In thinking about your question Marita, I turned my attention to some psychoanalysts on the topic of migraines.

Migraine headaches are produced by the non-expression of unconscious hateful and rageful feelings. Fromm-Reichmann spoke of her migraine patients as suffering from "unresolved ambivalence: they could not stand to be aware of their hostility against beloved persons; therefore they unconsciously tried to keep their hostility repressed and finally expressed it by the physical symptoms of migraines: (1937, p. 26). While the average person "feels conscious anger against an adversary," "the migraine patient . . represses his hostility against consciously beloved persons" (p. 28).

R.E. Money-Kryle understod migraine as a defense against seeing something about oneself - for example, envy. He spoke of a patient "losing the ability to have a migraine" (1963, 491). Migraine is not something that attacks, but something that one does.

Melitta Sperling said that "repression of rage and of the impulse to kill serves to protect both the object in the outer world and the patient himself. At the same time,the gratification of the impulse is achieved unconsciously in the symptom" (1952, 161). One of her patients reported beginning to develop a migraine on the way toa session,but then the headache stopped. "So," said the analyst, "you decided to let me live" (1964, 554). Sperling noticed that a manic depressive pattern alternates with the migraine.

Does the migraine offer an alternative to depression?

Each migraine attack represents a repetitive unconscious killing of the frustrating object. There is no conscious awareness and no depression (Sperling 1964, 550). The migraine is "a specific and early acquired attitude of the patient towards dealing with overwhelming strong destructive impulses" (p.556). A narcissistic injury, produces strong destructive impulses that have a few possible means of expression: (1) attacking the object; (2) attacking the self (depression); and (3) somatic expression. This destructiveness threatens to destroy the object relation, but the psychosomatic solution retains the object in reality, "but the tie is strengthened by the illness." There is a secondary gain. "By the very fact that he is sick, [the patient] can indulge himself and be indulged by others" (p.555). Sperling writes: "The onset of migraine in certain types of personalities . . . occurs in a situation which provokes intense rage and at the same time does not permit the discharge of this rage in overt behaviour " (1964, 551).

What about a migraine in the analyst?

I know I have not answered your question as I am not a medical doctor, but I wonder that if we were to examine physiologically a patient with a migraine, would there be any difference from a medical perspective? As psychoanalytic clinicians, we do come across psychosomatics, but we must also be aware that there are medical reasons for migraines such as the antiphospholipid antibody (Hughes) syndrome, or brain tumours. We must never assume that all physical symptoms are psychosomatics. I am not suggesting this is your view, but merely pointing out my experience of working with patients with medical conditions. 

I do think that when a medical doctor or analyst takes seriously what the patient is saying and thus listens with "an analytic attitude" that shows a respectful attention to the patient, that empathic listening contributes to the containment, or holding, that is necessary whether it is the medical doctor-patient relationship or the analytic relationship. In both cases, this would produce physiological responses in the patient who is in pain and distress. 

A cautionary note: George Gershwin suffered excruciating headaches for which he was referred to a psychoanalyst; at age 50 he died of an inoperable brain tumor.

My point is NOT to disparage psychoanalysis which I have found personally and professionally invaluable, but to underscore that headaches, including migraine headaches, need to be worked up by a neurologist with expertise in headaches before we assume they are "psychosomatic."

Article Reply letter to the editor: the continuing story of George G...

Thank you Renzo, could there even  be different kinds of migraine?

The International Headache Society (IHS) describes the different types of headache in its classification ICHD-II very well. I think this could help.

There is no medical healing. Migraine seems to be a recurrent syndrome, with quite variable expressions throughout life. There seem to be several factors favoring attacks: (1) some genetic, yet mostly ill-defined background, (2) the transition of stress to recovery from stress, (3) given the benefit of sports, especially those which require endurance, training effects of vegetative regulation. Migraines have lower sensory thresholds and less habituation at least when migraine is active. I guess that lowering the level of emotional stress eliminates one thing that puts migraines at risk.

Thank you all  of you. It is true also for me that migraine cannot be a reason for psychoanalysis. But sometimes analysands have also migraine as a symptom. Poor Gerschvin. such symptoms have to be consulted by a neurologist..Sometimes psychoanalysts have got such an understanding in their training at least being medical doctors.

Stress certainly is as you say one factor interesting in such a way that releasing it gves migraine. We call it sunday morning h-a

But is there any nosology physiological? 

