Why flushing with niacin

Thanks for visiting. Don't miss your FREE gift. Sign up to get tips for living a healthy lifestyle, with ways to fight inflammation and improve cognitive health , plus the latest advances in preventative medicine, diet and exercise , pain relief, blood pressure and cholesterol management, and more. Get helpful tips and guidance for everything from fighting inflammation to finding the best diets for weight loss Stay on top of latest health news from Harvard Medical School.

Recent Blog Articles. Why is topical vitamin C important for skin health? Preventing preeclampsia may be as simple as taking an aspirin. Caring for an aging parent? Tips for enjoying holiday meals. A conversation about reducing the harms of social media.

Menopause and memory: Know the facts. How to get your child to put away toys. The release of histamine or bradykinin causes a substantial rise in nitric oxide, which leads to increased intracellular release of cyclic guanosine monophosphate cGMP and vasodilatation. Prostaglandins PGs , specifically forms D 2 and E 2 , have been identified as participants in the niacin-induced flushing response 28 , PGs, prostacylcins, thromboxanes and leukotrienes, collectively considered eicosanoids, are hormone-like chemical messengers derived from arachidonic acid.

PGs have numerous biological effects, including essential roles in platelet aggregation, neurotransmitter release, and inflammatory and vasomotor responses. Individual prostaglandins can have both positive and negative effects i. As prostaglandins are rapidly metabolised and have short half-lives, their metabolic effects are typically localised and can be variable in different parts of the body.

Activation of the GPRA receptor by niacin initiates a signalling cascade that ultimately results in the production of prostaglandins, and thus, flushing Figure 1. Free arachidonic acid serves as a precursor to the production of eicosanoids, including lipoxygenases, thromboxanes and prostaglandins.

Niacin activates the arachidonic acid cascade to induce vasodilatation. Arachidonic acid is metabolised to produce prostaglandins, prostacyclin and thromboxane. The production of prostaglandins from arachidonic acid involves a complex cascade of enzymes.

The first step is the metabolism of arachidonic acid to prostaglandin H 2 PGH 2 by PGH synthase, an enzyme that has both cyclooxygenase and endoperoxidase activity, but is commonly referred to as COX. The inhibition of COX also eliminates the flushing response to niacin 28 , 31 — After their synthesis, prostaglandins exert their effects locally through downstream receptors. The receptors are categorised by their affinity for each respective prostaglandin agonist. The downstream effects of the activation of each individual receptor can be dependent on the tissue expression of the receptor as well as the G-protein to which the receptor is coupled.

These conditions allow some of the receptors to have opposing actions in the same tissue and result in complicated predictions of receptor activation. Based on this classification, the relaxant receptors would be expected to play a role in cutaneous vasodilatation, while the excitatory receptors would act as vasoconstrictors.

Although PGD 2 is known to have vasodilatory properties in the vascular endothelium, it can behave as a vasoconstrictor at higher concentrations and in separate tissues PGD 2 can also act through the chemoattractant CRTH2 DP 2 receptor, whose biological role appears to be regulating inflammatory allergic and asthmatic responses PGE 2 is perhaps the most widely produced prostaglandin, and as the highest-affinity agonist for the EP receptor family, it exerts the most diverse and versatile effects The EP 2 receptors are localised to smooth muscle in the trachea, GI tract and vascular system.

They, along with EP 4 receptors, are relaxant receptors and induce vasodilatation of various blood vessels through increasing cAMP. The PGE 2 -EP 4 receptor pathway may also mediate some anti-inflammatory effects and facilitate mobilisation, migration and maturation of Langerhans cells in the skin Prostacyclin is the major arachidonic acid product in vascular tissues PGI 2 is produced in blood vessels where it is a potent vasodilator and inhibitor of platelet aggregation through the IP receptor Thromboxane A2 TXA 2 plays an extensive role in haemodynamics and cardiovascular function.

The majority of thromboxane produced in vivo is made by platelets, where it exhibits opposing actions to PGI 2. TXA 2 can increase platelet aggregation, and thus deficiencies in the TP receptor can lead to bleeding disorders. TP receptors are expressed in the thymus, spleen and lungs. Increased TXA 2 has been linked to cardiovascular diseases including acute myocardial ischaemia and heart failure It increases blood pressure in experimental animals, but not humans.

