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Patients with severe, treatment-resistant familial benign pemphigus, or Hailey-Hailey disease (HHD), had rapid and dramatic responses to low-dose oral naltrexone, results from two small clinical series showed.

All six patients had significant improvement in skin lesions beginning as early as 1 week after starting low-dose oral naltrexone. In one series, all three patients had 80% to 90% clearance of lesions, reported Omer Ibrahim, MD, of the Cleveland Clinic, and colleagues.

Discontinuation of naltrexone led to disease flare, which resolved within a few days after retreatment with the opioid receptor antagonist, they wrote online in JAMA Dermatology.

Naltrexone is to treat opioid use disorders and alcohol use disorders.

"Although off label and not approved by the Food and Drug Administration, low-dose naltrexone may represent a low-cost and low-risk alternative or adjunct in the treatment of HHD," the authors concluded. "To mitigate possible confounders, concurrent therapy was not administered to our patients, and we hypothesize that greater improvement may have been possible with the use of concomitant therapies."

Low doses of naltrexone appear to induce paradoxical analgesic and anti-inflammatory effect, Ibrahim's group stated. Incomplete blockade of mu- and delta-opioid receptors may lead to compensatory production of additional endogenous opioids and opioid receptors to effect analgesia. Moreover, naltrexone blockade of Toll-like receptors leads to extensive downregulation of proinflammatory cytokines and other substances.

In an , Erik J. Stratman, MD, of the Marshfield Clinic in Wisconsin, noted that repurposing drugs for different clinical uses makes sense by providing a cheaper and faster route to therapeutic development. For instance, sildenafil (Viagra) was originally developed for angina, finasteride (Propecia) for hair growth was originally for benign prostate hyperplasia, bimatoprost (Latisse) for eyelash growth (glaucoma), and propranolol for infantile hemangiomas (hypertension) represent several examples of successful repurposing.

However, clinicians often see patients who want to talk about "outlandish claims of successful therapies" that have no scientific or evidentiary basis. Noting that most information about naltrexone for HHD has come from Internet-based patient support groups, Stratman asked, "How do we find the golden needle in the white noise haystack of absurd patient claims?"

Use of available technology to "mine" web-based and social media communications for information about alternative therapies is one potential strategy to learn more about alternative treatments, he added.

Stratman concluded with a relevant anecdote from his father, who grew up on a chicken farm. Farmers often recommended that people apply chicken manure to treat or prevent chapped lips. As a boy, Stratman gave little thought to the rationale for such advice, but while in medical school, he revisited the issue, asking his father whether people really used chicken manure to treat chapped lips.

"Nah. I said 'farmers around here would tell you to put chicken manure on your lips.' I didn't say they'd do it," the elder Stratman replied. "But it sure would keep you from licking your lips, don't you think?"

The three patients in consisted of a woman in her 40s and two men in their 60s. All had longstanding HHD that proved resistant to multiple prior therapies.

Each patient received naltrexone at doses of 1.5 to 3.0 mg/day. Clinical response included healing of erosions, improvement in erythema, and pain relief. No laboratory monitoring was performed.

All three patients had >80% clinical improvement, including one patient who had 90% improvement. All of the patients reported improved quality of life, and one reported improvement in depression. No adverse events were noted.

The consisted of a man in his 50s and two women in their 60s. HHD history ranged from 15 to 40 years, and all of the patients had involvement of body surface area. Each patient had tried at least four prior therapies, all of which proved unsuccessful, reported Ron J. Feldman, MD, PhD, of Emory University in Atlanta, and colleagues.

Patients received naltrexone doses of 3.0 to 4.5 mg/day. All of the patients attained complete clearance of skin lesions within 2 to 4 months, and lesion improvement occurred as early as 1 week after starting naltrexone. All three patients attempted to discontinue treatment, which resulted in flares in all cases within a few days. Retreatment with naltrexone led to clearance of skin lesions.

"The rapid and significant improvement of symptoms in these patients, along with the medication's low adverse effect profile and reasonable cost, suggest low-dose naltrexone as a novel treatment for HHD," Feldman's group concluded. "Larger studies are needed to verify these preliminary findings and to further explore the mechanism in HHD."

Given evidence that downstream signaling pathways from TLRs affect calcium homeostasis in keratinocytes, naltrexone also warrants consideration for treatment of other conditions involving calcium-transport defects, such as Darier disease, they added.