Period prevalence of self-reported headache in the general population in Germany from 1995-2005 and 2009: results from annual nationwide population-based cross-sectional surveys.

BACKGROUND: Although primary headache is the most frequent neurological disorder and there is some evidence that the prevalence rates have increased in recent years, no long-term data on the annual prevalence of headache are available for Germany. The objective of the study was therefore to obtain long-term data on the period prevalence of headache in the general population in Germany by means of population-based cross-sectional annual surveys (1995-2005 and 2009). METHODS: These surveys were conducted as face-to-face paper-and-pencil interviews from 1995 through 2004, and from 2005 onwards as computer-aided personal interviews. The reported headaches were self-diagnosed by the interviewees. Per year, approximately 640 trained interviewers interviewed between 10,898 and 12,538 German-speaking individuals aged 14 and older and living in private households in the whole of Germany (response rate: 67.4% and 73.1%, gross samples: 16,026 to 18,176 subjects). A total of more than 146,000 face-to-face interviews were analyzed. RESULTS: The one-year headache prevalence remained stable over the entry period, with 58.9% (95%CI 57.7-60.1) to 62.5% (95%CI 61.3-63.7) (p=0.07). Women showed consistently higher prevalence rates than men (females: 67.3 (95%CI 65.7-68.9) to 70.7% (95%CI 69.1-72.3), males: 48.4% (95%CI 46.5-50.3) to 54.3% (95%CI 52.4-56.2)), and both sexes showed a bell-shaped age dependence with peaks in the 30-39 age group. A stable slightly higher prevalence was observed in urban versus rural areas (p<0.0001), and there was also a significant trend towards higher prevalence rates in groups with a monthly household income larger than 3,500 € (p=0.03). CONCLUSION: The overall headache prevalence remained stable in Germany in the last 15 years.

Responsiveness of efficacy endpoints in clinical trials with over the counter analgesics for headache.

AIM: To quantify and compare the responsiveness within the meaning of clinical relevance of efficacy endpoints in a clinical trial with over the counter (OTC) analgesics for headache. Efficacy endpoints and observed differences in clinical trials need to be clinically meaningful and mirror the change in the clinical status of a patient. This must be demonstrated for the specific disease indication and the particular patient population based on the application of treatments with proven efficacy. METHODS: Patient's global efficacy assessment during two study phases (pre-phase and treatment phase) was used to classify patients as satisfied or non-satisfied with the efficacy of their medication. The analysis is based on 1734 patients included in the efficacy analysis of a randomized, placebo-controlled, double-blind, multi-centre parallel group trial with six treatment arms. Based on this classification and the pain intensity recorded by the patients on a 100 mm visual analogue scale, group differences by assessment categories and receiver operating characteristic (ROC) curve methods were used to quantify responsiveness of the efficacy endpoints 'time to 50% pain relief', 'time until reduction of pain intensity to 10 mm', 'weighted sum of pain intensity difference' (%SPIDweighted), 'pain intensity difference (PID) relative to baseline at 2 hours', and 'pain-free at 2 hours'. RESULTS: Clinically relevant differences between patients satisfied and non-satisfied with the treatment were observed for all efficacy endpoints. Patients with the highest rating of efficacy had the fastest and strongest pain relief. In comparison, patients assessing efficacy as 'less good' reached a 50% pain relief on average nearly an hour later than those scoring efficacy as at least 'good'. Simultaneously, their extent of pain relief was only half as great 2 hours after medication intake. Patients scoring efficacy as 'poor' experienced practically no pain relief within the 4 hour observation interval. ROC curve calculations confirmed an adequate responsiveness for all continuous endpoints. The following cut-off points for differentiating between satisfied and non-satisfied patients were deduced from the data in the pre- and treatment phase, respectively: 'time to 50% pain relief' 1:10 and 1:31 h:min, 'time until reduction of pain intensity to 10 mm' 2:40 and 3:00 h:min, '%SPIDweighted' 68 and 64%, 'PID at 2 hours' 35 and 35 mm. The sensitivity and specificity based on these cut-off points ranged from 70 to 79%. The binary endpoint 'pain-free at 2 hours' showed a clearly higher specificity (80 and 87%) than sensitivity (65 and 61%) in the pre- and treatment phase, respectively. CONCLUSIONS: When global assessment of efficacy by the patient was used as external criterion, ROC curve calculations confirmed a high responsiveness for all efficacy endpoints included in this study. Clinically relevant differences between patients satisfied and non-satisfied with the treatment were observed. The endpoint '%SPIDweighted' proved slightly but consistently superior to the other endpoints. SPID and %SPIDweighted are not easy to interpret and the time course of pain reduction is of high importance for the patients in the treatment of acute pain, including headache. The endpoint 'pain-free at 2 hours' showed the expected high specificity, but at the cost of a concurrently low sensitivity and clearly makes less use of the available information than the endpoint 'time to 50% pain reduction', which combines the highly relevant aspects of time course and extent of pain reduction. Responsiveness, the ability of an outcome measure to detect clinically important changes in a specific condition of a patient, should be added in future revisions of IHS guidelines for clinical trials in headache disorders.

Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

BACKGROUND: Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics. DISCUSSION: In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect.As an example the fixed-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy. SUMMARY: Multitarget therapeutics like combined analgesics broaden the array of therapeutic options, enable the completeness of the therapeutic effect, and allow doctors (and, in self-medication with OTC medications, the patients themselves) to customize treatment to the patient's specific needs. There is substantial clinical evidence that such a multi-component therapy is more effective than mono-component therapies.

OTC analgesics in headache treatment: open-label phase vs randomized double-blind phase of a large clinical trial.

OBJECTIVE: To compare the superior efficacy of the fixed combination of acetylsalicylic acid, paracetamol, and caffeine over the single substances, which was observed in the randomized, double-blind phase of the clinical trial, with the efficacy of the respective usual nonprescription medication taken by the patients in the open-label pre-phase of the same study. BACKGROUND: The "Thomapyrin Study" showed significant superiority of the fixed combination containing acetylsalicylic acid, paracetamol, and caffeine over the combination without caffeine, the single preparations, and placebo in the treatment of headache. METHODS: Prior to the randomized treatment phase, a headache episode treated with the patient's usual nonprescription medication was recorded (open-label pre-phase). Patients assessed their pain intensity on a 100-mm visual analog scale. For the 1734 patients included in the efficacy analysis, we compared the time course of the pain intensity difference (PID) to baseline after the patients took their usual medication with the time course of the PID after intake of the randomized study medication. RESULTS: Time course of PID after intake of the patient's usual medication was very similar to the time course of PID after intake of the randomized study medication. After 2 hours, pain reduction was on average 43.0, 38.2, 38.1, and 37.7 mm as assessed on the visual analog scale in the group of patients who took their usual triple combination containing acetylsalicylic acid, paracetamol, and caffeine, the single agents acetylsalicylic acid, paracetamol, and ibuprofen, respectively, in the open-label phase. The corresponding mean pain reduction was 44.7, 40.7, and 39.5 mm in patients allocated to the triple combination containing acetylsalicylic acid, paracetamol, and caffeine, the single agents acetylsalicylic acid, and paracetamol, respectively, in the randomized, double-blind phase.

Clinical relevance of efficacy endpoints in OTC headache trials.

OBJECTIVE: This analysis evaluates and ranks efficacy endpoints often used in headache trials concerning their clinical relevance in relation to the patient-related criterion "global assessment of overall efficacy" based on data gained in a large trial investigating different over-the-counter drugs in the treatment of headache. BACKGROUND: The original study showed a significant superiority of the fixed combination of acetylsalicylic acid+paracetamol+caffeine over the combination without caffeine, the single preparations, and placebo in the treatment of headache. METHODS: For 1734 patients included in the efficacy analysis we investigated the correlation of patient's global efficacy assessment with the endpoints "time to 50% pain relief" (primary endpoint), "time to be pain-free," pain intensity difference, sum of pain intensity difference, and extent of impairment of daily activities. Patients recorded pain intensity on a visual analog scale. Efficacy, tolerability, and extent of impairment of daily activity were assessed on verbal rating scales.A logistic regression, proportional odds model was adapted to the time to event data. RESULTS: The highest correlation with patient's global efficacy assessment was demonstrated for the primary endpoint time to 50% pain relief (r = 0.6727) and the sum of pain intensity difference (r = 0.7037). The frequency distribution of patient's global efficacy assessment depended primarily on the time to 50% pain relief and similarly, but to a somewhat lesser extent, on the reduction of pain intensity to 10 mm as assessed on the visual analog scale. More than 86% of the patients assessed efficacy as very good or good when their pain was reduced by 50% at least within 1 hour after drug intake. The patients accept a longer time span than 2 hours for reaching no pain to give a positive global evaluation of efficacy.

