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.