the drug moves further into the skin, it is absorbed into the local capillary vasculature and is then transported into the systemic circulation. As a result of this absorption process, there is a delay between TDDS application and the development of a desired minimum effective concentration (MEC). This delay varies between drugs. There is an initial period in which drug concentrations are hardly measurable. The time to reach steady-state plasma concentrations varies considerably and may be achieved completely only after two to three patch applications. Thereafter, the steady state is maintained for as long as a patch is applied. The advantage of

Skin structure
The skin is the largest organ in the body; it protects against the inux of toxins and the efux of water and is largely impermeable to the penetration of foreign molecules. Human skin consists of three main layers: the epidermis, dermis, and hypodermis (Fig. 1). The epidermis, in particular the stratum corneum, acts as the major barrier to drug absorption. The stratum corneum contains only 20% of water and is a highly lipophilic membrane; it is 10 20 mm thick depending on its state of hydration. The thickness of the epidermis varies from 0.06 mm on eyelids to 0.8 mm on the soles of the feet. An applied drug must traverse these structural layers, encountering several lipophilic and hydrophilic domains on the way to the dermis where absorption into the systemic circulation is

Lyn Margetts FRCA Specialist Registrar in Anaesthesia Derriford Hospital Plymouth UK Richard Sawyer FRCA FIPP Consultant in Anaesthesia and Pain Management Eric Angel Pain Clinic Level 7 Derriford Hospital Plymouth PL6 8DH UK Tel: 44 1752 792525 Fax: 44 1752 517556 E-mail: [email protected] (for correspondence)

doi:10.1093/bjaceaccp/mkm033 Continuing Education in Anaesthesia, Critical Care & Pain | Volume 7 Number 5 2007 & The Board of Management and Trustees of the British Journal of Anaesthesia [2007]. All rights reserved. For Permissions, please email: [email protected]

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Table 1 Transdermal patches licensed in the UK and conditions for which they are indicated Active ingredient Buprenorphine Clonidine Oestradiol Oestradiol and progesterone Ethinyloestradiol, Norelgestromin Fentanyl Glyceryl trinitrate Hyoscine Lisuride Nicotine Testosterone Indication Analgesia Hypertension Hormone replacement Hormone replacement Contraception Analgesia Angina Motion sickness Parkinsons disease/restless legs syndrome Smoking cessation Hypogonadism

Effect of drug characteristics

The properties of a drug that enable good penetration through the stratum corneum can be deduced from the equation for steady-state ux.2 When the cumulative mass of a diffusant, m, passing per unit area through a membrane is plotted, after time t, the graph approaches linearity and the slope yields the steady ux dm/dt, dm DCo K h dt where D is the diffusion coefcient, Co the constant concentration of drug in donor solution, K the partition coefcient of solute between membrane and bathing solution, and h the thickness of the membrane. Therefore, for a drug to penetrate well, it should have low molecular mass (high D), adequate solubility in oil (high Co), and a moderately high partition coefcient. All of the drugs currently available in patch formulation share three features that enable administration through a convenient area of skin: molecular mass ,500 Da; high lipophilicity; and low required daily dose (,2 mg). The comparison of the physicochemical properties of fentanyl, buprenorphine, and morphine (Table 2) demonstrates

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TDDS is that continuous drug delivery is provided with better patient compliance. Figure 2 shows the difference in plasma concentrations of buprenorphine achieved with regular sublingual dosing and with TDDS application. After removal of TDDS patches, drug concentrations decrease gradually. The rate of decline depends on the drugs context sensitive half-time and whether a reservoir has been formed in the skin.

Fig. 1 Cross-section through the skin.

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Fig. 2 Comparison of plasma concentrations of buprenorphine after single application of 35 mg h21 patch (removed after 72 h) and sublingual dosing of 400 mg buprenorphine, eight hourly.

Table 2 Physicochemical properties of fentanyl, buprenorphine, and morphine Fentanyl Molecular weight Aqueous solubility (mg ml21) Octanol/water coefcient (Log P) at pH 7.4 Skin ux (mg cm22 h21) 286 1:30 100 2.3 1 Buprenorphine 468 1:1000 10 000 4.98 1.4 Morphine 337 1:5000 20.1 0.006

why fentanyl and buprenorphine are suitable for transdermal delivery.3

Transdermal delivery systems

There are two designs of transdermal patch currently available: the reservoir, or membrane-controlled system, and the matrix system. A reservoir patch holds the drug in a gel or solution and delivery is determined by a rate-controlling membrane between the drug reservoir and the skin (Fig. 3). The matrix patch (Fig. 4) incorporates the drug into an adhesive polymer matrix, from which the drug is continuously released into the skin. The dose of drug delivered depends on the amount of drug held in the matrix and the area of the patch applied to the skin.

