Effectiveness and safety of Xuefu Zhuyu oral liquid on -stagnation and blood-stasis pattern in patients with stable angina, tension-type headache and primary dysmenorrhea: rationale and design of a master protocol.

We present the rationale and design of a master protocol study that clarifies the effectiveness and safety of Chinese herbal formulas on -stagnation and blood-stasis pattern (QBP). Three randomized controlled trials (RCTs) and real-world observational studies. Based on three registry cohorts of stable angina, tension-type headache and primary dysmenorrhea, patients with QBP will be enrolled in RCTs to receive either Xuefu Zhuyu (, XFZY) oral liquid or a placebo, while patients with non-QBP will be enrolled in the observational studies and experience follow-up. 1414 patients (RCTs: 574; observational studies: 840) will be recruited at seven centers in China over a 3-year period. The primary outcome is the visual analog scale of pain intensity. Adverse events will also be reported. The analysis will be undertaken separately in each sub-study, and then an overall analysis combining multiple subgroups will be performed to comprehensively investigate the effect of XFZY oral liquid. This study will provide high-quality evidence of XFZY oral liquid for QBP patients and show a paradigm of post-marketing evaluation of the effectiveness and safety for Chinese medicine following the notion of the pattern dominating different disease research models.

Does menstruation-related headache occur exclusively in women with migraine?

To determine the relation between headache and menstruation in women with migraine and the use of estrogen by these women. This was a prospective, cross-sectional, observational study with group comparison, using non-random sample and convenience. We interviewed 79 women diagnosed with migraine or tension-type headache (TTH), according to the ICHD-3, regarding the relation between headache and menstruation. Of the 79 women with headache, 60 (76%) had migraine and 19 (24%) had episodic TTH. The most frequent subtype of migraine was without aura (54/60, 90%). The age ranged from 18 to 42 years, with an average of 22.6 ± 4.1 years. Migraine affected women aged 22.4 ± 3.6 years, whereas in TTH, the age was 23.0 ± 5.4 years. Menstruation-related headache occurred in 41.9% of women with migraine and in only 6.3% of those with TTH. These differences were significant (χ2 = 5.2; p = 0.022). Of the five women diagnosed with migraine with aura, two used estrogen. Menstruation-related headache predominates in women with migraine and often women with migraine with aura use estrogen.

[Clinical and pharmacological approaches to the choice of a drug for a tension-type headache relief].

The article goes to describe clinical and pharmacological approaches to choosing a drug with an optimal efficacy/safety profile, providing the necessary analgesic effect in tension-type headache. TRPV1 brain receptors are considered the main action point of the mediator. AIM: The purpose of this study is a comparative analysis of the pharmacodynamic and pharmacokinetic parameters of ibuprofen and paracetamol as a part of fixed dose combination and as monotherapy in tension type headaches. MATERIALS AND METHODS: Comparative dissolution kinetics test; Comparative analysis of pharmacokinetic parameters using the PubMed/MEDLINE database. RESULTS: The median Tmax of ibuprofen as a part of a fixed-dose combination and as a monotherapy is 75 minutes. The median Tmax of paracetamol is 30 min when taken in a fixed dose combination and 40 min as a monotherapy. In patients who received the fixed dose combination, the concentration of ibuprofen in the blood plasma after 10 minutes 6.64 g/ml-1; after 20 minutes 16.81 g/ml-1, while when taken in the same dose in as a monotherapy, respectively, 0.58 and 9.00 g/ml-1. The mean plasma concentrations of paracetamol after 10 and 20 minutes in patients receiving the fixed combination were 5.43 and 14.54 g/ml-1, respectively, compared with 0.33 and 9.19 g/ml-1 for paracetamol as monotherapy. dissolution kinetics test of the Paracytolgin: after 5 minutes, 20% of paracetamol passed into the solution in a system with a pH of 1.2; in a system with a pH of 4.5 36.4%; in a system with a pH of 6.8 33.5%; after 10 minutes, respectively 68.5, 98.0 and 89.6%. After 15 minutes, almost complete dissolution was noted in all systems: 98.5, 98.8 and 100.5%, respectively. DISCUSSION: The combination of ibuprofen and paracetamol makes it possible to enhance the analgesic effect as a result of additive action by the help of central mechanisms. The fixed dose combination of ibuprofen and paracetamol significantly increases the rate of absorption of paracetamol, which has potential therapeutic benefits in terms of a faster analgesias onset. CONCLUSION: The fixed dose combination of ibuprofen and paracetamol provides faster and long-term anaesthesia with a comparatively lower dosage of each analgesic.

