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• Glyceryl trinitrate, headache and coronary artery disease: mechanistic and therapeutic uncertainties
  Vinod K Gupta
  Published on: 2 November 2005
• Patients who complain of headaches afler sublingual nitroglycerin usually have no coronary disease
  Tsung O. Cheng
  Published on: 9 September 2005

• Published on: 2 November 2005

  Glyceryl trinitrate, headache and coronary artery disease: mechanistic and therapeutic uncertainties

  • Vinod K Gupta, Physician

  Dear Ediutor

  Hsi et al. propose absence or presence of gyceryl trinitrate (GTN)- induced headache as a possibly useful clinical tool to assist in the initial risk stratification of patients with chest pain [1]. Several issues merit attention:

  1. The mechanism of action of GTN in precipitation of headache in patients – regardless of status of the coronary circulation – is unknown.

  2. Exc...

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  Dear Ediutor

  Hsi et al. propose absence or presence of gyceryl trinitrate (GTN)- induced headache as a possibly useful clinical tool to assist in the initial risk stratification of patients with chest pain [1]. Several issues merit attention:

  1. The mechanism of action of GTN in precipitation of headache in patients – regardless of status of the coronary circulation – is unknown.

  2. Excluding patients with a known history of chronic headache adds little in terms of mechanistic clarity about headache-provocation by GTN.

  3. It is difficult to understand why -- as suggested by Hsi et al. -- nitrates should selectively dilate coronary arteries more than cerebral arteries in patients with obstructive coronary artery disease (CAD). With established obstructive CAD, the only component that is significantly reversible is spasm. Second, regional distribution of GTN does not depend on distribution of atherosclerotic lesions. It is understandable that within one anatomical region, critically obstructive atherosclerotic lesions might overperfuse (luxury overperfusion or steal syndrome) lesion- free arteries but to apply the same principle across different regions is speculative.

  4. To reciprocally link CAD with cerebral circulation is a unique [1] albeit logically challenging research premise. It is a rare case in which a patient with atypical anginal pain might manifest a typical reassuring response to GTN; in any case since the response is but subjective, it is hardly advisable to lower the index of suspicion. To modify the index of suspicion on the basis of occurrence of headache following GTN administration does not appear to be a scientifically sound approach.

  5. It is currently not known why GTN might precipitate primary headaches such as migraine or cluster headache or non-primary headaches one hour after administration. A peculiar as yet undefined neuroantomic susceptibility seems to underlie provocation of headache following GTN administration; the headache response is neither uniform nor predictable indicating the importance of idiosyncratic features. To understand the biological basis of GTN-headache headache we have to reflect on the time elapsed between its sublingual administration and onset of headache. In my experience, some patients given GTN for suspected CAD (angina or infarction) develop a headache variant (not migrainous or cluster headache) within 10-15 minutes or earlier. It is a common practice to accept occurrence of headache as indicative of sufficient generalized and coronary vasodilatation and to ask the patient to expel the remaining part of the tablet.

  6. Onset of migraine after GTN manifests a significantly longer prodrome [2]. The physiological system(s) primarily affected in migraine must necessarily be afforded a considerable (but limited and exhaustible) degree of protection by homeostatic defense mechanisms, thereby allowing the subject to continue to function despite the stressful stimulus or situation; this protection is obviously unlimited or inexhaustible in the majority of the general population who are not susceptible to migraine [3] or GTN-induced non-migrainous headache. Opposing the headache-provoking effects of GTN is the parallel activation of a composite adaptive system comprised of vasopressin release coupled to hyperfunction of the sympathetic (noradrenergic) and serotonergic systems [4]. Pain of angina pectoris or acute myocardial infarction is commonly associated with a pronounced hyperactivation of the sympathetic nervous system that might underlie the fact that not all patients given GTN develop headache.

  7. The assumption that a diffuse cerebral vasodilatation underlies GTN-induced headache is open to debate. Propranolol and verapamil have opposite actions on intracranial circulation, decreasing and increasing it, respectively; yet both agents are used commonly for prevention of migraine [5], the prototypic primary vascular headache. Atenolol, nadolol, or verapamil do not cross the blood-brain-barrier and do not influence any neuronal function, whether central (brain, peripheral neural or central- peripheral neuronal connections). Migraine prevention does not involve critical alteration of either any known brain neuronal function or of cerebrovascular circulation [5, 6]. Finally, the vasodilator sildenafil can induce migraine without initial dilatation of the middle cerebral artery [7].

  8. GTN-induced ocular choroidal venous congestion may underlie the headache of migraine [8]; GTN associated rapid ophthalmic arterial vasodilatation may underlie cluster headache [9]. Headaches that do not fit into strictly defined definitive primary categories [10] may reflect attenuated or incomplete forms of such headaches.

