Can Pentoxifylline Improve Healing of Lower Extremity Ulcers?

Case

The patient, Mr. D, has been experiencing swelling in his legs for several years, and seven months prior, he noticed that his skin had started to develop ulcers. He has class 3 obesity, type 2 diabetes mellitus, and smokes a pack of cigarettes daily. Despite receiving home healthcare and outpatient wound-care clinic treatments, the venous stasis wounds continued to worsen and began to leak fluid. Recently, the wound dressings had become painful, and he was hospitalized due to his inability to care for the wounds himself.

Two common types of lower-leg wounds that hospitalists frequently encounter are venous insufficiency ulcers and diabetic foot wounds. For venous ulcers, doctors typically recommend reducing the venous pressure in the legs, which can be achieved through compression, elevation, and in rare cases, procedural intervention. For diabetic foot ulcers, doctors often recommend reducing pressure by avoiding weight-bearing, and may sometimes recommend revascularization, debridement, and clearing of any infection in the ulcer. Additionally, the use of pentoxifylline has been shown to improve healing in venous stasis ulcers.

Pentoxifylline is approved for intermittent claudication. It improves tissue oxygenation by lowering blood viscosity, increasing erythrocyte flexibility, increasing leukocyte deformability, and decreasing neutrophil adhesion and activation.¹ It has also been found to decrease histologic evidence of wound inflammation, reduce wound metalloproteinases, and increase TIMP-1 expression in rats with streptozotocin-induced, diabetic, foot wounds.² These effects could improve wound healing, especially in areas where oxygenated blood flow is reduced.

Cochrane Reviews has been updating reviews on pentoxifylline in venous leg ulcers, with the latest update completed in 2012. They found that pentoxifylline improved the healing of venous leg ulcers by 21% (95% confidence interval [CI], 8% to 34%). It was even more effective in patients who didn’t tolerate compression (Relative Risk [RR], 2.25; 95% CI, 1.49 to 3.39).³

A more recent meta-analysis found 13 randomized controlled trials meeting inclusion criteria, with 481 in the intervention group and 440 in the control group. All trials compared 400 mg of pentoxifylline three times a day versus placebo. One trial also had an arm of 800 mg three times a day. Pentoxifylline was found to increase ulcer healing rates (RR, 1.59; 95% CI, 1.22 to 2.07; P <.001) and decrease the amount of time to improvement (RR, 2.36; 95% CI, 1.31 to 4.24).⁴

In the Cochrane Review, adverse effects of pentoxifylline were higher than placebo (RR, 1.56; 95% CI, 1.10 to 2.22) and 72% of the side effects were gastrointestinal including nausea, vomiting, and abdominal pain. Pentoxifylline was generally well tolerated with low numbers of patients stopping the therapy and only 30% citing side effects as a reason they stopped the trial. Lexicomp cites gastrointestinal adverse effects to be between 1% and 10% with nausea being 2% and vomiting 1%. Other side effects were less than 1%.¹

The same mechanism by which pentoxifylline helps with venous-stasis ulcer healing could lead to better healing for diabetic foot ulcers.

Approximately 15% of individuals with diabetes will experience a foot wound at some point in their lifetime. These wounds can greatly impact their quality of life as they may need to avoid bearing weight on the affected foot, and they often require multiple visits to medical professionals over an extended period to properly heal.

Two-thirds of nontraumatic lower limb amputations are due to diabetic foot ulcers.5 Infected or ischemic diabetic foot ulcers are the cause of 25% of hospital stays for patients with diabetes. Mortality rates vary depending on the level of amputation, but for trans-tibial amputations, rates were 22% at 30 days, 44% at one year, and 77% at five years. Median survival was 20.3 months.⁶

To help heal wounds patients are asked to avoid putting pressure on the wound, which usually impairs weight bearing and ambulation. Besides pressure, other factors that can impair healing include infection, poor blood flow, and rarely, cancer in the wound.

In one study with 12 diabetic foot wounds and no comparator group, nine patients continued taking pentoxifylline for three months and eight had healing of the ulcers with one additional person having improvement in the ulcer.⁷

A study in India enrolled 30 patients in standard care plus pentoxifylline and another 32 patients in standard care without pentoxifylline. At 30 days of follow-up, they found out that 26 (86.66%) of the patients on pentoxifylline showed signs of ulcer recovery while 20 (62.5%) in the control group showed signs of recovery.⁸

Another study in India enrolled 40 patients admitted to the hospital for diabetic foot wounds; half were placed on pentoxifylline and half were a control group. 10 of 20 (50%) of the control group healed, while 16 of 20 (80%) of the pentoxifylline group healed. There were more toe amputations in the pentoxifylline group (10 versus 8) but fewer below-the-knee amputations (3 versus 0), and one above-the-knee amputation in the control group with none in the pentoxifylline group. There were three deaths in the control group and none in the pentoxifylline group. These are small numbers, but the overall risk of amputation was about 20% lower in pentoxifylline versus control.⁹

In a study presented as a poster, K Landry, et al. compared 70 consecutive patients referred to an advanced wound healing center, where 16 were prescribed pentoxifylline and 54 patients got standard of care without pentoxifylline. The patients chosen for pentoxifylline were based on patient and prescriber discussions. They were given 400 mg three times a day.

Using the Society for Vascular Surgery Lower Extremity Threatened Limb Classification System, or WIfI, to grade the severity of ulcers, patients on pentoxifylline had faster wound healing (mean of 64 days +/- 37 days versus 117 days +/- 84 days) and a higher probability of complete healing.¹⁰

There is also some evidence that pentoxifylline improves insulin resistance, diabetic neuropathy, diabetic nephropathy, and diabetic retinopathy, and improves liver steatosis while lowering elevated AST and ALT values, so there may be other beneficial effects for patients with diabetes treated for their venous stasis ulcers or foot ulcers.¹¹

Back to the case

Long-term-care admission was recommended by wound care and occupational therapy to assist Mr. D with wound care. This involved dressing changes three times a day due to the weeping fluid. Mr. D was started on pentoxifylline 400 mg three times a day and was discharged from the hospital. After a month he was discharged back home, as his wounds had healed.

Bottom line

High-quality evidence suggests that pentoxifylline can improve wound healing in venous stasis ulcers. There is weak evidence to support the idea that pentoxifylline can also improve the healing of diabetic foot ulcers and reduce the risk of or delay amputations.

Dr. Lehenbauer

Dr. Lehenbauer is a staff physician in the division of hospital medicine at the Minneapolis Veterans Affairs Medical Center and an assistant professor, department of medicine, at the University of Minnesota in Minneapolis.

References

1. UpToDate/Lexidrug. Pentoxifylline: drug information. https://www.uptodate.com/contents/pentoxifylline-drug-information. UpToDate website. Published 2024. Accessed April 1, 2024.
2. Babaei S, Bayat M, et al. Pentoxifylline improves cutaneous wound healing in streptozotocin-induced diabetic rats. Eur J Pharmacol. 2013;700(1-3):165-72.
3. Jull AB, Aroll B, et al. Pentoxifylline for treating venous leg ulcers. Cochrane Database Syst Rev. 2012;12(12):lowerCD001733. doi: 10.1002/14651858.CD001733.pub3.
4. Sun S, Li Y, et al. Efficacy and safety of pentoxifylline for venous leg ulcers: an updated meta-analysis. Int J Low Extrem Wounds. 2021;15347346211050769. doi: 10.1177/15347346211050769.
5. UpToDate. Lower extremity amputation. UpToDate website. https://www.uptodate.com/contents/lower-extremity-amputation. Published 2024. Accessed April 1, 2024.
6. Fortington LV, Geertzen JHB, et al. Short and long term mortality rates after a lower limb amputation. Eur J Vasc Endovasc Surg. 2013;46(1):124-31.
7. Adler PF. Assessing the effects of pentoxifylline (Trental) on diabetic neurotrophic foot ulcers. J Foot Surg 1991;30(3):300-3.
8. Rewale V, Prabhakar KR, Chitale AM. Pentoxifylline: a new armamentarium in diabetic foot ulcers. J Clin Diagn Res. 2014;8(1):84-6.
9. Ramani A, Kundaje GN, Naya MN. Hemorheologic approach in the treatment of diabetic foot ulcers. Angiology. 1993;44(8):623-6.
10. Landry K, Clor Z, et al. Effects of pentoxifylline on healing times in diabetic foot ulcers. American College of Foot and Ankle Surgeons website. https://www.acfas.org/getattachment/d271f718-a124-4928-86eb-88b3da192c5c/POST2020_SCI-1102.pdf. Published November 22, 2019. Accessed April 1, 2024.
11. Bell, DSH. Are the protean effects of pentoxifylline in the therapy of diabetes and its complications still relevant? Diabetes Ther. 2021;12(12):3025-35.