Abstract
Facilitation of nociceptive systems has been implicated in Chronic-Migraine pathogenesis. Daily consumption of medication may be a contributing factor. The patient was male, aged 76 years, with history of migraine without aura. Six years ago, he presented with a mild-moderate daily pulsating headache. He was overusing analgesics and ergotamine. After withdrawing, the patient started a non-pulsating headache, diffuse and constant. During follow up, he was refractive to several symptomatic and prophylactic treatments. When we treated him with placebo capsules, the headache responded very well. At first, pain-relief occurred for 6 h and progressively, extended. Two years later, when our patient started to use transdermal patches of fentanyl for treatment of a complex regional pain syndrome type 1, his headache did not improve. Patient has maintained prolonged response to placebo. Actually, he is pain-free for 2-3 days with 1 placebo capsule. We discuss mechanisms of chronic-migraine, drug-overuse, drug-induced headache and placebo addiction. Powerful psychological mechanisms could determine response to placebo in this patient.
Introduction
Chronic daily headache (CDH) is a heterogeneous group that includes primary and secondary headaches. Primary CDH affects 4–5% of the population and includes chronic-migraine (CM), chronic tension-type headache, new-onset daily persistent headache and hemicrania continua (1–3). Pathophysiology of CDH is not clearly understood. Some authors have suggested that each of the various subtypes of CDH could have a different pathogenesis (4).
Transformation of an episodic migraine into a continuous or almost continuous headache could be conditioned by an abnormal metabolic activity in the brain and resultant neuronal dysfunction. Daily intake of antimigraine drugs (analgesics, ergotamine or, more recently, triptans) could be in a contributing factor for CM through a hyperactivation of nociceptive facilitator system.
We present a patient with CM, with analgesic and ergotic overuse for over 11 years. After a period of weaning off, he started a different, diffuse and constant headache. During the last 5 years, the new headache has responded to placebo (bicarbonate). Two years ago, when the patient started to use transdermal patches of fentanyl for treatment of a complex regional pain syndrome type I, headache did not improve.
The exquisite and prolonged response to placebo in our patient is exceptional. We review the mechanisms involved in CM, pharmaceutical overuse, drug-induced headache and placebo addiction.
Case report
Male, 76-year-old with a history of well controlled high blood pressure, tuberculosis of the lungs during his youth and migraine attacks without aura from 17.
Six years ago, he consulted by a daily pulsating headache, hemicraneal, with slight nausea, of mild-moderate intensity, mainly in the morning, for over the last 20 years. Symptoms were occasionally more intense which forced him to remain in bed all day. Pain responded well to 1 mg of ergotamine plus 300 mg of paracetamol for 6 h before reappearing and forcing him to take another dose. At the time of interview, he was taking the mentioned combination 3 or 4 times a day alternating with aspirin 500 mg. Neurological and physical explorations were normal. Brain CT scan only revealed a small arachnoid cyst.
We treated him with flunarizine, betablockers and antidepressants with no success. During follow-up, he was hospitalized twice and we tried a weaning off period using steroids, naproxen, paroxetin and lorazepam, withdrawing the ergotamine and his usual painkillers. The first withdrawal was not successful. After a second withdrawal, a new diffuse cephalic pain appeared after a slight improvement of 48 h. The new headache was non-pulsating, holocraneal, constant (even then nocturnal) and refractory to extra doses of the prescribed non-steroid anti-inflammatory, which provoked great anxiety in the patient. Psychiatric evaluation of the patient ruled out personaliy disorder or depression. With the intention of reducing the intake of analgesics, we administered placebo capsules (5 mg of bicarbonate) warning him of its analgesic properties, and surprisingly, the pain disappeared for 6 h. During the following two days, due to the persistence of the pain, we progressively substituted the doses of analgesics for placebo, maintaining a daily dose of 20 mg of paroxetin. Fifteen days later, the patient still suffered from daily headache but refused to withdraw the placebo, which continued to be very efficient in eliminating the pain for approximately 8 h. Three months later, the patient was completely pain-free during 24 h with 2 placebo capsules and he decided to stop paroxetin. Two years ago, in relation to a traumatic humeral fracture, our patient developed a painful complex regional syndrome, type I. Transdermal patches of fentanyl rapidly relieved this pain but not headache, which only responded to placebo. Now, five years after withdrawing ergotamine, he still continues to respond well to placebo. The patient is pain-free during 2–3 days with 1 placebo capsule. He responds to placebo in approximately one hour.
Discussion
Transformed-migraine, recently called chronic-migraine (CM), is the most frequent subtype of CDH in the specialized headache clinic (5–7). A possible mechanism implicated in the pathogenesis of the CM is the increase of iron deposition in periaqueductal grey (PAG), probably due to impairment of the iron homeostasis (8) and a hyperoxide state in the red nucleus and substantia nigra (9). Hyperoxia generates free radicals which could interfere neuron excitability and vasomotor control, leading to disturbed nociception.
