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By Nat Jones, RPh, FAPC, PCCA Clinical Compounding Pharmacist
Topical preparations made of animal, mineral or plant extracts were in common use in ancient Egyptian and Babylonian medicine by 3000 BCE.1 Humans have known for a very long time that products may be applied to the skin for either local or systemic effects, and as our understanding of the anatomy and physiology of the skin has improved, science has brought about the development of technologies to effectively and quantitatively deliver substances across this barrier to specific target sites in the skin and systemically in the body.2 This brings us to modern health care, including pharmacy compounding.
Permeation Enhancement in Compounding
Compounding pharmacists have brought a variety of topical treatment options forward within the last 25 years in the field of pain therapy. Permeation-enhanced topical pain therapy (PETPT) has been commonly called transdermal pain therapy for a long time in our industry. More recently in the pharmaceutical industry, though, the word “transdermal” has primarily referred to manufactured patches (e.g., fentanyl) and not compounded creams or gels. With that being the case, the term “permeation-enhanced” seems appropriate.
In the practice of compounding, permeation enhancement can come from certain chemicals, some of which have dual function in formulating for topical applications. These agents can both increase penetration through the stratum corneum (permeation enhancers), and they can also improve incorporation of the active pharmaceutical ingredient (API) into the delivery base (wetting agents). Common examples would include propylene glycol, ethoxy diglycol or ethylene glycol monoethyl ether.3 It is also important when compounding to select a wetting agent that is compatible with the base, of course.
Over the years, compounding bases have become more advanced, with some having intrinsic permeation-enhancing properties. Compounders made the use of pluronic lecithin organogels (PLO gels) popular in the 1990s and early 2000s, but with the invention of Lipoderm® in the early 2000s, the landscape of delivering small to medium-sized molecules through the stratum corneum changed. Lipoderm was the first proprietary permeation-enhancing vehicle in the compounding industry, and it showed increased delivery of ketoprofen versus a PLO gel with Franz finite permeation testing.4 Other APIs were successfully tested for permeation through the skin, including a four-drug study of both Lipoderm and Lipoderm ActiveMax® proving delivery of ketamine, gabapentin, baclofen and clonidine simultaneously from the same permeation-enhancing topical base.5 More recently, PermE8® Anhydrous Gel shows promise as another option. Initial in vitro testing revealed that it delivered ketoprofen into and through human skin tissue comparably to Lipoderm.6 This leads to a discussion of the evidence we have for PETPT.
Levels of Evidence in Medicine
Clinical data about the efficacy of PETPT has presented various levels of evidence that is useful in helping our medical colleagues to treat patients experiencing pain. Evidence-based medicine is the hierarchical system of classifying evidence in order to be able to make more logical clinical decisions. There are many different levels of evidence that can be used. At one extreme, there are systematic reviews of multiple clinical trials with homogeneity. At the other end, there is expert opinion without explicit critical appraisal or that is based on physiology bench research or fundamental information (“first principles”).7 Table 1 explains this range of evidence.
Table 1. Levels of Evidence for Studies7
Level
Type of Evidence
1A
Systematic review (with homogeneity) of randomized, controlled trials (RCTs)
1B
Individual RCT (with narrow confidence intervals)
1C
All-or-none study
2A
Systematic review (with homogeneity) of cohort studies
2B
Individual cohort study (including low quality RCT, e.g., <80% follow-up)
2C
“Outcomes” research; ecological studies
3A
Systematic review (with homogeneity) of case-control studies
3B
Individual case-control study
4
Case series (and poor-quality cohort and case-control study)
5
Expert opinion without explicit critical appraisal or based on physiology bench research or first principles
In the practice of medicine, there is not always a systematic review of homogeneous, randomized clinical trials available for us to use when making every clinical decision. In fact, in the compounding world, that level of evidence is essentially nonexistent. It has been stated many times that we are attempting the practice of medicine and not the exact science of medicine, and that on many occasions the only level of evidence we have is an expert opinion without explicit critical appraisal, or we must base our decision on physiology bench research or first principles. This does not mean we are not practicing evidence-based medicine. We are, but just not with the highest level of evidence that could exist in an ideal world. The practice of medicine is still far from being perfected, and we still make great use of the information we have.
