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The Pharmacologic Vicissitudes of Wound Healing

Advances in Skin & Wound Care: March 2017 - Volume 30 - Issue 3 - p 102
doi: 10.1097/01.ASW.0000512923.39551.8f
Departments: Editorial

Richard “Sal” Salcido, MD, EdD, is the Editor-in-Chief of Advances in Skin & Wound Care; and is the William Erdman Professor, Department of Physical Medicine and Rehabilitation; Senior Fellow, Institute on Aging; and Associate, Institute of Medicine and Bioengineering, at the University of Pennsylvania Health System, Philadelphia, Pennsylvania.

This month’s continuing education (CE) article, “The Effect of Oral Medication on Wound Healing” by Jeffrey M. Levine, MD, on page 137, reminds us that a pharmacopeia for wound healing is lacking. Medications not FDA approved for wound healing are considered “off-label use” when specifically used to treat wounds.1

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Oral medications alter physiological or biochemical processes in the body to treat, prevent, or cure a disease, and their administration necessitates a comprehensive knowledge of the drug properties and their mechanism of action.2 The study of pharmacokinetics describes how the body processes the drug after its administration.2 Every drug has a pharmacokinetics profile unique to the patient, such as age, sex, weight, body mass index, hepatic function, and renal function. The body exerts a reaction on ingested drugs and breaks down the drug for its intended use, and it is metabolized and eliminated.

The study of pharmacodynamics describes the drug’s effect on the body (desired or toxic).2 When considering the active pharmaceutical ingredient (API) and what happens to it during the pharmacodynamics, pharmacologists use the following acronym L-ADME3:

* Liberation: How is the API disintegrated (for solid oral forms breaking down into smaller particles), dispersed, or dissolved from the medication?

* Absorption: How is the API absorbed (through the skin, the intestine, the oral mucosa)?

* Distribution: How does the API spread through the organism?

* Metabolism: Is the API converted chemically inside the body, and into which substances? Are these active (as well)? Could they be toxic?

* Excretion: How is the API excreted (through the bile, urine, breath, skin)?3

Medications approved by the FDA for therapeutic uses may also be used for off-label treatment, using the physician’s clinical judgment and a documented rationale in the patient record. The prescriber of any drug, device, or therapeutic agent should consider the safety/efficacy/cost/benefit ratio for the patient. The patient should be informed about the rationale for using a drug.1 As a caveat, given the heterogeneity of wound care patients, often with multiple comorbidities, clinicians should think about the mnemonic “ADD,” age-drug, drug-drug, and drug-disease interactions, when prescribing all drugs.

I have used off-label drugs with the clinical goal of wound healing, including basic and clinical research to assess the safety and efficacy of off-label drugs listed in our CE article. Specifically, I’ve explored the potential use of nonsteroidal anti-inflammatory drugs (NSAIDs).

In 1995, we hypothesized that the NSAID ibuprofen (IBU) would prevent pressure injuries in an animal model.4,5 The goal was to reduce the inflammation associated with the wound model, evidenced by a decrease in the neutrophil ischemia and reperfusion injury associated with infarction of the tissue at risk. We conducted a blinded study describing the effect of IBU on experimentally derived pressure injuries induced in the fuzzy rat model. Experimental pressure injuries were generated on the greater trochanters with the aid of computer control, using 5 daily, 6-hour pressure sessions. In the first study, 17 rats received intraperitoneal injection of IBU or saline control after each pressure session. In the second study, 44 rats received IBU or control, before, during, and after application of pressure by intraperitoneal or intramuscular injections. Unfortunately, our hypothesis was proven false; not only did IBU not enhance healing, but also it tended to make the lesions worse.4 There are no IBU human studies with good strength-of-evidence ratings, nor are there case reports in the literature about the use of NSAIDs on wound healing effects. Albeit, there exist some preliminary clinical studies attempting to explore topical IBU/foam combinations to ameliorate pain in wound changes.6

Levine’s CE article also lists methotrexate, a potent anti-inflammatory that interferes with wound healing—it is a cytotoxic drug. It is regularly used for inflammatory arthritis such as rheumatoid arthritis. In the past, methotrexate has been used to treat certain types of cancer of the breast, skin, head and neck, or lung. It suppresses cells that are metabolically active (the skin and mucosa). One way it does this is by antagonizing an enzyme involved in the metabolism of folic acid essential for wound healing. Therefore, patients on this drug should be supplemented with folic acid.7,8

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References

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1. US Food and Drug Administration. “Off-Label” and investigational use of marketed drugs, biologics, and medical devices—information sheet. www.fda.gov/RegulatoryInformation/Guidances/ucm126486.htm. Last accessed January 23, 2017.
2. Rosenbaum SE. Basic Pharmacokinetics and Pharmacodynamics: An Integrated Textbook and Computer Simulations. 2nd ed. Hoboken, NJ: John Wiley & Sons; 2017:1, 3, 9.
3. Wikipedia. Pharmacology. https://en.wikipedia.org/wiki/Pharmacology. Last accessed January 23, 2017.
4. Salcido R, Donofrio JC, Fisher SB, et al. Evaluation of ibuprofen for pressure ulcer prevention: application of a rat pressure ulcer model [published correction appears in Adv Wound Care 1995;8(6):6]. Adv Wound Care 1995;8(4):30-2, 34,–38-40 passim.
5. Salcido R. Do anti-inflammatories have a role in wound healing? Adv Skin Wound Care 2005;18:65–66.
6. Sibbald RG, Coutts P, Fierheller M, Woo K. A pilot (real-life) randomised clinical evaluation of a pain-relieving foam dressing: (ibuprofen-foam versus local best practice). Int Wound J 2007;4Suppl 1:16–23.
7. Bagheri M, Jahromi BM, Zamani A. Folic acid may be a potential addition to diabetic foot ulcer treatment–a hypothesis. Int Wound J 2001;8:658–60.
8. Shea B, Swinden MV, Tanjong Ghogomu E, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev 2013;(5):CD000951.
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