The problem of inter-patient variability in drug absorption by the skin is managed in both systems using a slow rate of drug release from the patch. In the reservoir patch, the membrane limits the rate of drug delivery; in the matrix system, it is the formulation of the drug/polymer matrix. Reservoir patches give tighter control of delivery rates but can have an initial burst of drug release. If the membrane is damaged, there is also a risk of sudden release of drug into the skin and overdose as potentially a larger area of skin is exposed for drug absorption. In a matrix patch, the active ingredient is distributed evenly throughout the patch. One-half of a patch will have half the original surface area and deliver half the original dose per hour. The matrix patch carries less risk of accidental overdose and offers less potential for abuse than the reservoir system. Common general problems with TDDS systems relate to the adhesive. Minor to severe local allergic skin reaction can occur. These are often managed by removing the TDDS; occasionally, a steroid-based cream may need to be applied to the affected area. TDDS may also be poorly adherent if the skin is oily, exposed to water or sweating. Each specic drug utilized in a TDDS will have its unique side-effects. This article will focus primarily on the opioid TDDSfentanyl and buprenorphine; the problems with these drugs are discussed later.

Fig. 3 Cross-section through a reservoir patch.

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Fig. 4 Cross-section through a matrix patch.

Improving transdermal drug delivery

The limitations on drug delivery caused by the barrier function of the skin have led to a search for methods of improving delivery of drugs through the stratum corneum. Many methods have been investigated; they can be either chemical or physical. Chemical methods that have been utilized include adding ethanol or propylene glycol to drugs to enhance solubility. Physical methods include the use of iontophoresis. This is the application of an electric eld to drive charged particles across the skin.4 The charged drug is dissolved in an electrolyte solution surrounding an electrode of the same polarity and placed in contact with the skin. The opposing electrode placed elsewhere on the body completes the circuit. When an electromotive force is applied, the drug is repelled from the electrode into the skin and passes across the stratum corneum, towards the opposite electrode. The movement of charged molecules causes convective motion of the solvent, which drags neutrally charged molecules along, a process called electro-osmosis. The passage of electric current may also transiently increase the permeability of the skin. Iontophoresis can be used to deliver boluses of a drug, and has been utilized in the development of the fentanyl PCA patch (discussed later).

Opioid transdermal drug delivery systems

The transdermal delivery of opioids provides some advantages. It avoids the peaks and troughs of intermittent dosage regimens that can lead to side-effects such as sedation, nausea and vomiting, and respiratory depression. The reduced need for dosage administration (72 hourly or weekly) also improves patient compliance. Fentanyl and buprenorphine patches are used in the treatment of cancer and chronic pain. Patch pharmacokinetics render them unsuitable for the treatment of acute pain. However, an iontophoretic patch with a facility for patient-controlled analgesia (PCA) and bolus fentanyl delivery has been developed recently.

The Durogesic reservoir patch is currently being phased out and replaced with DTransa matrix design. In addition to decreasing the risk of accidental overdose with membrane damage, the new matrix system is smaller and thinner than the reservoir. Fentanyl patches are designed to deliver fentanyl at four constant rates: 25, 50, 75, and 100 mg h21 for a period of 72 h. After initial application, a depot of fentanyl forms in the upper skin layers and serum fentanyl concentrations increase gradually, generally levelling off between 12 and 24 h. The steady-state serum concentration is reached after 24 h and maintained as long as the patch is renewed. However, variations have been found in serum fentanyl concentration during the 72 h period; concentrations tend to be higher in the rst 24 h and decrease on the second and third day due to the decreasing concentration gradient between patch and skin. Fentanyl delivery is not affected by local blood supply, but an increase in body temperature up to 408C can increase absorption rate by about 30%.5 Fentanyl is metabolized by the P450 cytochrome enzyme system to inactive metabolites and thus drugs that enhance or inhibit cytochrome function will affect metabolism, for example, cimetidine and isoniazid. The elimination half-life after patch removal is 13 22 h, this is probably due to slow release of fentanyl from the skin depot. The gradual increase in plasma concentration when a fentanyl patch is rst applied means that some other analgesic is likely to be necessary in the rst 12 h. The delayed fall in plasma fentanyl concentration means that replacement opioid therapy should be initiated gradually after patch removal, and those patients who have severe side-effects should be monitored for 24 h. Dosage adjustments should not be made at ,72 h intervals.

