topical nicotinamide compared with clindamycin gel in the treatment

International Journal of Dermatology, VoL 34, No. 6, June 1995
PHARMACOLOGY AND THERAPEUTICS
TOPICAL NICOTINAMIDE COMPARED WITH CLINDAMYCIN
GEL IN THE TREATMENT OE INELAMMATORY
ACNE VULGARIS
ALAN R. SHALITA, M.D., J. GRAHAM SMITH, M.D.,
LAWRENCE CHARLES PARISH, M.D., MICHAEL S. SOFMAN, M.D., AND DAN K. CHALKER, M.D.
other antimicrobials, is associated with emergence of resistant microorganisms, nicotinamide gel is a desirable alternative treatment for acne vulgaris.
Int J Dermatol 1995; 34:434-437
Abstract
Background. Systemic and topical antimicrobials are effective in the treatment of inflammatory acne vulgaris;
however, widespread use of these agents is becoming increasingly associated with the emergence of resistant
pathogens raising concerns about microorganism resistance and highlighting the need for alternative nonantimicrobial agents for the treatment of acne. Nicotinamide gel
provides potent antiinflammatory activity without the risk
of inducing bacterial resistance.
Systemic and topically applied antimicrobial agents
have been widely prescribed for the treatment of inflammatory acne vulgaris for over 30 years. Although
these agents generally continue to be effective,^"^ their
widespread use has also been associated with the emergence of resistant strains of Staphylococi and Propionibacterium.^"^ As early as 1976, samples of cutaneous
propionibacterium microorganisms taken from over
1000 acne patients were uniformly sensitive to antibiotics.'" In contrast, 17 years later, 40% of the 468
acne patients studied in England carried Propionibacteria strains that were resistant to one or more antibiotics." As a result, guidelines were proposed to restrict
the use of antimicrobial agents for the treatment of
acne. Propionibacteria resistance should be considered
as a cause of antimicrobial therapeutic failure.
These observations have spawned renewed interest
in the development of alternative therapy for acne providing the therapeutic characteristics of antimicrobial
agents without the problem of bacterial resistance.
Nicotinamide has potent antiinflammatory properties,^^"^^ and the compound has been used both topically and systemically in a variety of cutaneous inflammatory disorders."*"^" The present study was conducted to
determine the efficacy and safety of topically applied
4% nicotinamide gel compared to 1% clindamycin gel,
in treating inflammatory acne vulgaris.
Methods. In our double-biind investigation, the safety and
efficacy of topically applied 4% nicotinamide gel was compared to 1% clindamycin gel for the treatment of moderate
inflammatory acne vulgaris. Seventy-six patients were randomly assigned to apply either 4% nicotinamide gel (n = 38)
or 1% clindamycin gel (n = 38) twice daily for 8 weeks. Efficacy was evaluated at 4 and 8 weeks using a Physician's
Global Evaluation, Acne Lesion Counts, and an Acne Severity Rating.
Results. After 8 weeks, both treatments produced comparable (P = 0.19) beneficial results in the Physician's Global
Evaluation of Inflammatory Acne; 82% of the patients treated with nicotinamide gel and 68% treated with clindamycin
gel were improved. Both treatments produced statistically
similar reductions in acne lesions (papules/pustules; -60%,
nicotinamide vs. -43%, clindamycin, P = 0.168), and acne
severity (-52% nicotinamide group vs. -38% clindamycin
group, P = 0.161).
Conclusions. These data demonstrate that 4% nicotinamide
gel is of comparable efficacy to 1% clindamycin gel in the
treatment of acne vulgaris. Because topical clindamycin, like
From the Department of Dermatology, State University of
New York, College of Medicine, Brooklyn, New York, the
Division of Dermatology, University of South Alabama,
School of Medicine, Mobile, Alabama; the Department of
Dermatology, Jefferson Medical College, Thomas Jefferson
University, Philadelphia, Pennsylvania, and the Department of
Dermatology, Medical College of Georgia, Augusta, Georgia.
Materials and Methods
A multicenter, double-blind, randomized, parallel, active-control study was conducted for up to 12 weeks. Data compiled
during the first 8 weeks from all centers were analyzed,
whereas two of the centers followed patients for a period of
12 weeks. Unfortunately there was an insufficient number of
patients studied to allow meaningful analyses in the longer
treatment period.
Seventy-six men and women, aged 13 to 35 years, with
moderate inflammatory acne vulgaris enrolled in this study.
Moderate inflammatory acne was defined by the presence of
at least 15 papules and/or pustules on the face. Patients with
predominately comedonal acne were excluded. All concomi-
Supported in part by Genderm Corporation, Lincolnshire, IL.
Address for correspondence: Alan R. Shalita, M.D., Department of Dermatology, SUNY Health Sciences Center, Box
46, 450 Clarkson Avenue, Brooklyn, NY 11203.