Modulation of catecholamine release from rat striatal slices by the fixed combination of aspirin, paracetamol and caffeine.

The fixed combination of aspirin, paracetamol (acetaminophen) and caffeine has been used successfully to treat different kinds of pain including migraine attacks. Even when this formulation has been marketed for a long time, the exact molecular mechanisms underlying its therapeutic effectiveness have not been completely elucidated. In the present investigation, we have studied the effects of the fixed combination of aspirin, paracetamol and caffeine (APC) on the release of dopamine and noradrenaline from rat striatal slices in an attempt to find potential new mechanisms of action of this widely used analgesic combination. We found that APC produced a significant reduction in extracellular dopamine and a dramatic increase in norepinephrine release from the slices incubated with different concentrations of APC (dose relationship 1:1:0.2, corresponding to the dose-relationship of Thomapyrin). These findings suggest that the modulation of catecholaminergic neurotransmission is a new pharmacological effect of APC which could explain the mechanism of action of this formulation, considering that the independent effect of either compound alone does not explain the potent antinociceptive properties when observed in combination.

Efficacy and tolerability of ambroxol hydrochloride lozenges in sore throat. Randomised, double-blind, placebo-controlled trials regarding the local anaesthetic properties.

UNLABELLED: Two confirmatory clinical trials were performed to investigate the efficacy and tolerability of ambroxol lozenges at doses of 20 mg and 30 mg relative to placebo in relieving the symptoms of sore throat of at least moderately severe intensity in patients suffering from oro-pharyngeal catarrh accompanied by pain on swallowing, feeling of scratchiness, burning and urge to cough. OBJECTIVE: Description and comparison of the efficacy and tolerability of lozenges containing 20 mg or 30 mg ambroxol hydrochloride (trans-4-[(2-amino-3,5-dibrom-benzyl)amino]cyclohexano hydrochloride, CAS 18683-91-5) in relieving acute sore throat, in comparison to placebo. DESIGN: Two similar, multi-centre, prospective, placebo-controlled, randomised, double-blind trials involving three days of treatment with up to 6 lozenges containing 20 or 30 mg ambroxol hydrochloride per day. SUBJECTS: There were enrolled three-hundred-thirty-one (331, study I) and three-hundred-eighty-three (383, study II) outpatients with acute uncomplicated sore throat of at least moderately severe intensity which is not suspected to be due to bacterial pharyngitis. TREATMENTS: Double-blind treatment with up to six lozenges per day containing either 20 mg or 30 mg ambroxol hydrochloride or placebo (a lozenge with a distinct minty flavour). MAIN OUTCOME MEASURES: The time-weighted average pain relief over the first 3 h after the first lozenge as a ratio of the baseline pain intensity of sore throat (SPIDnorm) and the patients' evaluation of efficacy and tolerability at the end of each day of the three days treatment. RESULTS: All treatments led to a reduction of pain intensity; the means (+/- SD) SPIDnorm after the 1st lozenge were 0.53 +/- 0.28 or 0.50 +/- 0.30 or 0.38 +/- 0.28 with 20 mg or 30 mg ambroxol hydrochloride or placebo respectively in study I, and 0.53 +/- 0.30 or 0.60 +/- 0.28 or 0.39 +/- 0.31 in study II; the effect of treatment was statistically significant (p: 0.0002 or p: 0.0033 in study I and p: 0.0005 or p: 0.0001 in study II, respectively, for the comparison of 20 mg or 30 mg ambroxol hydrochloride vs. placebo). The improvement with the active treatments was greater than with placebo (95% confidence interval (CI) estimates of the mean treatment differences vs. placebo were 0.08 to 0.23 or 0.05 to 0.20 for lozenges with 20 mg or 30 mg ambroxol hydrochloride, respectively, in study I, and 0.06 to 0.21 or 0.13 to 0.28 in study II). At the end of each subsequent ambulatory treatment day with up to six lozenges per day, a statistically significantly higher proportion of patients scored a higher level of efficacy for the active treatments with ambroxol hydrochloride compared to placebo. The treatments investigated were equally well tolerated. CONCLUSIONS: Sucking lozenges containing 20 mg or 30 mg ambroxol hydrochloride has a beneficial pain-relieving effect in patients with acute sore throat, superior to that achieved by sucking a placebo lozenge. While both strengths were equally well tolerated, the higher strength of 30 mg ambroxol hydrochloride did not prove more effective. The findings confirm that the previously discovered local anaesthetic properties of ambroxol hydrochloride do have beneficial clinical implications.

