Hubertus Peil

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.

Efficacy and safety of metamizol vs. acetylsalicylic acid in patients with moderate episodic tension-type headache: a randomized, double-blind, placebo- and active-controlled, multicentre study.

We assessed the efficacy and safety of oral single doses of 0.5 and 1 g metamizol vs. 1 g acetylsalicylic acid (ASA) in 417 patients with moderate episodic tension-type headache included in a randomized, double-blind, placebo- and active-controlled, parallel, multicentre trial. Eligibility criteria included 18–65 years of age, history of at least two episodes of tension-type headache per month in the 3 months prior to enrolment, and successful previous pain relief with a non-opioid analgesic. Treatment arms were metamizol 0.5 g (n = 102), metamizol 1 g (n = 108), ASA 1 g (n = 102) and placebo (n = 105). The analgesic efficacy of 0.5 and 1 g metamizol vs. placebo was highly statistically significant (α: 0.025; one-sided) for sum of pain intensity differences, maximum pain intensity difference, number of patients with at least 50% pain reduction, time to 50% pain reduction, maximum pain relief and total pain relief. A trend towards an earlier onset of a more profound pain relief of 0.5 and 1 g metamizol over 1 g ASA was noticed. All medications including placebo were almost equally safe and well tolerated.

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.

Efficacy and safety of bisacodyl in the acute treatment of constipation: a double‐blind, randomized, placebo‐controlled study

Although laxatives are a first‐line treatment for constipation, there are few randomized placebo‐controlled trials assessing their efficacy.

Improvement of cutaneous microcirculation and oxygen supply in patients with chronic venous insufficiency by orally administered extract of red vine leaves AS 195: a randomised, double-blind, placebo-controlled, crossover study.

ObjectiveTo investigate the effect of the red vine leaf extract AS 195 on cutaneous microvascular blood flow, transcutaneous oxygen pressure (tcpO2), and leg oedema in patients with chronic venous insufficiency (CVI).Design and patientsThe study was a randomised, double-blind, placebo-controlled, crossover trial for which 129 men and women, aged ≥18 years, with CVI stage I or II were screened. Seventy-one fulfilled the inclusion criteria and were randomised.InterventionsA total of 71 patients were divided into two groups. The first group (n=36) received AS 195 360mg once daily during a first 6-week treatment period, followed by a 4-week placebo washout period and then placebo during the second 6-week treatment period. The second group (n=35) started with placebo and received AS 195 360mg after the placebo washout. The cutaneous microvascular blood flow in the malleolar region was measured using a newly developed laser Doppler device. TcpO2 was measured using a solid-state electrode.ResultsAfter 6 weeks, patients in the AS 195 group had increased microvascular blood flow values (+241.8±18.7 arbitrary units [AU] versus a decrease of −41.0±18.7AU in the placebo group; p < 0.0001). Oxygen increased to 1.35±0.97mm Hg (placebo: decrease of −7.27±0.97mm Hg; p < 0.0001). After 6 weeks of treatment the leg circumference was decreased (ankle level: by −0.39±0.09cm versus +0.29±0.09cm; p < 0.0001; calf level: by −0.54±0.05cm versus +0.14±0.05cm; p < 0.0001).ConclusionThe administration of AS 195 improved objective symptoms of CVI and may prevent CVI deterioration.

Comparison of bisacodyl and sodium picosulphate in the treatment of chronic constipation

ABSTRACT Background: Chronic constipation is a widespread condition. Although laxatives are generally accepted as being effective treatments, few studies have made formal comparisons of their efficacy and safety in chronic use. Objective: To compare the safety and efficacy of bisacodyl and sodium picosulphate in the treatment of chronic constipation over a 4-week period. Methods: Patients with chronic constipation (N = 144), recruited from out-patient clinics, were analysed for safety and efficacy in this open-label, randomised, parallel-group study. Patients were treated daily for 4 weeks (bisacodyl, 5–10 mg daily: 70 patients; sodium picosulphate, 5–10 mg daily: 74 patients). Primary efficacy criteria consisted of the number of bowel movements and stool consistency. Secondary efficacy criteria were straining at stool and physicians’ global efficacy assessment. Safety assessments included adverse event monitoring, tolerability and changes in laboratory parameters. Results: Both treatments were equally effective in treating chronic constipation, providing sustained improvement in symptoms. Compared to baseline, there were significant ( p < 0.001) improvements in stool frequency and consistency and in the occurrence of straining at 14 and 28 days for both treatment groups. Based on the physicians’ global assessment, a significant improvement was observed in 74.6% (bisacodyl) and 79.2% (sodium picosulphate) of patients. Neither treatment had significant effects on serum electrolytes. There was a trend for better tolerability in patients receiving bisacodyl treatment based on the number of drug-related adverse events (bisacodyl: 7; sodium picosulphate: 14, two patients withdrawn). Conclusions: Bisacodyl and sodium picosulphate are equally well tolerated and effective in the treatment of chronic constipation over a 4-week period.

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.

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.

Randomised, placebo-controlled, double-blind study to investigate the efficacy and safety of the acute use of sodium picosulphate in patients with chronic constipation.

There are few studies supporting the effective and safe use of laxatives for constipation. This study examined the short‐term efficacy and safety of sodium picosulphate in patients with chronic constipation. Patients with a history of chronic constipation for at least 3 months were randomised to receive 7 mg sodium picosulphate or placebo for three consecutive nights. Patients recorded stool frequency and consistency, straining, bloating, and pain at baseline and during treatment. Vital signs, haematocrit, serum creatinine and electrolytes were monitored. Primary end‐point for efficacy was the occurrence of a response to treatment, defined as improvement in stool frequency and occurrence of straining. All 57 randomised patients (sodium picosulphate n = 29, placebo n = 28; mean age 54.8 and 54.1 years) completed the study. Sodium picosulphate produced a treatment response (improved stool frequency and straining) in 82.8% compared with 50% in the placebo group (p = 0.010) and reduced bloating more often than placebo. There were no serious adverse events and one patient with diarrhoea and another with abdominal pain in each treatment group. There were no cardiovascular effects, changes in serum haematocrit, creatinine or electrolytes in either group. This study confirmed that sodium picosulphate is an effective, well‐tolerated and safe laxative in the acute treatment of constipation.