Ocular compression maneuver aborts benign cough-induced headache

Benign cough-induced headache is a short-lasting cranial discomfort. The therapeutic role of lumbar puncture (LP) or indomethacin in benign patients with benign cough-induced headache patients is debatable. Transient ocular compression (OC) raises intraocular pressure (IOP) and can limit the impact of cough-induced choroidal venous congestion. A self-applied maneuver that instantaneously aborts cough-induced headache is described in two patients. The effect of this maneuver supports a recent hypothesis that cough-induced headache may be due to ocular choroidal venous congestion and mechanical antidromic trigeminal nerve activation. The OC maneuver has several potential complications and its self-application in benign cough-induced headache should be regarded as an experimental procedure until more data regarding its efficacy and safety become available.     

Evidence for a central site of action for the antitussive effects of caramiphen

The antitussive properties of caramiphen edisylate were studied in the decerebrate cat in which cough was elicited by direct electrical stimulation of the cough center. In this preparation dextromethorphan hydrobromide was compared to caramiphen as an antitussive agent. Dextromethorphan was somewhat more potent when given i.v. as well as when given directly into the left vertebral artery (i.a.). Both agents were far more effective when given i.a. than when given i.v. The effective dose ratios of i.v./i.a. were about 12 and 14 for caramiphen and 11 and 7 for dextromethorphan (actual and cumulative doses). These ratios indicate that both agents have a central rather than a peripheral site of antitussive action. Both drugs had antitussive effects in i.a. doses which did not alter arterial blood pressure or respiration greatly. However, after i.v. administration transient changes in both arterial blood pressure and respiration were observed with both agents. It was concluded that the antitussive action of both caramiphen and dextromethorphan is due to a selective effect on the cough center in the brainstem of the cat. On a milligram per kilogram basis, caramiphen required a 3 to 4 times larger dose than dextromethorphan for equieffective antitussive effects.     

Dextromethorphan and codeine: objective assessment of antitussive activity in patients with chronic cough

Dextromethorphan, the most widely used cough suppressant in the U.S.A., was compared with codeine, the traditional European antitussive, in a double-blind, crossover trial using both an objective and subjective assessment of efficacy in sixteen patients with chronic, stable cough. Both preparations, at a dose of 20 mg, were similarly effective in reducing cough frequency. Dextromethorphan lowered cough intensity to a greater degree than codeine (p less than 0.0008) and was considered the better antitussive by the majority of patients (p less than 0.001). In view of its lack of side-effects, its safety even in overdose and its non-narcotic status, the increasing trend in Europe to use dextromethorphan as a substitute for codeine in the treatment of cough is to be welcomed.     

Studies on the localization of central cough mechanism; site of action of antitussive drugs.

The localization of the central cough mechanism was studied by electrically stimulating the lower brainstem in cats lightly anesthetized with pentobarbital sodium or in unanesthetized midcollicular decerebrate preparations. Cough responses were recorded with the aid of a microphone. The cough responsive region was concentrated in an area dorsomedial to the trigeminal tract and nucleus. The sites of action of antitussive agents (dextromethorphan, codeine, clonazepam, diazepam and caramiphen) were studied on the centrally induced cough responses. Each of these drugs was administered intravenously to determine the dorsal levels for cough suppression. In other series, the threshold dose via the intravertebral route was determined first. Because the agent necessary to prevent cough via this route was so small in amount, recovery usually occurred in 20 to 90 minutes. Then the same agent was given intravenously in an attempt to obtain an effective dose which was close to the minimum dose for blocking the cough. The mean effective doses of these agents to abolish the cough via the vertebral artery were only about 1/20 of those required via intravenous injection. The findings suggest that these agents act centrally to suppress the cough responses. Clonazepam was found to be the most potent antitussive among these agents, the mean effective dose being about 1/35 of that of codeine. The antitussive potency of benzodiazepines is not well correlated with their muscle relaxant activity. For instance, clonazepam and diazepam have the same potency in depressing polysynaptic spinal reflexes, whereas the former is 6 times more potent than diazepam as an antitussive. This finding indicates that clonazepam has a high specificity as an antitussive.     

