The results of this systematic review indicate that niacin may have a therapeutic effect on migraine headaches, tension-type headaches, and headaches of other etiologies. The quality of the evidence at this point, however, is only hypothesis generating, and randomized trials are required to determine the clinical implications of this novel treatment.
There are several important limitations to consider in the interpretation of this review. We did not find any randomized or controlled trials of niacin on these headaches. We cannot determine to what extent publication bias has on the results of this review. We are unable to draw clinical inferences on the results of the included studies as they were of low quality and have a low level of external generalizability. Despite these limitations, we attempted to conduct an exhaustive search and included all reports of relevance.
Reasons for niacin's effectiveness can only be considered hypothetical, and require clarification from future randomized controlled trials. In acute migraine headaches some of the symptoms arise from activation of the trigeminovascular complex. Activation of this complex leads to intracranial vasoconstriction causing the migraine aura, followed by headache due to vasodilation of the extracranial vessels and activation of the perivascular nociceptive nerves . When taken intravenously or orally, niacin causes cutaneous flushing that might abort the acute symptoms of migraine by vasodilating the intracranial vessels, thus preventing the subsequent vasoconstriction of the extracranial vessels. There is evidence that niacin is an effective peripheral vasodilator, but its ability to influence central mechanisms (i.e., cerebral blood flow and cranial hemodynamics) involved in migraine headaches have not been well studied. Niacin causes peripheral vasodilation and cutaneous flushing by inducing the production of prostaglandin D2 (PGD2) in the skin, leading to a marked increase of its metabolite, 9α, 11β-PGF2, in the plasma . When niacin is administered orally in amounts of 500 mg or topically via a 6-inch patch of 10-1 M aqueous methylnicotinate on the forearm, PGD2 is markedly released in the skin and its metabolite appears in high amounts in the plasma [22, 23]. It is not known if PGD2 causes vasodilation of the intracranial arteries, but niacin's ability to abort acute migraine headaches suggests that this might be what is occurring. Old reports cited by Bicknell and Prescott , demonstrate that niacin does indeed cause vasodilation of the cerebral and spinal vessels, and that intravenous administration increases the rate of intracranial blood flow in human beings for 20–60 minutes without any significant change in blood pressure. Unfortunately, there have not been more recent reports examining the effects that niacin has upon cerebral blood flow in human subjects.
In terms of tension-type headaches, it appears that intravenous niacin is of benefit acutely due to its presumed central vasodilatory properties. Like migraines, part of the underlying pathophysiology of chronic tension-type headaches involves central mechanisms, such as the trigeminal system . Chronic tension-type headaches are also associated with cerebrospinal pressure or intracranial venous pressure (or both) . In fact, tension-type headaches are more similar to migraine headaches than they are dissimilar, in that they seem to progress into migraine headaches due to an escalating pathophysiological process . Thus, niacin might mitigate the acute phase of tension-type headaches through the same hypothesized mechanism of action described earlier.
Some of the reports did demonstrate prophylactic benefits when niacin was administered orally every day. It is now recognized that a deficit of mitochondrial energy metabolism (i.e., impaired mitochondrial phosphorylation potential) plays a role in the pathogenesis of chronic migraine headaches . Niacin maintains adequate mitochondrial energy metabolism by increasing substrate availability to complex I , and this is how it might function as an effective prophylactic agent for migraine prevention. Two other nutritional agents (riboflavin and coenzyme Q10) augment complex I of the mitochondrial respiratory chain, and have been subjected to clinical trials demonstrating their effectiveness for the prevention of migraine headaches [30–32]. A deficit of mitochondrial energy metabolism may play a role in the pathogenesis of migraine. Since niacin improves mitochondrial energy metabolism by increasing substrate availability to complex I, it might also be an effective agent for migraine prevention.
Niacin might also prevent tension-type headaches by improving mitochondrial energy metabolism within the skeletal muscles, and by increasing blood flow and oxygenation to the skeletal muscles. The overall net-effect could be a reduction in lactic acid concentrations, leading to reduced episodes of muscular tension and soreness. Niacin may reduce lactic acid concentrations since supplemental niacinamide (the amide of niacin) has been shown to reduce blood lactate and pyruvate concentrations by more than 50% in a patient with MELAS (mitochondrial encephalopathy, myopathy, lactic acidosis, and stroke-like episodes) syndrome by the third day of treatment . This possible mechanism might only relate to migraine sufferers, however, since plasma levels of lactic and pyruvic acids were found to be significantly higher in migraine patients compared to patients with tension-type headaches and normal controls .
The side effects of intravenous niacin were found to be minimal from the summarized articles. The most common side effects were abdominal cramping, vomiting, and uncomfortable sensations of the skin and burning. A few of the patients described found the treatments to be worse than their headaches. In the articles where blood pressures were evaluated, little-to-no change occurred among the individuals treated with intravenous niacin. In a more recent study, parenteral niacin given to hypertensive and normotensive patients demonstrated a significant decrease in systolic, diastolic, and pulse pressures among the hypertensive subjects .
With respect to the oral administration of niacin, very few patients reported side effects. Even though niacin was well tolerated orally, we previously reported in a randomized placebo-controlled trial examining the safety of immediate-release or crystalline niacin, that it can be associated with intolerable side effects . The most common side effects found using 500 mg of immediate-release niacin were unpleasant warmth or flushing, pruritis, chills, tingling, nausea, and vomiting. Approximately 75% of the subjects who were given niacin found it tolerable or difficult to tolerate, but did not indicate that they would never take niacin again. Some 18.2% of the niacin subjects indicated that they found niacin to be intolerable and would never take it again . By contrast, very few of the patients from the summarized articles discontinued treatment due to the side effects of oral niacin.
The side effects of greater concern from oral niacin have to do with sustained- or slow-release preparations. These preparations are better in terms of compliance since patients experience less cutaneous flushing with them. However, the use of these preparations have been associated with reversible hepatic toxicity in doses equal to or greater than 1500 mg per day with an acute onset of clinical symptoms of hepatitis in a relatively short period of time (2 days to 7 weeks) . Other reports have demonstrated clinical symptoms of hepatitis when much larger doses of sustained-release niacin (greater than or equal to 3 grams per day) were used for months to years [38–42]. Sustained-release preparations have a higher incidence of hepatic toxicity in doses comparable to the immediate-release preparations , but these important differences are not typically mentioned in reviews of niacin's lipid lowering properties.