Abstract: The authors present the case of a patient with severe burning sensations in the soles of both feet. The patient was diagnosed as having diabetic neuropathy, which can result in extremely variable symptoms ranging from burning, shooting or stabbing pain to complete loss of sensation. The authors discuss treatment of this condition with topical doxepin. Twice daily treatment with doxepin for four weeks eliminated the severe burning sensation without side effects. While it appears that topical doxepin may be an alternative treatment in alleviating neuropathic pain in the diabetic patient, further controlled studies should be conducted to rule out placebo effects.

CME/CPME ACTIVITY

Department Editor: Tania J. Phillips, MD, FRCPC

Overall Learning Objective: The physician or podiatrist participant will develop a rational approach to the evaluation and treatment of a variety of uncommon wounds and will have an increased awareness of the differential diagnosis of cutaneous wounds and the systemic diseases associated with these wounds.

Submissions: To submit a case for consideration in Diagnostic Dilemmas, e-mail or write to: Executive Editor, WOUNDS, 83 General Warren Blvd., Suite 100, Malvern, PA 19355, eklumpp@hmpcommunications.com

Completion Time: The estimated time to completion for this
activity is 1 hour.

Target Audience: This CME/CPME activity is intended for dermatologists, surgeons, podiatrists, internists, and other physicians who treat wounds.

At the conclusion of this activity, the participant should be able to:
1. Describe and discuss diabetic neuropathy
2. Describe the possible role of hyperglycemia in the development of diabetic neuropathy
3. Describe the mechanism of action of doxepin in the management of pruritus and neuropathic pain
4. Administer topical doxepin safely.

Disclosure: All faculty participating in Continuing Medical Education programs sponsored by HMP Communications, LLC, are expected to disclose to the program audience any real or apparent conflict(s) of interest related to the content of their presentation. Drs. Al-Muhairi and Phillips disclose that they have no conflicts of interest relevant to the content of this article.

Accreditation: HMP Communications, LLC, is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. HMP Communications, LLC, is approved by the Council on Podiatric Medical Education as a sponsor of continuing education in podiatric medicine.

Designation: HMP Communications, LLC designates this continuing medical education activity for a maximum of 1 credit hour in category 1 credit toward the AMA Physician’s Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. HMP Communications designates this continuing medical activity for .1 CEUs available to participating podiatrists.

Method of Participation: Read the article, take, submit, and pass post-test by August, 2004.

This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies.

Release date: 8/10/03
Expiration date: 8/10/04

Burning Feet due to Diabetic Neuropathy

Presentation

A 66-year-old Caucasian woman recently presented at the wound clinic with severe burning sensations in both soles of her feet, which worsened at night and disturbed her sleep. She has been an outpatient at the clinic for several years for multiple lower-extremity ulcerations due to cryofibrinogenemia. The patient has insulin-dependent diabetes. Clinical exam revealed a pleasant, pale looking woman with normal vital signs. Examination of lower extremities revealed atrophic scars on left medial and lateral malleoli, the sites of healed ulcers. Skin on both feet was hypersensitive to touch and pressure, peripheral pulses were intact, and capillary refilling time was normal.

Diagnosis

The patient was diagnosed as having diabetic neuropathy.

Discussion

Diabetic neuropathy. The neuropathies are the most common of all the late complications of diabetes and give rise to much suffering among diabetic patients.[1] Diabetes causes nine percent of the peripheral neuropathies.[2] Symmetric sensory diabetic neuropathy is the most common form of diabetic neuropathy, with a gradual insidious onset and slow progression, generally paralleling the duration of diabetes and the development of microvascular complications (retinopathy and nephropathy).[3] Diabetic polyneuropathy causes symptoms in 15 percent of patients with insulin-dependent diabetes and 13 percent of patients with noninsulin-dependent diabetes.[3] The clinical presentation is extremely variable, ranging from severely painful extremities to the complete loss of sensation that may present with an insensitive foot ulcer.[3] The pain is most commonly described as burning, shooting, stabbing, extremely uncomfortable, distressing, and prone to nocturnal exacerbation.[1] Although painful neuropathies are usually the result of damage to the axons, no clear pathologic features have been associated with the presence of pain.[3]

Hyperglycemia is central to any pathogenetic scheme for the development of human diabetic neuropathy. Therefore, tight and stable glycemic control may be the only treatment that provides symptomatic relief as well as slowing the progression of the neuropathic state.[1] Because it has been suggested that blood glucose flux, with rapid swings from hypoglycemia to hyperglycemia, can aggrevate and induce neuropathic pain, the stability of glycemia rather than the actual level of glycemic control may be more important in relieving neuropathic pain.[1]

Tricyclic antidepressants (TCAs). TCAs are important drugs in the treatment of painful neuropathy.[3] Their analgesic effect is independent of their antidepressant activity and generally occurs at low doses with rapid onset of pain relief (one to two weeks).[3–5] The analgesic effect is the result of inhibiting norepinephrine and serotonin uptake, thereby increasing inhibitory neurotransmitter tone at the spinal cord level.[5] Despite the proven efficacy of oral TCAs in neuropathic pain, their use is frequently complicated by side effects, such as drowsiness, impaired cognitive function, and anticholinergic and cardiovascular adverse effects.[4,6] These adverse effects are experienced by almost one in three patients.[4] TCAs do not address the underlying cause or slow the progression of neuropathy, but they improve the quality of life by alleviating discomfort.[7]

