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A phase II study of hydrocodone for cough in advanced cancer
Abstract
Purpose: Cough is a common symptom in advanced cancer. The use of hydrocodone as an antitussive has not been studied previously in this setting. This study evaluates hydrocodone for cough in advanced cancer.
Methods: The results presented are from a phase II study with dose titration.
Setting: Palliative medicine program in a tertiary referral center.
Patients: 25 consecutive patients with cough from irreversible causes, on a stable opioid regimen for the prior 24 hours, and no previous or current use of hydrocodone for cough.
Intervention: 5 mg hydrocodone was administered twice daily. The dose was then titrated daily (maximum: 60 mg/24 h), if needed, until a ³ 50 percent improvement of the frequency of cough was achieved and then maintained for three consecutive days.
Measurements: Cough severity, frequency, complications, and hydrocodone side effects.
Results: 20 persons (10 women and 10 men) completed study evaluation. Median age was 63 years (range: 42-82). Nine patients had lung cancer and seven had lung or pleura metastases; 19 patients had at least 50 percent improvement of their cough frequency. The median best response was 70 percent improvement in the cough frequency (range: 50-90 percent). Median hydrocodone dose associated with the best response was 10 mg/day (range: 5-30 mg/day). Cough severity, frequency, associated symptoms and complications, and activities of daily living improved significantly. Side effects of hydrocodone (dry mouth, nausea, and drowsiness) were tolerable and rated as mild.
Conclusions: Hydrocodone is effective and safe to treat cough in advanced cancer. A starting dose of 10 mg per day in divided doses seems effective. Dose escalation may be required. Most improved within one day.
Methylphenidate (MPH) has been widely misused by children and adolescents who do not meet all diagnostic criteria for attention-deficit/hyperactivity disorder without a consensus about the consequences. Here, we evaluate the effect of MPH treatment on glucose metabolism and metabolic network in the rat brain, as well as on performance in behavioral tests. Wistar male rats received intraperitoneal injections of MPH (2.0 mg/kg) or an equivalent volume of 0.9% saline solution (controls), once a day, from the 15th to the 44th postnatal day. Fluorodeoxyglucose-18 was used to investigate cerebral metabolism, and a cross-correlation matrix was used to examine the brain metabolic network in MPH-treated rats using micro-positron emission tomography imaging. Performance in the light–dark transition box, eating-related depression, and sucrose preference tests was also evaluated. While MPH provoked glucose hypermetabolism in the auditory, parietal, retrosplenial, somatosensory, and visual cortices, hypometabolism was identified in the left orbitofrontal cortex. MPH-treated rats show a brain metabolic network more efficient and connected, but careful analyses reveal that the MPH interrupts the communication of the orbitofrontal cortex with other brain areas. Anxiety-like behavior was also observed in MPH-treated rats. This study shows that glucose metabolism evaluated by micro-positron emission tomography in the brain can be affected by MPH in different ways according to the region of the brain studied. It may be related, at least in part, to a rewiring in the brain the metabolic network and behavioral changes observed, representing an important step in exploring the mechanisms and consequences of MPH treatment.
Hydrocodone/chlorpheniramine is a prescription opioid licensed in the USA for the relief of cough and upper respiratory symptoms associated with allergy or cold in adults, previously contraindicated in children aged < 6 years. We present findings from a modern benefit risk review of hydrocodone/chlorpheniramine use as an antitussive agent in patients aged 6 to < 18 years. A cumulative search of the manufacturer’s pharmacovigilance database covering 1 January 1900–7 August 2017 identified all individual case safety reports (ICSRs) associated with product family name “hydrocodone/chlorpheniramine.” The search was inclusive of all MedDRA system organ classes, stratified by age (< 18 years). A comprehensive review of the scientific literature was conducted on safety and efficacy of opioids for pediatric treatment of cough. Three hundred and ninety-one ICSRs associated with hydrocodone/chlorpheniramine were identified; 35/391 ICSRs were in patients < 18 years of age; 18 were considered serious. Four fatalities were reported in patients 6 to < 18 years; two fatalities involved co-suspect medication azithromycin and two were poorly documented. Our literature search identified no robust efficacy data for hydrocodone/chlorpheniramine in the relief of cough and upper respiratory symptoms associated with allergy or cold in patients aged 6 to < 18 years. As we found no evidence of hydrocodone/chlorpheniramine efficacy in the pediatric population, we conclude that the benefit risk profile is unfavorable. This evidence contributed to the US Food and Drug Administration’s (FDA’s) recent decision that hydrocodone-containing cough and cold medications should no longer be indicated for treatment of cough in patients < 18 years, highlighting the value of proactive re-evaluation of the benefit risk profile of older established drugs.