Local anaesthetic properties of ambroxol hydrochloride lozenges in view of sore throat. Clinical proof of concept.

UNLABELLED: Acute oro-pharyngeal catarrh is characterised by mild to severe sore throat, such as pain on swallowing, feeling of scratchiness, burning and urge to cough. The present study was conducted to explore whether the test compound is going to show clinical relevance and is a suitable medication for the relief of these symptoms. OBJECTIVE: Description and comparison of the efficacy and tolerability of lozenges containing 20 mg ambroxol hydrochloride (trans-4-[(2-amino-3,5-dibrombenzyl)amino]cyclohexano hydrochloride, CAS 18683-91-5) in relieving acute sore throat, in comparison to placebo. DESIGN: Multi-centre, prospective, placebo-controlled, randomised, double-blind trial involving two days of treatment with up to 6 lozenges containing 20 mg ambroxol hydrochloride per day. SUBJECTS: Two-hundred-eighteen (218) patients were enrolled (97 males, 121 females, average age: 39.4 +/- 15 years, range: 17-81 years); 215 were treated: 107 with 20 mg ambroxol and 108 with placebo; 26 discontinued prematurely (13 in each treatment group). 208 patients constituted the intent-to-treat (ITT) dataset (105 and 103 for treatment with ambroxol and placebo, respectively); 196 patients constituted the perprotocol (PP) dataset (97 and 99, respectively); all treated patients were part of the dataset for safety analysis. TREATMENTS: Double-blind treatment with up to 6 lozenges per day containing 20 mg ambroxol hydrochloride or placebo (a lozenge with a distinct minty flavour). MAIN OUTCOME MEASURES: The time-weighted average pain relief over the first 3 h after the first lozenge as a ratio of the baseline pain intensity of sore throat (SPIDnorm) and the patients' evaluation of efficacy and tolerability at the end of each day of treatment. RESULTS: Both treatments led to a reduction of pain intensity; the mean (+/- SD) SPIDnorm after the 1st lozenge were 0.39 +/- 0.27 and 0.28 +/- 0.25 for 20 mg ambroxol hydrochloride and placebo, respectively; the treatment effect of ambroxol was statistically significantly superior compared to placebo (p: 0.0029; 95% confidence interval estimate of the mean treatment difference for ambroxol minus placebo: 0.04 to 0.18). At the end of each subsequent ambulatory treatment day with up to 6 lozenges per day, a statistically significantly higher proportion of patients scored a higher level of efficacy for the active treatments with ambroxol hydrochloride compared to placebo. The investigational treatments were equally well tolerated. CONCLUSIONS: Sucking lozenges containing 20 mg ambroxol hydrochloride has a beneficial pain relieving effect in patients with acute sore throat, superior to that which otherwise can be achieved by sucking a placebo lozenge. This finding confirms that the preclinical local anaesthetic properties of ambroxol hydrochloride may have beneficial clinical implications.