Patients with chronic headaches have a considerable risk of becoming drug-dependent and of acquiring analgesic-induced headache (10, 11). Our patient consumed analgesics and ergotamine for last 11 years, which usually relieved his headache. Antimigraine drugs become a remarkable contributing factor for chronic migraine, worsening the frequency and intensity of headache sufferers (12–15). A deficiency of inhibitory pain modulation, a hyperactivation of nociceptive facilitatory system, an altered function and density of postsynaptic neural receptors and the peripheral and central effects of the incriminating drugs are possible mechanisms involve. Abnormal metabolic activity in the brainstem could, also, make this area hypothetically vulnerable to receptor modulation after the frequent use of analgesic and abortive medications (12, 16). From PAG diffuse serotonergic projections go to the cerebral cortex and blood vessels. 5TH-2 A receptors mediate neuronal hyperexcitability and potentiate nociceptive transmission (17, 18). After long-term use of analgesic medications, Srikiathachorn et al. have demonstrated an up-regulation of the 5HT-2 A receptors which mediate a hyperalgesic state, an increased frequency and severity of head pain (19–21). The dysregulation in the endogenous opioid system through analgesic overuse has, also, a important role in the transformation of an episodic migraine to a CM (22, 23).
Discontinuation of daily symptomatic medication, however, can result in an increase in head pain (rebound headache) accompanied by nausea, vomiting and sleep disturbances. After this initial increasing headache, a improvement starts (24). Successful management of drug-induced headache is only possible by withdrawal therapy. Different methods of withdrawal therapy have been published, with similar effectiveness and long-term results (25, 26). Finally, discontinuation of the overuse analgesics and abortives enhances the beneficial effect of prophylactic medication (27) Our patient has a medical history compatible with the diagnostic of analgesics and ergotamine overuse headache for a period of years. As we have mentioned, an altered central excitability, expressed in a facilitation of nociceptive system (4, 8, 9) and the peripheral and central effects of long-term use of drugs could be implicated in the origin of medication-overuse headaches (14, 15). After the second withdrawing of ergotamine, the cephalagia improved, although it was only transitory in our patient. Then, he started a constant diffuse cephalic pain, with more imprecise characteristics and refractive to various symptomatic and prophylactic medications, generating an anxious state in the patient. When we decided to treat him with a placebo, surprisingly, this new headache responded very well to it. At first, the pain relief occurred for 6 h and progressively had reduced in frequency. When the patient had to treat his shoulder pain with transdermal patches of fentanyl, we checked that the opioid derivate was useful for it but not for new head pain. Actually, five years after, the cephalic pain still occurs every 48 or 72 h and responds, always, to placebo in the first hour. This exquisite and prolonged response to placebo allowed us to suppose that powerful psychological mechanisms determine the dependence of our patient. Also, the initial abuse of analgesics and ergotics could be sustained by psychotropic effect, contributing serotonergic regulation towards the appearance of dependence (28).
The analgesic effect of placebo for acute and prophylactic treatment of migraine or tension-type patients is a well known (29, 30). The placebo effect can induce a significant analgesia on average in 35% patients, with some variations according to the studied pathology and the modalities of the therapy (31, 32). This effect can be especially influenced by conditioning, expectations, the beliefs of the patient, the environment and the quality of the doctor-patient relationship. Psychological factors like the individual suggestibility, the verbal expectancy for drug efficacy or the desire for pain reduction can be possible mediators of placebo analgesia and contribute significantly to the magnitude of it (33, 34), without gender differences (35, 36). But the placebo effect does not occur in everyone and not at all times and a prolonged placebo response in a patient with chronic headache is exceptional. An increased and prolonged placebo response has been observed in a variety of psychiatric disorders (including obsessive compulsive disorder, social phobia, panic disorder and depression), personality disorders and alcohol overuser. Mental disorders in our patient were studied and ruled out (37). Placebo response can be conditionable in both a positive and negative directions (38). Negative information can reduce expectancy ratings and decrease the magnitude of pain reductions (39).
Physiologically, placebo induced-analgesia seems to involve both higher organized and somatotopic cognitive networks and endogenous opioid systems (40, 41). Recently, using positron emission tomography, Petrovic et al. (42) have confirmed that both opiod and placebo analgesia are associated with increased activity in the rostral anterior cingulated cortex and brainstem. Therapeutically, the placebo effect can also stimulate in patients their psychophysiological self-regulation abilities (43, 44). The better knowledge of the neurochemical mechanism for the placebo effect could be useful to treat complicated headache.
In our case, the positive conditioning motivated by the intake of a supposedly active substance, could be the most important factor in the continuation of the placebo response. Habitually, placebo treatment is prescribed when there is no adequate therapy for the disease or all medications have been completely ineffective. Placebo treatment should not have serious side-effect and not continue too long (45). The patient should be informed about the characteristics of the placebo composition and attempt its elimination. Despite such an explanation, some patients choose to continue with placebo, as did our patient.