[Medication overuse headache]. / Abuzusnaia golovnaia bol'.

Rebound headache (RH) is a chronic daily headache which occurs when analgesics, triptans, ergotamines are taken frequently (more than 15 days/month for more than 3 months) to relieve headaches. The prevalence of RH is 1 to 4% in the general population. RH commonly occurs in patients with migraine and tension-type headache. The deficit of central sensitization and psychological factors play an important role in initiating and maintaining of RH. Treatment of noofen for 2 months is effective in 75% of patients with RH.

Long-term safety and tolerability of apremilast in patients with psoriasis: Pooled safety analysis for ≥156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2).

BACKGROUND: Randomized, controlled trials demonstrated efficacy and safety of apremilast for moderate-to-severe plaque psoriasis and psoriatic arthritis. OBJECTIVE: Assess long-term safety of oral apremilast in psoriasis patients. METHODS: Safety findings are reported for 0 to ≥156 weeks from the Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis (ESTEEM) 1 and 2. RESULTS: The 0 to ≥156-week apremilast-exposure period included 1184 patients treated twice daily with apremilast 30 mg (1902.2 patient-years). During 0 to ≤52 weeks, the adverse events (AEs) that occurred in ≥5% of patients included diarrhea, nausea, upper respiratory tract infection, nasopharyngitis, tension headache, and headache. From 0 to ≥156 weeks, no new AEs (affecting ≥5% of the population) were reported. AEs, serious AEs, and study drug discontinuations caused by AEs did not increase with long-term exposure. During the 0 to ≥156-week period, the rates of major cardiac events (exposure-adjusted incidence rate [EAIR] 0.5/100 patient-years), malignancies (EAIR 1.2/100 patient-years), depression (EAIR 1.8/100 patient-years), or suicide attempts (EAIR 0.1/100 patient-years) did not increase in comparison with the rates found during the 0 to ≤52-week period. No serious opportunistic infections, reactivation of tuberculosis, or clinically meaningful effects on laboratory measurements were reported. LIMITATIONS: This study had a high dropout rate (21% of patients ongoing >156 weeks); most were unrelated to safety concerns. CONCLUSIONS: Apremilast demonstrated an acceptable safety profile and was generally well tolerated for ≥156 weeks.

The efficacy and safety of apremilast, etanercept and placebo in patients with moderate-to-severe plaque psoriasis: 52-week results from a phase IIIb, randomized, placebo-controlled trial (LIBERATE).

BACKGROUND: Apremilast, an oral, small-molecule phosphodiesterase 4 inhibitor, has demonstrated efficacy in patients with moderate-to-severe psoriasis. OBJECTIVE: Evaluate efficacy and safety of apremilast vs. placebo in biologic-naive patients with moderate-to-severe plaque psoriasis and safety of switching from etanercept to apremilast in a phase IIIb, randomized, double-blind, placebo-controlled study (NCT01690299). METHODS: Two hundred and fifty patients were randomized to placebo (n = 84), apremilast 30 mg BID (n = 83) or etanercept 50 mg QW (n = 83) through Week 16; thereafter, all patients continued or switched to apremilast through Week 104. The primary efficacy endpoint was achievement of PASI-75 at Week 16 with apremilast vs. placebo. Secondary endpoints included achievement of PASI-75 at Week 16 with etanercept vs. placebo and improvements in other clinical endpoints vs. placebo at Week 16. Outcomes were assessed through Week 52. This study was not designed for apremilast vs. etanercept comparisons. RESULTS: At Week 16, PASI-75 achievement was greater with apremilast (39.8%) vs. placebo (11.9%; P < 0.0001); 48.2% of patients achieved PASI-75 with etanercept (P < 0.0001 vs. placebo). PASI-75 response was maintained in 47.3% (apremilast/apremilast), 49.4% (etanercept/apremilast) and 47.9% (placebo/apremilast) of patients at Week 52. Most common adverse events (≥5%) with apremilast, including nausea, diarrhoea, upper respiratory tract infection, nasopharyngitis, tension headache and headache, were mild or moderate in severity; diarrhoea and nausea generally resolved in the first month. No new safety or tolerability issues were observed through Week 52 with apremilast. CONCLUSION: Apremilast demonstrated significant efficacy vs. placebo at Week 16 in biologic-naive patients with psoriasis, which was sustained over 52 weeks, and demonstrated safety consistent with the known safety profile of apremilast. Switching from etanercept to apremilast did not result in any new or clinically significant safety findings, and efficacy was maintained with apremilast through Week 52.

