Reed Huber, BSc1 and Aaron Wong, MD, FRCPC2

1Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
2Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

Conflict of interest: All of the authors have no conflicts to declare for this work.

Abstract:
Nicotinamide (or niacinamide), a form of vitamin B3 that is often confused with its precursor nicotinic acid (or niacin), is a low-cost, evidence-based oral treatment option for actinic keratosis, squamous cell carcinomas, basal cell carcinomas, and bullous pemphigoid. Despite its favorable safety profile and affordability, the integration of nicotinamide into clinical practice is an ongoing process, and like many over-the-counter supplements it has faced some barriers. The purpose of this article is to address some of those barriers by reviewing its efficacy, safety profile, and emphasizing the difference between nicotinamide and niacin. Lastly, we offer practical guidance around recommendations and the availability of nicotinamide, which can be hard to find for patients and providers alike.

Key Words:
nicotinamide, niacinamide, nonmelanoma skin cancer, squamous cell carcinoma, basal cell carcinoma, skin cancer, chemoprevention, bullous pemphigoid

Nicotinamide and How It Relates to Niacin

Nicotinamide is the amide version of its carboxylic acid precursor niacin (or nicotinic acid). Historically, niacin was identified as the first lipid-modifying drug when hypercholesteremia was beginning to be recognized as a risk factor for cardiovascular disease around the middle of the 20th century.1 However, the use of niacin in the treatment of dyslipidemia was limited due to common cutaneous adverse effects, mainly flushing and telangiectasias.2 Biochemically, nicotinamide and niacin are sequential precursors in the pathway converting the essential amino acid tryptophan into the ubiquitous electron acceptor cofactor nicotinamide adenine dinucleotide (NAD+) (Figure 1). Despite their structural and chemical similarity, nicotinamide and niacin differ significantly from a therapeutic standpoint, in that nicotinamide does not share either of the aforementioned lipid-modifying and vasodilatory effects of niacin.3 This dissimilarity is best explained by the release of prostaglandin D2 from the skin via an unknown mechanism causing cutaneous vasodilation and through specific nicotinic acid receptor binding interactions in adipose tissue3,4 An overview of the differences between nicotinamide and niacin are summarized in Table 1.

Nicotinamide: An Update and Review of Safety & Differences from Niacin - image
Figure 1: Metabolism of tryptophan to NAD+ and NADP.
NAD+ = nicotinamide adenine dinucleotide
NADP = nicotinamide adenine dinucleotide phosphate
Nicotinamide Niacin
Synonyms Niacinamide, NAM, vitamin B3 Nicotinic acid, vitamin B3
Indications
  • Chemoprophylaxis of AK and NMSC
  • In combination with tetracycline for BP
  • Pellagra
  • Topically for acne, rosacea, and aging skin
  • Dyslipidemia in specific clinical situations
  • Pellagra
Adverse events
  • Gastrointestinal (GI) upset (primarily in end-stage  renal disease [ESRD] patients)20
  • Elevated liver enzymes (only in dosages >3 g/day)17
  • Thrombocytopenia (only in ESRD patients)20
  • Skin flushing2,3
  • Pruritis and xerosis2,3
  • Headaches and GI upset2,3
  • Elevated uric acid levels2,3
  • Elevated liver enzymes2,18
  • Thrombocytopenia2,18
Table 1: Differences between nicotinamide and niacin.

Background

Niacin is synthesized from tryptophan, an essential amino acid obtained from dietary sources, including poultry, salmon, and red meat. In the body, niacin is converted to nicotinamide, and like most water-soluble vitamins, it functions as enzyme cofactors. Nicotinamide is the precursor of NAD+ and the reduced form NADP, which are implicated in oxidative phosphorylation and adenosine triphosphate (ATP) production, and function as enzyme cofactors in at least 200 different biochemical reactions.5

Actinic keratosis (AK) and nonmelanoma skin cancers (NMSC) are caused principally by ultraviolet (UV) radiation directly damaging DNA in keratinocytes and by immunosuppression. Nicotinamide works at multiple steps to counteract the carcinogenesis of squamous-cell carcinomas (SCC) and basal-cell carcinomas (BCC) (Figure 2). First, by preventing ATP depletion, nicotinamide boosts cellular energy which counteracts the “energy crisis” in photodamaged skin through an array of protective responses within keratinocytes, including DNA repair, anti-inflammatory effects, and by enhancing local cutaneous immunity.2 Nicotinamide is also the exclusive substrate for poly-ADP-ribose-polymerase (PARP-1), a key enzyme involved in DNA repair.6 Moreover, nicotinamide reduces the level of immunosuppression that results from UVB irradiation of lymphocytes in the skin through similar mechanisms by enhancing cellular energy and DNA repair enzyme activity without altering baseline immunity.7,8

Figure 2: Proposed chemoprotective actions of nicotinamide.

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.

