Increased pain sensitivity is not a risk factor but a consequence of frequent headache: a population-based follow-up study

Altered pain sensitivity is believed to play an important role for chronification of headache. It has however mainly been evaluated in highly selected patients from headache clinics and never in longitudinal studies. The present study is a 12-year follow-up of a population-based study of primary headache disorders and pain perception, combining a diagnostic headache interview with examination of muscle tenderness and measurement of pressure pain thresholds in 1000 subjects drawn randomly from the general population in Denmark. The aim of the study was to explore the cause–effect relationship between the increased pain sensitivity and the development of headache. The pressure pain thresholds were normal at baseline but had decreased at follow-up in subjects who developed chronic tension-type headache over the 12-year period (p = 0.025). In subjects who developed frequent episodic tension-type headache the tenderness was normal at baseline but had increased at follow-up (p < 0.01) while the pain thresholds were normal both at baseline and at follow-up. The findings demonstrate that increased pain sensitivity is a consequence of frequent tension-type headache, not a risk factor, and support that central sensitization plays an important role for the chronification of tension-type headache.     

Changes in Clinical Parameters in Patients with Tension-type Headache Following Massage Therapy: A Pilot Study

Abstract

Complementary and alternative medicine approaches to treatment for tension-type headache are increasingly popular among patients, but evidence supporting its efficacy is limited. The objective of this study was to assess short term changes on primary and secondary headache pain measures in patients with tension-type headache (TTH) receiving a structured massage therapy program with a focus on myofascial trigger point therapy. Participants were enrolled in an open label trial using a baseline control with four 3-week phases: baseline, massage (two 3-week phases) and follow-up. Twice weekly, 45-minute massage sessions commenced following the baseline phase. A daily headache diary was maintained throughout the study in which participants recorded headache incidence, intensity, and duration. The Headache Disability Index was administered upon study entry and at 3-week intervals thereafter. 18 subjects were enrolled with 16 completing all headache diary, evaluation, and massage assignments. Study participants reported a median of 7.5 years with TTH. Headache frequency decreased from 4.7±0.7 episodes per week during baseline to 3.7±0.9 during treatment period 2 (P<0.001); reduction was also noted during the follow-up phase (3.2±1.0). Secondary measures of headache also decreased across the study phases with headache intensity decreasing by 30% (P<0.01) and headache duration from 4.0±1.3 to 2.8±0.5 hours (P<0.05). A corresponding improvement in Headache Disability Index was found with massage (P<0.001). This pilot study provides preliminary evidence for reduction in headache pain and disability with massage therapy that targets myofascial trigger points, suggesting the need for more rigorously controlled studies.     

Changes in Clinical Parameters in Patients with Tension-type Headache Following Massage Therapy: A Pilot Study

Complementary and alternative medicine approaches to treatment for tension-type headache are increasingly popular among patients, but evidence supporting its efficacy is limited. The objective of this study was to assess short term changes on primary and secondary headache pain measures in patients with tension-type headache (TTH) receiving a structured massage therapy program with a focus on myofascial trigger point therapy. Participants were enrolled in an open label trial using a baseline control with four 3-week phases: baseline, massage (two 3-week phases) and follow-up. Twice weekly, 45-minute massage sessions commenced following the baseline phase. A daily headache diary was maintained throughout the study in which participants recorded headache incidence, intensity, and duration. The Headache Disability Index was administered upon study entry and at 3-week intervals thereafter. 18 subjects were enrolled with 16 completing all headache diary, evaluation, and massage assignments. Study participants reported a median of 7.5 years with TTH. Headache frequency decreased from 4.7±0.7 episodes per week during baseline to 3.7±0.9 during treatment period 2 (P<0.001); reduction was also noted during the follow-up phase (3.2±1.0). Secondary measures of headache also decreased across the study phases with headache intensity decreasing by 30% (P<0.01) and headache duration from 4.0±1.3 to 2.8±0.5 hours (P<0.05). A corresponding improvement in Headache Disability Index was found with massage (P<0.001). This pilot study provides preliminary evidence for reduction in headache pain and disability with massage therapy that targets myofascial trigger points, suggesting the need for more rigorously controlled studies.     