[Headaches and multiple sclerosis]. / Bóle glowy a stwardnienie rozsiane.

The article discusses the possible association between multiple sclerosis (MS) and headache. MS has a broad range of neurological symptoms, but headache is not included among them. Research on the link between MS and headache focuses on primary headaches such as migraine, tension-type headache and cluster headache. Studies on the possible association between MS and migraine have had conflicting results and have found a wide range of prevalence rates for migraine in MS patients. The possible mechanisms proposed linking migraine and MS can be unidirectional, bidirectional or involving a common cause. The prevalence of TTH in MS patients is similar to that observed in the general population. Immunotherapy may play a role in inducing headache.

When tension headaches become chronic.

This article provides background, diagnostic, treatment, and management information about the most common form of headache: tension-type headache (TTH). Using a typical patient case scenario, it illustrates evidence-based therapies that NPs can offer patients whose TTH has become chronic due to medication overuse.

Headaches related to psychoactive substance use.

AIM: To investigate a possible association between headache and psychoactive substance use. METHODS: 1055 psychoactive substance abusers were consecutively admitted. All patients filled out a detailed headache questionnaire and 1015 patients were included. RESULTS: Twenty seven percent of patients reported having headache. Eighteen percent of patients reported having headache attributed to a substance or its withdrawal and 1.4% had unclassified headache. The most commonly used substances were cannabis (80.5%), alcohol (74.6%), methylamphetamine (18.7%), benzodiazepine (10.4%), volatile solvent (5.8%), cocaine (4.4%), heroin (2.1%), opioids (0.5%), and other substances (1.7%). Fifteen patients reported that onset of headache occurred prior to onset of substance use, while 94.5% had headaches occurred after substance abuse. A higher incidence of headache was found in the benzodiazepine, methylamphetamine, cocaine, heroin, volatile solvent abusers. Seventy-eight percent of headache patients have never sought help from a physician despite the severity and frequency of headache. CONCLUSIONS: In our study, the prevalence of headache among all psychoactive substance abusers was 26.9%. Although this is one-group study without any comparison with non-addict population and associational data must be interpreted with caution, the results of this study indicate a possible relationship may exist between headache and substance use since 94.5% of substance users described headaches after the onset of substance use. The younger start and the longer duration of cannabis use caused the higher incidence of headache, but this correlation was not observed in other substance use. Migraine was far more prevalent in the abusers than in previously reported community populations.

Interactions between migraine and tension-type headache and alcohol drinking, alcohol flushing, and hangover in Japanese.

The aim of the study was to investigate associations between headache types and alcohol drinking, alcohol flushing, and hangover. Alcohol consumption is inhibited by the presence of inactive aldehyde dehydrogenase-2 (ALDH2) whose carriers are susceptible to alcohol flushing and hangovers. We conducted a cross-sectional study of the 2,577 subjects (men/women: 1,018/1,559) who reported having ever experienced headaches unrelated to common colds and alcohol hangovers among 5,408 (2,778/2,630) Tokyo health checkup examinees. We used a questionnaire inquiring about current and past facial flushing after drinking a glass of beer which identifies the presence of inactive ALDH2 with a sensitivity and specificity of approximately 90%. Based on ICHD-II criteria migraine was diagnosed in 419 (75/344) subjects, and tension-type headache (TTH) in 613 (249/364). We classified the headaches of the remaining 1,545 (694/851) of headaches sufferers into the category "other headaches (OH)". The migraineurs drank alcohol less frequently than the subjects with TTH among current/past alcohol flushers and than the subjects with OH regardless of flushing category. No such difference in drinking frequency was observed between TTH and OH. Current/past flushers drank alcohol less frequently than never flushers, and the likelihood that male migraineurs would avoid alcohol drinking than men with TTH or OH was stronger among current/past flushers than among never flushers. Flushers and women were more susceptible to hangover than never flushers and men, respectively, regardless of headache type. Among never flushers, women with migraine were more susceptible to hangover than women with OH. The difference in alcohol sensitivity may partly explain less alcohol consumption by migraineurs.