Background: This is an updated version of the original Cochrane review first published in Issue 9, 2010 on 'Interventions for cough in cancer'. Cough is a common symptom in patients with malignancies, especially in patients with lung cancer. Cough is not well controlled in clinical practice and clinicians have few management options to treat it. Objectives: The primary objective was to determine the effectiveness of interventions, both pharmacological and non-pharmacological, (other than chemotherapy and external beam radiotherapy) in the management of cough in malignant disease (especially in lung cancer). Search methods: For this update, we searched for relevant studies in CENTRAL and DARE (The Cochrane Library); MEDLINE; EMBASE; PsycINFO; AMED and CINAHL to 9 June 2014. In addition, we searched for ongoing trials via the metaRegister of controlled trials (mRCT), ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and the UK Clinical Research Network Study Portfolio. Selection criteria: We selected randomised controlled trials (RCTs) and clinical trials (quasi-experimental trials and trials where there is a comparison group but no mention of randomisation) in participants with primary or metastatic lung cancer or other cancers. Data collection and analysis: Two review authors independently assessed the titles and abstracts of all studies for inclusion, and extracted data from all included studies independently before reaching consensus. A third review author arbitrated on any disagreement. Meta-analysis was not attempted due to the heterogeneity of the studies. Main results: For the original version of the review, 17 studies met the inclusion criteria and examined either brachytherapy, laser or photodynamic therapy (eight studies) or a variety of pharmacological therapies (nine studies). Overall, there was an absence of credible evidence and the majority of studies were of low methodological quality and at high risk of bias. Brachytherapy in a variety of doses seemed to improve cough in selected participants, suggesting that possibly the lowest effective dose should be used to minimise side effects. Photodynamic therapy was examined in one study and, while improvements in cough were observed, its role in relationship to other therapies for cough was unclear. Some indication of positive effect was observed with morphine, codeine, dihydrocodeine, levodropropizine, sodium cromoglycate and butamirate citrate linctus (cough syrup), although all studies had significant risk of bias. For this update, we did not identify any additional trials for inclusion. Two ongoing trials were identified but no study results were available. Authors' conclusions: No new trials were included since the publication of the original version of this review, while 11 new studies that were identified were eventually excluded from this review. Therefore, our conclusions remain unchanged. No practice recommendations could be drawn from this review. There is an urgent need to increase the number and quality of studies evaluating the effects of interventions for the management of cough in cancer.
Patients with advanced lung diseases commonly experience burdensome symptoms like dyspnea, cough, anorexia, fatigue, and comorbid psychiatric symptoms like anxiety and depression that need to be treated aggressively. Progression of these symptoms is associated with diminishing quality of life and impairments in activities of daily living. The pathophysiology, pharmacological as well as non-pharmacological management of symptoms will be discussed. An interdisciplinary palliative care approach is essential to optimally manage distressing symptoms.
1. A new oral liquid formulation combining guaifenesin, pseudoephedrine and hydrocodone is effective in improving the symptoms of common cold. The pharmacokinetic properties of the individual components were evaluated in a randomized, open-label, four-period study in 12 healthy Chinese volunteers following single and multiple doses. The data were compared with data for the individual ingredients in Antuss®.