Tolerability and safety profile of 12- to 28-week treatment with interferon beta-1b 250 and 500 microg QOD in patients with relapsing-remitting multiple sclerosis: a multicenter, randomized, double-blind, parallel-group pilot study

BACKGROUND: It is not known whether the currently available treatment regimen of interferon beta-1b (IFNbeta-1b) 250 microg provides the maximum benefit possible in the treatment of relapsing-remitting multiple sclerosis (RRMS), or whether higher doses of IFNbeta-1b will prove to be more beneficial. OBJECTIVE: The objective of the present study was to evaluate the tolerability and safety profile of IFNbeta-1b 500 microg compared with the currently approved 250-microg dose. METHODS: A multicenter, randomized, double-blind, parallel-group pilot study was carried out to compare IFNbeta-1b 250 microg with IFNbeta-1b 500 microg, both self-administered SC QOD for >or=12 weeks in patients with RRMS. Patients in both groups started with 25% (0.25 mL) of their final dose and were scheduled to increase the dose by 0.25 mL every 2 weeks, so that the full dose (1.0 mL, 250 microg or 500 microg) would be reached by week 7. The primary outcome measure was the percentage of patients experiencing each of the following adverse events (AEs): influenza-like symptoms (general term used to code the presence of >1 symptom typical of influenza), fever, myalgia, asthenia, headache, injection-site reactions, injection-site pain, or liver or hematologic abnormalities. All patients underwent a priori magnetic resonance imaging (MRI) with 0.1 mmol/kg gadolinium (Gd)-diethylenetriaminepentaacetic acid as contrast medium at screening and at week 12. MRI evaluation was included as a safety measure to monitor for excessive new disease not visible through clinical symptoms. RESULTS: Seventy-seven patients were assessed for inclusion in the study. Of these, 6 patients were screening failures and the remaining 71 were randomized to treatment (38-250 and 33-500 microg IFNbeta-1b). The uneven numbers in the groups were a consequence of the randomization process. Two patients in the 250-microg group (withdrawal of consent) and 1 in the 500-microg group (not completing follow-up visit) prematurely discontinued medication. The demographic characteristics were not significantly different between the 250-microg (n=38; mean [SD] age, 37.9 [8.3] years; weight, 83.5 [19.0] kg; height, 168.4 [9.3] cm) and 500-microg (n=33; mean [SD] age, 37.8 [7.7] years; weight, 82.3 [19.5] kg; height, 169.9 [10.5] cm) treatment groups. The patients in both groups were mostly white (87% and 73%, respectively). Baseline Expanded Disability Status Scale scores also were not significantly different between the 2 groups (mean [SD] score, 2.8 [1.4] vs 2.0 [1.4], respectively). In the IFN(2)-1b 250-microg group, 97% of the patients titrated to the full dose at some point during the course of the study, compared with 91% of the 500-microg group (P=NS). A dose-response effect was observed in some of the more frequent AEs (no. [%]) that included influenza-like syndrome (250-microg group, 13 [34] vs 500-microg group, 16 [48]), asthenia (13 [34] vs 16 [48], respectively), headache (12 [32] vs 12 [36]), myalgia (10 [26] vs 13 [39]), hypesthesia (10 [26] vs 11 [33]), nausea (6 [16] vs 8 [24]), paresthesia (6 [16] vs 8 [24]), myasthenia (4 [11] vs 8 [24]), chills (3 [8] vs 6 [18]), depression (3 [8] vs 5 [15]), back pain (2 [5] vs 5 [15]), increased liver enzymes (4 [11] vs 6 [18]), lymphopenia (4 [11] vs 3 [9]), fever (2 [5] vs 4 [12]), and pain in extremities (1 [3] vs 4 [12]). The between-group incidence of injection-site reactions was not significantly different. No new or unexpected AEs were recorded. Changes in MRI parameters between screening and 12 weeks were not significantly different between dose groups; these included median T2 lesion volume, median Gd-enhanced lesion volume, median Gd-enhanced lesion number, and mean number of newly active lesions. CONCLUSIONS: IFNbeta-1b 500 microg administered SC QOD was generally well tolerated in these patients with RRMS. Large, randomized controlled studies are needed to determine if there are significant differences in MRI end points between the 250- and 500-microg doses.     