Neuronal nitric oxide synthase is involved in the induction of nerve growth factor-induced neck muscle nociception.

BACKGROUND: Neck muscle nociception mediated by nitric oxide may play a role in the pathophysiology of tension-type headache. OBJECTIVE: The present study addresses the involvement of neuronal nitric oxide synthase (nNOS) in the facilitation of neck muscle nociception after local application of nerve growth factor (NGF). METHODS: After administration of NGF into semispinal neck muscles, the impact of neck muscle noxious input on brainstem processing was monitored by the jaw-opening reflex in anesthetized mice. The modulatory effect of preceding and subsequent administration of an inhibitor of neuronal nitric oxide synthase on central facilitation was addressed in a controlled study. RESULTS: With preceding i.p. application of saline or 0.096 mg/kg of the specific nNOS inhibitor Nω-propyl-L-arginine (NPLA), NGF induced a sustained reflex facilitation within 60 minutes. Preceding injection of 0.96 mg/kg or 1.92 mg/kg NPLA completely prevented the potentially facilitatory effect of NGF. Subsequent administration of 0.96 mg/kg NPLA did not affect established NGF-evoked reflex facilitation. Thus, NPLA prevents facilitation of brainstem processing by noxious myofascial input from neck muscles in a dose-dependent manner. CONCLUSION: These findings suggest that nNOS is involved in the induction but not the maintenance of NGF-evoked facilitation of nociception in the brainstem. These results from an experimental animal model may support the idea of NOS and nNOS as potential targets for pharmacological treatment of tension-type headache.

Focus on headache as an adverse reaction to drugs.

There are a large number of drugs inducing headache as an adverse reaction. Nevertheless, headaches as adverse reactions to drugs have received limited attention. Non-serious adverse reactions, such as headache, are not quantified and described as accurately as serious, life threatening ones. However, non-serious reactions can also be extremely troublesome, above all when they are chronic: they can affect patients' quality of life and contribute to non-compliance. It is absolutely possible that the number of patients with headache as an adverse reaction, which is going to increase, considering the growing use of medications. Physicians should, therefore, be aware of this issue. Indeed, it is difficult to attribute the diagnosis of adverse drug reaction to a condition, headache, which is also a very common symptom in general population.

From drug-induced headache to medication overuse headache. A short epidemiological review, with a focus on Latin American countries.

Medication overuse headache (MOH) is a daily or almost-daily type of headache that results from the chronicization, usually migraine or tension-type headache, as a consequence of the progressive increase of intake of symptomatic drugs. MOH is now the third most frequent type of headache and affects a percentage of 1-1.4% of the general population. The currently available data on the impact of chronic headache associated with analgesic overuse in specialist headache centres confirm, beyond doubt, the existence of a serious health problem. Limited amount of data exists on the burden and impact of MOH in Latin American Countries. In this review, we summarise the reliable information from the literature on the epidemiological impact of MOH.

Medication-overuse headache: where are we now?

PURPOSE OF REVIEW: Many important studies on medication-overuse headache have been published in the last year. Some of them investigated the pathophysiology of headache chronicity, others focused on evaluation of risk factors. The International Headache Society revised the classification criteria. We provide a summary of the new findings and concepts. RECENT FINDINGS: Medication-overuse headache was previously defined by the International Headache Society as a chronic headache which occurs following overuse of headache drugs and improves after withdrawal. Hence, the improvement of headache after withdrawal was mandatory for diagnosis. The new appendix criteria appeared last year and established a broader concept of medication-overuse headache no longer requiring improvement after discontinuation of medication overuse. Several large population-based longitudinal studies clearly demonstrated that overuse of any kind of acute headache medication is the main risk factor leading to development of chronic headache. Imaging studies provided new important insights into the pathophysiology of headache chronicity. New treatment strategies have been suggested. SUMMARY: Recent data provide better insight into pathophysiology of medication-overuse headache. Epidemiological studies clearly demonstrate the necessity of establishing a predictive model for early recognition of patients at high risk to intervene early and avoid development of chronic headache.

[Medication-overuse headache]. / Patient nimmt häufig Kopfschmerzmittel. So erkennen Sie, ob ein Entzug nötig ist.