Adverse Effects and Potential Drug Interactions

Unlike other oral agents used for prevention of NMSC, such as systemic retinoids or chemotherapeutic agents in organ transplant recipients, nicotinamide has a much more favorable safety profile. Furthermore, nicotinamide is not associated with the undesirable side effects of its biochemical precursor niacin, such as skin flushing, pruritis, and xerosis.18,19 In the two largest phase 3 studies involving nicotinamide, the ONTRAC study (n = 386) outlined above and the ENDIT study (n = 552) involving patients at risk of developing Type 1 diabetes mellitus, both showed that there was no difference in patient tolerability and laboratory adverse events between nicotinamide (1-3 g/day) and placebo.12,20 Other reported adverse events of nicotinamide include thrombocytopenia and hepatotoxicity, however, the ONTRAC study showed no difference in platelet counts between nicotinamide versus placebo groups, and evidence of liver toxicity has only been reported at extremely high dosages of nicotinamide in excess of 3 g/day.12,18 Nicotinamide is renally cleared and 1 study in patients with ESRD on dialysis receiving nicotinamide reported thrombocytopenia, though reassuringly all cases resolved upon cessation of nicotinamide.21

In summary, 1g daily of nicotinamide is well tolerated as highlighted by multiple reports of minimal if any adverse events.12,14,15,21 Unlike niacin, nicotinamide does not cause flushing, and thrombocytopenia and hepatotoxicity are rare, isolated effects in patients receiving hemodialysis or at extremely high dosages in excess of 3 g per day.

Regarding potential drug interactions, Lexicomp reports both niacin and nicotinamide as potentially increasing the adverse effects of statins, with a risk rating to monitor therapy. Clinical trials involving statin-niacin combination therapy have not reported myopathy, however, there have been case reports of niacin in combination with specific statins associated with rhabdomyolysis and transaminase elevations.22 Though, upon searching the Ovid MEDLINE database using the nicotinamide synonyms and medical subject heading for HMG-CoA reductase inhibitors, there were no adverse drug interactions cited between nicotinamide and statins. Thus, as with statin monotherapy, patients should be cautioned to report symptoms suggestive of myopathy and consideration should be given to monitoring creatinine kinase (CK) and transaminase levels.

Real World Experience

Despite nicotinamide’s potential benefit to a large cohort of patients as a safe and inexpensive over-the-counter vitamin supplement for NMSC prevention, its translation into clinic practice has been hindered, mainly due to difficulties of finding it in stores, confusion over labeling, and relation to niacin. Notably, both products may be labeled vitamin B3, with niacin being the acid form and nicotinamide the amide form. Also, the labeling of North American products is predominantly niacinamide rather than nicotinamide, but both are the same thing.

In our own experience, drug store chains and other retailers are more likely to sell niacin and vitamin B-50 and B-100 complexes, the latter two only contain 50 mg and 100 mg of nicotinamide (or niacinamide), respectively. However, most large naturel health product stores we’ve encountered sell nicotinamide/niacinamide 500 mg products in the vitamin aisle along with other B vitamins. In addition, nicotinamide/niacinamide is easily accessible online (Table 2) and from specialty vitamin stores. The authors have had some success writing this as a prescription and having the pharmacist order in or locate the niacinamide/nicotinamide for patients (Figures 3 and 4).

Brand Name (niacinamide 500 mg) Price per Bottle (size & dosage form)
NOW Foods $6.48 – $21.22 (100 capsules)
Westcoast Naturals $14.99 (90 tablets)
Jarrow Formulas $6.84 (100 capsules)
Major $11.99 (100 tablets)
Nature’s Plus $10.50 (90 tablets)
Nature’s Way $6.90 – $10.99 (100 tablets)
Solaray $6.97 (100 VegCaps)
Source Naturals $15.88 (100 tablets)
Thorne Research $26.71 (180 capsules)
Trophic Canada $11.49 (90 caplets)
21st Century Pharmacy $5.05 (110 tablets)
Table 2: Online commercially available nicotinamide/niacinamide. Retailers include Amazon.ca, iHerb.ca, Vitamart.ca, Walmart.ca and Well.ca. Prices shown in Canadian dollars.
Availability and prices subject to change by retailers.
Figure 3: Sample prescribing sheet for practitioners for actinic keratosis and nonmelanoma-skin cancer.
Figure 4: Sample prescribing sheet for practitioners for bullous pemphigoid.

Conclusion

In summary, oral nicotinamide is an affordable over-the-counter supplement with demonstrated benefit in the treatment of a range of skin conditions, most notably AK and NMSC. Furthermore, it has a favorable safety profile with minimal if any adverse effects or potential drug interactions. The proven chemoprotective action of nicotinamide offers an opportunity for its use as an adjunctive treatment or on its own for patients at risk of NMSC, however, due to confusion around its naming and availability, its adoption into practice has been met with some resistance. Thus, we hope that this article is able to shed some light on the differences between nicotinamide and its precursor niacin and offer practical information around recommending nicotinamide to patients, including where to purchase it.

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