Reconciling Combination Therapy With EBM: Where Do We Go From Here?

Pages: 22 - 27
By Kathleen Satterfield, DPM

   One will not find combination therapies mentioned in evidence based medicine (EBM) journals or in research trials. In fact, one will rarely find combination therapies mentioned in many trade publications either. Purists often claim this concept presents a mixed message. How can one track performance and outcomes if he or she is using combination therapies? What component worked?    Detractors sometimes call the practice of using combination therapy “the shotgun approach.” They say it does not denote much finesse and represents excess. Proponents weigh in on the other side with the declaration that it is more important to provide a patient with a successful treatment than being concerned about which component of the treatment was most beneficial.    It is an admonition that we often hear when dealing with heel pain as there is perhaps no other podiatric complaint that is treated more often with combination therapy. When a patient arrives in exquisite pain, which has been present for months, few podiatrists would use a single line of treatment for this patient. Most would deliver some unique combination of nonsteroidal antiinflammatories (NSAIDs), steroids, taping, padding, orthotics and perhaps physical therapy modalities in order to maximize the patient’s immediate relief.

Combination Therapy: It May Not Be Ideal But Is The Reality

The detractors point to valid reasons why combination therapy is not preferred. Some of these reasons are as follows.    • Research is often funded by industry and the economic reality of the situation is that industry interests are not well served by combination therapy trials. Industry wants a clear-cut example of the impact of the product, whether it is a device or a pharmaceutical.    • Educators want EBM to prove effectiveness. The Cochrane Collaboration and the Oxford group, two respected EBM coalitions, look for singularity in trials for tracking outcomes specifically correlated to a particular product or action.    • Government agencies — such as the Food and Drug Administration (FDA), the National Institutes of Health (NIH) and others — also want individualized trials in order to draw specific conclusions.    However, the purist approach is rarely the reality, especially when it comes to treating complications in patients with diabetes. Seasoned physicians, with the wisdom of their experience over the years, will often combine therapies in order to maximize results. Over the past two months, lecturers and experienced practitioners at a variety of educational conferences offered examples of combination therapy for the needs of patients with diabetes.

Weighing Combination Approaches To Neuropathy

   Years ago, there were few treatment options for neuropathy, a common symptom of uncontrolled diabetes, and patients often left the office without a prescription in hand. Physicians would lend a sympathetic ear but had little more than oral tricyclic antidepressants to use and these were not always successful in curbing the progression of painful neuropathy.    Pharmaceutical companies recognized that and have now offered other oral medications including anti-epileptics such as pregabalin (Lyrica, Pfizer) and antidepressants including duloxetine HCl (Cymbalta, Eli Lilly).    However, not every podiatrist is equally comfortable in prescribing these medications for their patients and would like an alternative with fewer side effects.    The concept of the compounding pharmacy is to alter, combine and create new formulations of medications, which is the very essence of combination therapies. Physicians with practices that concentrate on neuropathic treatments, both medical and surgical, have found value in compounded preparations for the treatment of painful neuropathy.    Serrina Yozsa, DPM, of Scottsdale, Ariz., lectured at the American Association for Women Podiatrists meeting in Colorado recently. While she often utilizes a full range of oral medications and may perform surgical nerve decompression to help restore sensation to the neuropathic patient with diabetes, Dr. Yozsa has also turned to the compounding pharmacy for practical answers. She recommends a compound topical formulation of ketoprofen (Oruvail®, Wyeth), gabapentin and clonidine.    Kimberly Eickmeier, DPM, another respected lecturer and noted surgeon, recommends a similar compounded formulation of gabapentin, amitriptyline (Elavil, AstraZeneca) and ketamine for the topical treatment of neuropathic pain.    Topical treatments for neuropathic pain eliminate the possibility of systemic side effects when patients take oral medications. Indeed, some patients have described adverse effects with gabapentin at a severity level that caused them to discontinue the medication prior to achieving any beneficial effects. Topical administration avoids central nervous system complications. Similarly, ketamine is known for creating psychosis when clinicians use it as an intravenous anesthetic.

