Transdermal Analgesia

The only whiff of this topic comes from the core curriculum, which asks for knowledge of 'drug delivery systems: e.g. transdermal patch and iontophoretic systems'.

A 2018 SAQ on fentanyl patches and chronic pain (74% pass rate) was well answered, although examiners lamented a lack of knowledge of buprenorphine treatment.

A similar CRQ from 2020 (71% pass rate) left examiners feeling 'candidates lacked knowledge in the management and implications of analgesic patches', including perioperative implications.

Resources

Transdermal delivery is a non-invasive method of delivering medication through the skin surface, to achieve either a local or systemic effect

Advantages of transdermal drug administration

Simple

Non-invasive

Painless

Consistent delivery

More uniform plasma drug concentrations
i.e. avoids peak/trough levels associated with other routes

↓ adverse effects due to steadier plasma concentration

Improved bioavailability by avoiding hepatic 1^st-pass metabolism

Improved bioavailability by avoiding enzymatic & pH-associated deactivation

Easy & flexible termination of drug administration by removing the patch

↑ patient compliance due to ease of administration & convenience

Disadvantages of transdermal drug administration

Local irritation or sensitisation of the skin

Not all drugs suitable for transdermal delivery

Not suitable for those with poor peripheral blood flow e.g. the acutely shocked patient

Longer time to reach peak or steady-state concentrations

Opioid-induced respiratory depression which is not remedied by removing the patch

Relatively expensive compared to other routes of administration

Drug is stored in the transdermal drug delivery system (i.e. patch) in a reservoir or impregnated into the fabric of the patch
There's a high concentration of the drug in solution within the patch, which creates the concentration gradient for drug diffusion from the patch to the skin
Drug diffuses into the skin and creates a 'depot' in the stratum corneum
The drug is absorbed by the local capillary network and transported into the systemic circulation, thus maintaining the patch-skin concentration gradient

The rate of permeation (dm/dt) through the skin is governed by a variation of Fick's law:

The diffusion coefficient of the drug (D)
The constant concentration of the drug in the patch (Co)
The partition coefficient between the drug solution and the skin (P)
The thickness of the skin (h)

Where dm/dt = DCoP/h

It may take time for the drug to reach its minimum effective concentration, depending on drug characteristics
Once steady-state plasma concentration is reached, it is maintained as long as the patch is applied
When the patch is removed, drug concentrations decrease gradually according to context-sensitive half-time and the degree of reservoir in the skin

Drug factors favouring transdermal permeation

Low molecular weight (<500Da)
Affinity for both lipophilic and hydrophobic phases
Low melting point (which affects drug release)
Non-ionic
High potency i.e. effective at low dosage
Short half-life

A backing laminate or layer, which protects the patch from the environment
A membrane which controls the release of the drug from its reservoir and multi-layer patches
An adhesive which adheres the patch together, and the patch to the skin
The drug solution, in direct contact with the release liner
A release liner, which is removed before use

Types of patches

Single layer drug-in-adhesive patch

The adhesive layer adheres the various layers together and sticks the system to the skin and is responsible for releasing the drug

Multi-layer drug-in-adhesive patch

Multiple adhesive layers are responsible for release of the drug; one of the layers is for immediate release and the other layer is to control release of the drug from a reservoir

Reservoir patch

There is a separate drug layer as a liquid compartment, containing a drug solution or suspension, between a backing layer and a rate-controlling membrane; this results in a zero-order rate of release

Matrix patch

Contains a semi-solid matrix comprising a drug solution/suspension dispersed within a polymer pad in direct contact with the skin
The adhesive layer surrounds the drug layer partially overlaying it

Drug class	Drug name	Patch concentrations/dose
Opioid	Fentanyl	72hr patches of 12/25/50/75/100μg/hr
Opioid	Buprenorphine	7-day patch of 5/10/20µg/hr 96hr patch of 35/52.5/70µg/hr
Opioid	Sufentanil	Trial phase
Opioid	Oxycodone	Trial phase
NSAID	Diclofenacepolamine 1%	140mg/patch BD
TRPV1 antagonist	Capsaicin 8%	Trial phase
Local anaesthetic	Lidocaine 5%	700mg/patch for 24hrs
Local anaesthetic	Tetracaine 4%	Ametop; 45min pre-procedure
Local anaesthetic	Lidocaine 2.5% & Prilocaine 2.5%	EMLA; 1hr pre-procedure
Local anaesthetic	Lidocaine & Tetracaine	70mg each; 30min pre-procedure
Local anaesthetic	Bupivacaine	Trial phase

Fentanyl

Matrix or reservoir type patches
Licensed for palliative care, or in the BNF 'Chronic severe pain currently treated with an opioid analgesic (administered on expert advice)'
Maintains a constant plasma fentanyl concentration over a 72hr application, with a maximum between 12 and 24hrs