Levodropropizine in the management of cough associated with cancer or nonmalignant chronic disease--a systematic review

Cough associated with cancer or nonmalignant chronic disease is common and distressing. Levodropropizine, a peripherally acting drug, has been used as an alternative antitussive to opioids. The authors aimed to determine the efficacy and safety of levodropropizine in relieving cough associated with cancer or nonmalignant chronic disease. The authors searched five databases and hand searched relevant journals to identify randomized and nonrandomized controlled trials assessing the antitussive effect of levodropropizine for cough associated with cancer, chronic obstructive pulmonary disease (COPD), interstitial lung disease, or chronic heart failure. Study quality was assessed using a modified version of the Centre for Reviews and Dissemination criteria. The search yielded 58 references. Six were checked in more detail, and four studies were included. Two were randomized controlled trials (RCTs) testing levodropropizine against dihydrocodeine and moguisteine, and two were nonrandomized placebo-controlled studies, all with important limitations and high risk of bias. Levodropropizine was significantly more effective than placebo in reducing cough frequency and severity, and equally effective as dihydrocodeine or moguisteine. It was generally well tolerated. The authors conclude that the evidence for the antitussive efficacy of levodropropizine in these patients is scarce, and is further limited by the methodological weaknesses of the primary studies. Further well-designed research is needed to support its use.     

枇杷花镇咳活性部位筛选

目的 探寻枇杷花95%乙醇提取物 （Flower of Eriobotrya japonica,FEJ） 的止咳活性部位.方法 枇杷花醇提物依次用石油醚、氯仿、乙酸乙酯及水层萃取,得4个部位.分别给予小鼠灌胃,采用氨水喷雾法记录小鼠3min咳嗽次数和咳嗽潜伏期.结果 FEJ氯仿萃取部位、乙酸乙酯萃取部位和水层高剂量组明显减少小鼠咳嗽次数和咳嗽潜伏期（P＜0.01）.结论 FEJ有镇咳作用,其氯仿和乙酸乙酯萃取部位及水层均有显著的镇咳作用,尤其是氯仿和水层高剂量组效果最好.     

Cough-induced rib fractures

OBJECTIVES: To define the demographic, clinical, and radiological features of patients with cough-induced rib fractures and to assess potential risk factors. PATIENTS AND METHODS: For this retrospective, single-center study, we identified all cases of cough-induced rib fractures diagnosed at the Mayo Clinic in Rochester, Minn, over a 9-year period between January 1, 1996, and January 31, 2005. Bone densitometry data from patients' medical records were analyzed, and T scores were used to classify patients into bone density categories. RESULTS: The mean +/- SD age of the 54 study patients at presentation was 55+/-17 years, and 42 patients (78%) were female. Patients presented with chest wall pain after onset of cough. Rib fracture was associated with chronic cough (> or =3 weeks' duration) in 85% of patients. Rib fractures were documented by chest radiography, rib radiography, computed tomography, or bone scan. Chest radiography had been performed in 52 patients and revealed rib fracture in 30 (58%). There were 112 fractured ribs in 54 patients. One half of patients had more than one fractured rib. Right-sided rib fractures alone were present in 17 patients (26 fractured ribs), left-sided in 23 patients (35 fractured ribs), and bilateral in 14 patients (51 fractured ribs). The most commonly fractured rib on both sides was rib 6. The fractures were most common at the lateral aspect of the rib cage. Bone densitometry was done in 26 patients and revealed osteopenia or osteoporosis in 17 (65%). CONCLUSIONS: Cough-induced rib fractures occur primarily in women with chronic cough. Middle ribs along the lateral aspect of the rib cage are affected most commonly. Although reduced bone density is likely a risk factor, cough-induced rib fractures can occur in the presence of normal bone density.     

