Low-Dose Aspirin and Ibuprofen Reduce the Cutaneous Reactions Following Niacin Administration

Dunn, Raymond T.; Ford, Marjorie; Rindone, Joseph P.; Kwiecinski, Fabia A.

doi:10.1097/00045391-199506000-00006

Cited by 33 publications

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“…decrease to 41% of subjects taking daily 325 mg of ASA for 4 days and to 29% subjects on 4 days of daily 650 mg of ASA before niacin, but there was no statistical difference between the two treatments (Jungnickel et al, 1997). In another double-blinded, crossover study, pretreatment with 325 mg but not 165 mg of ASA or 200 mg of ibuprofen partially reduced flush-related symptoms because of 500 mg of immediate-release niacin (Dunn et al, 1995). It should be pointed out that these modest (about 30%) reductions were for flush caused by 500 mg of niacin, whereas 1500 to 2000 mg is required for effective treatment, suggesting that these amounts of ASA are likely to be even less effective at the higher niacin doses used clinically.…”

Section: Discussionmentioning

confidence: 95%

“…The actual cell type responsible for PGD 2 release in response to niacin is unknown, but dermal macrophages (Urade et al, 1989) and Langerhans cells (Benyó et al, 2006) have been implicated. However, coadministration of acetylsalicylic acid (ASA) to reduce PGD 2 levels has not been particularly effective (only 30% inhibition) in blocking niacin flush (Dunn et al, 1995;Jungnickel et al, 1997), implying that molecules other than PGD 2 may be involved. These may include histamine and serotonin, which could be released from mast cells (Kushnir-Sukhov et al, 2007).…”

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confidence: 99%

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Niacin-induced “Flush” Involves Release of Prostaglandin D₂from Mast Cells and Serotonin from Platelets: Evidence from Human Cells in Vitro and an Animal Model

Papaliodis

Boucher²,

Kempuraj³

et al. 2008

J Pharmacol Exp Ther

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Niacin lowers serum cholesterol, low-density lipoprotein, and triglycerides, and it raises high-density lipoprotein. However, most patients experience cutaneous warmth and vasodilation (flush). Acetylsalicylic acid (ASA) can reduce this flush, presumably by decreasing prostaglandin D 2 (PGD 2 ) release from macrophages. Here, we show that methylnicotinate induces significant PGD 2 release from human mast cells and serotonin from human platelets. Intradermal injection of methylnicotinate induces rat skin vasodilation and vascular permeability. Niacin increases plasma PGD 2 and serotonin in a rat model of flush. The phenothiazine prochlorperazine, the H 1 , serotonin receptor antagonist cyproheptadine, and the specific serotonin receptor-2A antagonist ketanserin inhibit niacin-induced temperature increase by 90% (n ϭ 5, p Ͻ 0.05), 90 and 50% (n ϭ 3, p Ͻ 0.05), and 85% (n ϭ 6, p ϭ 0.0008), respectively, in this animal model. These results indicate that niacin-induced flush involves both PGD 2 and serotonin, suggesting that drugs other than ASA are required to effectively inhibit niacin-induced flush.

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Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

Niacin-induced “Flush” Involves Release of Prostaglandin D₂from Mast Cells and Serotonin from Platelets: Evidence from Human Cells in Vitro and an Animal Model

Papaliodis

Boucher²,

Kempuraj³

et al. 2008

J Pharmacol Exp Ther

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“…Administration of cyclooxygenase (COX) inhibitors, such as aspirin and indomethacin, before ingestion of NA can attenuate the NA-induced cutaneous reactions in most patients (9-13) without affecting its plasma free fatty acid-lowering effect (14). However, doses of aspirin of 325 mg or higher are generally required to significantly block flushing (15), which compromises the utility of this approach for the chronic suppression of flushing. Although the mechanism of action of NA-induced flushing is not completely understood, the sensitivity to COX inhibitors suggests that prostanoids are involved.…”

mentioning

confidence: 99%

Antagonism of the prostaglandin D ₂ receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans

Cheng¹,

Wu²,

Wu³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

263

188

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Nicotinic acid (NA) is commonly used to treat dyslipidemia, but it elicits an adverse effect, termed flushing, which consists of cutaneous vasodilation with associated discomfort. An animal model of NA-induced flushing has been established in mice. As in humans, NA stimulated vasodilation in a dose-dependent manner, was associated with an increase of the vasodilatory prostaglandin (PG) D2 in plasma and could be blocked by pretreatment with aspirin. Two PGD2 receptors have been identified: PGD2 receptor 1 (DP1, also called DP) and PGD2 receptor 2 (DP2, sometimes termed CRTH2). DP2 does not mediate NA-induced vasodilation; the DP2-specific agonist DK-PGD2 (13,14-dihydro-15-keto-PGD2) did not induce cutaneous vasodilation, and DP2 ؊/؊ mice had a normal vasodilatory response to NA. By contrast, BW245C, a DP1-selective agonist, induced vasodilation in mice, and MK-0524, a DP1-selective antagonist, blocked both PGD2-and NA-induced vasodilation. NA-induced vasodilation was also studied in DP1 ؉/؉ , DP1 ؉/؊ , and DP1 ؊͞؊ mice; although NA-induced vasodilation depended almost completely on DP1 in female mice, it depended only partially on DP1 in male mice. The residual NA-induced vasodilation in male DP ؊͞؊ mice was aspirin-sensitive. Thus, in the mouse, DP1 appears to be an important component involved in NA-induced vasodilation, but other cyclooxygenase-dependent mechanisms also may be involved. A clinical study in healthy men and women demonstrated that treatment with MK-0524 reduced the symptoms of flushing and the increase in skin perfusion after the administration of NA. These studies suggest that DP1 receptor antagonism may be an effective means to suppress NA-induced flushing in humans.aspirin ͉ prostaglandin D2 receptor 1 antagonist ͉ MK-0524 ͉ niacin ͉ flushing N icotinic acid (NA), sometimes called niacin, is a watersoluble B vitamin that has been used to treat dyslipidemia for almost 50 years (1, 2). Used in high doses, it reduces plasma low-density lipoprotein cholesterol, apolipoprotein B, triglycerides, and lipoprotein(a) and increases high-density lipoprotein cholesterol and apolipoprotein A-I (3, 4). NA has been shown to have cardiovascular benefit when used alone or in combination with statins (hydroxymethylglutaryl-CoA reductase inhibitors) in several clinical trials (5-7).Despite these demonstrated beneficial effects, widespread use of NA for dyslipidemia has been limited by symptoms of flushing, which is associated with cutaneous vasodilation of the face, neck, and torso that occurs in nearly all patients (5, 8). Administration of cyclooxygenase (COX) inhibitors, such as aspirin and indomethacin, before ingestion of NA can attenuate the NA-induced cutaneous reactions in most patients (9-13) without affecting its plasma free fatty acid-lowering effect (14). However, doses of aspirin of 325 mg or higher are generally required to significantly block flushing (15), which compromises the utility of this approach for the chronic suppression of flushing. Although the mechanism of action of NA-induced flushi...

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“…Findings from studies specifically evaluating adjunctive or prophylactic aspirin or NSAIDs to attenuate niacin flushing are summarized in eTable 2 (available online, linked to this article). [129][130][131][132][133][134] Of note, 325 mg of aspirin significantly (P<.001 vs placebo) attenuated flushing symptoms when administered 30 to 60 but not 15 or 120 minutes before immediate-release niacin, and an aspirin dose of 650 mg was not superior to 325 mg. 132 In another study, pretreatment with 325 mg of aspirin 30 minutes before niacin was significantly superior to 200 mg of ibuprofen in blunting flushing and itching in patients experiencing these manifestations. 133 In a previous study, 325 mg of aspirin was superior to 80 mg of aspirin in mitigating flushing with 0.5 g of immediaterelease niacin.…”

Section: What Can You Do To Prevent or Reduce Niacin Flushing (Besidementioning

confidence: 99%

“…[129][130][131][132][133][134] Of note, 325 mg of aspirin significantly (P<.001 vs placebo) attenuated flushing symptoms when administered 30 to 60 but not 15 or 120 minutes before immediate-release niacin, and an aspirin dose of 650 mg was not superior to 325 mg. 132 In another study, pretreatment with 325 mg of aspirin 30 minutes before niacin was significantly superior to 200 mg of ibuprofen in blunting flushing and itching in patients experiencing these manifestations. 133 In a previous study, 325 mg of aspirin was superior to 80 mg of aspirin in mitigating flushing with 0.5 g of immediaterelease niacin. 134 The flushing-specific discontinuation rate in a recent 4-week study was 1.8% among patients randomized to receive 325 mg of aspirin before extended-release niacin treatment compared with 9.4% among those receiving extended-release niacin without aspirin (P=.007).…”