Changes in Psychological Parameters in Patients with Tension-type Headache Following Massage Therapy: A Pilot Study

Abstract

Investigations into complementary and alternative medicine (CAM) approaches to address stress, depression, and anxiety of those experiencing chronic pain are rare. The objective of this pilot study was to assess the value of a structured massage therapy program, with a focus on myofascial trigger points, on psychological measures associated with tension-type headache. Participants were enrolled in an open-label trial using a baseline control with four 3-week phases: baseline, massage (two 3-week periods) and a follow-up phase. Eighteen subjects with episodic or chronic tension-type headache were enrolled and evaluated at 3-week intervals using the State-Trait Anxiety Inventory, Beck Depression Inventory, and the Perceived Stress Scale. The Daily Stress Inventory was administered over 7-day periods during baseline and the final week of massage. Twice weekly, 45-minute massage therapy sessions commenced following the baseline phase and continued for 6 weeks. A significant improvement in all psychological measures was detected over the timeframe of the study. Post hoc evaluation indicated improvement over baseline for depression and trait anxiety following 6 weeks of massage, but not 3 weeks. A reduction in the number of events deemed stressful as well as their respective impact was detected. This pilot study provides evidence for reduction of affective distress in a chronic pain population, suggesting the need for more rigorously controlled studies using massage therapy to address psychological measures associated with TTH.     

Relationship between chronic tension-type headache, cranial hemodynamics, and cerebrospinal pressure: study involving provocation with sumatriptan

OBJECTIVE: To study the relationship between chronic tension-type headache, cranial hemodynamics, and cerebrospinal pressure. BACKGROUND: Cerebrospinal pressure has been found to be above 200 mm in about 50% of patients with chronic tension-type headache. METHODS: Heart rate, blood pressure, common carotid artery diameter and blood flow, and craniovascular resistance and pain at regular intervals before, during, and after head-down tilt-a procedure which increases cerebrospinal pressure, were recorded. After head-down tilt, subcutaneous injections of either placebo or 6 mg of sumatriptan were administered. Chronic tension-type headache intensity before and after withdrawal of 20 mL of cerebrospinal fluid was documented. Cerebrospinal pressure and chronic tension-type headache intensity were measured after subcutaneous injection of 6 mg of sumatriptan. RESULTS: Head-down tilt provoked an increase of headache compared with baseline. Common carotid artery blood flow decreased and craniovascular resistance increased after sumatriptan injection, but not after placebo injection. The pain decreased after head-down tilt and placebo injection, but not after sumatriptan injection. Chronic tension-type headache intensity decreased in all 4 patients studied after withdrawal of 20 mL of cerebrospinal fluid. Cerebrospinal pressure increased in 5 patients with chronic tension-type headache after subcutaneous injection of 6 mg of sumatriptan with slight or no increase of pain. CONCLUSION: The results indicated that cerebrospinal pressure or intracranial venous pressure (or both) are related to chronic tension-type headache.     

Chronic Tension-Type Headache, Mood Depression and Serotonin: Therapeutic Effects of Fluvoxamine and Mianserine

SYNOPSIS
Forty out-patients affected by chronic tension-type headache were selected according to the diagnostic criteria of International Headache Society (IHS) Headache Classification Committee. In a controlled trial patients received placebo for a four-week baseline period, then they were randomized in double-blind fashion to therapy with mianserine (30-60 mg/day) or fluvoxamine (50-100 mg/day) for another eight-week period. Frequency of headache, pain severity and analgesic consumption were evaluated using a self-monitoring system. Mood depression was evaluated at 0, 4 and 8 weeks by using Zung'ss Self-Rating Depression Scale and Hamilton Rating Scale for Depression. Both drugs were beneficial in the treatment of chronic tension-type headache. Non-depressed subjects with more severe headache responded best to fluvoxamine, whereas mianserine was more effective in the treatment of depressed patients with moderate headache. These results suggest that central serotoninergic neurotransmission can play a role in the pathophysiology of chronic tension-type headache also in non-depressed patients.     

