Wound Healing Pharmaceuticals: What the EBM Tells Us

Wound Healing Pharmaceuticals: What the EBM Tells Us Robert G. Smith DPM., MSc., R.Ph., C.Ped PharmCon 2008 Pharmcon is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education

Learning Objectives • Appreciate the selection of the most appropriate wound healing product with regard to a presenting wound type as supported by relevant clinical evidence based data. • Develop a wound care product formulary for use in a clinical practice supported by available evidence based medicine. • Appreciate the clinical data regarding medicinal alternative wound care products as found in the literature

Total: 20.8 million people—7 percent of the population—have diabetes. Diagnosed: 14.6 million people Undiagnosed: 6.2 million people Approximately 15% of patients with diabetes will have a foot ulcer and those who develop an ulcer, 6% will be hospitalized due to infection or other ulcer related complications Prevalence of Diabetes Mellitus

Three Major Problems of an Open Wound • Hemorrhage • Mechanical Disruption of Tissues • Infection

Lower Extremity Wounds • Diabetic • Venous • Ischemic • Combination

Wound Types • Acute Wounds: Wounds that heal with an orderly and timely restoration of anatomic and functional integrity • Chronic Wounds: Wounds that appear to be stagnated in the inflammatory or proliferative phase. Accumulation of excess extracellular matrix components or matrix metalloproteinases (collageases-elastase)

Wound Care Product History • Early accounts from 1650 BC described standard treatments to include grease, honey, and lint. • The Egyptians and Greeks introduced various metallic salt compounds, astringents, and antiseptics. • Joseph Lister addressed wound sepsis leading to the use of specific chemical therapies to manage wounds. • Winter’s 1962 observations of the benefits of a moist wound environment regarding scar formation

Selection based on experience not scientific knowledge Studies focused on dressings as related to wound type and cost factors Morrison 1987 Gwyther 1988 Luker & Kenrick 1992 Flanagan 1992 Benbow 1994 Bell 1994 Bux & Malhi 1996 Vermeulen et 2006 Central Dressing Selection Theme

Evidence Base Medicine • Evidence-based medicine is conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. (Waldman 2006) • Since wound care products are pharmaceuticals -evidence is drug data, what the drugs are, how they are used, and the latest recommendations for common and uncommon conditions.

Evidence Base Medicine Five Step EBM Model (Akobeng 2005) • A. Convert information needs into answerable questions. • B. Find the best evidence which will answer the questions. (Decide where to search) • C. Critical appraising of the evidence for its validity and usefulness. (Relevant) • D. Applying the results of the appraisal into clinical practice. • E. Evaluating performance (Final outcome on patient care)

Evidence Base Medicine Category of Evidence • Ia – Evidence from meta analysis of RCTs • Ib – Evidence from at least once RCT • IIa – Evidence from at least one controlled study without randomization • IIb – Evidence from at least one other type of quasi experimental study • III – Evidence from non-experimental descriptive studies • IV- Evidence from committee reports or opinions or clinical experience of respected authories

Evidence Base Medicine- Strength of Recommendations • A – Directed based on category I evidence. • B – Directed based on category II evidence or extrapolated Directed based on category III or extrapolated recommendation from category I or II evidence. • C – Directed based on category III or extrapolated recommendation from category I or II evidence. • D -Directed based on category IV or extrapolated recommendation from category I, II, III evidence.

Evidence Based Medicine in Wound Care • Much information available on evidence-based medicine, including numerous useful books, publications, journal articles, and websites. • The search for evidence based medicine in wound care is still in the developmental stages. • Much of the work in wound care has been left to interpretation by wound care teams.

Searching for Evidence-Based Medicine Related to Wound Care Pharmaceuticals Review Ryan et al 2003 OWM 49 (11) 67-75

Alignates Antiseptics Enzymatic Products Foams Gauze Hydrocolloids Hydrogels Antimicrobial or “biocides” Alternative Medicinals Wound Care Products

ALGINATES • These products are produced from naturally occurring calcium and sodium salts of alginic acid found in a family of brown seaweed. • Alginates are rich in either mannuronic acid or guluronic acid, the relative amount of each influence the amount of exudate absorbed and the shape the dressing will retain.

Alginate Dressings (RCTs) • Donaghue et al (1998) Evaluation of collagen-alginate dressing in diabetic foot ulcers. • 75 patients (2:1 ratio) for the collagen-alginate vs gauze • 80.6% reduction wound area vs 61.1% • Complete healing was achieved in 24 (48%) vs 9 (36%) after 8 weeks

Alginate Dressings (RCTs) • Bales et al (2001) Exploring the use of an alginate dressing for diabetic foot ulcers. • Non-comparative, two center study not a RCT • 41 patients in two sites • 6 weeks or until ulcer healed • 11 of 39 patients (28.2%) healed

Antiseptics • Antiseptics are disinfectants used on body surfaces to reduce the number of normal flora and pathogenic contaminants • Antiseptics function as non-specific microbial inhibitors without a specific cellular target. • Smith A Critical Discussion of the Use of Antiseptics in Acute Traumatic WoundsJ Am Podiatr Med Assoc 2005 95: 148-153

Antiseptic Concerns (Level “D”) • Brennan & Leaper-microcirculatory • Cooter attractive agent • Lineaweaver-Fibroblast retards epithlialization • Kozol-Neutrophils “NO SAFE [ ]

Tap Water Irrigation • A review of the reference material used to support this declaration of water’s negative effects could not be substainated. • Only one reference could be found declaring tap water contact with living cells at the wound’s edge caused cell break down with resulting tissue damage and pain discomfort.