2. In the single-dose period, exposure levels (AUC and Cmax) for guaifenesin, pseudoephedrine and hydrocodone increased directly as the dose of the oral liquid formulation increased from 5 to 15 mL. Only minor amounts of guaifenesin and hydrocodone were excreted in urine (∼0.10% and 4.66%, respectively). Pseudoephedrine was mainly excreted unchanged, with 44.95% of the dose excreted in urine within 24 h. After multiple dosing, there was no obvious accumulation of any drug, as assessed by AUC. When considering Cmax, there was a trend toward accumulation of hydrocodone and pseudoephedrine. The pharmacokinetic profiles of guaifenesin and pseudoephedrine in the oral liquid formulation were similar to those in the branded preparation, Antuss®.
3. The newly developed oral liquid formulation combining guaifenesin, pseudoephedrine and hydrocodone was safe and well tolerated and might provide a reliable alternative to the branded formulation for patients with common colds.
Advanced disease is associated with much suffering. Emotional, spiritual, and social pains are a significant component of this distress. Alleviation of physical discomforts allows patients to cope with other aspects of suffering. The common symptoms of pain, nausea, and vomiting, respiratory distress, cachexia, delirium, and insomnia readily respond to systematic treatment. The use of pharmacologic and nonpharmacologic tools is described in this chapter.
: Acute bronchitis is a common respiratory infection seen in primary care settings. This article examines the current evidence for diagnosis and management of acute bronchitis in adults and provides recommendations for primary care clinical practice.
A novel abuse deterrent, prolonged release tablet formulation of Hydrocodone for once-daily dosing has been developed, based on the novel proprietary Egalet® ADPREM technology. The tablet is an injection molded polymer system consisting of an erodible matrix in which the Active Pharmaceutical Ingredient (API), such as Hydrocodone, is dispersed. The matrix is partly covered with a water-impermeable, non-erodible shell which leaves both ends of the cylindrical tablet exposed to erosion by the gastrointestinal (GI) fluid. In vivo-in vitro correlation (IVIVC) was initiated and validated with three formulations. A good internal predictability was observed for the three formulations. How the changing conditions in the GI tract influenced in vivo performance of an erosion based product was discussed. The validated IVIVC could be used to optimize the tablet formulation and to obtain a desired profile. In addition, this technique could help to establish the dissolution limits in which a certainty of bioequivalence is calculated. Based on this validated level A IVIVC, dissolution can be used as surrogate of bioequivalence for development, but also scale up post approval changes.
Many patients with lung cancer will develop symptoms related to their disease process or the treatment they are receiving. These symptoms can be as debilitating as the disease progression itself. To many physicians these problems can be the most difficult to manage.
A detailed review of the literature using strict methodologic review of article quality was used in the development of this article. MEDLINE literature reviews, in addition to Cochrane reviews and other databases, were used for this review. The resulting article lists were then reviewed by experts in each area for quality and finally interpreted for content.
We have developed recommendations for the management of many of the symptom complexes that patients with lung cancer may experience: pain, dyspnea, airway obstruction, cough, bone metastasis, brain metastasis, spinal cord metastasis, superior vena cava syndrome, hemoptysis, tracheoesophageal fistula, pleural effusions, venous thromboembolic disease, depression, fatigue, anorexia, and insomnia. Some areas, such as dyspnea, are covered in considerable detail in previously created high-quality evidence-based guidelines and are identified as excellent sources of reference. The goal of this guideline is to provide the reader recommendations based on evidence supported by scientific study.
Improved understanding and recognition of cancer-related symptoms can improve management strategies, patient compliance, and quality of life for all patients with lung cancer.
Context:
Cough is a common distressing symptom in lung cancer patients. Its assessment is hampered by the lack of a validated scale to measure the complex cough experience in this population.
Objectives:
To describe the development and preliminary validation of a scale to measure cough in lung cancer patients.