Specificity and Sensitivity of Temporalis ES2 Measurements in the Diagnosis of Chronic Primary Headaches

We have evaluated the specificity and sensitivity of temporalis ES2 measurements for the diagnosis of primary headaches. Ninety-four outpatients diagnosed according to IHS criteria were prospectively included: 25 had chronic tension-type headache (code 2.2.), 15 episodic tension-type headache (code 2.1.), 20 migraine without aura (code 1.1.) and 34 chronic daily headaches with daily analgesics/ergotamine abuse (code 8.2.). In chronic tension-type, the sensitivity of the ES2 test was 84% at the 0.1 and the 0.5 Hz, but only 56% at the 2Hz stimulation rates. Its specificity was 100% at 0.1Hz, 90% at 0.5Hz and 95% at 2Hz compared to migraine; positive predictive values were at similar levels. Sensitivity of ES2 at 0.1 Hz was 67% in episodic tension-type headache, but its positive predictive value versus migraine was excellent. Comparing chronic tension-type headache and analgesic abusers, the specificity and positive predictive value of the ES2 test for diagnosing chronic tension-type headache were less satisfactory (60%) while the negative predictive values, however, remained good (83% at 0.1Hz).
The results confirm that the temporalis ES2 test has a higher diagnostic sensitivity in chronic and episodic tension-type headache, but that it has a high negative predictive value for both types of tension-type headache compared to other primary headaches. For diagnostic purposes, the 0.1Hz stimulation rate seems optimal. The 2Hz stimulation rate is the least sensitive, although it may induce total disappearance of ES2 in up to 40% of patients. ES2 is of limited usefulness for separating chronic tension-type headache and chronic drug-abuse headache, possibly because the latter group comprises both tension-type headache and migraine patients.     

Traditional Chinese acupuncture in tension-type headache: a controlled study.

Thirty patients with tension-type headache were randomly chosen to undergo a trial of traditional Chinese acupuncture and sham acupuncture. Five measures were used to assess symptom severity and treatment response: intensity, duration and frequency of headache pain episodes, headache index and analgesic intake. The five measures were assessed during a 4 week baseline period, after 4 and 8 weeks of treatment, and 1, 6 and 12 months thereafter. Before the start of the study, each patient was administered the MMPI. Split-plot ANOVAs showed that, compared to baseline, at 1 month after the end of treatment and for the 12 month follow-up, the frequency of headache episodes, analgesic consumption and the headache index (but not the duration or intensity of headache episodes) significantly decreased over time; however, no difference between acupuncture and placebo treatment was found. No single MMPI scale predicted the response to treatment, but the mean MMPI profile of acupuncture non-responders showed the presence of 'Conversion V'.     

Efficacy of physiotherapy including a craniocervical training programme for tension-type headache; a randomized clinical trial

We conducted a multicentre, randomized controlled trial with blinded outcome assessment. The treatment period was 6 weeks with follow-up assessment immediately thereafter and after 6 months. The objective was to determine the effectiveness of a craniocervical training programme combined with physiotherapy for tension-type headache. Eighty-one participants meeting the diagnostic criteria for tension-type headache were randomly assigned to an exercise group (physiotherapy and an additional craniocervical training programme) and a control group (physiotherapy alone). The primary outcome measure was headache frequency. Secondary outcomes included headache intensity and duration, Quality of Life (SF-36) and the Multidimensional Headache Locus of Control scale (MHLC). At 6 months' follow-up, the craniocervical training group showed significantly reduced headache frequency, intensity and duration (P < 0.001 for all). Effect sizes were large and clinically relevant. Loss to follow-up amounted to 3.7%. Physiotherapy including craniocervical training reduces symptoms of tension-type headache significantly over a prolonged time frame.     

A pilot methodological validation study for a population-based survey of the prevalences of migraine,tension-type headache and chronic daily headache in the country of Georgia

Abstract We report the methodology of an epidemiological survey of the prevalences of migraine, tension-type headache and chronic daily headache in Georgia. Medical residents visited adjacent households in Tbilisi to interview a pre-defined target of 100 biologically unrelated subjects. All respondents reporting headache in the previous year, as well as random 20 non-headache controls, were examined by a neurologist. The response rate was 70%. Of 156 respondents, 93 were biologically unrelated and 45 (48%) reported headache in the previous year. Eight subjects fulfilled all IHS criteria for migraine (1-year prevalence 8.6% [95% CI: 2.9–14.3%]), and 13 had probable migraine, meeting all but the criterion for duration. Nineteen had tension-type headache (20.4% [95% CI: 12.2–28.6%]) and five had chronic daily headache (5.4% [95% CI: 1–10.0%]). In comparisons of diagnoses by questionnaire and neurologist (considered the gold standard), sensitivities for the questionnaire of 89% for migraine and 67% for tension-type headache were calculated (overall kappa=0.74).     