There are abnormalities of the trigeminovascular reflex described. But I think to construct a link to psychoanalysis would prove difficult, as the physiology pf psychoanalysis is, to the best of my knowledge, poorly elucidated.

One important thing I forgot when talking about treatment effects, especially in migraine: consider spontaneous remission irrespective of treatment or not as well as the placebo effect.

If I  have understood correctly it has been spoken of vascular reasons for this kind of headache. Arteries on the brain membranes. There must be a physiological mechanism of contraction or something. What's interesting is the barrier between soma and psyche. Have we found something new there.

The glasses with which one peers through the haze of migraine pathophysiology do not flatter those who do not acknowledge the fundamentals of the syndrome/illness/entity. The question that precedes the link between migraine and psychoanalysis lies submerged deep in the hidden recesses of origin of migraine itself. Human beings have a tested propensity to ignore the ummeasurable but important for the sake of the measurable but unimportant. Then, we might also consider the vested interest of not seeing/acknowledging what is obvious to other researchers--having fallen in love with our own perceptions/hypotheses. We might begin by stating clearly that we have absolutely no clue at all as to how stress induces migraine. Then again, most researchers have spent little effort in understanding the adaptive mechanisms that underlie migraine. Migraine will not yield its secrets to reams of words or to undirected research--that is an absolute that has stood time and human effort--both froth and fervor.  The remarkable resilience of migraine to human endeavors--regardless of fancy terms such as placebo effect/nosology/statistics/threshold/habituation/feelings et al.--clearly indicates that we do not know where we are headed or where we intend to go. Fence-sitting with words such as if , may, might and above all, mathematics-- leads us further into the cul-de-sac that is migraine--the double-blind leading the blind with, of course, flair.

Migraine has evolved into a giant puzzle and its literature comprises a vast loosely linked enterprise challenging human problem solving capacity. There is no central idea in migraine to elaborate a general theory which in turn could ultimately lead to creation of a unifying hypothesis that collects the various strands of evidences into a coherent and logically defensible intelligible synthesis. Current pathogenetic concepts of migraine, in particular cortical spreading depression (CSD), do not focus on the precise onset of the attack. Neither the aura nor the headache represents the true beginning of a migraine attack. The primary or causal physiological alteration underlying migraine lies in the ‘pre-prodromal’ phase, the variable interim between exposure to the headache-provoking stimulus or situation and the onset of the migraine prodrome. The migraine prodrome itself can last several hours to a few days. Since CSD is believed to underlie both the migrainous scintillating scotoma as well as the headache, it cannot be regarded as an early or initial ‘pre-prodromal’ physiological event. The biology of migraine is not the study of laboratory ‘markers’ but the elucidation of physiological forces (trait and/or state factors) that push (precipitate) or pull (predispose) patients towards aura/headache or aura/headache-free state. The pathophysiology of migraine has been hitherto confined to analyses of diverse precipitating and remitting factors and uncertain postulations about recorded laboratory aberrations into presumptive causal algorithms--the measurable (but unimportant) has completely overwhelmed the immeasurable (but important). The key cranial physiological system involved in migraine remains elusive and unidentified. Migraine attacks occur during stress and, more commonly, after cessation of stress. The author has earlier proposed that a physiological neuroendocrine ‘system’ comprised of well-regulated parallel activation of the vasopressinergic, intrinsic brain serotonergic, and intrinsic brain noradrenergic systems constitutes an important adaptive mechanism that governs vascular integrity, antinociception, behavior and overall function during stressful occasions, including migraine attacks. Such a conceptual template can be used to segregate the vast phenomenology of migraine into primary pathogenetic or secondary non-pathogenetic divisions; non-pathogenetic migrainous phenomena can be further subdivided into adaptive and concomitant (epiphenomenal) physiological events. Nausea and/or vomiting, facial pallor, Raynaud’s phenomenon, episodic daytime sleepiness, and relative hypotension (both spontaneous as well as induced by prophylactic anti-migraine pharmacologic agents) likely reflect the non-pathogenetic (adaptive or epiphenomenal) clinical components of migraine. The pathophysiological basis of aura/headache and nausea/vomiting of migraine is very unlikely to be identical. Exogenous magnesium does not readily cross the intact blood-brain barrier and decreases the permeability of the blood-brain barrier. Magnesium depletion appears to serve an important adaptive function; its utility in migraine management is not convincing. Magnesium depletion, platelet activation, peripheral alterations in serotonin and catecholamine metabolism, hyper-responsiveness of brain noradrenergic, serotonergic, vasopressinergic, and dopaminergic systems, parasympathetic nevous system activation, pupillary miosis, and cutaneous allodynia probably represent some of the secondary adaptive physiological mechanisms operative in migraine. A critical or central role for brain neuronal involvement in migraine pathogenesis appears unikely as established migraine preventive agents like atenolol, nadolol, and verapamil do not readily cross the intact blood-brain barrier or influence brain neuronal function. Antidepressants, including amitriptyline, induce brain noradrenergic and serotonergic hyperfunction, rendering highly unlikely that such brain states underlie migraine. Elucidation of adaptive physiological mechanisms in migraine can rationalize important epidemiological, clinical, and pharmacological features and sow the seeds for evolution of an integrative synthesis which process, in turn, might herald the creation of a comprehensive thought framework and research vision for migraine.-- Back-cover blurb of my book: Adaptive Mechanisms In Migraine. A Comprehensive Synthesis In Evolution. Breaking The Migraine Code. Nova Science Publishers, Inc., New York, 2009. pp 1-126. 