Methods:
In the first phase, collection of qualitative data from patient interviews, a review of literature, and identification of noncancer cough scales resulted in the development of a pool of 30 items. This item pool was tested for appropriateness of content and breadth of coverage with 18 patients with lung cancer and 25 health care professionals. The second phase was the operationalization/phrasing of items. The final phase was the scale's field testing with 139 patients, 49 of whom repeated the assessment after one week.
Results:
The first phase led to the deletion of several items and the addition of four, resulting in a final scale for field testing of 21 items. In the field testing, the scale was decreased to 10 items, eliminating items on psychometric grounds. The final scale's Cronbach alpha (internal consistency) was 0.86, item to total correlations ranged from 0.40 to 0.76, and test-retest reliability was high (intraclass correlation=0.83).
Conclusion:
We have developed a promising tool to assess cough in lung cancer, but this needs validation, and future studies should determine whether this is a sensitive and responsive tool. A fully validated tool can be used in the clinical assessment of cough in cancer patients, and as a unidimensional impact scale in the measurement of cough as an outcome in intervention studies.
Patients with lung cancer experience significant symptom burden, particularly symptoms of a respiratory nature. Such symptom burden can be distressing for patients and negatively impact their functional status and quality of life. The aim of this review is to evaluate studies of nonpharmacological and noninvasive interventions for the management of respiratory symptoms experienced by patients with lung cancer. In total, 13 studies met the inclusion criteria for this review and included 1383 participants of which 1296 were lung cancer patients. The most frequently assessed and reported symptom was breathlessness (n = 9 studies). Cough and haemoptysis were reported in one study. A variety of outcome measurement tools were used and a broad range of intervention strategies evaluated. Lack of consistency between studies impinged on the ability to combine studies. It is not possible to draw any firm conclusion as to the effectiveness of nonpharmacological interventions for the management of respiratory symptoms in lung cancer. Nonpharmacological interventions may well have an important role to play in the management of some of the respiratory symptoms (or combinations of respiratory symptoms), but more work of higher quality is necessary in the future.
Patients with advanced lung cancer experience a high symptom burden with great impact upon functional status and quality of life and poor long-term survival. Respiratory symptoms, like dyspnea, cough, and hemoptysis, are highly prevalent and cause profound distress at the time of diagnosis and as disease progresses. This review discusses common reversible causes of dyspnea and examines pharmacologic and nonpharmacologic approaches to symptom management of dyspnea, cough, and hemoptysis.
Chronic cough is a disruptive and exhausting symptom, reported as very distressing in a quarter of those in their last year of life. Existing guidelines for management of chronic cough primarily deal with the commonest benign causes of cough: asthma; eosinophilic bronchitis; gastro-oesophageal reflux disease; rhinosinusitis. AIM/DESIGN: to examine what literature evidence exists and formulate recommendations for managing chronic cough in patients with advanced, progressive, life-limiting illnesses.
Electronic databases (MEDLINE, EMBASE, CINAHL, Cochrane Library, Google Scholar); hand-search; grey literature.
Of 11 initially eligible studies, 5 provided evidence at level 2 or better. The small size of these studies, heterogeneity of study population and diversity of interventions and outcome measures used meant that comparison across studies and compilation of guidelines based on high-quality evidence was not possible. Pragmatic recommendations based on available evidence were formulated, drawing on the included studies and, in addition, extrapolating from two other well-designed studies involving patients with chronic cough. They also took into consideration convenience, toxicity and minimizing burden and harm of intervention, as well as considering the potential for disease-directed treatment and the possibility of pharmacological and co-existing benign causes of chronic cough.
These recommendations (Grade D) include simple linctus, therapeutic trial of sodium cromoglycate and then prescription of an opioid or opioid derivative (dextromethorphan, morphine or codeine). Further research is clearly and urgently required in this area for more effective approaches to managing cough, tested in trials that have sufficient size, power and validity.
Cough is a common and distressing symptom in lung cancer patients. The clinical management of cough in lung cancer patients is suboptimal with limited high quality research evidence available. The aim of the present paper is to present a clinical guideline developed in the UK through scrutiny of the literature and expert opinion, in order to aid decision making in clinicians and highlight good practice.
Two systematic reviews, one focusing on the management of cough in respiratory illness and one Cochrane review specifically on cancer, were conducted. Also, data from reviews, phase II trials and case studies were synthesized. A panel of experts in the field was also convened in an expert consensus meeting to make sense of the data and make clinical propositions.
A pyramid of cough management was developed, starting with the treatment of reversible causes of cough/specific pathology. Initial cough management should focus on peripherally acting and intermittent treatment; more resistant symptoms require the addition of (or replacement by) centrally acting and continuous treatment. The pyramid for the symptomatic management starts from the simpler and most practical regimens (demulcents, simple linctus) to weak opioids to morphine and methadone before considering less well-researched and experimental approaches.
The clinical guidelines presented aim to provide a sensible clinical approach to the management of cough in lung cancer. High quality research in this field is urgently required to provide more evidence-based recommendations.
Background:
Cough is a common symptom in patients with malignancies, especially in patients with lung cancer. Cough is not well controlled in clinical practice and clinicians have few management options to treat it.
Objectives:
The primary objective of this review was to determine the effectiveness of interventions, both pharmacological and non-pharmacological, (other than chemotherapy and external beam radiotherapy) in the management of cough in malignant disease (especially in lung cancer).
Search strategy:
Databases searched included: The Cochrane Central Register of Controlled Trials (CENTRAL) and the Database of Abstracts of Reviews of Effectiveness (DARE) (The Cochrane Library issue 4, 2009); MEDLINE (1966 to May 2010); EMBASE (1980 to May 2010); CINAHL (1980 to May 2010); PSYCHINFO (1980 to May 2010); AMED (1985 to May 2010); SIGLE (1980 to May 2010); British Nursing Index (1985 to May 2010); CancerLit (1975 to May 2010). We searched for cough suppressants, antitussives and other drugs with antitussive activity as well as non-pharmacological interventions (see Appendices 1-4 for search terms).
Selection criteria:
We selected randomised controlled trials (RCTs) and clinical trials (quasi-experimental trials, and trials where there is a comparison group but no mention of randomisation) in participants with primary or metastatic lung cancer or other cancers.
Data collection and analysis:
Two review authors independently assessed titles and abstracts of all studies, and extracted data from all selected studies before reaching consensus. A third review author arbitrated with any disagreement. Meta-analysis was not attempted due to the heterogeneity of studies.
Main results:
Seventeen studies met inclusion criteria and examined either brachytherapy, laser or photodynamic therapy (eight studies) or a variety of pharmacological therapies (nine studies). Overall, there was absence of credible evidence and the majority of studies were of low methodological quality and high risk of bias. Brachytherapy seemed to improve cough in a variety of doses in selected participants, suggesting that possibly the lowest effective dose should be used to minimise side effects. Photodynamic therapy was examined in one study, and while improvements in cough were observed, its role over other therapies for cough is unclear. Some indication of effect was observed with morphine, codeine, dihydrocodeine, levodropropizine, sodium cromoglycate and butamirate citrate linctus (cough syrup), although all studies had significant risk of bias.
Authors' conclusions:
No practice recommendations could be drawn from this review. There is an urgent need to increase the number and quality of studies evaluating the effects of interventions in the management of cough in cancer.
Chronic cough is common and distressing, especially against the background of life-threatening illness. It is a symptom that has received scant attention, often eclipsed by pain, breathlessness, nausea and vomiting.
This paper reviews the recent literature in cough research: its mechanism, assessment and management. There is so little research from supportive and palliative care that much of our knowledge is extrapolated from research elsewhere. Objective measurement of cough has been facilitated by advances in measuring devices, while subjective assessment tools including cough-specific quality of life questionnaires are now available. These are practical, simple to use and can be incorporated into daily practice. A few drugs have come in and out of favour but there has been no solid advance in therapeutic options in over a decade.
