Bernhard Aicher

The Fixed Combination of Acetylsalicylic acid, Paracetamol and Caffeine is more Effective than Single Substances and Dual Combination for the Treatment of Headache: a Multicentre, Randomized, Double-Blind, Single-Dose, Placebo-Controlled Parallel Group Study

We investigated efficacy, safety, and tolerability of two tablets of the fixed combination of 250 mg acetylsalicylic acid (ASA) + 200 mg paracetamol + 50 mg caffeine (Thomapyrin®) in comparison with two tablets of 250 mg ASA + 200 mg paracetamol, two tablets of 500 mg ASA, two tablets of 500 mg paracetamol, two tablets of 50 mg caffeine, and placebo in patients who were used to treating their episodic tension-type headache or migraine attacks with non-prescription analgesics. For the primary endpoint ‘time to 50% pain relief’ in the intention-to-treat dataset (n = 1743 patients), the fixed combination of ASA, paracetamol and caffeine was statistically significantly superior to the combination without caffeine (P = 0.0181), the mono-substances ASA (P = 0.0398), paracetamol (P = 0.0016), caffeine (P < 0.0001) and placebo (P < 0.0001). All active treatments except caffeine differed significantly (P < 0.0001) from placebo. The superior efficacy of the triple combination could also be shown for all secondary endpoints such as time until reduction of pain intensity to 10 mm, weighted sum of pain intensity difference (%SPIDweighted), extent of impairment of daily activities, global assessment of efficacy. All treatments were well tolerated. The incidence of adverse events observed was low.

Pain measurement: Visual Analogue Scale (VAS) and Verbal Rating Scale (VRS) in clinical trials with OTC analgesics in headache

Aim: The aim was to assess the performance of the Visual Analogue Scale (VAS) in patients recruited in a clinical trial with over the counter analgesics in headache. Methods: The Thomapyrin Study showed the 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. Patients enrolled into the study were trained in the handling of the VAS by naming categories of a 6-point Verbal Rating Scale (VRS). These data were used to evaluate the level of order consistency between the VAS and VRS, to deduce cut-off points for rescaling the continuous VAS into a discrete ordinal scale using the receiver operating characteristic methodology, and to assess the test-retest performance. Results: Approximately 75% of the patients recorded the pain intensity on the VAS in the same order as given on the VRS. However, in 12.6% of patients, the German terms ‘leicht’ (mild) and ‘mäßig’ (moderate) were mixed up regarding their order on the VAS. Substantial overlapping of the frequency distributions of the VAS assessment were found for the VRS categories mild and moderate pain as well as severe and very severe pain. Grouping of the VAS assessments into a discrete ordinal scale necessitated a non-equidistant rescaling based on the categories of the VRS. By means of analysis of the receiver operating characteristic curves, the following cut-off points were determined on a 100 mm VAS: no pain 0–2 mm, mild pain 2–17 mm, moderate pain 17–47 mm, severe pain 47–77 mm, very severe pain 77–96 mm, most severe pain imaginable 96–100 mm. Repeated assessment up to several months after the first assessment demonstrated a test-retest agreement on the VAS in 61.0–91.4% of the patients, depending on the VRS category. Conclusions: This study shows that the VRS categories cannot be presented in an equidistant manner on the VAS, and that contrary to previous assumptions, the pain intensity descriptors are less clear and can have different meanings in different languages. Therefore, both in the 3rd edition of the International Headache Classification (ICHD-III) and in the guidelines for clinical trials of patients with headache illnesses, rather than a 4-grade VRS, a 6-grade or higher level VRS or a VAS should be recommended, with correspondingly broadly defined anchor points.

The efficacy and tolerability of a fixed combination of acetylsalicylic acid, paracetamol, and caffeine in patients with severe headache: a post-hoc subgroup analysis from a multicentre, randomized, double-blind, single-dose, placebo-controlled parallel group study.

