Use of a clonidine patch in the treatment of ischemic ulcerations of the foot

To the Editor:

Clonidine is indicated for the treatment of hypertension and may be used alone or in combination with other antihypertensive medications. Clonidine is a centrally acting α₂-agonist.

Clonidine was originally marketed as a nasal decongestant in 1962. At that time, clonidine was also found to cause hypotension, sedation, and bradycardia. Taking advantage of its side effects, researchers began to use it to treat hypertension in the 1970s and also for Tourette’s syndrome beginning in the 1980s. Recently it has been used for behavioral symptoms of attention-deficit hyperactivity disorder, hyperarousal syndromes associated with post-traumatic stress disorder, and aggression [1].

Clonidine is available in patch form as the Catapres- TTS Transdermal Therapeutic System (Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut). Catapres-TTS is available in three strengths: 1, 2, and 3, which correspond to a clonidine content of 2.5 mg, 5.0 mg, and 7.5 mg, respectively. These patches deliver daily doses of 0.1 mg, 0.2 mg, and 0.3 mg, respectively. Catapres-TTS patches are available in boxes of four packets. Each packet consists of a patch on a plastic sheet and a round adhesive cover [2].

Clonidine stimulates the α2-adrenergic receptors in the brain stem. This causes a reduced sympathetic outflow from the central nervous system along with a decrease in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. Renal blood flow and glomerular filtration rate remain largely unchanged. Normal postural reflexes remain intact; therefore, orthostatic hypotension is infrequently encountered [2].

Catapres-TTS was developed to release clonidine at an approximately constant rate for 7 days. During long-term therapy, cardiac output tends to return to pretherapy levels while peripheral resistance remains low.

Sudden cessation of clonidine has in some cases resulted in nervousness, agitation, headache, and confusion accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. The likelihood of these reactions to discontinuation of clonidine therapy appears to be greater after administration of higher dosages or continuation of other β-blocker treatment [2]. Special caution, therefore, is recommended in such situations.

Clonidine may potentiate the depressive effects of alcohol, barbiturates, or other sedating drugs on the central nervous system. Owing to the potential for additive effects, such as bradycardia and atrioventricular block, caution is advised in patients receiving clonidine along with agents known to affect sinus node function or atrioventricular nodal conduction. Transdermal therapeutic systems may induce localized miliaria, microbial growth, and allergic contact dermatitis [3].

Most adverse systemic effects during clonidine therapy are mild and tend to decrease with continued therapy. Reported systemic effects include dry mouth, drowsiness, fatigue, headache, lethargy, sedation, insomnia, dizziness, impotence or other sexual dysfunction, dry throat, constipation, nausea, change in taste, and nervousness. However, in a 3-month trial, 51 of 101 patients had localized skin reactions that included erythema, pruritus, or both. Allergic contact sensitization was also seen in five patients [2]. These reactions, however, subsided with subsequent treatments.

A study conducted in 1997 found that Catapres- TTS lowers both systolic and diastolic blood pressure within the first 24 hours of application. The antihypertensive effect persists at the end of the first week, as well as after 14 days. Clonidine seems to act as an antihypertensive agent rather than a hypotensive drug, as it normalizes blood pressure without lowering it below physiologic levels [4].

Catapres-TTS has been shown to reduce the cardiovascular impact of hypertension in patients with diabetes mellitus. Clonidine significantly reduced systolic (153 versus 163 mm Hg) and diastolic (88 versus 98 mm Hg) blood pressure, left ventricular mass (94 versus 99 g/m2), and fasting blood glucose levels. Urinary albumin excretion was also noted to decrease with the use of Catapres-TTS [5].

Bathing appears to have a negligible effect on plasma concentration levels of clonidine. However, the plasma clonidine concentration was found to be greater in patients during the summer months than during the winter. It is theorized that the passage of an agent across the skin might be enhanced by greater hydration of the stratum corneum due to sweating [6]. Increased blood flow through the dermal vessels as well as higher relative humidity levels could also contribute to the higher plasma clonidine levels seen during the hot summer months.

Podiatric Applications

Podiatric applications include the administration of Catapres-TTS on the lower extremity as a means of increasing perfusion in vascularly compromised regions. The administration of clonidine results in a decreased sympathetic outflow from the central nervous system. This in turn produces a vasodilation response in the peripheral vessels, thereby decreasing peripheral resistance. The authors theorize that this results in an increase in oxygenation and blood tissue perfusion to previously ischemic areas. Distal lowerextremity ulcerations are often the consequence of chronic ischemic disease that cannot be treated with bypass surgery, such as frostbite, Mönckeberg’s sclerosis, Buerger’s disease, and Raynaud’s phenomenon. In other circumstances, the patient may not be a candidate for a bypass of the diseased vessel. Catapres-TTS thus offers the physician a viable alternative treatment.

Although the Catapres-TTS patch is available in formulations that deliver 0.1 mg, 0.2 mg, or 0.3 mg of clonidine per day, only the 0.1-mg system is used for lower-extremity applications. This low dose reduces the risks of possible systemic side effects that may result from stronger concentrations of the drug.

The Catapres-TTS patch therapy is used in cooperation with the patient’s primary-care physician owing to the systemic effects of the drug. The patient applies the 0.1-mg patch once a week. Its placement depends on the location of the ulceration. When the ulceration is located on the rearfoot or midfoot, the patch is applied just proximal to the lesion. If the ulceration is located on a digit, the patch is applied at the proximal aspect of the affected digit. The patch is changed weekly, and the patient is permitted to get it wet. The authors stress that this treatment acts as an adjunct therapy and does not replace local wound care and supportive therapies.

Patients treated with Catapres-TTS by the authors were selected on the basis of their nonresponse or minimal response to local wound therapy and recommendations from vascular surgeons that bypass surgery would be ineffective. Patients were also chosen on the basis of their history of compliance with therapeutic regimens. Because this medication has potentially serious side effects, compliance and follow-up visits are important. Blood pressure readings were taken at each visit to ensure that no significant pressure problems developed during treatment. If it is necessary to discontinue the medication, the patient must be closely monitored, as sudden cessation can lead to serious systemic problems. As mentioned earlier, the use of clonidine patches to treat ischemic foot ulcerations should be avoided in patients taking medications that affect sinus node function or atrioventricular nodal conduction. It should also be avoided or closely monitored in patients who are taking sedatives or barbiturates.

The authors have used this therapeutic modality in 30 patients who were not considered candidates for surgery. Of these 30 patients, 18 had ischemic digital ulcerations. In 13 of these patients, healing of the ulcerations occurred with local wound care in conjunction with use of the 0.1-mg clonidine patch, while 4 patients underwent digital amputations and 1 had a transmetatarsal amputation. The remaining 12 patients had ulcerations on the midfoot or rearfoot. Of these, 8 went on to heal, while 2 had transmetatarsal amputations and 2 had below-the-knee amputations. In treating these 30 patients, the authors encountered minimal adverse reactions to the use of this medication, in part because the lowest concentration of clonidine available was used. Two patients experienced mild pruritus around the patch; one experienced headaches; and three experienced dry mouth. None of these reactions were severe enough to require discontinuation of the medication. However, patients need to receive thorough instructions on the proper application of the patch and its potential for side effects. The patch was applied for a period ranging from 10 weeks to 5 months, depending on the treating physician and the success or lack of success of the treatments rendered.

Conclusion

The authors have found that Catapres-TTS can be successfully used to increase local blood flow to vascularly compromised areas and may act as an adjunct in the treatment of ischemic ulcerations. Catapres- TTS does not replace current treatment modalities; rather, it serves to complement current wound-healing methodologies. When Catapres-TTS is used, a team approach by the internist and the podiatric physician is needed to monitor any possible systemic effects of the drug. A study should be conducted to fully evaluate the effect of Catapres-TTS on ischemic ulcers, but the authors believe that their findings are valuable and should prompt discussion. Catapres- TTS may offer the physician another alternative in the treatment of ischemic ulcerations of the lower extremity.