Literature Review of PETPT
Last year, we at PCCA undertook a literature review of PETPT, totaling 168 single-API studies and 48 multi-API studies. We looked at the design and outcomes of these studies published from around the world. Their size and quality varied from single-patient case studies to larger randomized, placebo-controlled clinical trials. Most of them showed an effective outcome for the patients treated (153 out of 168 single-API studies, or 91%, and 38 out of the 48 multi-API studies, or 79%). The researchers used a variety of APIs in these studies, such as amitriptyline, baclofen, capsaicin, clonidine, diclofenac, doxepin, gabapentin, ibuprofen, ketamine, ketoprofen, lidocaine and piroxicam, along with others. Navigating this bulk of literature and deciding which articles to share with prescribers to help make clinical decisions can be difficult and time consuming. A brief summary of some selected studies from our review (Table 2 and Table 3) can serve as a reference guide for pharmacists and prescribers in choosing an effective API for incorporation into their PETPT for various types of patients. We hope it will make the selection process a little easier and, ultimately, help you to serve your patients.
Table 2. Single-API PETPT Studies
Clinical Use
Size
Ingredient
Outcomes
Citation
Central neuropathic pain
1
Amitriptyline
EFFECTIVE: Patient noted that in the week of using the active cream, no allodynia was present, with a carryover effect of one day. She did not need to use the escape medication in the week of using the active cream, though she frequently used the escape medication in the placebo weeks.
Kopsky, D. J., Liebregts, R., Keppel Hesselink, J. M. (2012). Central neuropathic pain in a patient with multiple sclerosis treated successfully with topical amitriptyline. Case Reports in Medicine, 2012. https://doi.org/10.1155/2012/471835
Chemotherapy-induced neuropathies
44
EFFECTIVE: The median VAS pain score decreased from 7 (4–9) at baseline to 2 (0–4) after 4-week topical treatment.
Rossignol, J., Cozzi, B., Liebaert, F., Hatton, S., Viallard, M.-L., Hermine, O., & Greco, C. (2019). High concentration of topical amitriptyline for treating chemotherapy-induced neuropathies. Supportive Care in Cancer, 27(8), 3053–3059. https://doi.org/10.1007/s00520-018-4618-y
Hemorrhoid post-op pain
66
Baclofen
EFFECTIVE: Baclofen group has significantly lower pain score on week 1 and week 2 than placebo.
Baclofen group consumed significantly less analgesic agents on week 1 and week 2.
Ala, S., Alvandipour, M., Saeedi, M., Mansourifar, M., Monajati, M., & Shiva, A. (2020). Effect of topical baclofen 5% on post-hemorrhoidectomy pain: Randomized double blind placebo-controlled clinical trial. Journal of Gastrointestinal Surgery, 24, 405–410. https://doi.org/10.1007/s11605-019-04147-7
Diabetic Neuropathy
102
Amitriptyline vs. Capsaicin
EFFECTIVE: Both drugs significantly relieved pain in 12 weeks compared with baseline values. Treatment responders were similar in both groups (P = 0.545).
Kiani, J., Nasrollahi, S. A., Esna-Ashari, F., Fallah, P., & Sajedi, F. (2015). Amitriptyline 2% cream vs. capsaicin 0.75% cream in the treatment of painful diabetic neuropathy (Double blind, randomized clinical trial of efficacy and safety).Iranian Journal of Pharmaceutical Research, 14(4), 1263–1268.
Diabetic neuropathy
139
Clonidine, capsaicin
EFFECTIVE: Both drugs significantly relieved pain at 12 weeks, but no significant difference in the efficacy between the 2 treatments was observed.
Kiani, J., Sajedi, F., Nasrollahi, S. A., & Esna-Ashari, F. (2015). A randomized clinical trial of efficacy and safety of the topical clonidine and capsaicin in the treatment of painful diabetic neuropathy.Journal of Research in Medical Sciences, 20(4), 359–363.