Hall reviewed the medical literature regarding the effect of tap water verses normal saline on infection rates in acute traumatic wounds. No association with the use of tap water and an increase rate of infection. Angeras et al conducted a randomized study comparing the use of tap water with saline to cleanse acute traumatic soft tissue injuries. Lower rate of infection in those wounds where tap water had been used to cleanse wounds; 5.4% with tap water compared to 10.3% with the saline group. Bansal et al and Valente et al compared tap water and saline wound irrigation of simple lacerations in pediatric patients. Bansal et al performed a blinded investigation while Valente et al conducted an unblinded non-randomized investigation. Despite positive post irrigation cultures were found in Bansal et al’s investigation and clinical determination of infection in Valente et al’s study determined these findings were not significantly different between the normal saline solution and tap water groups. Clinical Trials on Tap Water

Antiseptics in Practice • The level of dilution that caused no damage to fibroblasts at the same time maintaining bactericidal activity was a 1/1000 concentration for povidone iodine and 1/100 concentration for sodium hypochlorite.While hydrogen peroxide and acetic acid solutions lose their bactericidal activity before they lose their tissue toxicity during dilution. Interestingly, the dilutions utilized in the cell culture experiments are below the strengths used in clinical practice.

Enzymatic Debriders • Collagenase-Based Products • Papain-Based Products • Papain-Urea-Chlorophyllin Copper Complex

Collagenase-Based Products • Collagenase, is an enzymatic debriding agent derived from Clostridium histolyticum belonging to the metallopeptidase family. • It specifically hydrolyzes peptide bonds and digests all triple helical collagen and will not degrade any other proteins lacking the triple helix. This is a unique feature of bacterial collagenase; since none of the other available proteases can digest collagen.

Collagenase-Based Products • The enzyme liquefies necrotic tissue without damaging granulation tissue. Collagenase digests the lower portion of an escar working from the bottom up giving the appearance of working more slowly. • Collagenase has been shown to be gentle to viable cells and might promote angiogenesis and epithelialization.

Papain-Based Products • Papain is a nonspecific proteolytic enzyme derived from the fruit of the papaya tree (Carica papaya). • Papain breaks down fibrinous material in necrotic tissue and requires the presence of sulfhydryl groups, such as cysteine, for its activity. • It does not digest collagen,and it requires specific activators that are present in necrotic tissue in order to be stimulated.

Papain-Based Products • Papain-urea preparations produce more exudate digesting eschar from the top which may irritate the surrounding skin. • Papain-urea products should be applied daily with a moisture retentive dressing. • Hydrogen peroxide solution may inactivate papain as well as salts of heavy metals such as lead, silver, and mercury have been shown to inactivate papain.

Papain-Urea-Chlorophyllin Copper Complex • Chlorophyllin, an anti-agglutinin, has been added to preparations of papain/urea in an attempt to reduce the pain. • Brett summarizes that there are favorable clinical results that reveal papain-urea chlorophyllin copper complex’s proteolytic action thoroughly cleanses lesions of all necrotic tissue debris and then maintains optimal circulation so that affected tissue will benefit from both hematological and nutritive elements.

Enzymatic Clinical Trials • Study Enzymatic Agent Level of Evidence • Lee & Ambrus (1975) Collagenase B • Parish & Collins (1979) Collagenase B • Rao et al (1975) Collagenase B • Vetra & Whittaker (1975) Collagenase B • Hansbrough et al (1995) Collagenase B • Muller et al (2001) Collagenase A • Pullen et al (2002) Collagenase A

Enzymatic Clinical Trials • Konig (2005) Collagenase A • Marazzi et al (2006) Collagenase B • Gasser (1940) Papain Emulsion B • Miller (1956) Papain-Urea B • Morrison & Casali (1957) Papain-Urea-Chlorophyllin B • Katz el at (1956) Papain-Urea-Chlorophyllin B • Carter (1958) Papain-Urea-Chlorophyllin B • Burke & Golden (1958) Papain-Urea-Chlorophyllin B • Alvarez et al (2002) Collagenase A Papain-Urea-Chlorophyllin

CMS Statement 2008 • FDA approved Santyl will not be affected • Products contain papain/urea and chlorophyll complex are scheduled to be removed from 2008 Medicare Formulary Reference File

FOAMS • Foam dressings are manufactured as either polyurethane or silicone form with either hydrophilic or hydrophobic properties. • They transmit moisture vapor, O2, and thermal insulation.