Benefits

Significantly improved pain control in patients with chronic pain
Blood flow and site of anatomical application does not affect rate of drug delivery
Slow elimination due to skin depot formation

Issues

Heat sources or increased body temperature can increase fentanyl delivery by up to a third
Slow increase in initial plasma fentanyl concentration so may need additional analgesia in the initial period
Unintentional overdose due to dosing errors, accidental exposure, and exposure of a patch to a heat source
Elimination slowed by CYP3A4 inhibiting drugs (ketoconazole, clarithromycin, verapamil, diltiazem, and amiodarone)

Fentanyl hydrochloride iontophoretic transdermal system

Transdermal opioid licensed for acute pain; for patient-controlled management of moderate-severe post-operative pain in the hospital environment
Incorporates a PCA system

The patient can press the on-demand button and receive a 40μg bolus over a 10min period
10min lockout (i.e. max six doses/hr)
Lasts for 24hrs and is then discarded

Benefits

Faster time to peak concentration (39min) than passive patches
No depot formation so rapid decrease in plasma concentrations as with IV administration
Equivalent analgesia to standard IV PCA morphine
No reports of ventilatory depression

Issues

Standard mild opioid-related side effects such as nausea, vomiting and pruritus
Application site reactions (erythema, vesicles, itching) in 13%

Buprenorphine

Comes as either 96hr (Transtec) or 7 day (Butrans) patches, both of a matrix design
Used for:

Moderate to severe chronic pain unresponsive to non-opioid analgesics in opioid-naïve patients (administered on expert advice)
Moderate-severe cancer and non-cancer pain in patients currently treated with an opioid analgesic

Benefits as for any transdermal system, especially increased compliance
Issues include higher rates of some opioid-associated side effects such as nausea/vomiting, dizziness and constipation with the 7 day patch vs. oral weak opioids

NSAIDs

1% diclofenacepolamine patches are licensed for epicondylitis and ankle sprains
Work via local/topical effect rather than a systemic effect
Slower onset than oral diclofenac (4.5hrs) but much longer duration of action after patch removal (9-12hrs)
Equi-analgesic as oral diclofenac, possibly superior
Only 2% systemic transfer so low rates of systemic NSAID-associated side-effects such as GI bleeding

Local anaesthetics

Lidocaine 5% patches work via direct local action with limited systemic absorption
Licensed for post-herpetic neuralgia
Used off-license for acute traumatic pain e.g. rib fractures, surgical chest drains

Perioperative considerations for the patient receiving transdermal opioids

Early identification of complex patients during pre-assessment process to facilitate forward planning
Involvement of an MDT of anaesthetists, pain specialists, psychologist, GP, occupational therapists and physiotherapists

Prevention of withdrawal

Sudden cessation, rapid reduction or reversal of opioid transdermal analgesia risks withdrawal symptoms
Generally recommended that the patient's baseline opioid is continued in the post-operative period

Buprenorphine patches of 70μg/hr are unlikely to interfere with the use of full opioid agonists for acute pain management

Acute post-surgical pain is then managed with additional, immediate-release opioids

Intra-operative considerations

Perioperative warming devices may increase drug delivery
Equally, reduced temperature may reduce delivery
Poor perfusion to the patch e.g. due to hypotension, tourniquets, may reduce drug delivery

Use of opioid-sparing techniques

Regular simple analgesics i.e. paracetamol and NSAIDs

Use of local or regional anaesthetic techniques including catheters and neuraxial locks
IV lidocaine infusions, either intra- or post-operatively

Beneficial in those with chronic pain/opioid tolerance/substance abuse or at risk of acute pain on a background of hyperalgesia

Ketamine is recommended in the management of acute pain in the opioid-tolerant patient

Reduces post-operative pain scores and opioid use
Attenuates opioid-induced hyperalgesia
Low-dose, continuous IV or subcutaneous infusion for 24-72hrs

E.g. 100-200mg/24hrs (200mg ketamine and 5mg midazolam made up to 48ml infused at a rate of 1-2ml/hr)

Gabapentinoids may play a role as an opioid-sparing adjunct in the opioid-tolerant patient, even though they are less beneficial for opioid-naïve patients

E.g. gabapentin 100-300mg TDS or pregabalin 50-75mg BD

Involvement of the acute pain service
Dose of immediate-release opioids required may be greater than expected
Traditionally, the 4hrly PRN dose is 1/6th of the cumulative oral opioid dose in the preceding 24hrs
May be safer to start at 'standard' doses and up-titrate as necessary
Patients may require a PCA, with the bolus dose based on the patient's usual 24hr opioid requirement