Gøril Bruvik Gravdahl

Management of Medication Overuse Headache: 1-Year Randomized Multicentre Open-Label Trial

It is a general belief that patients with medication overuse headache (MOH) need withdrawal of acute headache medication before they respond to prophylactic medication. In this 1-year open-labelled, multicentre study intention-to-treat analyses were performed on 56 patients with MOH. These were randomly assigned to receive prophylactic treatment from the start without detoxification, undergo a standard out-patient detoxification programme without prophylactic treatment from the start, or no specific treatment (5-month follow-up). The primary outcome measure, change in headache days per month, did not differ significantly between groups. However, the prophylaxis group had the greatest decrease in headache days compared with baseline, and also a significantly more pronounced reduction in total headache index (headache days/month x headache intensity x headache hours) at months 3 (P = 0.003) and 12 (P = 0.017) compared with the withdrawal group. At month 12, 53% of patients in the prophylaxis group had ≥ 50% reduction in monthly headache days compared with 25% in the withdrawal group (P = 0.081). Early introduction of preventive treatment without a previous detoxification programme reduced total headache suffering more effectively compared with abrupt withdrawal. (ClinicalTrials.gov number, NCT00159588).

A comparative study of candesartan versus propranolol for migraine prophylaxis: A randomised, triple-blind, placebo-controlled, double cross-over study.

Objective The objective of this article is to see whether the effect of candesartan for migraine prevention, shown in one previous study, could be confirmed in a new study, and if so, whether the effect was comparable to that of propranolol (non-inferiority analysis), and whether adverse events were different. Methods In a randomised, triple-blind, double cross-over study, 72 adult patients with episodic or chronic migraine went through three 12-week treatment periods on either candesartan 16 mg, propranolol slow-release 160 mg, or placebo. The main outcome measures were days with migraine headache per four weeks (primary outcome), days with headache, hours with headache, proportion of responders (>50% reduction of migraine days from baseline), and adverse events. Results In the modified intention-to treat-analysis, candesartan and propranolol were both superior to placebo: 2.95 (95% confidence interval: 2.35–3.55%) and 2.91 (2.36–3.45%), versus 3.53 (2.98–4.08%) for migraine days per month (p = 0.02 for both comparisons, Wilcoxons paired signed rank test, blinded statistical analysis). Candesartan was non-inferior to propranolol (and vice versa). The proportion of responders was significantly higher on candesartan (43%) and propranolol (40%) than on placebo (23%) (p = 0.025 and <0.050, respectively). There were more adverse events on candesartan (n = 133%) and propranolol (n = 143%) than on placebo (n = 90%), and the adverse event profiles of the active substances differed somewhat. Conclusion It is confirmed that candesartan 16 mg is effective for migraine prevention, with an effect size similar to propranolol 160 mg, and with somewhat different adverse events. Trial registration: EUDRACT (2008-002312-7), ClinicalTrials.gov (NCT00884663).

Sleep quality, arousal and pain thresholds in migraineurs: a blinded controlled polysomnographic study

BackgroundOur aim was to compare subjective and objective sleep quality and arousal in migraine and to evaluate the relationship between sleep quality and pain thresholds (PT) in controls, interictal, preictal and postictal migraine.MethodsPolysomnography and PT (to pressure, heat and cold) measurements were done in 34 healthy controls and 50 migraineurs. Subjective sleep quality was assessed by sleep diaries, Epworth sleepiness scale, Karolinska sleep questionnaire and Pittsburgh sleep quality index. Migraineurs who had their sleep registration more than 48 h from an attack were classified as interictal while those who were less than 48 h from an attack were classified as either preictal or postictal.ResultsMigraineurs reported more insomnia and other sleep-related symptoms than controls, but the objective sleep differences were smaller and we found no differences in daytime sleepiness. Interictal migraineurs had more awakenings (p=0.048), a strong tendency for more slow-wave sleep (p=0.050), lower thermal pain thresholds (TPT) (heat pain thresholds p=0.043 and cold pain thresholds p=0.031) than controls. Migraineurs in the preictal phase had shorter latency to sleep onset than controls (p=0.003). Slow-wave sleep correlated negatively with pressure PT and slow bursts correlated negatively with TPT.ConclusionLower PT in interictal migraineurs seems related to increased sleep pressure. We hypothesize that migraineurs on the average suffer from a relative sleep deprivation and need more sleep than healthy controls. Lack of adequate rest might be an attack-precipitating- and hyperalgesia-inducing factor.