Foams (RCTs) • Lohmann M et al (2004) Safety and performance of a new-adhesive foam dressing for the treatment of diabetic foot ulcers. • Open Non-comparative, prospective study • 35 out of 37 patients completed study • 6 weeks • Relative wound area reduction from 100% to 40%

Gauze and Sponges • This cotton product has relative wide weave through which new tissue can grow. • Gauze dressings are manufactured in many forms.

Gauze and Sponges • Gold standard (Wet to Dry Gauze Dressing) • Comparative studies with impregnated products • Randomized Controlled Studies • Often used for economic studies for cost analysis-Material cost for the dressing and labor expenses

Hydrocolloids • Hydrocolloids are hydrophilic colloid particles (sodium carboxymethycellulose, gelatin, pectin, elastomers, and adhesives) bound to polyurethane foams that are impermeable to bacteria and facilitating wound debribement

Hydrocolloids RCTs • Apelqvist et al (1990) Topical treatment of necrotic foot ulcers in diabetic patients: a comparative trial of DuoDerm and MeZinc • An Open Randomized Controlled Trial • 44 patients • 14 of the 21 patients treated with MeZinc had their necrotic ulcers improve by at least 50% compared to 6 out of 21 of hydrocolloid dressing

Hydrocolloids RCTs • Varma et al (2006) Efficacy of Polyurethane Foam Dressing in Debrided Diabetic Lower Limb Wounds. • Patients randomly assigned to study or control group (conventional gauze dressing) • 48 patients (24 patients in each group) • There was a significant reduction in the time taken for wounds to heal 22.5 compared to 52 days.

Hydrogels • Hydrogels are non-adherent, water based, or glycerin based amorphous, crossed-linked polymer gels. • Hydrogels can help reduce pain, decrease wound temperature and inflammation.

Hydrogels RCTs • Smith (2002) Debridement of diabetic foot ulcers. • Three Hydrogel RCTs suggested that hydrogels are significantly more effective than gauze or standard of care in healing diabetic foot ulcers. • Scanlon (2003) Review: debridement using hydrogel appears to be more effective than standard wound care for healing diabetic foot ulcers • There is little good quality clinical evidence to indicate superiority of any one hydrogel over another

Broad-Spectrum Antimicrobials (Biocides) • Cadexomer iodine • Silver

Cadexomer Iodine • Iodine is a potent broad spectrum antiseptic agent. • Improved formulations of iodophors “carriers” release low levels of iodine over a longer period of time. • Over the recent years the clinical use of silver and polyhexamethylene biguanide products have been favorably embraced when compared to cadexomer Iodine

Cadexomer Iodine RCTs • Apelqvist et al (1996) An economic analysis of cadexomer iodine ointment and standard therapy. • Compare Clinical effect and economic cost of cadexomer iodine ointment and standard therapy. • 12 week open randomized comparative study • 25 patients • Treatment with cadexomer iodine ointment show no clinical difference compared to standard therapy

Silver • Silver ions attack the cell membrane, the membrane transport system, the RNA, the DNA function, protein function, and inhibits bacterial mutation. • The longevity of silver ions in dressing material due to controlled release mechanisms insures that the wound environment is hostile to bioburden

Silver Dressing (RCTs) • Rayman et al (2005) clinical and safety of sustained silver-releasing foam dressing. • 27 patients 6 weeks • Cross over study using Biatain dressings • Silver foam is safe and easy to use and effectively supports healing and good wound progress of diabetic ulcers

Alternative Medicinals • Honey- Molan (2006) reviews the literature to describe the evidence supporting honey as a wound dressing. • Phenytoin – Scheinfeld (2003) Descriptive review • Estrogen- (2005) A review of medical literature • Topical Insulin- (1999) 2 RCT double blind placebo control trial

Alternative Therapies • Honey- Honey consists of simple sugars and is both sterile and inhibits growth of both Gram-negative and Gram-positive organisms. Its antibiotic properties are attributed to its low pH, a thermolabile substance called inhibine, and its hygroscopic properties. • Molan summarized the clinical base evidence supporting the use of honey as a wound dressing. This review reported the findings of 17 randomized controlled trials involving 1965 participants, as well as 5 clinical trials of other forms involving 97 participants treated with honey.

Alternative Medicinals • The wound types treated with honey during these control trials were either superficial burns, partial thickness wounds, moderate burns, third degree burns, chronic leg ulcers, pressure ulcers, and surgical wounds. • These studies compared honey to either silver sulfadiazine, amniotic membrane, Vaseline gauze, an occlusive dressing, mupirocin, povidone-iodine, or a boiled potato peel. • Commercial products released in 2007

Alternative Medicinals • This review presents a large body of evidence supporting the use of honey as a wound dressing for a wide range of wounds because its antibacterial activity rapidly clears infection and protects the wound and it provides a moist healing environment without the risk of bacterial growth occurring. Also, honey rapidly debrides wounds and removes malodor and its anti-inflammatory activity reduces edema and exudate and prevents or minimizes hypertrophic scarring.

Wound Healing Pharmaceuticals: What the EBM Tells Us