An analgesic effect of the topically applied TCA, doxepin hydrochloride, in chronic human neuropathic pain has recently been described.[4,6] It is known to have strong H1 and H2 antihistaminic effects.[8] It is indicated for the short-term topical application (up to 8 days) in relieving pruritus associated with various forms of eczematous dermatoses.[8] Several studies showed that topically applied doxepin is safe.[9] Serum levels using the cream are usually immeasurable but when detected, are 25 times lower than the serum level required for the doxepin to have any therapeutic central nervous system activity as a tricyclic agent (150–250ng/mL).[9,10] In a randomized, double-blind, placebo-controlled study of 200 adult patients, topical application of doxepin had an analgesic effect in neuropathic pain with fewer side effects reported compared with oral administration.[4] Minimal percutaneous absorption of topical doxepin occurred with plasma levels of topical doxepin ranging from 0 to 47ng/mL compared to 30 to 150ng/mL reported for orally administered doxepin.[11] However, some researchers believe the analgesic effect is attributable to systemic absorption because onset of analgesia becomes apparent after two weeks, coinciding with the time to steady-state concentration after oral dosing.[4] In addition, the extension of the effect of topical doxepin beyond treated areas and the previous reports of drowsiness associated with topical doxepin use all imply considerable systemic absorption.[11] Despite this, topical doxepin is well tolerated and has fewer side effects than orally administered doxepin,[11] the most prominent being a transient somnolence.[10] Contact sensitization and dermatitis has also been reported.[6,12,13] Rational use of doxepin cream will minimize side effects. Thin films of doxepin cream should be applied to no more than 10 percent of body surface area, and under no circumstances should occlusive dressings be used.[14]

Conclusion

Topical doxepin could be an alternative and relatively safe treatment in alleviating neuropathic pain in the diabetic patient,[6] especially when the use of systemic treatment is contraindicated. Further controlled studies are needed to evaluate the role of placebo effect.

Patient Management

In this patient, the soles of her feet were treated with topical doxepin 5% twice daily for four weeks. The patient responded dramatically with loss of the severe burning sensation and no side effects reported.

How to obtain educational credits by reading this article

Learning Assessment: Successful completion entails scoring at least 70 percent on the questions, completing the entire evaluation form by printing it out, marking answers on the print off, and sending it to the correct address listed below. Certificates will be mailed to those who successfully complete the learning assessment by August 10, 2004.

Fax the completed form to: (610) 560-0501 or mail the completed form to: Trish Levy, CME Director, HMP Communications, LLC, 83 General Warren Blvd., Suite 100, Malvern, PA 19355

Questions

1. The clinical presentation of sensory diabetic neuropathy may include the following except:
A. Loss of sensation
B. Foot ulcer
C. Burning pain
D. Cold feet
E. Paraesthesia

2. The most common form of diabetic neuropathy is:
A. Symmetric sensory neuropathy
B. Proximal neuropathy
C. Mononeuropathy
D. Autonomic neuropathy
E. Motor neuropathy

3. The most common late complication of diabetes is:
A. Retinopathy
B. Nephropathy
C. Diabetic foot
D. Neuropathy
E. Silent myocardial infarction

4. The analgesic effect of tricyclic antidepressants can be attributed to:
A. Depletion of substance-P
B. Antagonism of histamine receptors
C. Anticholinergic effect
D. Norepinephrine and serotonin uptake inhibition
E. None of the above

5. The FDA approved use of doxepin cream is:
A. Neuropathic pain
B. Chronic pain
C. Pruritus in adult patients
D. Insomnia
E. Urinary incontinence

6. The most common side effect of topical doxepin is:
A. Drowsiness
B. Seizure
C. Anticholinergic effects, such as dry mouth, blurred vision, and constipation
D. Allergic reactions, such as skin rash
E. Tremors

7. To avoid the development of side effects, doxepin cream should not be used more than:
A. Three weeks
B. One week
C. Four weeks
D. Six weeks
E. None of the above

8. Doxepin is:
A. Tricyclic antidepressant
B. Potent H1 and H2 histamine receptor blocker
C. Formulated as a 5% cream
D. Used for the management of neuropathic pain
E. All of the above

Burning Feet due to Diabetic Neuropathy Answer Form and Evaluation

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Now that you have read this article, can you:

1. Describe and discuss diabetic neuropathy? YES NO
2. Describe the possible role of hyperglycemia in the development of diabetic neuropathy? YES NO
3. Describe the mechanism of action of doxepin in the management of pruritus and neuropathic pain? YES NO
4. Administer topical doxepin safely? YES NO

What questions do you still have?_________________________________

How will you use what you have learned from this activity?______________

All tests must be received by 8/10/04.