Visual Evoked Potentials in Interictal Migraine: No Confirmation of Abnormal Habituation

We intended to study the effect of check size on visual evoked potential habituation in interictal migraine, using the faster 3 per second reversal rate and an improved analytic procedure with block‐number blinding.

Sleep-related and non-sleep-related migraine: interictal sleep quality, arousals and pain thresholds

BackgroundThe mechanisms associating sleep and migraine are unknown. No previous polysomnographic (PSG) or pain-threshold (PT) study has compared patients with sleep-related migraine attacks (SM), non-sleep related migraine attacks (NSM) and healthy controls.MethodsWe have performed a blinded, prospective exploratory study with case–control design. Thirty-four healthy controls, 15 patients with SM and 18 patients with NSM had interictal PSG heat-, cold- and pressure PT (HPT, CPT, PPT) recordings and completed diary- and questionnaire on sleep and headache related aspects.ResultsNSM patients had more slow-wave sleep (SWS) and more K-bursts than SM patients (K-bursts: p = 0.023 and SWS: p = 0.030) and controls (K-bursts: p = 0.009 and SWS: 0.041). NSM patients also had lower HPT and CPT than controls (p = 0.026 and p = 0.021). In addition, SM patients had more awakenings and less D-bursts than controls (p = 0.025 and p = 0.041).ConclusionSM- and NSM patients differed in objective-, but not subjective sleep quality. NSM patients had PSG findings indicating foregoing sleep deprivation. As foregoing sleep times were normal, a relative sleep deficit might explain reduced PT among NSM patients. The SM patients had signs of slightly disturbed sleep.

The effect of sleep restriction on laser evoked potentials, thermal sensory and pain thresholds and suprathreshold pain in healthy subjects

OBJECTIVE Sleep restriction seems to change our experience of pain and reduce laser evoked potential (LEP) amplitudes. However, although LEP-habituation abnormalities have been described in painful conditions with comorbid sleep impairment, no study has previously measured the effect of sleep restriction on LEP-habituation, pain thresholds, and suprathreshold pain. METHOD Sixteen males and seventeen females (aged 18-31years) were randomly assigned to either two nights of delayed bedtime and four hours sleep (partial sleep deprivation) or nine hours sleep. The study subjects slept at home, and the sleep was measured with actigraphy both nights and polysomnography the last night. LEP, thermal thresholds and suprathreshold pain ratings were obtained the day before and the day after intervention. The investigator was blinded. ANOVA was used to evaluate the interaction between sleep restriction and day for each pain-related variable. RESULTS LEP-amplitude decreased after sleep restriction (interaction p=0.02) compared to subjects randomized to nine hours sleep. LEP-habituation was similar in both groups. Thenar cold pain threshold decreased after sleep restriction (interaction p=0.009). Supra-threshold heat pain rating increased temporarily 10s after stimulus onset after sleep restriction (interaction p=0.01), while it did not change after nine hours sleep. CONCLUSION Sleep restriction reduced the CNS response to pain, while some of the subjective pain measures indicated hyperalgesia. SIGNIFICANCE Since LEP-amplitude is known to reflect both CNS-pain-specific processing and cognitive attentive processing, our results suggest that hyperalgesia after sleep restriction might partly be caused by a reduction in cortical cognitive or perceptual mechanisms, rather than sensory amplification.