Ketoprofen, paracetamol and placebo in the treatment of episodic tension-type headache

The aim of the study was to assess the efficacy and tolerability of a single oral dose of ketoprofen 25 mg in comparison with single doses of ketoprofen 2 × 25 mg, paracetamol 500 mg and 1,000 mg, and placebo in the treatment of episodic tension-type headache. The study was conducted as a single centre, double-blind, randomized, placebo-controlled, five-period, within-patient comparative trial in outpatients with episodic tension-type headache according; to the International Headache Society's diagnostic criteria. Each patient had to treat five attacks of episodic tension-type headache with a single dose of each of the tested medications with a minimum interval o 72 h between two attacks. Details of the attack and response to treatment were recorded on a diary card Altogether 30 patients treated 5 attacks and 2, 3, 1 and 4 patients treated 4, 3, 2 and 1 attack, respectively, The primary variable was decrease in headache pain intensity from baseline to 2 h after intake, evaluated by means of a 100 mm visual analogue scale. Ketoprofen 50 mg was significantly better than placebo an paracetamol for this main criterion. Neither of the paracetamol groups differed from the placebo group, Only a few adverse events were reported, usually of mild or moderate severity, with no difference between the treatments. Ketoprofen 50 mg may be considered an effective and well tolerated analgesic in the treatment of episodic tension-type headache of moderate or severe intensity.     

The natural history of headache: predictors of onset and recovery

The objective of this study was to determine predictors of onset of new headache episodes and recovery from headache over one year. A population-based cohort study was conducted, comprising a baseline postal survey to a random sample of adults aged>or=18 years, with follow-up survey after 1 year. Risk factor data at baseline were compared with headache status at follow-up in two groups: (i) those free of recent headache at baseline and (ii) those with a recent headache at baseline. In respondents free of recent headache at baseline, previous headache [risk ratio (RR) 4.15], the presence of other pain at baseline (RR 1.43), severe sleep problems (RR 1.67) and drinking caffeine (RR 1.99) increased the risk of a new headache episode during the follow-up year. In respondents with recent headache at baseline, less severe headaches at baseline predicted recovery during the follow-up year, as did the absence of anxiety [recovery ratio (ReR) 2.84] and of sleep problems (ReR 2.77). Risks for increased headache-related disability reflected those for onset of a new episode and these risks increased in strength for large increases in disability. Sleep problems and caffeine consumption increase the risk of developing headache and thus provide targets for prevention. Low levels of anxiety, sleep problems and the absence of other pain improve the likelihood of recovering and remaining free from headache.     

Acupuncture for Tension-Type Headache: A Meta-Analysis of Randomized,Controlled Trials

We investigated the efficacy and safety of acupuncture for the treatment of tension-type headache by conducting a systematic review and meta-analysis of randomized, controlled trials. The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, and PsycINFO were searched from inception through August 2007. No search or language restrictions were applied. Eight randomized, controlled trials met our inclusion criteria. Pooled data from 5 studies were used for the meta-analysis. Our primary outcome was headache days per month. We assessed data from 2 time points: During treatment and at long-term follow-up (20–25 weeks). The weighted mean difference (WMD) between acupuncture and sham groups was used to determine effect size, and a validated scale was used to assess the methodological quality of included studies. During treatment, the acupuncture group averaged 8.95 headache days per month compared with 10.5 in the sham group (WMD, −2.93 [95% CI, −7.49 to 1.64]; 5 trials). At long-term follow-up, the acupuncture group reported an average of 8.21 headache days per month compared with 9.54 in the sham group (WMD, −1.83[95% CI, −3.01 to −0.64]; 4 trials). The most common adverse events reported were bruising, headache exacerbation, and dizziness.PerspectiveThis meta-analysis suggests that acupuncture compared with sham for tension-type headache has limited efficacy for the reduction of headache frequency. There exists a lack of standardization of acupuncture point selection and treatment course among randomized, controlled trials. More research is needed to investigate the treatment of specific tension-type headache subtypes.     