 Fantastic Great!! Thank you, you have a great research of migraine and it's physiology and all those difficulties and certainly new ways of grasping it in the future. Many thanks Vinor of your sharing it with us here!

Marita, you are welcome!!  It takes a big heart to show such appreciation!!! Such a role model for future generations is truly invaluable and reflects scientific equipoise and a willingness to accept the truth. Although several versions of any truth usually abound -- each version being vehemently defended by its proponents -- science has a peculiar propensity to gravitate towards one absolute unwavering rock-solid version. My article on patent foramen ovale closure and migraine prevention is open access --Expert Review of Neurotherapeutics 2010;10(9):1409-1422. I would suggest a reading of the same for a better grasp of what constitutes migraine. The other pillar of my understanding of migraine is the absolute demolition of the theory of cortical spreading depression (CSD) for genesis of migraine (CSD, BBB, and MMP-9: animal experiments versus clinical phenomena in migraine. Expert Reviews in Neurotherapeutics 2009. www.ncbi.nlm.nih.gov/pubmed/19903020). Like a drowning person clutches straws, the neurological community grasped at CSD as their saviour for their long-standing conviction of the migrainous ictus/explosive central/brain neuronal discharge. Only few migraine researchers today comprehend or would like to recall that the negative discharges noticed by Leao were completely unexpected. The discovery of CSD was as incidental or serendipitous as the discovery of the therapeutic role of beta-blockers in migraine prevention. Current and (foreseeable) future migraine research rests buried between these two giant serendipitous pillars. Myths are re-invented in every generation, and, gain strength with the passage of time and reiteration, much like political statements. Migraine cannot claim to be an exception.   

Being in its infancy, migraine research needs to define the tools that will prise these closely guarded secrets of Nature for us. The Randomized Controlled Trial (RCT) is the sledge-hammer that is frequently (mis)used to define various therapeutic aspects of migraine (and other medical entities). RCT is a human endeavour performed on human migraine sufferers--the scope for erroneous extrapolation of such mathematical wisdom -- labelled grandly in Discussion as confounding -- is immense. To err is human; all human efforts are susceptible to error. The RCT is, and. cannot be an exception. Randomization itself is not based on scientific principles. Mathematics has hijacked biological sciences, particularly in those entities that offer few if any objective parameters for evaluation. Migraine has, to date, no objective parameter for scientific evaluation. At this stage of evolution of migraine research, RCT has but one feature to add to migraine pathophysiology--confusion (see my letters in The BMJ on RCT and migraine--6 July 2004 and 8 July 2004). The other pillar of migraine research, serendipity, cannot be allowed to run riot but has to brought back skillfully into the scientific mainstream of migraine. If we do not know what we are treating, we are in the unenviable position of firing shots in the dark (of course, also without night-vision glasses).  The sheer breadth of treatments approved or suggested for migraine is in parallel with the starkly limited understanding of its genesis.

For progress in any field, and, in particular, in an obscure medical entity such as is migraine, theory must well precede data. However, since no well-nurtured/cultivated theory of migraine has hitherto been all-inclusive or has gathered strength with the passage of time with increasing associations and answers to questions that expectedly or unexpectedly do arise, data in migraine have shackled theory (of migraine genesis--why, what, when, who, where, how) to a degree that appears irremediable. Data, however, cannot supplant theory of migraine, an absolute that cannot be colored in any hue. 