Osteoarthritis of the knees
216
Diclofenac
EFFECTIVE: This topical diclofenac solution demonstrated relief of the symptoms of primary osteoarthritis of the knee at 6 weeks.
Baer, P. A., Thomas, L. M., & Shainhouse, Z. (2005). Treatment of osteoarthritis of the knee with a topical diclofenac solution: A randomised controlled, 6-week trial [ISRCTN53366886]. BMC Musculoskeletal Disorders, 6. https://dx.doi.org/10.1186%2F1471-2474-6-44
33
Ketamine
EFFECTIVE: Daily 75 mg S(+)-ketamine showed significant improvements on the Pain Disability Index, on the EQ-5D, and on the SF-36. Daily 50 mg was not effective.
Vranken, J. H., Dijkgraaf M. G. W., Kruis, M. R., van Dasselaar, N. T., & van der Vegt, M. H. (2005). Iontophoretic administration of S(+)-ketamine in patients with intractable central pain: A placebo-controlled trial. Pain, 118(1–2), 224–231. https://doi.org/10.1016/j.pain.2005.08.020
Complex regional pain syndrome, type 1 (CRPS I)
EFFECTIVE: Improvement of the report of pain intensity, measured by the visual analog scale, in 4 patients with acute early dystrophic stage of CRPS I. Swelling of the affected limbs subsided as well. No apparent changes were noticed in 1 patient with chronic atrophic stage of CRPS I and in both patients with CRPS II.
Ushida, T., Tani, T., Kanbara, T., Zinchuk, V. S., Kawasaki, M., Yamamoto, H. (2002). Analgesic effects of ketamine ointment in patients with complex regional pain syndrome type 1.Regional Anesthesia & Pain Medicine, 27(5), 524–528. https://doi.org/10.1053/rapm.2002.35517
Post herpetic neuralgia and neuropathic pain syndromes
23
Gabapentin
EFFECTIVE: Collectively, 20 of the 23 patients benefited from topical gabapentin, with a reduction in mean pain scores after 1 month, and 11 achieved a clinically meaningful 30% reduction in pain.
Hiom, S., Patel, G. K., Newcombe, R. G., Khot, S., & Martin, C. (2015). Severe postherpetic neuralgia and other neuropathic pain syndromes alleviated by topical gabapentin. British Journal of Dermatology, 173(1), 300–302. https://doi.org/10.1111/bjd.13624
Refractory, focal peripheral neuropathic pain
Gabapentin 6% in Lipoderm
EFFECTIVE: Topical gabapentin resulted in rapid improvement of symptoms (<1 month) when compared to the gradual titration required with oral administration (<8 weeks), with the associated patient and institution benefits.
Results support anecdotal evidence that topical gabapentin is safe and efficacious for use in refractory focal peripheral neuropathic pain.
Hiom, S., Khot, S., Mogford, S., Hart, C., Patel, G., Roberts, G., Martin, C., & Newcombe, R. (2015). Topical delivery of gabapentin (GabaGel™) for neuropathic pain: A ‘proof of concept’ study.International Journal of Pharmacy Practice, 23(Suppl. S2), 23–106. https://doi.org/10.1111/ijpp.12213
Table 3. Multi-API PETPT Studies
Ingredients
Radicular pain
Case series
Diclofenac, ibuprofen, baclofen, cyclobenzaprine, bupivacaine, gabapentin, pentoxifylline
EFFECTIVE: The topical formulation addresses both neuropathic and inflammatory components of radicular pain. It was found to be well tolerated, reduce radicular pain, and improve function and sleep in this case series of 3 patients who had failed other conservative or surgical treatment.
Safaeian, P., Mattie, R., Hahn, M., Plastaras, C. T., & McCormick, Z. L. (2016). Novel treatment of radicular pain with a multi-mechanistic combination topical agent: A case series and literature review. Anesthesiology and Pain Medicine, 6(2). http://dx.doi.org/10.5812/aapm.33322
Diabetic neuropathy and other chronic pain conditions
283
Ketamine, baclofen, gabapentin, amitriptyline, bupivacaine, clonidine, also a + nifedipine arm
EFFECTIVE: Both creams significantly decreased pain score. Also effective in all secondary outcomes.