Headache associated with the chronic use of medications has become a significant problem in the management of headache. Typically, patients overusing analgesics suffer from tension headache, whereas those over-using triptans may experience daily migraine-type headaches or an increase in the frequency of migraine attacks. The treatment of choice in such cases is withdrawal of the medication followed as early as possible by medicinal prophylaxis of the primary headache.

Brainstem and cervical spinal cord Fos immunoreactivity evoked by nerve growth factor injection into neck muscles in mice.

Although myofascial tenderness is thought to play a key role in the pathophysiology of tension-type headache, very few studies have addressed neck muscle nociception. The neuronal activation pattern following local nerve growth factor (NGF) administration into semispinal neck muscles in anaesthetized mice was investigated using Fos protein immunohistochemistry. In order to differentiate between the effects of NGF administration on c-fos expression and the effects of surgical preparation, needle insertion and intramuscular injection, the experiments were conducted in three groups. In the sham group (n=7) cannula needles were only inserted without any injection. In the saline (n=7) and NGF groups (n=7) 0.9% physiological saline solution or 0.8 microm NGF solution were injected in both muscles, respectively. In comparison with sham and saline conditions, NGF administration induced significantly stronger Fos immunoreactivity in the mesencephalic periaqueductal grey (PAG), the medullary lateral reticular nucleus (LRN), and superficial layers I and II of cervical spinal dorsal horns C1, C2 and C3. This activation pattern corresponds very well to central nervous system processing of deep noxious input. A knowledge of the central anatomical representation of neck muscle pain is an essential prerequisite for the investigation of neck muscle nociception in order to develop a future model of tension-type headache.

[Long-term prognosis of analgesics abuse headache].

OBJECTIVE: To evaluate the long-term prognosis of analgesics abuse headache. METHODS: Ninety-five consecutive patients with analgesics abuse headache were treated in Toyonaka Municipal Hospital. Seventy-three patients (76.8%) had migraine, eighteen (19.0%) had tension-type headache and four (4.2%) new daily persistent headache. Seventy-seven (81.1%) were females and eighteen (18.9%) males. All patients were treated for six years from November 1997 to October 2003 and a total of sixty-nine patients were available for interview as of October 2004 at a mean time interval of 41.5 months after drug withdrawal therapy. Twenty-two patients were admitted to our inpatient withdrawal unit, twenty-five patients were treated by outpatient withdrawal therapy. Tapering analgesics gradually in conjunction with instituting preventive therapy treated twenty-two patients. RESULTS: Inpatient-Nine cases (41%) reported intake of analgesics on < or = 8 days/month, five cases (23%) on 9-15 days/month and eight cases (36%) > 15 days/month. Three cases (14%) developed recurrent analgesic abuse. Outpatient (abrupt discontinuation)--Twelve cases (48%) reported intake of analgesics on < or = 8 days/month, five cases (20%) on 9-15 days/month and eight cases (32%) >15 days/month. One case (4%) reported on recurrent analgesic abuse. Outpatient (tapering analgesics gradually)--One case (5%) reported intake of analgesics on < or = 8 days/month and twenty-one cases (95%) reported daily intake. Fifteen cases (68%) reported continuous analgesic abuse. Comparison between migraine and tension-type headache suggested that patients with migraine showed a tendency towards a better prognosis than patients with tension-type headache. CONCLUSIONS: These results demonstrate the efficacy of withdrawal treatment in difficult cases suffering from analgesics abuse headache. If patients cannot be safely or adequately treated as outpatients, inpatient treatment may be needed.

Long-term potentiation of orofacial sensorimotor processing by noxious input from the semispinal neck muscle in mice.

Tension-type headache is the most common type of primary headaches but no conclusive concept of pathophysiology exists. This may be due to a lack of an appropriate animal model. This study addressed the hypothesis that noxious neck muscle input induces central sensitization of orofacial sensorimotor processing. The effect of hypertonic saline injection into the semispinal neck muscle on the jaw-opening reflex (JOR) was investigated in anaesthetized mice (n = 11). Hypertonic saline injection into the neck muscle facilitated the JOR for at least one hour: integral (+94.5%) and duration (+18.7%) increased, latency decreased (-7.5%). The reflex threshold decreased to 61% after injection. Isotonic saline injection into the neck muscle (n = 11) or hypertonic saline injection into a hindpaw muscle (n = 10) did neither change the reflex integral nor the threshold. Long-term potentiation of the JOR by noxious neck muscle input may be an appropriate model to investigate tension-type headache pathophysiology.