Frequency of headache is related to sensitization: a population study

Central sensitization is thought to play an important role in the chronification of tension-type headache and in the maintenance and exacerbation of the migraine attack. It has, however, almost exclusively been studied in highly selected patients from headache clinics. The aim of the present study was to evaluate pain perception in primary headaches in the general population. Stimulus-response functions for pressure versus pain, tenderness and pressure pain thresholds were studied in a random sample of 523 adults from the general population. All results were controlled for the effects of age and gender. The area under the stimulus-response function was increased in chronic- and frequent episodic tension-type headache compared with subjects without headache (p<0.001, p<0.001) and in chronic tension-type headache compared with migraine (p=0.01). Increasing slope (p<0.0001) and displacement towards lower pressures was found in the following order: no headache, migraine, frequent episodic tension-type headache, chronic tension-type headache. The displacement of the stimulus-response function was closely associated with frequency of headache. Finally, the stimulus-response function tended to be qualitatively altered in patients with frequent headache. The findings demonstrate, for the first time in a population-based study, a close relation between altered pain perception and chronification of headache, which most likely can be explained by central sensitization.     

Effect of acupuncture-like electrical stimulation on chronic tension-type headache: a randomized, double-blinded, placebo-controlled trial

OBJECTIVE: The aim of this study was to examine the effect of acupuncture-like electrical stimulation on chronic tension-type headache (TTH) in a randomized, double-blinded, placebo-controlled study. METHODS: Thirty-six patients (18 men, 18 women) with chronic TTH in accordance with the criteria of International Headache Society were investigated. The patients were randomly assigned into 2 groups: a treatment group and a placebo group. Pain duration, pain intensity on a 0 to 10 cm visual analog scale, number of headache attacks, and use of medication were recorded in a diary for 2 weeks before treatment (baseline), early stage of treatment (Treat-1; 2 wk), late stage of treatment (Treat-2; 4 wk), and after the end of treatment (Post-1, Post-2, Post-3 corresponding to 2, 4, and 6-wk follow-up). The patients also provided an overall evaluation of the treatment effect at each stage. Patients were taught how to use either an acupuncture-like electrical stimulator or a sham stimulator (identical but incapable of delivering an electric current) and then instructed to use the device at home. Six acupoints, bilateral EX-HN5, GB 20, LI 4, were selected to be stimulated 3 minutes for each point, twice a day. Friedman repeated measure analysis of variance on rank was used to test the data. RESULTS: The pain duration was shortened at Treat-1 and pain intensity was decreased at Treat-1 and Treat-2 compared with baseline. The overall evaluation of the 2 treatments indicated improvements in both the treatment and the placebo groups, but with no significant difference between the groups (P>0.061). Despite the apparent improvement in both the treatment and placebo groups, a decrease in analgesic use was only observed in the treatment group. There was also a significant positive correlation between the reported intensity of the stimulus-evoked sensation and the evaluation of the effect of either active or placebo treatments (P=0.039). CONCLUSIONS: The use of acupuncture-like electrical stimulation was not associated with significant adverse effects. These results indicate that acupuncture-like electrical stimulation is a safe and potentially analgesic-sparing therapy that may be considered as an adjunctive treatment for patients with chronic TTH although the clinical effect on pain seems to be marginal in the present set-up.     

Assessment of comparative pain relief and tolerability of SKI306X compared with celecoxib in patients with rheumatoid arthritis: a 6-week, multicenter, randomized, double-blind, double-dummy, phase III, noninferiority clinical trial

