Transdermal Opoids

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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, oint-

ments, 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 first 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 nico-

tine patches for smoking cessation were intro-

duced in 1991.

TDDS offer pharmacological advantages

over the oral route and improved patient accept-

ability 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 suit-

able are detailed in Table 1.

Skin structure

The skin is the largest organ in the body; it pro-

tects against the influx of toxins and the efflux

of water and is largely impermeable to the pen-

etration of foreign molecules. Human skin con-

sists of three main layers: the epidermis, dermis,

and hypodermis (Fig. 1). The epidermis, in par-

ticular the stratum corneum, acts as the major

barrier to drug absorption. The stratum corneum

contains only 20% of water and is a highly lipo-

philic membrane; it is 10–20 mm thick depend-

ing 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 struc-

tural layers, encountering several lipophilic and

hydrophilic domains on the way to the dermis

where absorption into the systemic circulation is

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 flux. 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.

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 capil-

lary 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 com-

pletely only after two to three patch applications.

Thereafter, the steady state is maintained for as

long as a patch is applied. The advantage of

Key points

The transdermal route fordrug delivery avoids firstpass metabolism and largevariations in plasma drugconcentrations.

The stratum corneum is the

greatest barrier totransdermal transport.

Drugs suitable fortransdermal administrationhave a low molecular weightand high lipid solubility.

There are two types of patches available: reservoirand matrix systems.

Opioid patches arefrequently utilized inchronic malignant and non-malignant pain management.

Lyn Margetts FRCA

Specialist Registrar in AnaesthesiaDerriford Hospital

PlymouthUK

Richard Sawyer FRCA FIPP

Consultant in Anaesthesia andPain Management

Eric Angel Pain ClinicLevel 7

Derriford HospitalPlymouth PL6 8DH

UK Tel: þ44 1752 792525Fax: þ44 1752 517556

E-mail: [email protected] (for correspondence)

171doi:10.1093/bjaceaccp/mkm033Continuing 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]



TDDS is that continuous drug delivery is provided with better

patient compliance. Figure 2 shows the difference in plasma con-

centrations 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 drug’s context sensi-

tive half-time and whether a reservoir has been formed in the skin.

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

flux.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 flux dm /dt ,

dm

dt ¼ DC oK

h

where D is the diffusion coefficient, C o the constant concentration

of drug in donor solution, K the partition coefficient 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 mole-

cular mass (high D), adequate solubility in oil (high C o), and a

moderately high partition coefficient. 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

Fig. 1 Cross-section through the skin.

Table 1 Transdermal patches licensed in the UK and conditions for which they are

indicated

Active ingredient Indication

Buprenorphine Analgesia

Clonidine Hypertension

Oestradiol Hormone replacement

Oestradiol and progesterone Hormone replacement

Ethinyloestradiol, Norelgestromin Contraception

Fentanyl Analgesia

Glyceryl trinitrate Angina

Hyoscine Motion sickness

Lisuride Parkinson’s disease/restless legs syndrome

Nicotine Smoking cessation

Testosterone Hypogonadism

Transdermal drug delivery

172 Continuing Education in Anaesthesia, Critical Care & Pain j Volume 7 Number 5 2007



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 over-

dose as potentially a larger area of skin is exposed for drug absorp-

tion. In a matrix patch, the active ingredient is distributed evenly

throughout the patch. One-half of a patch will have half the orig-

inal 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 specific drug utilized in a TDDS will have its unique

side-effects. This article will focus primarily on the opioid

TDDS—fentanyl and buprenorphine; the problems with these

drugs are discussed later.

Fig. 3 Cross-section through a reservoir patch.

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 Buprenorphine Morphine

Molecular weight 286 468 337

Aqueous solubility (mg ml21

) 1:30 –100 1:1000 –10 000 1:5000

Octanol/water coefficient (Log P)

at pH 7.4

2.3 4.98 20.1

Skin flux (mg cm22 h21) 1 1.4 0.006


Continuing Education in Anaesthesia, Critical Care & Pain j Volume 7 Number 5 2007 173



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 beeninvestigated; they can be either chemical or physical. Chemical

methods that have been utilized include adding ethanol or propy-

lene glycol to drugs to enhance solubility.

Physical methods include the use of iontophoresis. This is the

application of an electric field to drive charged particles across the

skin.4 The charged drug is dissolved in an electrolyte solution sur-

rounding 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, aprocess 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 iontophor-

etic patch with a facility for patient-controlled analgesia (PCA)

and bolus fentanyl delivery has been developed recently.

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.

The Durogesic reservoir patch is currently being phased out and

replaced with DTrans—a 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 con-

stant 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, gene-

rally 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 first 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 fenta-

nyl from the skin depot.

The gradual increase in plasma concentration when a fentanyl

patch is first applied means that some other analgesic is likely to

be necessary in the first 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.

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 fixed 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

Fig. 4 Cross-section through a matrix patch.





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 pre-

programmed fixed dose; although this eliminates the possibility of

programming errors, it means that the device will be unsuitable forthose 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 h

21 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 affinity of buprenorphine for opioid receptors. Patients withsevere side-effects should be observed for 30 h after removal of

the patch. A recent development is the release of a 7 day buprenor-

phine patch. This buprenorphine patch is a matrix system, available

in three sizes, delivering 5, 10, or 20mg h21 of buprenor-

phine over 7 days, and licensed for the treatment of moderate to

severe pain.

Clinical efficacy of opioid TDDS

Opioid TDDS have proven to be efficacious in the long-term man-

agement 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 prefer-

ence for transdermal drug delivery as this is associated with less

side-effects (e.g. constipation) and is more convenient. Improve-

ments 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, con-

centration, and memory. Ability to drive motor vehicles has been

investigated; there was no significant difference in performance

measures between patients with fentanyl patches and controls.

However, it is probably wise to advise patients to abstain from

driving if their opioid dose is being changed or if they are experi-

encing any neuropsychological side-effects.

Unintended exposure is also a real but rare complication.

Children can be exposed to the drug by patches being inadvertentlytransferred 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 patientsusing opioid patches

There is little evidence-base to guide the most appropriate manage-

ment of acute pain in patients on long-term opioid medication. As

a general principle, the patient’s 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 patient’s 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 patient’s usual opioid dose will

lead to withdrawal symptoms.

† The opioid dose given via TDDS must never be adjusted inan 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.

References

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