Levodropropizine in the Management of Cough Associated with Cancer or Nonmalignant Chronic Disease–A Systematic Review

ABSTRACT

Cough associated with cancer or nonmalignant chronic disease is common and distressing. Levodropropizine, a peripherally acting drug, has been used as an alternative antitussive to opioids. The authors aimed to determine the efficacy and safety of levodropropizine in relieving cough associated with cancer or nonmalignant chronic disease. The authors searched five databases and hand searched relevant journals to identify randomized and nonrandomized controlled trials assessing the antitussive effect of levodropropizine for cough associated with cancer, chronic obstructive pulmonary disease (COPD), interstitial lung disease, or chronic heart failure. Study quality was assessed using a modified version of the Centre for Reviews and Dissemination criteria. The search yielded 58 references. Six were checked in more detail, and four studies were included. Two were randomized controlled trials (RCTs) testing levodropropizine against dihydrocodeine and moguisteine, and two were nonrandomized placebo-controlled studies, all with important limitations and high risk of bias. Levodropropizine was significantly more effective than placebo in reducing cough frequency and severity, and equally effective as dihydrocodeine or moguisteine. It was generally well tolerated. The authors conclude that the evidence for the antitussive efficacy of levodropropizine in these patients is scarce, and is further limited by the methodological weaknesses of the primary studies. Further well-designed research is needed to support its use.     

What has dry cough in common with pruritus? Treatment of dry cough with paroxetine

Distressing persistent dry cough is commonly the consequence of sensitization of the cough reflex. A slight and transient peripheral nociceptive impulse, such as bronchitis, may be perpetuated for weeks because of sensitization of the cough reflex. Cough usually can be inhibited by opioids, but some types of cough can be out of opioid control or even be induced by opioids. We describe here a series of 5 patients with dry cough that did not respond to codeine. Because two of these patients also suffered with pruritus, paroxetine was tried. In all patients, cough ceased within hours to days. The only observed adverse effect was sleepiness in the first days of therapy. Paroxetine should be investigated as antitussive in cases of opioid-resistant cough. The putative mechanism of action of paroxetine on pruritus and rough is discussed.     

Chronic cough: an approach to management

Management of chronic cough is complex and warrants careful evaluation. Some patients cough for years without help because of the indiscriminate use of antitussive medications. All patients should be evaluated in a specific manner. The cause of cough can be found and effectively treated in almost all patients. Antitussive therapy should only be used as adjuvant therapy or when a cause cannot be found and the patient is not harmed by decreasing the cough. When used, the safest, least expensive antitussive drug should be instituted for a limited time pending re-evaluation of the patient's clinical course.     

Comparative study of two antitussive drugs in the treatment of acute dry cough of infectious origin (prospective,randomized, single blind study)

The objective was to compare, during a 5-day therapy, the efficacy and tolerability of an antihistaminic antitussive syrup, oxomemazine, combining a small quantity of guaifenesine (T), with a centrally acting antitussive, clobutinol (S), in adult patients aged from 18 to 70 years and presenting with a dry cough of infectious origin. This study was performed by 22 general practitioners and 130 ambulatory patients were enrolled. The primary criterion of this multicenter, randomized, single blind study was to compare the evolution of cough intensity using a Visual Analog Squale (VAS) graduated from 0 to 10 cm. Nine secondary criteria including tolerability were also assessed. With regard to cough intensity, the treatments were not equivalent. A greater reduction was observed with T (-5.2 +/- 2.3 versus -4.3 +/- 2.3). This result was confirmed by a further reduction in cough intensity at days: 2 (p = 0.04), 4 (p = 0.05), and 5 (p = 0.02). The frequency of cough disappearance before the end of the study was significantly greater for T than for S: 46% versus 29% (p = 0.05). The time before disappearance of the cough was 4.0 + 1.1 days for both medicines. Induction of sleep and the frequency of nocturnal wakening were significantly better for T from day 4 (p = 0.02). The drowsiness induced by T meant that diurnal quality of life was better with S on days 1 (p = 0.002) and 2 (p = 0.01). Tolerability was similar for both medicines. In conclusion, as a symptomatic treatment of dry cough, T is efficient and well tolerated. Moreover, we have observed a tendency towards superior efficacy of T than S. T is therefore a useful alternative in the therapeutic armamentarium available to the general practitioner.     