Several prostaglandins with vasodilatory properties are influenced by niacin. After oral niacin treatment, PGD 2 levels in the venous blood draining the skin are 14— times higher than the levels in arterial blood The production of PGI 2 and PGD 2 decreases after repetitive administration of niacin in parallel with the development of flushing tolerance In comparison, deletions of COX in mice completely eliminate flushing after niacin treatment Mice that do not express the IP receptor still flush after niacin Besides COX, arachidonic acid can be metabolised by a family of enzymes called lipoxygenases to produce leukotrienes LT , a group of inflammatory lipid mediators.

They are released from neutrophils, eosinophils, mast cells and macrophages to play a role in innate immunity Leukotriene B 4 LTB 4 applied directly to the skin can cause vasodilatation that is not decreased by COX inhibitors, indicating that the vasodilatation is not mediated by prostaglandins The downstream mechanism of LTB 4 -mediated vasodilatation is currently unknown.

Any potential effects of LTE 4 on niacin-induced flushing have not been reported, and its role in vasodilatation is unclear.

As attenuation to flushing rapidly develops 28 , dose titration is important in reducing flushing in patients. Educating patients about the benefits of niacin therapy may also increase the likelihood that patients are willing to tolerate any of the minor bothersome effects of flushing Flushing can persist as long as plasma niacin levels are rising, but abates when constant plasma niacin levels are reached Therefore, flushing is also related to the rate of niacin absorption, as a higher rate of absorption is associated with a higher rate of flushing 50 , Crystalline, immediate-release IR niacin is rapidly absorbed by the body, and peak blood levels can be reached in as quickly as 30—60 min To reduce flushing, several alternate formulations of niacin have been made.

Sustained-release SR niacin formulations were created to delay niacin absorption during treatment. Although SR niacin decreases flushing, it can also cause hepatotoxicity and has shown inconsistent effects on lipids 55 , Inositol hexanicotinate is commonly referred to as no-flush niacin or flush-free niacin, but this dietary supplement has not been shown to have any beneficial effects on lipid parameters 57 , Trials involving the combination of NER and a statin also show little evidence of hepatotoxicity 61 — This combination therapy does not appear to worsen flushing side effects, and NER has not been shown to potentiate statin-induced myopathies.

NSAIDs are convenient cotherapies with niacin to reduce flushing. They decrease the production of multiple prostaglandins by preventing COX from metabolising arachidonic acid.

In a flush-provocative study, using healthy volunteers, aspirin given 30 min before a mg dose of NER decreased the incidence, duration and severity of flushing compared with placebo pretreatment Aspirin given concomitantly with NER was also effective at reducing flushing incidence, duration and severity compared with placebo, but not as effective as aspirin min pretreatment In a prospective, randomised, double-blind, placebo-controlled trial, mg aspirin given 30 min before a dose of NER reduced both the number and intensity of flushing episodes, resulting in a lower rate of discontinuation because of flushing in the aspirin group compared with placebo 1.

Along with aspirin, indomethacin 33 , ibuprofen 69 and naproxen 32 have been shown in subjects to decrease the flushing effects of IR niacin.

The most common dose of aspirin used to effectively reduce flushing in IR niacin is mg, with mg offering no further benefit Recent efforts to decrease the flushing effects of niacin have focused on eliminating the downstream effects of prostaglandins that play a role in cutaneous vasodilatation.

In a small clinical trial, using healthy volunteers, LRP administered along with niacin decreased the symptoms of flushing compared with niacin plus placebo This high incidence is likely caused by other pathways involved in the niacin flushing response. LRP is highly selective for DP 1 and has no affinity for inhibiting the EP 2 or EP 4 receptors 72 , which are also highly likely involved in flushing This situation underscores the difficulty in modulating the downstream actions of prostaglandins for pharmacological effect.

Inhibiting the GPR receptor would theoretically mitigate the flushing response. Antagonism of the GPR receptor to reduce flushing while preserving adipocyte antilipolytic activity would require targeting the Langerhans-specific GPRA receptor.