The term "biological" has itself lost its meaning in migraine research. Biological is not a synonym for "laboratory" or "laboratory markers''. The biology of migraine is the elucidation of physiological forces  (trait and/or state factors) that push (precipitate) or pull (predispose) patients towards aura/headache state or aura/headache free state (Gupta, 2009). With one firm step forward through generalization of adaptive mechanisms in migraine, we can dare to hope without hype for the eventual resolution of the massive Gordian knot of this entity.. No scientific theory can ever be true without generalization. A theory that stands the test of time, gaining mass and momentum with scattered studies/observations spanning  decades/centuries, adding meaning to otherwise unsupported evidences and therapies, bridging seamlessly divergent streams of extant thought, crossing the artificial boundaries of specialization with consummate grace and ease, assimilating seemingly conflicting data effortlessly into its folds, telescoping the templates of the past, the present and the future into a gradually cementing matrix, accounting for all or most aura/headache precipitating factors and relieving factors, elucidating the mechanisms that underlie the mysterious onset and the equally mysterious cessation of migraine aura/headache, providing a sound pharmacological and neurological basis for the currently incomprehensible and varied spectrum of migraine therapies, and erasing the artificial borders of advanced/advancing nosology is the need of the hour for migraine research. Proponents of the theory of CSD for migraine pathogenesis have never even attempted to explain the theory in the context of the precipitating and relieving factors -- a sine qua non.

The solution of the hitherto undecipherable  migraine code appears imminent. The moment of truth and discovery -- lifting gently the delicate yet elusive veils of Nature one by one -- is upon us. Will we seize the moment now or freeze it for several millenia to come? All re-search is, after all, bringing to our comprehension that what is already known to Nature, and, already placed by way of a dormant gift in the inscrutable processes of the human mind, waiting for the time to ripen and disseminate -- a time determined by Nature's choice of the template (Man, The Unknown--Alexis Carrel, Nobel Laureate, Hamish Hamilton, London, 1959). Nothing in this Universe or under our Sun is original -- all Originality is a mere re-presentation at a foretold happenstance (Aldous Huxley, The Perennial Philosophy, Triad Grafton Books, London/Glasgow /Toronto Sydney/Auckland, 1946). The body and the mind, the sense-organs and the intellect, are instruments only...cut free from the fruit of the act, a man finds peace in the work of the Spirit... Man, deluded by his egoism, thinks: 'I am the doer'. (The Song of God, Bhagavad Gita. Translated by Swami Prabhavananda and Christopher Isherwood. Introduction by Aldous Huxley, A Mentor Religious Classic, Published by The New American Library. Copyright, 1944, 1951, by The Vedanta Society of Southern California).

Scientific re-search is the art of the probable. All scientific research is a relentless but balanced pursuit of a belief that skirts and pushes at the frontiers of human knowledge or speculation. To make significant forward progress--rather than the lateral progress offered by linguistic finesse, mathematical stochaistics/statistics, and phenotypic collapse and expansion of nosology (purposeful but mindless lumping versus splitting--errors of commission and omission must be strictly avoided. Also, a newly coined word or phrase or the in-vogue acronym in medical science does not always indicate new insight e,g., week-end headache, Harlequin syndrome, Alice in Wonderland syndrome etc.; more commonly it indicates fudging or obfuscation of ignorance. The privilege of carrying out research carries in its fold the responsibility of acknowledging error. While medical publications expand exponentially, nobody ever acknowledges self-error--these are the trying times in which we live and do research. Ergo, we are always correct and defensible. It is always the other seekers that are are in or might be susceptible to error. In this manner, decades and centuries forlornly pass by us in the defense of untenable but beloved theories -- falling in love with one's own hypotheses. Or we engage in fence-sitting or needless/avoidable obstructionism. One of the most reprehensible but well-documented function of medical periodicals that do publish research as well as of medical conferences (?at par with religious conclaves) is to keep egg off prominent/established faces. In this manner, important facts may be completely ignored through an oblique/conspiratorial sanction of the majority of the scientific community. At other times, even established high-impact journals have initiative-throttling practices that can have peculiar and unexpected science-tilting effects. A most unsettling example is of an American Neurological Journal that is almost an institution by itself. This journal follows the revenue-generating principle of accepting letters-to-the-Editor only from members of the American Association of Neurologists (AAN) as well as the most peculiar practice of offering comments with the same title as the index article. Consequently, sometimes amazing results follow. My letter-to-the-Editor has been the most quoted of my publications listed with ResearchGate but for the exactly opposite reason for which it was penned.-- Percutaneous closure of patent foramen ovale reduces the frequency of migraine attacks. Neurology Article in Neurology 63(9):1760-1761 · November 2004 Impact Factor: 8.29 · DOI: 10.1212/WNL.63.9.1760-a. While I wanted to deny this mythical association in the columns of Neurology, a simple reading of the title suggests that I would support  PFO closures for migraine prevention. Many times, also, the CME linked to an article is a money spinner. Again, how could a medical periodical allow a simple response to an article jeopardize the anticipated revenue? Finally, some journals may take the onerous responsibility of supplying ideas to their authors from rejected letters-to-the-Editor on the basis of space constraints resulting in total loss of scientific equipoise and copyright:.(Article: Should intellectual property be disseminated by "forwarding" rejected letters without permission? J Med Ethics 1996;22:243-246 doi:10.1136/jme.22.4.243"). Luckily, better sense prevailed and the policy was nipped in the bud, at least at the BMJ. 