434
Nicotinamide Gel in Acne Vulgaris
Shalita et ai.
tant treatments were withdrawn according to the following
schedule: topical acne preparations, topical antimicrobial
agents, medicated cosmetics, soaps, or shampoos, and radiation therapy, topical corticosteroids, and investigational
drugs at least 2 weeks before entry; systemic antimicrobials
corticosteroids at least 12 weeks before entry; and oral
isotretinoin at least 2 years before entry. The only concomitant medications permitted were oral contraceptives, if they
had been used continuously for at least 3 months before
entry and the dosage schedule was not expected to change
during the study period. Exclusion criteria included: pregnant or lactating women; patients with more than three
nodular lesions on the face; patients with any active skin
diseases other than inflammatory acne vulgaris; patients
with a history of allergy to study-medications; patients with
a previous history of regional enteritis, ulcerative colitis, or
antibiotic-associated colitis. Prior to enrollment, a signed informed consent was obtained.
At the initial qualifying visit, a medical history was obtained and patients were given a dermatologic examination
to determine eligibility for study, A lesion count of the entire face was taken, noting the number of papules, pustules,
and cysts (baseline only). Additionally, the investigator determined an acne severity grade using Allen and Smith's^^
modification of the Cook et al,^^ procedure (Table 1).
Patients who met all eligibility criteria were assigned to
receive either 4% nicotinamide gel or 1% clindamycin phosphate gel in a double-blind, randomized manner. Each patient was instructed to apply the medication to the face
twice a day. Patients were supplied with adequate quantities
of Ivory® soap and Suave® shampoo to be used exclusively
for facial and hair cleansing during the course of the study.
Each patient was required to return for follow-up visits
after 4 and 8 weeks of therapy to assess clinical improvement and to elicit information regarding adverse effects. At
each follow-up visit, the investigator repeated the Acne
Severity Rating and Acne Lesion Count, and also rated the
overall improvement of acne compared to pre-treatment
examination using a Physician's Global Evaluation of Inflammatory Acne: +3 = much better; +2 = moderately better,
+1 = slightly better, 0 = no change, -1 = worse.
Demographic data were analyzed using Student's T-test.
The Cochran-Mantel Haenszel (CMH) chi-square test with riditassigned scores was used for analysis of the Physician's
Global Evaluation, Percent change from baseline in the
Acne Severity Rating and the Acne Lesion Count were analyzed using analysis of covariance. All statistical tests were
two-tailed and statistical significance was defined as P <
0,05, Results are expressed as Mean ± SEM.
RESULTS
Seventy-six patients, 23 men and 53 women, age 13 to
35 years (mean age 21,3 years) were enrolled in the
study. There were no significant demographic differences between the two treatment groups. Seventeen patients failed to complete the study; nine in the nicotinamide treatment group and eight in the clindamycin
group. Reasons for premature withdrawal included adverse experience (nicotinamide 2), lost to follow-up
(nicotinamide 7, clindamycin 5), tion-medical reasons
(clindamycin 2) or condition unchanged/worsened from
baseline (clindamycin 1), Efficacy results were based on
49 evaluable subjects (nicotinamide 2 1 , clindamycin
28), who participated in at least one evaluation during
the treatment period with no protocol violations.
Both clindamycin and nicotinarnide treatment was
associated with a progressive reduction in acne severity
after 4 and 8 weeks of therapy (Fig. 1). At baseline, the
mean acne severity rating for the nicotinamide treatment group (4,78 ± 0,19) was nearly identical to the
rating for the clindamycin-treated patients (4,84 ±
0.19), After 8 weeks of therapy, the acne severity ratings decreased to 2,48 ± 0.39 in nicotinamide-treated
patients (-51.6 + 7.0%) and to 3.07 ± 0.33 in clindamycin-treated patients (-38,4 ± 6,1%), No significant differences between nicotinamide- and clindamycin-treated patients were evident. Similarly,
nicotinamide and clindamycin produced comparable reductions in the number of acne lesions (papules and
pustules) after 8 weeks of therapy. The acne lesion
count decreased from 27,6 ± 2,1 to 13,5 + 2,8 (-59,5 ±
9,0%) in the nicotinamide treatment group compared
•c -20
d)
CO
a> -40
<
Tahle 1, Acne Severity Rating
Grade 0
Grade 2
Grade 4
Grade 6
Grade 8
Facial skin is clear or a few scattered comedones
or papules are visible on close examination.
About one-fourth of face is involved with small
papules (6 to 10) and comedones, A few pustules
or prominent papules may he present.
About one-half of the face is involved with small
papules and comedones, A few pustules or
prominent papules are usually present.
About three-fourths of the face is involved with
papules and/or large open comedones. Numerous
pustules are usually present.
I -60
p=0.16
p=0.16
-80
4 weeks
nicotinamide gel
8 weeks
Treatment Period
clindamycin gel
Figure 1. Acne Severity Rating: percent reduction in acne
severity compared to baseline.
Practically all of the face is involved with highly
inflammatory lesions.