  As the letter of Professor Cheng testifies, the index idea seems attractive and even persuasive. Nevertheless, where one starts often affects where one ends. Belief in any hypothesis is a powerful philosophic commitment, one that can lead forward as well as to nowhere. Worse, the need to believe can impede scientific progress by coming up with data that challenge and defy logic and cannot be integrated into an intelligible synthesis. That GTN might cause headache more frequently in patients with normal coronary arteries [1] is a hypothesis that challenges rational thinking. The best biological explanation for the statistically valid results of this study may lie in the differences between the test and control cohorts. CAD positive patients were over a decade older than CAD negative patients; also, the sex ratio was markedly skewed between the two cohorts, with the percentage of male patients being far higher in the CAD positive group (Table 1). While CAD progresses with age particularly in males, the migrainous tendency in adulthood primary affects females (F:M=5:1).

  References

  1. Hsi DH, Roshandel A, Singh N, Szombathy T, Meszaros. Headache response to gylceryl trinitrate in patients with and without obstructive coronary artery disease. Heart 2005;91:1164-1166.

  2. Thomsen LL, Kruuse C, Iversen HK, Olesen J. A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks. Eur J Neurol 1994;1:73- 80.

  3. Gupta V. Stress, adaptation, and traumatic-event headaches: pathophysiologic and pharmacotherapeutic insights. BioMed Central (Published on 26 November 2004). Available at: http://www.biomedcentral.com/1471-2377/4/17/comments/comments

  4. Gupta VK. A clinical review of the adaptive potential of vasopressin in migraine. Cephalalgia 1997;17:561-569.

  5. Gupta V. Silent or non-clinical infarct-like lesions in the posterior circulation territory in migraine: brain hypoperfusion or hyperperfusion? Brain 2005 (In press).

  6. Gupta VK. Migraine, cortical excitability and evoked potentials: a clinico-pharmacological perspective. Brain 2005;128:E36.

  7. Kruuse C, Thomsen LL, Birk S; Olesen J. Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain 2003 ;126:241-7.

  8. Gupta VK. Glyceryl trinitrate and migraine: nitric oxide donor precipitating and aborting migrainous aura. J Neurol Neurosurg Psychiatry Published online (24 October 2005). Available at : http://jnnp.bmjjournals.com/cgi/eletters/76/8/1158

  9. Gupta V. Does the eye modulate the clinical expression of cluster headache? BMC Neurology (17 May 2005). Available at: http://www.biomedcentral.com/1471-2377/5/6/comments

  10. Headache Classification Subcommittee of the International Headache Society. The Interrnational Classification of Headache Disorders. 2nd edition. Cephalalgia;2004;24 (Suppl 1):9--160.

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  Conflict of Interest:
  None declared.

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• Published on: 9 September 2005

  Patients who complain of headaches afler sublingual nitroglycerin usually have no coronary disease

  • Tsung O. Cheng, Professor of Medicine

  Dear Editor,

  It is indeed very gratifying to read the report by Hsi et al.[1] that sublingual nitroglycerin (NTG) administration causes significantly more frequent headaches in patients with normal or minimally diseased coronary arteries than in patients with significant coronary artery disease (CAD). Over the years I have always felt that patients with chest pain who complained of significant headaches following s...

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  Dear Editor,

  It is indeed very gratifying to read the report by Hsi et al.[1] that sublingual nitroglycerin (NTG) administration causes significantly more frequent headaches in patients with normal or minimally diseased coronary arteries than in patients with significant coronary artery disease (CAD). Over the years I have always felt that patients with chest pain who complained of significant headaches following sublingual NTG administration usually do not have CAD of any significance. Now my clinical impression receives scientific confirmation by the elegant study of Hsi et al.[1] Their “headache test” had a sensitivity of 77% for predicting underlying CAD if no headache followed NTG and a specificity of 73% in predicting no or minimal CAD if headache developed following NTG administration.[1]

  Of course, one must always be sure that the sublingual NTG tablets are fresh. NTG tablets tend to lose their strength over a period of time, especially if they are not kept in a dark-coloured vial or not stored in a relatively cool environment. Oftentimes, my patients will tell me that they no longer experience headaches from their sublingual NTG only to find out that the medicines they kept in their pockets have lost their potency. I always advised my patients to carry just a few pills of sublingual NTG in a small pillbox to be put in their pocket, while keeping the rest in a dark-coloured bottle placed in the medicine cabinet. If they still do not experience headaches following the sublingual administration of NTG, I would ask them to get a fresh bottle of the medicine from their pharmacies. Sublingual NTG is so cheap that every patient can afford to get a fresh supply every once in a while. This habit is particularly relevant when patients are reluctant to take their sublingual NTG because of the resultant headaches and thus let the medicine lose the potency.

  Tsung O. Cheng, M.D.
  Professor of Medicine
  George Washington University
  Washington, D.C.

  Reference

  1. Hsi DH, Roshandel A, Singh N, Szombathy T, Meszaros ZS: Headache response to glyceryl trinitrate in patients with and without obstructive coronary artery disease. Heart 2005;91:1164-1166.

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  Conflict of Interest:
  None declared.

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