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By Beau Harger, PharmD, PCCA Clinical Compounding Pharmacist

I remember my first experience with compounding, which interestingly turned out to be a topical pain preparation using a permeation-enhancing base. I was a pharmacist intern at a compounding pharmacy back in the summer of 1998, in a small town on the Mississippi Gulf Coast. We were using a combination of ibuprofen, piroxicam and cyclobenzaprine in PLO (PCCA Formula #3444) for patients with inflammatory conditions.

I couldn’t believe that it would be possible to drive these drugs through the skin to the site of inflammation. They didn’t teach this in pharmacy school. It was such an influential experience that the light bulb went on in my head, and I knew I was going to have a future in compounding. Now here I am, working at PCCA. Some of the compounding tools have changed, and the needs of patients have multiplied.

Patients in Pain

An analysis of data from the 2019 National Health Interview Survey showed that nearly 50.2 million adults (20.5%) in the United States reported pain on most days or every day. Common locations of pain were the back, hip, knee or foot.1 Aside from the pain epidemic in general, this is especially important in the current environment of drug addiction and opioid abuse. The Centers for Disease Control and Prevention found that almost 50,000 Americans died from opioid-related overdoses in 2019 alone. It has also estimated that the total cost of prescription opioid misuse in the United States is as much as $78.5 billion per year. The National Institute on Drug Abuse characterizes opioid misuse and addiction as “a serious national crisis that affects public health as well as social and economic welfare.”2

Physicians are coming under scrutiny for prescribing opioid medications as well, and they are looking for better options for their patients. Furthermore, The BMJ recently published a meta-analysis of data on 446,763 Canadian and European patients suggesting that oral NSAID use for more than one week increases the risk of myocardial infarction, and that higher doses corresponded with greater risk.3 This is where the compounding pharmacist comes in.

Also on The PCCA Blog: Lidocaine vs. Lidocaine HCl in Pharmacy Compounding

There is a need and a place for the delivery of drugs through the skin due to the side-effect profile of many oral medications, a tendency for abuse of and addiction to opioid medications, administration challenges, prescriber challenges, and lack of efficacy of traditional therapies. 4 Benefits of topical administration using a permeation-enhancing base may include convenience and ease of administration, improved patient compliance, and allowing for less frequent dosing.5

As a result, the use of permeation-enhancing topical pain medications may be considered a viable alternative to oral pain therapies in many patients. There are a multitude of studies to show that the active pharmaceutical ingredients (APIs) we use have merit and clinical relevance today. 6,7 (For clinical information on a specific API, PCCA members can click on the Clinical References tab when viewing the API on PCCA’s website after logging in.)

Evolution of Pain Creams

Human skin has many functions, and its most apparent one is that of a defense organ, both physical and biological. Penetration of any compound into the body is primarily prevented by the corneal layer of the epidermis. This outer layer is just a few micrometers thick, but effectively forms a barrier that preserves life. The 500 Dalton rule states that when molecular weight increases to over 500 Daltons, absorption of molecules through normal skin rapidly declines.8 This further highlights the importance of using a base that will transverse the skin.

First Generation

The first widely recognized compounded topical base with permeation enhancement was Pluronic® lecithin organogel (PLO). This is an oil-and-water emulsion introduced as a drug-delivery vehicle in the 1990s. 9 The technology was derived from studies on “organogels” created from incorporating lecithin into organic solvents.10 One study involved using Pluronic 20% with ketoprofen on carrageenan-induced paw edema in rats.11 This base was quite revolutionary in the compounding world and led to many drugs being used that had never been delivered in this way before. However, PLO is considered first generation, and more advanced versions of permeation-enhancing topical bases have been introduced.

Current Generation

The Lipoderm® family is a collection of current-generation, proprietary, permeation-enhancing bases that are improvements over PLO in consistency, stability and penetration.12,13,14,15 In a comparison study, Lipoderm outperformed PLO when evaluating the percutaneous absorption of promethazine.15 Lipoderm also has been shown to successfully deliver four pain medications, including ketamine hydrochloride, gabapentin, clonidine hydrochloride and baclofen, simultaneously into human skin.12 A topical cream base without permeation-enhancing properties does not have these characteristics and may stay on top of the epidermis. Physicians may be very interested in the differences and the importance of using true permeation-enhancing vehicles versus topical vehicles when considering positive patient outcomes. Topical pain management with the permeation-enhancing bases in the Lipoderm family can be used to address patients with conditions of inflammation, musculoskeletal pain and neuropathic pain, to name a few. Prescribers can review clinical data on these bases on the PCCA Science webpage .