435
International Journal of Dermatology
Vol. 34, No. 6, June 1995
cologic agent, nicotinamide has been used for its antiinflammatory properties in such cutaneous disorders as
bullous pemphigoid,'** necrobiosis lipoidica," and dermatitis herpetiformis.^^ In our investigation, we found
nicotinamide gel, presumably acting through an antiinflammatory mechanism of action, to be equivalent in
efficacy to topical clindamycin for the treatment of
acne vulgaris.
The precise mechatiism(s) by which nicotinamide
exerts a therapeutic effect in acne vulgaris is unclear.
Nicotinamide has been shown to blunt potassium
iodide-induced inflammation in human volunteers'^
and markedly suppress 12-O-tetradecanoyl-phorbol13-acetate-induced cutaneous inflammation in mice.'^
Nicotinamide may exert an antiitiflamrnatory action
through inhibition of mast cell histamine release,''' inhibition of neutrophil chemotaxis and secretion of inflammatory mediators,'^ blockade of histamine receptors,'^ or suppression of lymphocyte transformatioti.'^
Nicotinamide has other diverse actions such as electron scavenging,^^ inhibition of phosphodiesterase activity,^'' or increased synthesis of serotonin^^ which
may also contribute to the pharmacologic activity of
this compound. Some or all of these pharmacologic effects of nicotinamide may contribute to the resolution
and prevention of inflammatory acne lesions.
-20-
•~ O
O <D
-40-
-60
p=0,06
T
p=0,17
-80
4 weeks
nicotinamide gel
8 weeks
Treatment Period
clindamycin gel
Figure 2. Acne Lesion Count: percent reduction in the number of acne lesions (papules and pustules) compared to baseline.
to a reduction from 29.3 ± 2.0 to 17.0 ± 2.4 (-42.7 ±
7.8%) in the clindamycin treatment group (Fig. 2). Finally, there were no significant differences in the Physician's Global Evaluation of Inflammatory Acne for
overall change in acne condition from baseline between
the nicotinamide- and clindamycin-treated patients at
any time during the study (Fig. 3). At Week 4, 36% of
the patients being treated with nicotinamide were rated
as either moderately or much better compared to 40%
of the clindamycin group. After 8 weeks of treatment,
the response rate increased to 86% for nicotinamide
compared to 68% for clindamycin (P = 0.19).
The frequency of adverse reactions was similar in
both treatment groups (10 nicotinamide-treated patients
and nine clindamycin-treated patients) and consisted entirely of local application-site reactions. Localized mild
to moderate pruritus and production of excessive oiliness at the application site were reported with topical
clindamycin, whereas mild stinging or burning at the
site of application was reported with topical nicotinamide. Application site reactions with topical treatment of acne vulgaris have been attributed to vehicle
components in previous studies.''-^
After 8 weeks of therapy, 4% nicotinamide and 1%
clindamycin gels were equivalent in efficacy for the
treatment of inflammatory acne vulgaris as shown by
Physician's Global Evaluation, Acne Lesion Count, and
Acne Severity Rating. Unlike topical clindamycin,^
100
DISCUSSION
4 weeks
Nicotinamide is the physiologically active form of
niacin and is the source of vitamin B3 found in a majority of multivitamin products. Nicotinamide serves as
a precursor in the synthesis of the coenzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide
adenine dinucleotide phosphate (NADP). AS a pharma-
nicotinamide gel
8 weeks
Treatment Period
clindamycin gel
Figure 3. Physicians Global Evaluation of Inflammatory
Acne: percent of patients whose acne condition was rated as
moderately better or much better.
436
Nicotinamide Gel in Acne Vutgaris
Shalita et al.
topical nicotinamide use is not associated with the
emergence of resistant strains of microorganisms nor
with pseudomembranous colitis. Caution regarding the
use of topical and systemic antimicrobial agents, such
as clindamycin, erythromycin, and tetracycline, is now
commonly advised due to concern about antimicrobial
resistance.'^
propionibacteria in acne: need for policies to modify
antibiotic usage. BMJ 1993; 306:555-556.
12.
Bernstein JE, Lorincz AL. The effects of topical nicotinamide, tetracycline and dapsone on potassium iodideinduced inflammation. J Invest Dermatol 1980; 74:
257-258.
13.
Ludwig A, Dietel M, Schafter G, et al. Nicotinamide
and nicotinamide analogues as tumor promoters in
mouse skin. Gancer Res 1990; 50:2470-2475.
14.
Bekier E, Wyczolkowska J, Szyc H, Maslinski GZ. The
inhibitory effect of nicotinamide on asthma-like symptoms and eosinophilia in guinea pigs, anaphylactic mast
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Bakier E, Maslinski GZ. Antihistaminic action of
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Berk MA, Lorincz AL. The treatment of bullous pemphigoid with tetracycline and niacinamide. Arch Dermatol 1986; 2:318-321.
DRUG NAMES
clindamycin phosphate gel 1%: Cleocin
nicotinamide gel: Papulex
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