The potential side effects are unknown. Another potential target would be to inhibit the ability of PLA 2 to produce arachidonic acid, thereby eliminating the production of prostaglandins upstream of COX. Glucocorticoids can indirectly inhibit PLA 2 73 , 74 , but there are currently no approved therapies that specifically target this enzyme. One of the easiest ways that medical personnel can help improve their patients compliance with niacin therapy is to provide their patients with a clear understanding of the clinical benefits of niacin as well as what to expect and how to manage flushing While improvements in lipid profiles are meaningful to physicians, patients may be more willing to tolerate the transient flushing symptoms that can occur if they realise that niacin reduces cardiovascular risk, as determined by both mortality and cardiovascular event rates, and that this benefit extends beyond the duration of active therapy.

Patients should be counselled to take aspirin mg 30 min before a snack and extended-release niacin. The importance of continuing to take the final daily maintenance dose of niacin extended-release should be emphasised.

If there is a period of discontinuation, the titration procedure has to be followed again, although it maybe possible to accelerate it at the discretion of the prescriber. Patients are also advised to avoid hot beverages, spicy foods and hot showers near the time of taking niacin. Therefore, it is currently difficult to separate the two effects, but flushing can be effectively managed in patients.

As tolerance to flushing develops rapidly, healthcare professionals should particularly address flushing during dose titration of niacin. Clinically, unlike LRP, aspirin is not only an established agent to reduce flushing but it is also indicated for use in most dyslipidemic patients to reduce atherothrombotic complications, which is also the reason to prescribe niacin. Initial data indicate that aspirin or LRP combined with extended-release niacin formulations have similar impacts on niacin-induced flushing in patients, although it is difficult to directly compare separate clinical studies.

A clinical trial to assess the relative efficacy of these two agents is needed. Aspirin has a well-known safety profile, while long-term data on the safety of LRP is awaited. The authors would like to acknowledge Nathan A. Styles, Ph. Horton, BGS, Abbott employees, for medical writing and editing assistance in developing this article.

Vaijinath S. Kamanna, Ph. Ganji, Ph. Kashyap, M. National Center for Biotechnology Information , U. International Journal of Clinical Practice. Int J Clin Pract. Apply market research to generate audience insights. Measure content performance. Develop and improve products.

List of Partners vendors. A niacin flush is a side effect of taking large doses of niacin vitamin B3 supplements. The flush happens when the niacin causes the small blood vessels in your skin to dilate so more blood can rush through. Almost everyone who takes large doses of niacin experiences this flush. It isn't harmful, but it can scare you if you don't know it's coming.

While no one needs large doses of niacin, some people take it as a supplement to reduce the risk of heart disease and atherosclerosis. Large daily doses of niacin may help to lower LDL cholesterol the bad cholesterol and increase HDL cholesterol the good form of cholesterol.

A niacin flush starts about 30 minutes after you take a large dose 30 to 50 milligrams or more. The flush includes reddening of the skin accompanied by a burning or itching sensation.

The flush gets better over time and is usually gone within an hour or two. The niacin flush is generally harmless, but may occasionally be accompanied by a headache, dizziness, or drop in blood pressure. If you experience these symptoms with a niacin flush, you should call your doctor for advice.

You won't get the niacin flush reaction after taking multiple vitamins that contain smaller amounts of niacin. It only happens when you take massive doses. The average adult needs about 14 milligrams per day, so megadoses of individual niacin supplements are far more than anyone needs. To avoid or lessen the niacin flush, you could use time-release forms of niacin, which are absorbed and metabolized slower than regular niacin.

Taking a regular aspirin about 30 minutes before taking niacin supplements may also help reduce the discomfort, but probably won't eliminate it altogether. Another alternative is inositol hexanicotinate, which your body converts to niacin. The conversion is slow enough that it doesn't cause a flush in most people.

The problem is that you may not get the same lipid-lowering benefit as regular niacin. A review study reported that inositol hexanicotinate was no better than a placebo for lowering cholesterol levels. Along with thiamin, riboflavin , and others, niacin is an essential B-complex vitamin your body needs to convert macronutrients from the food you eat into energy for daily activities.