Background: We investigated efficacy and tolerability of two tablets of the fixed combination of 250 mg acetylsalicylic acid (ASA) + 200 mg paracetamol + 50 mg caffeine (Thomapyrin) in comparison to two tablets of placebo in a post-hoc analysis of a subgroup of patients with severe headache. Methods: Patients where included if they were used to treating their episodic tension-type headache or migraine attacks with non-prescription analgesics and reported a history of headache attacks characterized by at least severe pain and greatly impaired usual daily activities and treated headaches with pain intensity of at least 48 mm assessed on a 100-mm visual analogue scale and associated with greatly impaired usual daily activities. Results: For the primary endpoint ‘time to 50% pain relief’ in this intention-to-treat subset (n = 179 patients), the fixed combination of ASA, paracetamol, and caffeine was statistically significantly superior to placebo (p = 0.0008). The superior efficacy of the triple combination could also be shown for all secondary endpoints such as time until reduction of pain intensity to 10 mm, weighted sum of pain intensity difference (%SPIDweighted), extent of impairment of daily activities, and global assessment of efficacy. Both treatments were well tolerated. The incidence of adverse events observed was low. The results for this subgroup analysis are consistent with respect to all endpoints and to the patients with non-severe headache and the overall patient population. As with all post-hoc subgroup analyses, the findings are hypothesis generating only and must be interpreted with caution. Discussion: The results of this subgroup analysis confirm that the fixed combination of ASA (250 mg), paracetamol (200 mg), and caffeine (50 mg) is effective and well tolerated in a broad spectrum from mild to severe migraine and tension-type headache severity independently of the headache diagnosis.

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

BackgroundAlthough 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).MethodsThese 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.ResultsThe 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).ConclusionThe overall headache prevalence remained stable in Germany in the last 15 years.

Headache classification by history has only limited predictive value for headache episodes treated in controlled trials with OTC analgesics.

We investigated the consistency between the headache diagnosis based on medical history and three treated headache episodes diagnosed based on a diary. In a randomized double-blind study including individuals with either migraine or tension-type headache (TTH) we showed 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. A neurologist performed a classification of the usual headache episodes and each of the three treated ones in a blinded fashion based on a structured questionnaire. This was done for the 1734 patients included in the efficacy analysis who usually treated their episodic TTH or migraine attacks with non-prescription analgesics. The overall percentage of patients with migraine and TTH remained relatively stable. The treated headache episodes were between 75 and 77% migraine, 18–20% were TTH and 5–7% could not be classified. We observed some shift in headache type within patients from prior history and in treated attacks. In 60% of patients all three treated episodes were of the type initially diagnosed by the neurologist by history (56% migraine and 4% episodic TTH). Of those with an initial diagnosis of migraine, 24% had at least one attack meeting criteria for TTH. Of patients with an initial diagnosis of TTH, 54% had at least one attack meeting the diagnostic criteria for migraine. Our results demonstrate that an initial headache diagnosis does not accurately predict the headache type treated in a randomized trial. Symptom features of treated headaches should be captured to ensure that the attack is of the type targeted by the clinical trial. The International Headache Society Guidelines for controlled clinical trials should be updated accordingly.

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.

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.

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.

The Fixed Combination of Acetylsalicylic Acid, Paracetamol and Caffeine: Reply

Dear Sir Diener et al. (1) convincingly demonstrate in a very large (n = 1743), double-blind trial that the combination of aspirin, paracetamol and caffeine is statistically superior to the combination without caffeine and superior to the mono-substances in patients who normally treat their migraine attacks or episodic tension-type headache with over-thecounter (OTC) medication. From a clinical point of view, however, the superiority of the combination vs. aspirin is only modest even if the patients rated the combination (73% very good or good) better than aspirin (67% very good or good). Furthermore, the authors do not discuss the problem of drug overuse with mixed analgesics. In the third edition of The Headaches published this year one finds the following statements by Diener and Silberstein in the chapter on medication overuse headaches: ‘Migraine drugs that contain barbiturate, caffeine, codeine, or tranquilizers, as well as mixed analgesics, should be avoided. Patients who take over-thecounter (OTC) medications should be advised to avoid caffeine combinations’ (2). Should the results of the present trial change the advice we currently give to patients about the use of combination drugs?