An Overview Of Combination Therapy In Wound Care

   The needs of the wound are multi-faceted. Exudates require active control. Contamination requires antimicrobial agents. Angiogenesis requires growth factors to develop. Podiatric physicians need to eliminate harmful matrix metalloproteases from the wound base and hyperkeratotic tissue requires debridement.    At the recent Oklahoma Podiatric Medical Association meeting in Tulsa, there was much discussion about successes enjoyed by practitioners who used VAC therapy (KCI) in concert with other modalities and topical medications (see “Combining VAC Therapy With Advanced Modalities: Can It Expedite Healing?” pages 18-24, September 2005 issue).    Silver dressings have been a longtime choice for use with the VAC in order to control contamination at the interface with the sponge dressing. The spectrum of microbial presence is difficult to assess without laboratory testing. As it progresses from colonization to contamination to critical contamination, the burden on the wound becomes onerous, delaying healing and predisposing the patient to active, overt infection.    The presence of silver, with its known antimicrobial properties, reduces the potential for that infection. Physicians have often utilized Acticoat (Smith & Nephew), Silverlon and other interface materials between the wound and the sponge. A recent development by KCI, the creators of negative pressure therapy technology, is a silver-impregnated sponge that allows for the same effect achieved by combining products.    The antimicrobial effects of silver have been identified for more than 100 years. Scientific examination has shown that silver is effective against a wide range of organisms, including difficult to treat vancomycin resistant strains, viruses and fungus.    However, researchers have raised concerns recently about the strength of silver and its effects on the wound bed. Multiple studies have found that silver may be toxic to multiple cell types, including keratinocytes and fibroblasts, at high concentrations. The fibroblasts, in particular, appear to be most sensitive to silver-impregnated dressings.    In response to this concern, Johnson & Johnson developed a lower strength silver dressing, Promogran Prisma. Practitioners who were uncomfortable with the higher strength products have now incorporated this dressing with VAC therapy.    Combined therapies can also involve combining technological modalities. In the case of VAC therapy, some practitioners report using the VersaJet™ (Smith & Nephew) hydrosurgery wound debridement system for wound bed preparation prior to applying split thickness skin grafts, VAC therapy or synthetic skin replacements such as Dermagraft (Smith & Nephew) or Apligraf (Organogenesis).

Emphasizing Informed Choices About Combination Therapies

   Granted, the acceptance and expectation of EBM has rightfully become pervasive in the schools. While some practitioners may be reluctant to mix medications and modalities without research evidence, the reality is the majority of us still use the mainstays of medicine: our personal clinical experiences, recommendations from mentors and the never-ending pursuit for better answers.    If indeed a combined therapy appears to be a better solution for a patient’s problem, it will be to the advantage of the medical community to examine it anew under the standards of EBM. However, until that point in time, what physician will turn his or her back on a better answer for a patient? Dr. Satterfield is an Adjunct Clinical Associate Professor at the University of Texas Health Science Center at San Antonio. Dr. Steinberg is an Assistant Professor in the Department of Surgery at the Georgetown University School of Medicine in Washington, D.C. He is a Fellow of the American College of Foot and Ankle Surgeons.



1. Staker LV. Teaching performance improvement: an opportunity for continuing medical education. J Contin Educ Health Prof 2003 Spring;23 Suppl 1:S34-52.
2. Dowsett C. The use of silver-based dressings in wound care. Nurs Stand 2004 Oct. 27-Nov. 2;19(7):56-60.
3. Brem H, Kirsner RS, Falanga V. Protocol for the successful treatment of venous ulcers. Am J Surg 2004 Jul;188(1A Suppl):1-8.
4. Brem H, Sheehan P, Boulton AJ. Protocol for the treatment of diabetic foot ulcers. Am J Surg 2004 May;187(5A):1S-10S.
5. Poon VK, Burd A. In vitro cytotoxicity of silver: implication for clinical wound care. Burns 2004 Mar;30(2):140-7.
6. Schaller M, Laude J, Bodewaldt H, Hamm G, Korting HC. Toxicity and antimicrobial activity of a hydrocolloid dressing containing silver particles in an ex vivo model of cutaneous infection. Skin Pharmacol Physiol 2004 Jan-Feb;17(1):31-6.
7. Snyder RJ. Treatment of nonhealing ulcers with allografts. Clin Dermatol 2005 Jul-Aug;23(4):388-95.


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