Headaches precipitated by cough,prolonged exercise or sexual activity: a prospective etiological and clinical study

Headaches provoked by cough, prolonged physical exercise and sexual activity have not been studied prospectively, clinically and neuroradiologically. Our aim was to delimitate characteristics, etiology, response to treatment and neuroradiological diagnostic protocol of those patients who consult to a general Neurological Department because of provoked headache. Those patients who consulted due to provoked headaches between 1996 and 2006 were interviewed in depth and followed-up for at least 1 year. Neuroradiological protocol included cranio-cervical MRI for all patients with cough headache and dynamic cerebrospinal functional MRI in secondary cough headache cases. In patients with headache provoked by prolonged physical exercise or/and sexual activity cranial neuroimaging (CT and/or MRI) was performed and, in case of suspicion of subarachnoid bleeding, angioMRI and/or lumbar tap were carried out. A total of 6,412 patients consulted due to headache during the 10 years of the study. The number of patients who had consulted due to any of these headaches is 97 (1.5% of all headaches). Diagnostic distribution was as follows: 68 patients (70.1%) consulted due to cough headache, 11 (11.3%) due to exertional headache and 18 (18.6%) due to sexual headache. A total of 28 patients (41.2%) out of 68 were diagnosed of primary cough headache, while the remaining 40 (58.8%) had secondary cough headache, always due to structural lesions in the posterior fossa, which in most cases was a Chiari type I malformation. In seven patients, cough headache was precipitated by treatment with angiotensin-converting enzyme inhibitors. As compared to the primary variety, secondary cough headache began earlier (average 40 vs. 60 years old), was located posteriorly, lasted longer (5 years vs. 11 months), was associated with posterior fossa symptoms/signs and did not respond to indomethacin. All those patients showed difficulties in the cerebrospinal fluid circulation in the foramen magnum region in the dynamic MRI study and preoperative plateau waves, which disappeared after posterior fossa reconstruction. The mean age at onset for primary headaches provoked by physical exercise and sexual activity began at the same age (40 years old), shared clinical characteristics (bilateral, pulsating) and responded to beta-blockers. Contrary to cough headache, secondary cases are rare and the most frequent etiology was subarachnoid bleeding. In conclusion, these conditions account for a low proportion of headache consultations. These data show the total separation between cough headache versus headache due to physical exercise and sexual activity, confirm that these two latter headaches are clinical variants of the same entity and illustrate the clinical differences between the primary and secondary provoked headaches.     

Cough headache: frequency, characteristics and the relationship with the characteristics of cough.

Cough headache (CH) is a relatively rare, but an important complication of cough. The aim of this cross-sectional clinical study was to evaluate the frequency, characteristics and etiology of CH among the patients referred to our Outpatient Department with the complaint of cough, and to investigate the relationship between their cough and headache characteristics. We evaluated 96 females and 69 males, a total of 165 patients with cough. Among those, 57 patients (34.5%) had one or more cough complications and 32 patients (19.3%) were diagnosed as CH. Although it was known that most of the patients with CH had benign headache characteristics, the ratio of the symptomatic CH was not low (37.5% of the CH patients and 7% of patients with cough). Also, there was a significant correlation between the frequency of cough and the severity of headache. Logistic regression analysis showed that the incidence of CH was increased 0.4-fold, when frequency of cough increased. Age, sex, tobacco use ad the duration of cough were not found to be predictive factors for CH. Logistic regression analysis showed that the rate of cough complications increased 2.08-fold, when the duration of cough was longer than eight weeks (p=0.03) and 0.4-fold when the frequency of cough increased (p=0.02). In conclusion, CH is a relatively rare, but an important complication of cough and it commonly has an effective treatment available. Radiological work-up was crucial in ruling out other causes of headache and to confirm that the CH was truly benign.     

The “Other” Headaches: Primary Cough,Exertion, Sex,and Primary Stabbing Headaches

Primary cough headache, primary exertional headache, primary sexual headache, and idiopathic stabbing headache are included in “Other Primary Headaches” (Group 4) in the International Classification of Headache Disorders, 2nd edition (ICHD-II). Headaches provoked by cough, exertion, and sex have different age distributions, but they do share some clinical and pathogenic characteristics. The triggering activities frequently involve Valsalva-like maneuvers, which may explain part of the pathogenesis. Primary stabbing headache is common and characterized by ultra-short stabbing headaches. All these headache disorders respond well to indomethacin, and they are commonly comorbid with migraine except for primary cough headache. Of note, some patients with sexual headache had reversible cerebral vasoconstriction syndromes. Recent large-scaled studies have revealed that the ICHD-II criteria of these four headache disorders cannot be completely fulfilled. Further revisions for the ICHD-II criteria are required based on these results of the evidence-based studies.     