He who rides a tiger cannot dismount. A new work in medical research always entails that a lifetime/or several lifetimes of a carefully executed work/or theory and the prestige that goes with it is jeopardized. The researcher becomes dangerous precisely at the point that she/he becomes prominent/established (Alexis Carrel). The pursuit of knowledge for the sake of knowledge itself has become extinct. Then again, multicentre/multi-country trials abound. No work of art has ever been produced by a committee of artists, nor a great discovery made by a committee of scholars, The syntheses needed for the progress of our knowledge (of man) should be elaborated in a single brain (Alexis Carrel). 

Obviously science follows no plan. It develops at random and depends on fortuitous conditions (Alexis Carrel). Great sums of money are wasted every year on scientific research, in America as well as in Europe. Not every scientist can be a researcher, but, yes, every scientist can pretend to be a researcher--can learn the so-called game of research. More colloquially, every scientist can learn the ropes of research. All the grants in the world, if single-mindedly devoted to migraine research for the next several millenia, cannot extricate the entity from the deep chasm in which it currently lies dormant or worse, unfathomable/beyond human comprehension.  Here, a searing, self-excoriating re-think is required.

The past offers some solace to those lost in the present. With Holmesian deductive spirit, I predict that the the genesis of migraine attacks might not remain forever embedded in the mains (electrical systems) of the CNS.  The time has come to coldly, dispassionately, re-examine all possible sources of trigeminal nerve activation in the real world. CSD does not lie in the real world; we have found no central neuronal source (cortical or brain stem) to explain the strikingly periodical vagaries of the migraine syndrome, including its self-remitting nature. Occasionally, the peripheral of the cranial region has been evoked as a migraine generating structure--but no further progress has been made. The time has come for the eye to be re-examined as the migraine/cluster headache generating epicentre -- a plumbing rather than a primary mains defect in the cranial region (Article: Migrainous scintillating scotomata and headache is ocular in origin: a new hypotheses. Medical Hypotheses  2006;66 (3):454-460;  Gupta VK. 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#201461).

I begin the process of generalization of a possible peripheral source for trigeminal nerve activation in migraine and cluster headache. The road ahead cannot be easy. Comments are more than welcome. If you do not partake in this experiment, the loser will ultimately be the human race and, of course, immediately our children. The quest: a perennial theory for migraine. The price: a decapitation of the old. The reward: a recreation of history.

Migraine and melatonin: a need to refocus on the basic sciences

Peres and colleagues [JNNP, Online First published on May 10, 2016 as 10.1136/jnnp-2016-313485, Produced by the BMJ Publishing Group Ltd. Under licence] carried out a clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for prevention of migraine. Migraine is a poorly understood disease. The sheer breadth of treatments approved or suggested for migraine is in parallel with the starkly limited understanding of its genesis. The headache and the other accompaniments of migraine are remarkably protean in nature. The severity, duration of pain, and other accompaniments of migraine during serial migraine attacks differ commonly and widely even in the same patient. In a strict sense, no two attacks of migraine are precisely comparable even in the same patient. The randomized controlled / clinical trial (RCT), however, seeks to compare therapies in a large body of (migraine) patients in the same study center or across several study centers in varied countries across a period of time. The methodology of the RCT assumes that the parameter (more correctly, variable) under evaluation would remain steady and replicable over the arbitrarily decided period of observation. Placed as it is at the pinnacle of the medical research pyramid, the RCT, by and large, lies beyond the pale of disapproval or critique; data generated through RCTs find ready acceptance and quick publication. Not only is the pre-publication passage of RCTs smoother, even post-publication review/critique by the scientific community is muted or muzzled by the periodical(s) involved. If a revenue-generating CME is associated with the publication of a RCT, it becomes almost impossible to critically evaluate – and get that critical evaluation published in the columns of the publishing journal. By encouraging RCTs in primary vascular headaches, the non-suitability of migraine to the methodology of the RCT has been obscured to a non-issue. Randomization is itself not a scientific method but an invaluable strategy for mathematically managing uncertainty.[Feinstein, 1994].1 Moreover, the hijacking of biological commonsense in medical research (insight) by mathematics is not generally appreciated [Gupta, 2004].2 The mathematical basis of the RCT through statistics and its inability to distinguish between relatively small effects has generated a very large mass of data in primary headache research that is not only often conflicting but also frequently misguiding. Migraine, thus, has evolved into a giant puzzle whose literature comprise a vast loosely-linked and very often un-linked enterprise (data, hypotheses, syntheses, and myths) that currently severely tests human problem-solving capacity. Migraine remains a classical example of a clinical entity that has not yet yielded its secrets to statistical legerdemain. Perhaps in no other clinical entity has the immeasurable [Alexis Carrel, 1956] proven so much more important than the measurable. Science in medicine, however, carries in its folds an intolerance, an irreverence, an impatience, a sledge-hammer like either/or approach through advanced technology and/or RCT-related statistical mathematics that is often ill-suited to approach the unknown (“wow factor”).3 Nevertheless, the recipe for perpetual ignorance is to be satisfied with your opinions and content with your knowledge.—Elbert Hubbard.

To be content with one’s approach (RCT) is the other pitfall. The RCT significantly re-shapes or distorts the Introduction, the Result and the Discussion of such submissions. 1,3 Regardless of current guidelines, amitriptyline is a very well-established and a very old migraine prophylactic agent that is a favorite first-line drug for the practicing neurologist/physician, both in the community as well as in the hospital. Most migraine patients respond well to a low (10 mg) dose of amitriptyline, more so in combination with propranolol. At this dose of amitriptyline, there is no existing study that has demonstrated unequivocally any significant gain in weight. At the dose of 25 mg, the weight gain effect of amitriptyline over three  months, again will be modest to nil in non-obese patients. Amitriptyline should, of course, be avoided in frankly or grossly obese patients. The index study of Peres et al has not stratified its patients into obese and non-obese groups. Finally, like propranolol, there is no dose-responsive curve for amitriptyline. A dose of 25 mg versus 10 mg of amitriptyline does not, as a rule, bring more migraine responders in its prophylactic fold; side-effects certainly come to the fore more often. The absence or presence of side-effects can, nevertheless, unmask the placebo involved. That the combination of propranolol and amitriptyline is pharmacologically paradoxical has never been formally acknowledged in the migraine research literature. Medicine is both a social science and an art; the laws of insurrection in art apply equally well to medicine. Discovery in medicine depends solely on insurrection. The art of medicine can frequently become tinged with politics.  At times, a primary function of referees for a submission involves keeping egg off prominent faces [Drummond Rennie]. With due process of peer-review in modern medical journalism, the pedigree of the originality sometimes becomes far more important the than the originality itself. High citadels naturally lend themselves more easily to originality, acknowledgment, and applause. The article presenting the anti-platelet effect of aspirin was rejected initially. Originality, frequently, does not reach first base. In a clinical entity such as migraine, with its pathophysiology at its infancy, there is nothing original in any carefully designed RCT.3

The use of the term “biological” in migraine research has lost its way in sandy deserts of habit and convenience. Biological is not synonymous with “physiological” or “laboratory”.  The “biology” of migraine is not the study of laboratory “markers” but the elucidation of physiological forces (both physical and chemical/neurochemical) that push (precipitate) or pull (predispose) patients towards aura/headache state or aura/headache free state. In migraine research, the term biological is frequently misused to buttress a study towards its publication.3 As “biological” seems close to molecular, the trend of the times appears preserved. A complex and uncertain relation prevails between aberrations of prolactin, melatonin, and migraine.4 Alterations in prolactin and melatonin secretion suggest a hypothalamic chronobiologic involvement in migraine: however, the cause/effect debate has not been resolved. Melatonin, in striking contrast to hyperprolactinaemia, lowers the intraocular pressure, is acutely suppressed in humans by exposure to sunlight and artificial light (2500 lux but not by light of ordinary indoor intensity), and can itself precipitate headache in migraine patients.4  

The inclusion criteria in the index study merit some attention. Migraine patients tend to maintain a low blood pressure.3 A cut-off of 160/90 is acceptable for the general population but not for a cohort of migraine patients. There is no generally accepted criteria for inclusion of migraine patients into to RCT. As suggested previously, migraine patients refractory to a three-month trial of combination propranolol-amitriptyline (120 mg / 10 mg daily) should be regarded as refractory and, therefore, acceptable for clinical trials. Patients with asthma intolerant to beta-blockers should be excluded from clinical trials. Patients with associated comorbidities such as anxiety / panic attacks / past trauma / seizure disorders / bipolar disorders other medical disorders are best excluded. Bias and suggestion affect patients beginning with the screening questions; such evaluations heighten anticipation and apprehension. The ready availability of unfiltered information from the Internet does not make matters easy. Participation in a clinical trial also creates a halo of dedicated heroism through a kind of sacrificial empathetic commitment for the welfare of others (non-participants / future generations). Such psychological features have neurohormonal and neurochemical correlates, that can presently only be speculated about, but can and do impact on the outcomes of therapeutic clinical trials.      

Informed consent and ethics-committee approval are two of the standard must-have components of RCTs. When migraine researchers themselves do not know the “why” and “how” of migraine, what are they going to tell the participants of a clinical trial? Also, unless the members of the Ethics Committee are hard-core migraine / headache researchers, they can and will be easily mislead by the trialists. These limitations of the RCT cannot simply be wished away or argued about. The time for such introspection is way overdue. Continued neglect of these issues allows performance of RCTs at a cost – confusion. The double-blind frequently lead the blind into a cul-de-sac (Blau, JN). Such confusion can never be redeemed—it persists to perpetuity. Moreover, Governmental registration of trials adds weight but no mass or insight to the process or outcome of the RCT. Finally, statistics used in the index study empowered inclusion of patients who took a single dose of the study medication, and, who provided only one post-baseline efficacy assessment. Missing data were also analyzed through statistics.

Migraine prophylaxis needs to be round-the-clock. An extended-release preparation of melatonin failed to show promise (Alstadhaug et al., 2010).5 Melatonin, in comparison with amitriptyline, has a relatively short life, a 90% hepatic first-pass metabolism, and no cumulative pharmacologic effect. Use of amitriptyline as comparator in the index trial is incongruous and should have been avoided. Weight variations of less than 1 Kg, as in the index study, can be given mathematical importance only through the RCT. The index study has been propelled by the imperative to highlight the weight-loss / weight-gain paradigm through the pairing of melatonin-amitriptyline.

Any prophylactic agent, in contrast to abortive agents, works at the core of migraine pathogenesis. Melatonin is no exception. Prophylactic use of melatonin mandates that melatonin provide a rational defensible explanation for the characteristic onset and offset of migraine as well as the peculiar precipitating and relieving factors.6 In the absence of such an integrated synthesis, use of melatonin to prevent migraine will be labelled as empirical at best. A more critical view would regard such use of melatonin as misguided and unwarranted. When technology is applied without foresight (have machine-will publish) or when trials are conducted without pharmacological /pathophysiological insight (have funds-will publish), a sea of confusion ensues; currently, in medicine, no sea of confusion is larger or deeper than is migraine.3

References:

1. Feinstein AR. Clinical judgment revisited: the distractions of quantiitative models. Ann Intern Med. 1994;120:799-805.

2.  Gupta VK. Randomized controlled trials: the hijacking of basic sciences by mahematical logic. BMJ 8 July 2004.

3. Gupta VK. Adaptive Mechanisms In Migraine. A Comprehensive Synthesis In Evolution. Breaking the Migraine Code. Nova Science Publishers, Inc. New York. 2009,pp.1-126.

4. Gupta VK. Prolactin, Melatonin, Stress And Migraine. In: Adaptive Mechanisms In Migraine (ed) VK Gupta. Nova Science Publishers, Inc. New York, pp 47-50.