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Fentanyl patient-controlled transdermal system

The fentanyl patient-controlled transdermal system (PCTS) is approximately the size of a credit card and is worn on the upper arm or chest.6 Iontophoresis is utilized to deliver xed drug boluses. There is no background infusion, and passive absorption from the system is negligible. Plasma fentanyl concentrations decline rapidly after patch removal. Fentanyl PCTS 40 mg has been shown to be superior to placebo7 and equivalent to

Fentanyl TDDS (reservoir and matrix)

Fentanyl is soluble in both fat and water; with a low molecular weight and high potency, it is ideal for transdermal delivery.

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i.v. morphine PCA for the treatment of acute postoperative pain.8 The fentanyl PCTS has the advantage of being less cumbersome than i.v. systems but a potential disadvantage is the preprogrammed xed dose; although this eliminates the possibility of programming errors, it means that the device will be unsuitable for those patients with higher opioid requirements.

Buprenorphine TDDS (matrix)

Buprenorphine is a partial agonist at m-receptors; it is 60 times more potent than morphine. A ceiling effect is reached at doses of .16 mg day21. This does not happen in clinical practice as the patches are designed to deliver 35, 52.5, or 70 mg h21 and the maximum dose is 3.36 mg day21 (two 70 mg h21 patches). Effective plasma concentrations are reached within 12 24 h of patch application. As with fentanyl, metabolism is by the CYP 3A4 system, but offset after patch removal is slower due to the high afnity of buprenorphine for opioid receptors. Patients with severe side-effects should be observed for 30 h after removal of the patch. A recent development is the release of a 7 day buprenorphine patch. This buprenorphine patch is a matrix system, available in three sizes, delivering 5, 10, or 20 mg h21 of buprenorphine over 7 days, and licensed for the treatment of moderate to severe pain.

However, it is probably wise to advise patients to abstain from driving if their opioid dose is being changed or if they are experiencing any neuropsychological side-effects. Unintended exposure is also a real but rare complication. Children can be exposed to the drug by patches being inadvertently transferred onto the child after hugging an adult with a patch on. It is very important to avoid children coming into contact with opioid patches; fatal consequences have been reported.

Perioperative pain management of patients using opioid patches

There is little evidence-base to guide the most appropriate management of acute pain in patients on long-term opioid medication. As a general principle, the patients usual pre-admission regimen should be maintained where possible and additional analgesia given to cover the acute painful stimulus. The following are general guidelines. Involve the hospital acute pain team early. Cover the patients baseline opioid requirement, the options are to leave the TDDS on or to change to an equivalent opioid dose via i.v. infusion. Where possible, continue the usual TDDS regimen to cover the chronic pain element. Remember to use multi-modal analgesia; regional blocks, NSAIDs, acetaminophen. If using strong opioids for postoperative analgesia, higher than usual bolus doses will be needed. Cessation or reduction of the patients usual opioid dose will lead to withdrawal symptoms. The opioid dose given via TDDS must never be adjusted in an attempt to control the acute pain. Ensure that everyone involved in the care of the patient is aware of the TDDS and the strategy for pain management.

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Clinical efcacy of opioid TDDS

Opioid TDDS have proven to be efcacious in the long-term management of chronic malignant and non-malignant pain.9,10 Transdermal opioids have found applications in managing patients suffering with chronic low back pain and chronic musculoskeletal disorders. In both groups, patient satisfaction is greater with preference for transdermal drug delivery as this is associated with less side-effects (e.g. constipation) and is more convenient. Improvements in measures of quality of life have also been reported in cancer pain patients receiving opioid TDDS. Transdermal patches are open to abuse, sometimes with fatal consequences. There are reports of fentanyl being extracted from patches for i.v. injection. This was a particular problem with the reservoir patch. Respiratory depression and cognitive dysfunction are important side-effects of opioid patches. Patients should be clearly educated about the potential adverse effects and cautioned against using alcohol or other sedative medication concurrently with opioid patches. Because of the unique pharmacokinetics of the TDDS systems, the depressive effects are not immediately reversed by patch removal; in emergency situations, i.v. naloxone may be required to reverse this sedative effect. Patients and carers must be clearly educated about this. Cognitive dysfunction can present with a wide range of neuropsychological side-effects, including mental dullness, euphoria, and reduced attention, concentration, and memory. Ability to drive motor vehicles has been investigated; there was no signicant difference in performance measures between patients with fentanyl patches and controls.

References
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postoperative analgesia: a multicenter, placebo-controlled trial. Anesth Analg 2004; 98: 42733 8. Viscuzi ER, Reynolds L, Chung F, Atkinson LE, Khanna S. Patient-controlled transdermal fentanyl hydrochloride vs. intravenous morphine pump for postoperative pain. JAMA 2004; 291: 1333 41

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