Section: What Can You Do To Prevent or Reduce Niacin Flushing (Besidementioning

confidence: 99%

A “Hot” Topic in Dyslipidemia Management—“How to Beat a Flush”: Optimizing Niacin Tolerability to Promote Long-term Treatment Adherence and Coronary Disease Prevention

Jacobson

2010

Mayo Clinic Proceedings

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Niacin is the most effective lipid-modifying agent for raising highdensity lipoprotein cholesterol levels, but it also causes cutaneous vasodilation with flushing. To determine the frequency of flushing in clinical trials, as well as to delineate counseling and treatment approaches to prevent or manage flushing, a MEDLINE search was conducted of English-language literature from January 1, 19851, , through April 7, 2009. This search used the title keywords niacin or nicotinic acid crossed with the Medical Subject Headings adverse effects and human. Niacin flushing is a receptormediated, mainly prostaglandin D 2 -driven phenomenon, the frequency, onset, and duration of which are largely determined by the distinct pharmacological and metabolic profiles of different niacin formulations. Subjective assessments include ratings of redness, warmth, itching, and tingling. In clinical trials, most (>60%) niacin users experienced mild or moderate flushing, which tended to decrease in frequency and severity with continued niacin treatment, even with advancing doses. Approximately 5% to 20% of patients discontinued treatment because of flushing. Flushing may be minimized by taking niacin with meals (or at bedtime with a low-fat snack), avoiding exacerbating factors (alcohol or hot beverages), and taking 325 mg of aspirin 30 minutes before niacin dosing. The current review advocates an initially slow niacin dose escalation from 0.5 to 1.0 g/d during 8 weeks and then from 1.0 to 2.0 g in a single titration step (if tolerated). Through effective counseling, treatment prophylaxis with aspirin, and careful dose escalation, adherence to niacin treatment can be improved significantly. Wider implementation of these measures should enable higher proportions of patients to reach sufficient niacin doses over time to prevent cardiovascular events. Proc. 2010;85(4):365-379 GPR = G i protein-coupled receptor; HDL-C = high-density lipoprotein cholesterol; NSAID = nonsteroidal anti-inflammatory drug; PG = prostaglandin; RCT = randomized controlled trial R educing low-density lipoprotein cholesterol levels is the primary treatment for preventing cardiovascular disease, largely because of robust evidence from randomized controlled trials (RCTs) involving statins. Mayo Clin

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Low-Dose Aspirin and Ibuprofen Reduce the Cutaneous Reactions Following Niacin Administration

Cited by 33 publications

References 0 publications

Niacin-induced “Flush” Involves Release of Prostaglandin D₂from Mast Cells and Serotonin from Platelets: Evidence from Human Cells in Vitro and an Animal Model

Niacin-induced “Flush” Involves Release of Prostaglandin D₂from Mast Cells and Serotonin from Platelets: Evidence from Human Cells in Vitro and an Animal Model

Antagonism of the prostaglandin D ₂ receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans

A “Hot” Topic in Dyslipidemia Management—“How to Beat a Flush”: Optimizing Niacin Tolerability to Promote Long-term Treatment Adherence and Coronary Disease Prevention

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Low-Dose Aspirin and Ibuprofen Reduce the Cutaneous Reactions Following Niacin Administration

Cited by 33 publications

References 0 publications

Niacin-induced “Flush” Involves Release of Prostaglandin D2from Mast Cells and Serotonin from Platelets: Evidence from Human Cells in Vitro and an Animal Model

Niacin-induced “Flush” Involves Release of Prostaglandin D2from Mast Cells and Serotonin from Platelets: Evidence from Human Cells in Vitro and an Animal Model

Antagonism of the prostaglandin D 2 receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans

A “Hot” Topic in Dyslipidemia Management—“How to Beat a Flush”: Optimizing Niacin Tolerability to Promote Long-term Treatment Adherence and Coronary Disease Prevention

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Niacin-induced “Flush” Involves Release of Prostaglandin D₂from Mast Cells and Serotonin from Platelets: Evidence from Human Cells in Vitro and an Animal Model

Niacin-induced “Flush” Involves Release of Prostaglandin D₂from Mast Cells and Serotonin from Platelets: Evidence from Human Cells in Vitro and an Animal Model

Antagonism of the prostaglandin D ₂ receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans