Orbitofrontal cortex hypometabolism, medication overuse headache, substance abuse and migraine: key pathophysiological issues
Received March 4, 2006. Revised March 29, 2006. Accepted April 4, 2006.
Sir, Professor Schoenen and colleagues show reversible metabolic changes in pain processing structures along with persistent orbitofrontal cortex (OFC) hypofunction in patients with medication overuse headache (MOH); these investigators extrapolate these positron emission tomography (PET) findings to both analgesic drug-dependence as well as to the pathogenesis of MOH itself (Fumal et al., 2005
). At the outset, the basic research premise of a causal relation between medication overuse and aggravation or transformation of primary headache disorders is uncertain and likely linked to headache frequency (Tepper and Dodick, 2002; Lipton and Bigal, 2003). The present paper (Fumal et al., 2005) does not emphasize that: (i) Few migraine patients regularly using analgesics develop chronic daily headache (CDH) or MOH or chronic migraine. This issue needs to be distinguished from the incidence of acute medication overuse in a substantial fraction of patients with chronic headaches seen in prospective studies in specialized headache centres or the general population (Zwart et al., 2003; Katsarava et al., 2004). The key pathophysiological concern in MOH is not the incidence of acute medication overuse but its role in transformation of episodic migrainous headache to a more frequent/daily occurrence. Epidemiological evidence is quite unlikely to settle the cause–effect relationship between acute medication overuse and MOH or chronic migraine. (ii) While analgesic abuse is a self-determined unsupervised activity, analgesic withdrawal is a medically controlled activity—supervised analgesic withdrawal involves the placebo effect of the therapist's reassurance. Every therapeutic intervention—including supervised analgesic withdrawal—involves a placebo effect (Bignall, 1994). (iii) Analgesic withdrawal in clinical practice is commonly accompanied by other interventions undertaken simultaneously (Lipton and Bigal, 2003). (iv) No particular temporal pattern has emerged between regular analgesic use and development of daily headache in migraine patients; a prolonged interval of several years of analgesic consumption often precedes onset of daily headache (Colás et al., 2004). (v) The parallel sought by Fumal et al. (2005) between drug-dependence and MOH is rather limited since episodic or chronic headache/pain is not a feature of the former. Again, association between chronic forms of pain and analgesic/substance abuse does not validate the suggested aetiological link of such behaviour to the development of MOH. (vi) In cocaine-dependent patients with migrainous headaches, withdrawal or abstinence of cocaine rather than its consumption is associated with headache; such headaches tend to subside immediately with the readministration of cocaine (Satel and Gawin, 1989; Dhuna et al., 1991). (vii) Caffeine is another habituating widely used chemical. Caffeine withdrawal over the weekend, rather than caffeine consumption itself is associated with migraine (Couturier et al., 1992). (viii) Some people smoke to reduce dysphoria and anxiety; cigarette smoking (experimental and usual) promotes the release of ß-endorphin (Houezec and Benowitz, 1991), the endogenous opiate known to relieve pain and anxiety that may reduce the urge of using analgesics (Chen et al., 1987; Simons et al., 2005). Nicotine readily crosses the blood–brain barrier and releases acetylcholine, norepinephrine, dopamine, serotonin, vasopressin and adrenocorticotropic hormone (Houezec and Benowitz, 1991). (ix) Dextroamphetamine significantly decreases activation in dopamine-rich regions of the brain, including the OFC (Tremblay et al., 2005), but offers significant prophylaxis in some patients with chronic tension-type or migraine headaches (Hass and Sheehe, 2004). (x) Long-term consumption of analgesics is very likely to attenuate the various components of the endogenous pain control mechanism, as has been seen with low ß-endorphin and other opioid levels in CDH (Anselmi et al., 1997). In presumptively linking amphetamine, cocaine or nicotine induced persistent structural changes of dendritic trees and spines in brain regions involved in incentive motivation and reward to persistence of OFC hypoactivity long after drug withdrawal as well as to predisposition of a subgroup of migraine patients to relapse of MOH, Fumal et al. (2005) ignore contrary clinical and experimental evidences. Also, while phenylethylamine has been postulated to play an aetiological role in migraine, it has been conceptualized as the body's natural amphetamine (Wolf and Mosnaim, 1983).
These authors assert that patients with psychiatric disease were excluded from this study (Fumal et al., 2005). Depression is not the only psychiatric illness or psychological or behavioural pattern linked with chronic headache (Andrasik, 1990). Attention-seeking behaviour and drug-dependence is not a feature of depressive illness. On the other hand, depression is not independently correlated with OFC metabolism (Goldstein et al., 2005). Exclusion of MOH patients with depression (Fumal et al., 2005) appears to constitute a form of selection (inclusion) bias; more refractory and less responsive patients probably constituted this study cohort. Hypochondriacal patients and those with other refractory personality traits but without overt psychiatric diseases are particularly difficult to manage while being prone to poly-pharmacy and poly-medicine. The results of this study, therefore, very likely apply to that small fraction of selected, tertiary care primary headache patients with MOH who are refractory to most management strategies, are prominently susceptible to placebo or nocebo effects, have complex psychological backgrounds, invariably seek or demand particular therapeutic attention and actively seek alternative therapies. Practically, there is little behavioural difference between such patients and those who are drug dependent. Second, in contrast to its acute effect, acamprosate does not predictably alter craving in the long-term due to development of tolerance (Cowen et al., 2005). Third, withdrawal of acamprosate 7 days before Scan 2 (Fumal et al., 2005) left this cohort without any anti-craving medication. Since pain levels at Scan 1 and Scan 2 were similar—as acknowledged by Fumal et al. (2005), the need for analgesics remained unchanged at both PET scans. Drug-dependent patients or substance abusers are notoriously unreliable in their medication history; pain is an additional incentive to violate any research study protocol. Self-declared analgesic consumption pattern by MOH patients in this study is largely unreliable or fallacious and poses a major confounding factor. Fourth, to confirm their hypothesis, Fumal et al. (2005) suggest testing for persistent OFC hypoactivity in MOH patients long after analgesic drug withdrawal. Even short-term drug withdrawal under controlled conditions is difficult in such patients; verifiable longer term drug withdrawal in such patients is practically impossible. Overall, this study cohort does not represent primary headache (including MOH) patients in the general population. Therefore, the conclusion that OFC hypofunction in concert with a poorly defined genetic liability could have a pathogenetic role in MOH (Fumal et al., 2005) is premature and likely to increase conceptual confusion in primary headache pathophysiology; the pathophysiology of substance abuse itself is incompletely understood. To their credit, the investigators (Fumal et al., 2005) acknowledge that their research premise and conclusions are speculative.
The brain monoaminergic system has attracted much attention in the pathophysiology of primary headaches and has directed research efforts and opinion over past several decades. Involvement of the intrinsic noradrenergic system is widely believed to underlie the development of migraine attacks, both with aura and without aura (Welch, 1987). Welch (1987), however, clearly acknowledged the speculative nature of the proposal. Fumal et al. (2005) extend the assumption that brain serotonin abnormalities critically underlie the pathogenesis of migraine. There is little evidence to substantiate the putative aetiological role of either the noradrenergic or the serotonergic brain system in migraine and such theories of origin of migraine remain speculative. In the context of this study (Fumal et al., 2005), as discussed in this critique earlier, amphetamine, cocaine and caffeine ameliorate migraine or significantly delay onset of attacks; all these agents stimulate the brain intrinsic noradrenergic system. Amitriptyline, a fairly established migraine prophylactic agent in the ‘proven’ or ‘well-accepted’ category (Goadsby et al., 2002), unambiguously stimulates both brain noradrenergic and serotonergic systems. The evidence that amitriptyline is a brain serotonin agonist is overwhelming and inexhaustible. Amitriptyline can cause the serotonin syndrome (Mathew et al., 1996), the clearest clinical indication of its brain serotonomimetic effect. Further, apomorphine is a potent dopamine agonist that can reduce the frequency and severity of migraine attacks when infused continuously for 3 weeks (Lai et al., 1997). Finally, atenolol does not freely cross the intact BBB or critically influence any brain neuronal function yet it prevents both migraine with aura and migraine without aura as effectively as propranolol (Stensrud and Sjaastad, 1980). Such pharmacological absolutes caution against uncritical acceptance of a vital pathogenetic role for the brain monoaminergic system in the development of primary headaches, including MOH.
The putative pathogenetic relevance of dopaminergic or serotonergic innervation of the OFC or of OFC dysfunction to MOH or to migraine itself (Fumal et al., 2005) must not be dissociated from both clinical reality as well as the fundamentals of basic sciences.
Physician, Dubai Police Medical Services P.O. Box 12005, Dubai, United Arab Emirates
Correspondence to: Dr Vinod Kumar Gupta, Dubai Police Medical Services, P.O. Box 12005, Dubai, United Arab Emirates E-mail: dr_vkgupta{at}yahoo.com
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