BACKGROUND: SKI306X, which consists of biologically active ingredients from Clematis mandsburica, Tricbosantbes kirilowii, and Prunella vulgaris, was developed and tested in preclinical trials in Korea. Those studies found that SKI306X was associated with an anti-inflammatory and analgesic effect, and that it can delay the destruction of cartilage in rheumatoid arthritis (RA). OBJECTIVE: The aim of this study was to compare the pain relief and tolerability of SKI306X and celecoxib in patients with RA. METHODS: This study was a 6-week, multicenter, randomized, double-blind, double-dummy, Phase III, noninferiority clinical trial. Eligible patients were aged 18 to 80 years, had a history of RA with a disease duration of > or =3 months, and were functional American College of Rheumatology (ACR) class I, II, or III before entry. After a washout period of 2 weeks, patients were randomized to SKI306X 200 mg TID or celecoxib 200 mg BID for 6 weeks. The primary end point was a change in patient assessment of pain intensity using a visual analog scale (VAS). The secondary end points were a 20% improvement in response rate as defined by the ACR (ACR20) and the frequency of rescue medication use. Results after 3 and 6 weeks of treatment were compared with baseline and between treatment groups, and all patients were assessed for adverse events (AEs), clinical laboratory data, and vital signs. AEs were identified based on spontaneous reports by patients during interviews conducted by the investigators and the study coordinator. RESULTS: Two hundred twenty-two Korean patients from 7 medical centers were assessed and 183 were enrolled and randomized to 1 of 2 treatment groups. Ninety-one patients (10 male, 81 female; mean [SD] age, 52.13 [12.64] years; mean [SD] duration of RA, 9.08 [10.23] years; no. [%] of ACR class I, II, and III, 13 [14.29], 44 [48.35] and 34 [37.36] patients, respectively) received SKI306X 200 mg TID and 92 patients (10 male, 82 female; mean [SD] age, 51.78 [10.94] years; mean [SD] duration of RA, 8.78 [7.78] years; no. [%] of ACR class I, II, and III, 14 [15.22], 44 [47.83], and 34 [36.96] patients, respectively) received celecoxib 200 mg BID. An analysis of the change in reported pain intensity as determined by VAS (mm) score between baseline and week 3 (mean [SD], 13.64 [16.62] vs 14.45 [15.89]), and between baseline and week 6 (18.4 [20.8] vs 17.9 [19.1], respectively) suggested that SKI306X was not inferior to celecoxib. The number of patients who achieved ACR20 response rate was not significantly different between the SKI306X group and the celecoxib group at week 3 (16/87 [18.4%] vs 24/87 [27.6%], respectively) and at week 6 (29/87 [33.3%] vs 29/87 [33.3%]). The frequency of rescue medication use was not significantly different between the SKI306X group and celecoxib group at week 3 (54/87 [62.1%] vs 47/87 [54.0%], respectively) or week 6 (57/87 [65.5%] vs 49/87 [56.3%]). Drug-related AEs were reported by 27 (29.7%) patients in the SKI306X group and 22 (23.9%) patients in the celecoxib group. The most frequent drug-related AEs were epigastric pain (9/91 [9.9%]) in the SKI306X group and glutamyltranferase elevation (4/92 [4.3%]) in the celecoxib group. No significant between-group differences were observed in the prevalence of drug-related clinical- or laboratory-determined AEs. CONCLUSION: The results of this study suggest that SKI306X was generally well tolerated and not inferior to celecoxib in regard to pain relief in these Korean patients with RA.     

Chronic daily headache prophylaxis with tizanidine: a double-blind,placebo-controlled,multicenter outcome study

OBJECTIVE: To assess the efficacy of tizanidine hydrochloride versus placebo as adjunctive prophylactic therapy for chronic daily headache (chronic migraine, migrainous headache, or tension-type headache). BACKGROUND: Tizanidine is an alpha2-adrenergic agonist that inhibits the release of norepinephrine at both the spinal cord and brain, with antinociceptive effects that are independent of the endogenous opioid system. Previous open-label studies have suggested the drug may be effective for treatment of chronic daily headache. METHODS: Two hundred patients completed a 4-week, single-blind, placebo baseline period, with 134 fulfilling selection criteria and then randomized to tizanidine or placebo. Ninety-two patients completed at least 8 weeks of treatment (tizanidine, n = 45; placebo, n = 47), and 85 patients completed 12 weeks of treatment (tizanidine, n = 44; placebo, n = 41). Most patients (77%) met the diagnostic criteria for migraine of the International Headache Society; 23% had either chronic migrainous headache or chronic tension-type headache. Tizanidine was slowly titrated over 4 weeks to 24 mg or the maximum dose tolerated (mean, 18 mg; SD, 6.4; median, 20.0; range, 2 to 24), divided equally over three dose intervals per day. Overall headache index ([headache days x average intensity x duration in hours]/28 days) was the primary end point. RESULTS: Tizanidine was shown to be superior to placebo in reducing the overall headache index (P =.0025), as well as mean headache days per week (P =.0193), severe headache days per week (P =.0211), average headache intensity (P =.0108), peak headache intensity (P =.0020), and mean headache duration (P =.0127). The mean percentage improvement during the last 4 weeks of treatment with tizanidine versus placebo was 54% versus 19% for the headache index (P =.0144), 55% versus 21% for severe headache days (P =.0331), 35% versus 19% for headache duration (P =.0142), 35% versus 20% for peak headache intensity (P =.0106), 33% versus 20% for average headache intensity (P =.0281), and 30% versus 22% for total headache days (P =.0593). Patients receiving tizanidine also scored higher ratings of overall headache improvement on a visual analog scale (P =.0069). There was no statistically significant difference in outcome for patients with chronic migraine versus those with only migrainous or tension-type headache. Adverse effects reported by more than 10% of the patients included somnolence (47%), dizziness (24%), dry mouth (23%), and asthenia (19%). Dropouts due to adverse events did not differ significantly between tizanidine and placebo. CONCLUSIONS: The results support tizanidine as an effective prophylactic adjunct for chronic daily headache, including migraine, migrainous headache, and tension-type headache. These results also suggest the possible importance of an alpha2-adrenergic mechanism underlying the pathophysiology of this spectrum of headache disorders.     