Codeine for acute cough in children

QUESTION: Owing to Health Canada's recent recommendations to avoid the use of over-the-counter cough and cold medications in preschool children, I was looking at other antitussive medications for acute cough. Codeine was recommended in the past for this indication. What is the evidence for its use and how effective and safe is it? ANSWER: Cough is one of the most common symptoms in children, and the opioid codeine has known antitussive qualities mediated by a central nervous system pathway. However, current evidence finds codeine to be no more effective than placebo for acute cough in children. Its safety profile and recent advances in understanding codeine's variable effectiveness prohibit recommending codeine for cough in children.     

Autonomic mechanisms in the heart rate response to coughing

To differentiate between the possible reflex and mechanical components in the heart rate response to cough, eight healthy subjects performed a standardized cough test before and after pharmacological autonomic blockade; to test the clinical usefulness of the cough manoeuvre two groups of diabetic patients (without and with autonomic neuropathy) were compared with a group of age-matched normal subjects. Because of the use of abdominal and expiratory muscles during cough, the cardioacceleratory response was compared with that induced by an intense contraction of the arm muscles (handgrip). The cardioacceleratory response was completely abolished by atropine while propranolol failed to affect it. The diabetic patients with autonomic neuropathy showed a response similar to that after cholinergic blockade. The response was similar to that induced by muscular contraction for 4 s, after which it differed showing a continued cardioacceleration. The patterns of recovery were not different. The cough-induced cardioacceleration is essentially reflex in nature and under cholinergic control; initially the mechanism may be partially related to the intense contraction of abdominal and expiratory muscles; later, the arterial hypotension related to the cough may contribute to the more sustained shortening of the R-R interval. The cough test may be useful for the evaluation of cardiac parasympathetic integrity.     

Dose-response relationship with increasing doses of dextromethorphan for children with cough

BACKGROUND: The efficacy of dextromethorphan (DM) for treating acute cough is uncertain, and its use is not supported by the American Academy of Pediatrics. Nevertheless, DM is often administered to children as an antitussive. DM dosages are based on age rather than body weight, resulting in substantial variability in the relative amount of drug administered. OBJECTIVE: The aim of this work was to determine whether a dose-response relationship existed among a group of children administered a single nocturnal dose of DM for cough due to an upper respiratory tract infection. METHODS: As part of a larger double-blind, placebo-controlled trial of over-the-counter cough medications, children received DM. The administered doses (per manufacturer recommendations) were as follows: ages 2 to 5 years, 7.5 mg; ages 6 to 11 years, 15 mg; and ages 12 to 18 years, 30 mg. This resulted in a range of 0.35 to 0.94 mg/kg per dose. Subjective parental assessments of cough and sleep were obtained using a 7-point Likert-type scale that compared symptoms after medication with symptoms during the prior night (without medication). Three dose ranges were compared as a subset analysis of the group that received DM. RESULTS: Thirty-three patients (19 girls, 14 boys; median [interquartile range] age, 4.90 [2.90-6.80] years; age range, 2.10-16.50 years) received DM and completed the study. No significant differences were found for any of the outcome measures when comparing the effects of different doses of DM, but our observations suggested somewhat more symptomatic relief for patients receiving medium-dose DM (0.45 to <0.60 mg/kg per dose) or high-dose (HD) DM (0.60-0.94 mg/kg per dose) compared with low-dose DM (0.35 to <0.45 mg/kg per dose). Adverse events occurred most often in the HD group. CONCLUSIONS: Although no statistically significant differences were detectable for the outcomes studied, our observations suggest the potential for improved clinical symptom control with increasing doses of DM. Our findings may further suggest that a dose of 0.5 mg/kg should be considered in future assessments of the antitussive effect of DM in pediatric studies, to balance symptomatic relief with the avoidance of adverse events.     

