Nicotinamide: An Update and Review of Safety & Differences From Niacin

Reed Huber, BSc; Aaron Wong, MD, FRCPC

Disclosures

Skin Therapy Letter. 2020;25(5):7-11. 

In This Article

Uses in Dermatology

Nicotinamide therapy has been studied in both the prevention of NMSC and in the treatment of bullous pemphigoid (BP). Both disease processes involve a degree of immune dysregulation and are on opposite ends of the spectrum of epidemiological significance. Together, AK, SCCs, and BCCs account for at least 14% of all dermatology office visits and the incidences of all three are currently rising.[9,10] On the other hand, BP is an autoimmune subepidermal bullous disorder affecting about 10 per million of the general population, however, it is associated with considerable mortality, especially among elderly patients. The mean age of disease incidence ranges between 60 and 80 years.[11]

Actinic Keratosis and Nonmelanoma Skin Cancer

The Oral Nicotinamide to Reduce Actinic Cancer (ONTRAC) study, a phase 3 double-blinded randomized clinical trial published in the NEJM in 2015, concluded that oral nicotinamide was safe and effective in reducing the rates of NMSC and AK in high-risk patients.[12] The study was conducted in Australia. High-risk patients included study participants who had at least two NMSC in the previous 5 years, and groups were randomly assigned to receive either 500 mg nicotinamide BID (n = 193) or placebo for 12 months (n = 193). At 12 months, the rate of new BCCs was 20% lower in the nicotinamide group and with respect to AK and SCCs, the incidences were 13% and 30% lower, respectively. Overall, the rate of new NMSC was 23% lower (p = 0.02) in the nicotinamide group versus the placebo group and there was no difference in safety between groups.[12]

The authors concluded that nicotinamide treatment was safe and effective, especially among patients with higher numbers of prior NMSC. Moreover, two earlier phase 2 studies showed that 500 mg of oral nicotinamide taken once or twice daily in individuals with sun-damaged skin (4 or more AK and with or without a history of skin cancer) significantly reduced AK counts and the incidence of new NMSC.[13] In addition, the authors of the ONTRAC study performed a similar, albeit smaller study (n = 22) in immunosuppressed solid organ transplant recipients.[14] Nicotinamide 500 mg BID was associated with a non-significant 35% relative reduction in the rate of NMSC (p = 0.36) compared to placebo and there were no safety differences between groups.[14] Thus, it appears that oral nicotinamide is an effective chemoprotective agent for most patients with varying degrees of immunological status and sun-damaged skin, and the effects are observed as early as 2 months with 500 mg of nicotinamide either once or twice daily.[12–14]

A recent systematic review looking at treatments for AK covered 18 topical treatments, 1 oral option, which was an oral retinoid, and 3 chemical interventions, including cryotherapy.[15] The authors concluded that photodynamic therapy and some topical treatments, namely diclofenac, 5-fluorouracil, imiquimod, and ingenol mebutate all had similar efficacy, and thus the choice of treatment should be guided by the patient's tolerances and preferences. However, some of the aforementioned agents can be cost prohibitive for some patients, whereas oral nicotinamide is a low-cost option that has proven clinical efficacy and a favorable safety profile. Additionally, as an oral agent it can be used as an adjuvant to an existing topical or office-based treatment regimen. Though its use in conjunction with existing treatment options, such as topical immunomodulators and office-based interventions including cryotherapy and photodynamic therapy, has not been directly studied, as an oral agent we believe it can be safely used as an adjuvant to a patient's existing regimen or on its own for the chemoprevention of AKs and NMSC.

A recent systematic review looking at treatments for AK covered 18 topical treatments, 1 oral option, which was an oral retinoid, and 3 chemical interventions, including cryotherapy.[15] The authors concluded that photodynamic therapy and some topical treatments, namely diclofenac, 5-fluorouracil, imiquimod, and ingenol mebutate all had similar efficacy, and thus the choice of treatment should be guided by the patient's tolerances and preferences. However, some of the aforementioned agents can be cost prohibitive for some patients, whereas oral nicotinamide is a low-cost option that has proven clinical efficacy and a favorable safety profile. Additionally, as an oral agent it can be used as an adjuvant to an existing topical or office-based treatment regimen. Though its use in conjunction with existing treatment options, such as topical immunomodulators and office-based interventions including cryotherapy and photodynamic therapy, has not been directly studied, as an oral agent we believe it can be safely used as an adjuvant to a patient's existing regimen or on its own for the chemoprevention of AKs and NMSC.

Bullous Pemphigoid

An alternative use in dermatology for nicotinamide is in combination with tetracycline antibiotics for the treatment of BP. A small (n = 20) unblinded randomized trial did not find significant differences in efficacy between traditional systemic steroid therapy versus tetracycline plus nicotinamide.[16] The duration of treatment in the study was 8 weeks and the outcomes assessed were lesion counts and pruritis. Out of the 14 patients treated with tetracycline (500 mg QID) plus nicotinamide (500 mg TID), there were 5 each of complete and partial responses, and 1 each with no response and worsening BP. Among the 6 patients treated with systemic steroids (prednisone 40 to 80 mg/day), 1 had complete resolution while the other 5 responded partially. In summary, a larger blinded randomized trial is needed, but tetracycline plus nicotinamide is likely a useful alternative to systemic steroids, with similar efficacy and fewer side effects, especially among BP patients who tend to be older than 70 years of age and more prone to developing serious adverse effects from corticosteroid therapy. The side effects observed in the tetracycline plus nicotinamide arm included GI upset and acute tubular necrosis. Because of the potential of nephrotoxicity in patients with baseline severely decreased glomerular filtration rate (GFR), the authors of the study recommended exclusion of patients with a serum creatinine level >177 μmol/L or blood urea nitrogen (BUN) >14.3 mmol/L. However, more recently the BLISTER trial published in the Lancet comparing doxycycline (200 mg daily) alone to corticosteroids demonstrated non-inferiority in patients with BP, while showing long-term safety benefits in the doxycycline group.[17] Assuming a class-effect for tetracycline antibiotics, a suitable regimen for the treatment of BP patients (in whom high-dose corticosteroid therapy should be avoided) that reduces the pill burden and eliminates the need for renal monitoring, would be doxycycline 200 mg daily plus nicotinamide 500 mg BID or TID.

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