Onabotulinum toxin A treatment of cervicogenic headache: A randomised, double-blind, placebo-controlled crossover study

Aims: Preliminary reports regarding injections in the neck of onabotulinum toxin A have been positive in cervicogenic headache (CeH). The aim was to perform the first methodologically rigorous trial. Methods: A randomised, placebo-controlled, patient-, injector- and evaluator-blinded crossover study included 28 adult patients with a long-standing and treatment-resistant CeH. After a baseline period, injections of either onabotulinum toxin A or placebo were given in fixed sites in the neck muscles on the pain side. Second injections were given after ≥8 weeks. Patients were thereafter followed for another 8 weeks. A detailed headache calendar was filled in, and patients were followed with quality-of-life (QoL) questionnaires, algometry and neck mobility measurements. Results: There was no significant difference between verum and placebo in a mixed linear model analysis (p = 0.084) with regard to the primary end-point, reduction of days with moderate to severe headache. Six patients withdrew from the study before the second injections, but an intention-to-treat (ITT) analysis gave a similar result (p = 0.27). There were no significant differences favouring verum in any of the secondary efficacy measures. Side-effects of onabotulinum toxin A were minor and short-lasting. Conclusion: Onabotulinum toxin A in neck muscles does not seem to be beneficial in CeH.

Increased baroreflex sensitivity and heart rate variability in migraine patients

Objectives –  We investigated whether spontaneous baroreflex sensitivity and heart rate variability (HRV) are different in migraine patients compared to healthy controls.

Acetyl-l-carnitine versus placebo for migraine prophylaxis: A randomized, triple-blind, crossover study.

Background Preventive medication is indicated for many migraine patients, but is used in relatively few. The aim of the present study was to evaluate the efficacy of acetyl-l-carnitine as a prophylactic drug in migraine patients. Methods A single-center, randomized, triple-blind, placebo-controlled, crossover study was carried out. Men and women, age 18–65 years, with episodic migraine but otherwise healthy, were recruited mostly through advertisements. After a four-week run-in-phase, 72 participants were randomized to receive either placebo or 3 g acetyl-l-carnitine for 12 weeks. After a four-week washout, treatment was switched. The primary outcome was days with moderate or severe headache per four weeks. Secondary outcomes were days with headache, hours with headache, proportion of responders (>50% reduction in migraine days from baseline) and adverse events. Results In the complete case analyses, no statistically significant differences were found between acetyl-l-carnitine and placebo in severe or moderate headache days per month (3.0 versus 3.1, p = 0.80), headache days per month (5.1 versus 5.2, p = 0.73) or for the other secondary outcome measures. Conclusion In this triple-blind crossover study no differences were found in headache outcomes between acetyl-l-carnitine and placebo. Our results do not provide evidence of benefit for efficacy of acetyl-l-carnitine as prophylactic treatment for migraine. Trial registration: EUDRACT (2012-001624-36), ClinicalTrials.gov (NCT01695317).

Non-invasive cortical modulation of experimental pain in migraine.

OBJECTIVE To test the hypothesis that secondary somatosensory cortex (S2) is involved in the migraine pathogenesis, by exploring the effect of navigated repetitive transcranial magnetic stimulation (rTMS) to S2 on thermal perception and pain. METHODS In this blinded sham-controlled case-control study of 26 interictal migraineurs and 31 controls, we measured thermal detection and pain thresholds on the hand and forehead, and pain ratings to heat stimulation on the forearm and temple, after real and sham 10Hz rTMS. RESULTS rTMS increased cold and heat pain thresholds in controls as compared to interictal migraineurs (p<0.026). rTMS decreased forehead and arm pain ratings (p<0.005) and increased hand cool detection thresholds (p<0.005) in both interictal migraineurs and controls. CONCLUSIONS The effects of rTMS to S2 on thermal pain measures differed significantly between migraine and control subjects, although the effects were generally low in magnitude and not present in pain ratings. However, the lack of cold and heat pain threshold increase in migraineurs may reflect a hypofunction of inhibitory pain modulation mechanisms. SIGNIFICANCE The expected rTMS-induced cold and heat hypoalgesia was not found among migraineurs, possibly a reflection of reduced intracortical inhibition.