Also on The PCCA Blog: Compounding for Patients in Hospice Care

Newest Innovation

With more recent industry changes related to stability requirements and higher workflow demands, compounders are looking for cost-effective ways to extend beyond-use dates and save money on stability testing. To help meet these needs, PermE8® Anhydrous Gel is a base from PCCA that uses new technology to deliver drugs through the skin using an anhydrous vehicle. This will allow the compounder to use extended beyond-use dates according to USP 795 standards and still provide the same permeation-enhancing quality that compounders are used to with the Lipoderm family.16

This is an incredible opportunity for compounding pharmacists. Patients in pain can be very challenging to treat, and their quality of life is often negatively affected by their painful conditions. Compounding pharmacists can be of great value to both prescribers and their patients who are suffering.

PCCA members with Clinical Services support can access many PCCA formulas in our database that are commonly requested for patients with inflammatory pain , musculoskeletal pain , general neuropathic pain and diabetic neuropathy , among others. If they have any questions about permeation-enhancing topical compounds, they can contact our Clinical Services team.

Also on The PCCA Blog: Permeation-Enhanced Topical Pain Therapy: A Literature Review

Beau Harger, PharmD, is a graduate of the University of Mississippi. He joined the staff of PCCA in January 2015 as a full-time clinical compounding pharmacist after working as a part-time consultant for the previous year and a half. He came to PCCA with 15 years of compounding experience. He also taught pharmacology at William Carey College in Gulfport, Mississippi, and was the pharmacist in charge of Nucara Compounding Pharmacy in Austin, Texas, for eight years.

Photo by Nati Melnychuk on Unsplash.

A version of this article originally appeared in PCCA’s members-only magazine, the Apothagram.

References

  1. Yong, R. J., Mullins, P. M., & Bhattacharyya, N. (2021). Prevalence of chronic pain among adults in the United States. Pain. Advance online publication. https://doi.org/10.1097/j.pain.0000000000002291
  2. National Institute on Drug Abuse. (2021). Opioid overdose crisis. Retrieved December 16, 2021, from https://www.drugabuse.gov/drug-topics/opioids/opioid-overdose-crisis
  3. Bally, M., Dendukuri, N., Rich, B., Nadeau, L., Helin-Salmivaara, A., Garbe, E., & Brophy, J. M. (2017). Risk of acute myocardial infarction with NSAIDs in real world use: Bayesian meta-analysis of individual patient data. The BMJ, 357. https://doi.org/10.1136/bmj.j1909
  4. Branvold, A., & Carvalho, M., (2014). Pain management therapy: The benefits of compounded transdermal pain medication. Journal of General Practice, 2(6). http://dx.doi.org/10.4172/2329-9126.1000188
  5. Paudel, K. S., Milewski, M., Swadley, C. L., Brogden, N. K., Ghosh, P., & Stinchcomb, A. L. (2010). Challenges and opportunities in dermal/transdermal delivery. Therapeutic Delivery, 1(1), 109-131. https://doi.org/10.4155/tde.10.16
  6. PCCA. (n.d.). Drugs used in transdermal pain management: References [PCCA Document #99047]. Available from https://www.pccarx.com/Documents/M-Files/99047_PainAlgorithm_REFERENCES.pdf
  7. PCCA. (n.d.). Information regarding drug usage – links to abstracts and research articles: Pain-focused [PCCA Document #98735]. https://www.pccarx.com/Documents/M-Files/98735_Drug_Abstracts_Pain.pdf
  8. Bos, J. D., & Meinardi, M. M. (2000). The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Experimental Dermatology, 9(3), 165-169. https://doi.org/10.1034/j.1600-0625.2000.009003165.x
  9. Murdan, S. (2005). A review of pluronic lecithin organogel as a topical and transdermal drug delivery system. Hospital Pharmacist, 12(7), 267-270.
  10. Willimann, H., Walde, P., Luisi, P. L., Gazzaniga, A., & Stroppolo, F. (1992). Lecithin organogel as matrix for transdermal transport of drugs. Journal of Pharmaceutical Sciences, 81(9), 871-874. https://doi.org/10.1002/jps.2600810906
  11. Chi, S. C., & Jun, H. W. (1990). Anti-inflammatory activity of ketoprofen gel on carrageenan-induced paw edema in rats. Journal of Pharmaceutical Sciences, 79(11), 974-977. https://doi.org/10.1002/jps.2600791106
  12. 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. https://doi.org/10.1111/pme.12899
  13. 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). https://doi.org/10.4172/2325-9604.1000131
  14. 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. https://doi.org/10.1080/00325481.2016.1144448
  15. 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. https://ijpc.com/Abstracts/Abstract.cfm?ABS=2782
  16. PCCA. (2019). Evaluation of the in vitro human skin percutaneous absorption of ketoprofen in PCCA PermE8 vs. PCCA Lipoderm [PCCA Document #99732]. https://www.pccarx.com/Documents/M-Files/99732_TR_Ketoprof-PermE8-Lipoderm.pdf

These statements are provided for educational purposes only. They have not been evaluated by the Food and Drug Administration, and are not to be interpreted as a promise, guarantee or claim of therapeutic efficacy or safety. The information contained herein is not intended to replace or substitute for conventional medical care, or encourage its abandonment.



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