Clues in the Differential Diagnosis of Primary vs Secondary Cough,Exercise, and Sexual Headaches

Activity‐related headaches can be provoked by Valsalva maneuvers (“cough headache”), prolonged exercise (“exertional headache”) and sexual excitation (“sexual headache”). These entities are a challenging diagnostic problem as can be primary or secondary and the etiologies for secondary cases differ depending on the headache type. In this paper we review the clinical clues which help us in the differential diagnosis of patients consulting due to activity‐related headaches. Cough headache is the most common in terms of consultation. Primary cough headache should be suspected in patients older than 50 years, if pain does not predominate in the occipital area, if pain lasts seconds, when there are no other symptoms/signs and if indomethacin relieves the headache attacks. Almost half of cough headaches are secondary, usually to a Chiari type I malformation. Secondary cough headache should be suspected in young people, when pain is occipital and lasts longer than one minute, and especially if there are other symptoms/signs and if there is no response to indomethacin. Every patient with cough headache needs cranio‐cervical MRI. Primary exercise/sexual headaches are more common than secondary, which should be suspected in women especially with one episode, when there are other symptoms/signs, in people older than 40 and if the headache lasts longer than 24 hours. These patients must have quickly a CT and then brain MRI with MRA or an angioCT to exclude space‐occupying lesions or subarachnoid hemorrhage.     

Pharmacology and antitussive efficacy of 4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid (5-trifluoromethyl-pyridin-2-yl)-amide (JNJ17203212), a transient receptor potential vanilloid 1 antagonist in guinea pigs

Transient receptor potential vanilloid 1 (TRPV1) plays an integral role in modulating the cough reflex, and it is an attractive antitussive drug target. The purpose of this study was to characterize a TRPV1 antagonist, 4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid (5-trifluoromethyl-pyridin-2-yl)-amide (JNJ17203212), against the guinea pig TRPV1 receptor in vitro followed by a proof-of-principle study in an acid-induced model of cough. The affinity of JNJ17203212 for the recombinant guinea pig TRPV1 receptor was estimated by radioligand binding, and it was functionally characterized by antagonism of low-pH and capsaicin-induced activation of the ion channel (fluorometric imaging plate reader and electrophysiology). The nature of antagonism was further tested against the native channel in isolated guinea pig tracheal rings. Following pharmacokinetic characterization of JNJ17203212 in guinea pigs, pharmacodynamic and efficacy studies were undertaken to establish the antitussive efficacy of the TRPV1 antagonist. The pK(i) of JNJ17203212 for recombinant guinea pig TRPV1 was 7.14 +/- 0.06. JNJ17203212 inhibited both pH (pIC(50) of 7.23 +/- 0.05) and capsaicin (pIC(50) of 6.32 +/- 0.06)-induced channel activation. In whole-cell patch clamp, the pIC(50) for inhibition of guinea pig TRPV1 was 7.3 +/- 0.01. JNJ17203212 demonstrated surmountable antagonism in isolated trachea, with a pK(B) value of 6.2 +/- 0.1. Intraperitoneal administration of 20 mg/kg JNJ17203212 achieved a maximal plasma exposure of 8.0 +/- 0.4 microM, and it attenuated capsaicin evoked coughs with similar efficacy to codeine (25 mg/kg). Last, JNJ17203212 dose-dependently produced antitussive efficacy in citric acid-induced experimental cough in guinea pigs. Our data provide preclinical support for developing TRPV1 antagonists for the treatment of cough.     

Cough headache: a study of 83 consecutive patients

To delineate the differences in clinical characteristics and evaluate the outcome between primary and secondary cough headache, 83 consecutive patients (59M/24F, mean age 61.5 ± 17.7 years) with cough headache (1.2%) out of 7100 patients in a headache clinic were studied. All of them received brain imaging studies. Most did not have relevant brain lesions ( n  = 74, 89.2%, primary group) except for nine patients (10.8%, the secondary group). Most of the intracranial lesions were located in the posterior fossa ( n  = 6, 67%), including only two patients with Chiari malformation. The primary group had a higher response rate to indomethacin than the secondary group (72.7% vs. 37.5 %, P  = 0.046). Mild to moderate headache intensity and age onset < 50 years predicted a favourable response. At a mean follow-up of 51.4 months, 83.9% of patients with primary cough headache completely remitted. Inconsistent with the proposed International Classification of Headache Disorders, 2nd edn criteria, 10.8% of patients with primary cough headache had headache duration of > 30 min. Clinical features, neurological examinations and drug response could not safely differentiate primary from secondary cough headache. Neuroimaging studies are required in each patient.