Transdermal Medications

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Transdermal is a delivery system designed to allow for the penetration of a medication through the skin. In Musculoskeletal and Pain Medicine it refers to medications applied topically to treat pain. This could be Medsafe approved products or compounded products.

Introduction

There are some potential advantages of transdermal over oral medications.

  • Negligible systemic effect
  • Lowers adverse drug interactions
  • Direct delivery to pain receptors, potentially at higher concentrations
  • Minimal abuse and addiction
  • Avoid first-pass effect and reduces organ toxicity
  • Reduces opioid tolerance
  • Rapid termination and likely to produce fewer side effects
  • Combining multiple medications in a single product

Absorption is affected by

  • Skin type: from best absorption to worst is genitals > head/neck > trunk > arm > leg
  • Age: Skin is more permeable in the very young and elderly.
  • Vicinity to vessels. Applying close to a vessel will increase systemic absorption.

Bases

Skin has an aqueous environment in the dermis along with a lipid rich environment in the stratum corneum. This poses a challenge for transdermal delivery of medications.

The challenge was initially solved through the development of Pluronic Lethicin Organogel (PLO). This compound has a hydrophilic base called pluronic and a lipophilic base called lethicin isopropyl palmitate. This combination was mixed together (along with the drug) under pressure producing an ointment with both lipophilic and hydrophilic properties with drug micelles that are able to penetrate through this skin. This was the gold standard for many years but had downsides. It was very tacky and greasy, and if it got too cold it would split.

Later the base Lipoderm was developed which was superior in many respects. This is a creamer base than PLO and so is cosmetically more acceptable. It does not separate and has less chance of sensitivity. Compared to PLO lipoderm significantly increased skin penetration and retention, sometimes up to three times as effective as PLO. It can be further modified for example by adding pentylene glycol which enhances permeation slightly.

The base for mucosal tissue (such as for intravaginal use) is Mucolox.

There are multiple other specialised bases for different uses.

Options for Compounding

Agents can be mixed together to allow for the targeting of multiple receptors.

  • NSAIDs: Diclofenac (up to 10% compared to 2% OTC), ibuprofen (up to 20%), ketoprofen (up to 20%).
  • Neuropathic agents: Amitriptyline 2%, Gabapentin 6%
  • Anaesthetics: Lidocaine 6%, Benzocaine 20%, Tetracaine 4%
  • Muscle Relaxants: Baclofen 5%., Guaifenesin 10%, Magnesium Chloride Hexahydrate 10%, Sodium Bicarbonate 1% Topical Lipoderm
  • Clonidine: alpha receptor agonist, decreases sympathetic flow and suppresses the release of Na in sympathetic nerves
  • Menthol/camphor: counter irritants
  • Loperamide: mu receptor agonist can be exchanged for morphine.'
  • Ketamine: High potency NMDA antagonist with minimal absorption. For example 2%.

Prescribing

Writing a compounded transdermal pain prescription includes the percentages of active pharmaceutical ingredients and the transdermal base. The following is an example for the prescribing of a compounded product for neuropathic pain. API means active pharmaceutical ingredient. APIs should be kept at less than 30% total to be cosmetically acceptable.

  • API (anaesthetic) %
  • API (anticonvulsant) %
  • API (hypotensive) %
  • API (muscle relaxant)%
  • Transdermal Base (Example: Lipoderm)

Some examples:

  • Knee pain: Ketoprofen 20%, lidocaine 5% +/- gabapentin 6% if burning, in lipoderm
  • Sciatica: Gabapentin 5%, ketoprofen 10%, lidocaine 2%, in lipoderm
  • Trigger points: Ketamine 5%, gabapentin 10%, clonidine 0.2%, baclofen 2%, in lipoderm
  • Muscle spasms: Guaifenesin 10%, magnesium sulfate heptahydrate 10%, in lipoderm
  • Back pain: Guaiphensen 10%, ketoprofen 10%, in lipoderm
  • Burning mouth syndrome: Amitriptyline 2%, gabapentin 6%, lidocaine 0.5%, in MucoLox.
  • Shingles: Gabapentin 6%, ketamine 10%, clonidine 0.2%, lidocaine 5%, in Lipoderm
  • Nuclear options: Ketamine 10%, diclofenac 8%, gabapentin 6%, cyclobenzaprine 2%, baclofen 2%, in Lipoderm ActiveMax

There is limited information exactly how deep the medications can penetrate.

Application

A pump is a good option which give a controlled amount of drug.

The patient should wash their hands before and after use and they may wish to use a glove. The cream should be rubbed into the affected area gently until it is no longer visible, and then continue rubbing for another 60 seconds to allow for deeper penetration. Don't allow the area to get wet for at least one hour as peak absorption may only occur after an hour. No occlusive dressings/bandages are required.

Standards

The PCCA have meticulous standards for approved compounders. The standards are around efficacy, safety, and use by dates.

Cost

Compounded transdermal formulations are very expensive, typically costing several hundred dollars a month.

Bibliography

Bassani, A. S., & Banov, D. (2016). Evaluation of the percutaneous absorption of ketamine HCl, gabapentin, clonidine HCl, and baclofen, in compounded transdermal pain formulations, using the Franz finite dose model. Pain Medicine, 17(2), 230-238. DOI

Bassani, A. S., Banov, D., & Phan, H. (2015). In vitro characterization of the percutaneous absorption of lorazepam into human cadaver torso skin, using the Franz skin finite dose models. Journal of Pharmaceutics & Drug Delivery Research, 4(2). DOI

Bassani, A. S., Banov, D. & Phan, H. (2016). Characterization of the percutaneous absorption of ketoprofen using the Franz skin finite dose model. Postgraduate Medicine, 128(2), 262-267. DOI

Bassani, A. S., Banov, D., Simmons, C., & Phan, H. (2015). In vitro characterization of the percutaneous absorption of tramadol into inner ear domestic feline skin using the Franz skin finite dose model. Veterinary Medicine and Animal Sciences, 3(3). DOI

Bassani, A. S., Banov, D., & Lehman, P. A. (2008). Evaluation of the percutaneous absorption of promethazine hydrochloride, in vitro, using the human ex vivo skin model. International Journal of Pharmaceutical Compounding, 12(3), 270-273. Retrieved from https://www.ijpc.com/

Branvold, A. & Carvalho, M. (2014). Pain management therapy: The benefits of compounded transdermal pain medication. Journal of General Practice, 2(6). DOI