Blood pool scintigraphy of the skull in relation to head-down tilt provocation in patients with chronic tension-type headache and controls

OBJECTIVE: To investigate the mechanisms behind the increase of chronic tension-type headache during head-down tilt. BACKGROUND: The pathophysiology of chronic tension-type headache is unknown. DESIGN AND METHODS: Ten patients suffering from chronic tension-type headache and 10 age- and sex-matched controls were studied with respect to pain intensity and alterations in cranial blood volume using planar scintigraphy and radiolabeled autologous erythrocytes before, during, and after head-down tilt, a procedure known to increase chronic tension-type headache. RESULTS: Four of 8 patients with chronic tension-type headache studied had increased cerebrospinal fluid pressure. During head-down tilt, the pain increased significantly in the group with chronic tension-type headache (P <.001) while the procedure did not cause headache in the controls. Blood volume significantly increased extracranially and decreased intracranially in both groups during head-down tilt. The extracranial nasal blood volume was significantly related to the pain experienced by the patients with chronic tension-type headache before and during head-down tilt. CONCLUSIONS: Although the changes in blood volume and, presumably, the increase of intracranial pressure were similar in the patients with chronic tension-type headache and the controls, only the patients experienced pain and pain increase during head-down tilt. This indicates that the pre-head-down tilt conditions must be different in the 2 groups and should be related to increased cerebrospinal fluid pressure/intracranial venous pressure in patients with chronic tension-type headache compared with controls. A difference in central mechanisms may, however, also be of importance for the difference in headache provocation in the 2 groups during head-down tilt.     

Treating chronic tension-type headache not responding to amitriptyline hydrochloride with paroxetine hydrochloride: a pilot evaluation

CONTEXT: In some individuals, chronic tension-type headache fails to respond to tricyclic antidepressant medications that often serve as first-line therapy. OBJECTIVE: To evaluate the clinical efficacy of paroxetine hydrochloride for chronic tension-type headache not responding to amitriptyline hydrochloride. DESIGN AND SETTING: Open-label trial of paroxetine conducted at 2 outpatient sites in Ohio. PARTICIPANTS AND INTERVENTION: Thirty-one adults (mean age, 37 years; 20 women) with chronic tension-type headache (mean, 25 headache days per month) who had failed to respond (less than 30% improvement) to treatment with either amitriptyline (n = 13) or matched placebo (n = 18). All participants were treated with paroxetine (up to 40 mg per day) in a 9-month protocol. OUTCOME MEASURES: Monthly headache index calculated as the mean of pain ratings (0 to 10 scale) recorded by participants in a diary 4 times per day, number of days per month with at least moderate pain (pain rating of 5 or greater), and analgesic medication use. RESULTS: In patients who had not responded to amitriptyline, paroxetine failed to reduce chronic tension-type headaches or analgesic medication use. In patients who had not responded to placebo, paroxetine produced modest reductions in chronic tension-type headaches and analgesic use. CONCLUSIONS: We found no evidence that chronic tension-type headaches that failed to respond to tricyclic antidepressant therapy with amitriptyline improved when subsequently treated with paroxetine. More support was found for the efficacy of paroxetine in patients with chronic tension-type headaches who had failed to respond to placebo.