5. Alstadhaug KB et al. Prophylaxis of migraine with melatonin. Neurology 2010;75:1527-32. 

6. Gupta V. Pharmacotherapeutics of migraine and the blood-brain barrier: serendipity, empiricism, hope and hype. Medicine General Medicine. 2006;8(2):89. 

Journal of Neurology Neurosurgery & Psychiatry (JNNP) refused to publish this critique as an e-letter submitted on May 13, 2016.

I was a De Facto of a native Australian man called Bradley Paul Neal in 2001. He ruined my life, and I am still enduring the worst world atrocities in First World, and that happens for now more than 14 years, because of his decisions and crimes from 2002, believe it or not. This man, after I came back from Brazil in 2001, used to say he had migraines every second day, so that I would basically be forbidden from hugging, kissing or making love to him and from being hugged, kissed, and having love made to me. I was put into a situation in which I had to decide if he did drugs (he did do them, and I think he did mostly heroin), was epileptic (I found some writing of his mentioning a dog and epilepsy and I then thought he could be referring to himself like that) or was a promiscuous person.  In the end he was all of those but epileptic. He was also a psychopath. He also had sex with men and therefore was at least bisexual. I believe his migraines were definitely psychological and used as a tool to avoid conflict and get what he wanted. In the past, plenty of women denied intimacy to the husbands alleging migraine, as far as I know. Such cases would obviously be healed with work toward becoming assertive, so that Psychology or Psychoanalysis or even Psychiatry could be healing them. 

I had a boyfriend who had a physical problem, a tumor on the knee, and the Brazilian doctors kept on prescribing Aspirin. Were it malign, he would have died, is it not? What happens is that they may put that on the medical records, that he had migraine, but he did not have migraine, he had a physical disease. With this, your medical statistics may go wrong, just to let you know also this one. 

You talk about physiological changes. I am not so sure about what physiology involves, but Bradley would stop making faces and holding his head on the second days, for instance, if he simply told the truth. 

Even though 'the ladies' would probably get a divorce, their physiology should remain unaltered, since they say women lie much better than men. 

There is somatization however, and they could actually feel that pain. Someone wrote in Brazil that the poet pretends to feel the pain that he indeed feels as he writes. 

Since you, Marcia, are not sure about what physiology of migraine involves, I suggest a reading of my book: Adaptive Mechanisms In Migraine, Nova Science Publishers, New York 2009. This is currently the only comprehensive source of the physiology of migraine that takes you step-by-step on a fascinating journey into the mind of a migraine patient. I warn you that it is not an easy read like a story-book or a novel. Also you have to have quite a bit of background medical knowledge of neurophysiology to begin with. It is available in softcover as well as an e-book. 

Behind lying lies motive and behind motive lies comprehension and intellect and design. Lying and its cover-up depends upon intellect/intelligence and not on sex. Possessiveness, desperation, jealousy, and envy are the emotions that guide men and women below the belt.   

Intellectual is one who has found something more interesting than sex. Getting a divorce is no plaything but has many seen and unseen layers and features. It will be a rare human being indeed whose physiology is not affected by divorce, a gut-wrenching, heart-breaking and mind-numbing exhaustive activity peculiar to human beings. And then you have to grasp the meaning of the term "physiology". Having general intelligence does not translate into understanding of human physiology or a reading of the mind or comprehension of the complexities if our origin or deviations of human behaviour from the "norm". Where you start inevitable affects where you end. Migraine is no more psychological than is a heart attack or a stroke or typhoid fever -- but all these events have psychological overtones which sometimes appear dominant. 

Poets empathize, They never pretend. Only pseudo-poets pretend. Having won the bronze in World poetry competition in 2003, I know what I am saying. Poets tango with the measurable and the immeasurable, the seen and the unseen, the known and the unknown I leave with a quartet:

Since you have seen the dust, see the WIND

Since you have seen the foam, see the OCEAN,

Come, see it, for insight is the only thing in you that AVAILS;

the rest of you is a piece of flesh and FAT.

Beyond knowledge lies wisdom, and beyond wisdom lurks faith. Faith, that can move mountains...(Gupta, 2009).

I've become mute. It is so much Vinod...you are so wise. 

moving mountains in our terms seems like omnipotens, even if I can feel in a way what you mean...or then not.

What has been amazing in analysis is that people who have become in touch with their envy have been able to let the headache come and go away as they want. Even playing with that new ability!! Marita