Somberg, J. C., & Molnar, J. (2015). Retrospective study on the analgesic activity of a topical (TT-CTAC) cream in patients with diabetic neuropathy and other chronic pain conditions. American Journal of Therapeutics, 22(3), 214–221. https://doi.org/10.1097/mjt.0000000000000253
Chronic neuropathic pain
200
Doxepin,
capsaicin, combination of
doxepin and capsaicin
EFFECTIVE: Topical application of doxepin, capsaicin and doxepin/capsaicin produced analgesia of similar magnitude. However, the combination produced more rapid analgesia.
McCleane, G. (2000). Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic human neuropathic pain: A randomized, double-blind, placebo-controlled study.British Journal of Clinical Pharmacology, 49(6), 574–579. https://doi.org/10.1046/j.1365-2125.2000.00200.x
Neuropathic pain
16
Amitriptyline, ketamine, lidocaine
EFFECTIVE: The APIs significantly reduced (p<0.05) pain intensity, sharpness, burning, sensitivity, itchiness, unpleasantness and depth of pain levels on a short-term basis (i.e., between pre-treatment and 30 min post-treatment). They significantly reduced (p<0.05) burning levels on a long-term basis (i.e., between pretreatment and 2 weeks post-treatment).
Uzaraga, I., Gerbis, B., Holwerda, E., Gillis, D., & Wai, E. (2012). Topical amitriptyline, ketamine, and lidocaine in neuropathic pain caused by radiation skin reaction: A pilot study. Supportive Care in Cancer , 20(7), 1515–1524. https://doi.org/10.1007/s00520-011-1240-7
Nat Jones, RPh, FAPC, graduated from the Virginia Commonwealth University, Medical College of Virginia’s School of Pharmacy in 1979. In 2014, after 20 years of owning a compounding pharmacy, he joined PCCA’s staff. Nat has given continuing education lectures at medical professional seminars and webinars on numerous topics, including general compounding, wound care, pain management, nutrition, otolaryngology, women’s health, sexual dysfunction, insulin resistance, hormone replacement therapy, neurotransmitter imbalance and dermatology. He has published many articles and case studies in magazines and professional journals along with an open-access ebook titled Advances in Psoriasis with Avid Science. Since 2016, Nat has served on the Texas State Palliative Care Interdisciplinary Advisory Council.
A version of this article originally appeared in PCCA’s members-only magazine, the Apothagram.
References
1. Geller, M. J. (2010). Ancient Babylonian medicine. Malden, MA: Wiley-Blackwell.
2. Benson, H. A. E., Grice, J. E., Mohammed, Y., Namjoshi, S., & Roberts, M. S. (2019). Topical and transdermal drug delivery: From simple potions to smart technologies. Current Drug Delivery, 16 (5), 444–460. https://doi.org/10.2174/1567201816666190201143457
3. Osborne, D. W. (2011). Diethylene glycol monoethyl ether: An emerging solvent in topical dermatology products. Journal of Cosmetic Dermatology, 10(4), 324–329. https://doi.org/10.1111/j.1473-2165.2011.00590.x
4. 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
5. Bassani, A. S., & Banov, D. (2015). 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
6. PCCA Science. (2019). Evaluation of the in vitro human skin percutaneous absorption of ketoprofen in PCCA PermE8 Anhydrous Gel vs. PCCA Lipoderm [PCCA Document #99732]. http://beta.pccarx.com/pdf_files/PCCA%20Science/Technical%20Reports/99732_TR_Ketoprof-PermE8-Lipoderm.pdf
7. Burns, P. B., Rohrich, R. J., & Chung, K. C. (2011). The levels of evidence and their role in evidence-based medicine. Plastic and Reconstructive Surgery, 128(1), 305–310. https://dx.doi.org/10.1097%2FPRS.0b013e318219c171
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.