The availability of simple assessment tools places the imperative on clinicians to be more systematic in assessment of cough and its interventions. The mainstay of oral therapy for symptom control remains dextromethorphan, codeine and morphine. The potential for research is huge: from basic scientific understanding to clinical trials of innovative therapies.
Chronic cough is a debilitating symptom for which patients commonly seek medical attention. Among adult non-smokers who are not taking an angiotensin-converting enzyme inhibitor and have a normal or near normal chest radiograph, postnasal drip syndrome caused by a variety of rhinosinus conditions, asthma and non-asthmatic eosinophilic bronchitis and gastro-oesophageal reflux disease singly or in combination, are the most common diagnoses underlying chronic cough. Pharmacotherapy for chronic cough can be either specific or non-specific. Specific therapy is preferable and the most effective as it is directed at the aetiologies and pathophysiological mechanisms responsible for cough. In contrast, non-specific therapy is used only in limited clinical settings, as it is directed at the symptom rather than underlying aetiologies and aims only to control, rather than eliminate cough.
GOALS/OBJECTIVES: To review the scientific evidence on cough associated with tumors in the lungs.
MEDLINE literature review (through March 2004) for all studies published in the English language, including case series and case reports, since 1966 using the medical subject heading terms "cough" and "lung neoplasms."
Primary bronchogenic carcinoma is the most common lethal neoplasm in the United States. Malignancies that arise in other organs will often metastasize to the lungs. Any form of cancer involving the lungs may be associated with cough. However, cough is far more likely to indicate involvement of the airways than the lung parenchyma because of the location of cough receptors. Cough is present in >65% of patients at the time lung cancer is diagnosed, and productive cough is present in >25% of patients. While cough as a presenting symptom of lung cancer is common, many studies have shown that lung cancer is the cause of chronic cough in <or=2% of all patients who present with a chronic cough.
Bronchoscopy is usually indicated when there is suspicion of airway involvement by a malignancy. Conversely, bronchoscopy usually should not be performed to assess a cough for the possibility of lung cancer when there is little risk for lung cancer (nonsmokers) and when there are normal findings on a plain chest radiograph. If the lung cancer can be removed surgically, cough will usually abate. Radiation therapy, chemotherapy (especially with gemcitabine), and endobronchial treatment methods likely will improve cough caused by lung cancer. Centrally acting narcotic antitussive agents are usually administered for the control of cough caused by lung cancer when other treatment methods fail.
The common cold is a viral illness that affects persons of all ages, prompting frequent use of over-the-counter and prescription medications and alternative remedies. Treatment focuses on relieving symptoms (e.g., cough, nasal congestion, rhinorrhea). Dextromethorphan may be beneficial in adults with cough, but its effectiveness has not been demonstrated in children and adolescents. Codeine has not been shown to effectively treat cough caused by the common cold. Although hydrocodone is widely used and has been shown to effectively treat cough caused by other conditions, the drug has not been studied in patients with colds. Topical (intranasal) and oral nasal decongestants have been shown to relieve nasal symptoms and can be used in adolescents and adults for up to three days. Antihistamines and combination antihistamine/decongestant therapies can modestly improve symptoms in adults; however, the benefits must be weighed against potential side effects. Newer nonsedating antihistamines are ineffective against cough. Topical ipratropium, a prescription anticholinergic, relieves nasal symptoms in older children and adults. Antibiotics have not been shown to improve symptoms or shorten illness duration. Complementary and alternative therapies (i.e., Echinacea, vitamin C, and zinc) are not recommended for treating common cold symptoms; however, humidified air and fluid intake may be useful without adverse side effects. Vitamin C prophylaxis may modestly reduce the duration and severity of the common cold in the general population and may reduce the incidence of the illness in persons exposed to physical and environmental stresses.
Cough is a common symptom in cancer. Its underlying cause should be managed when identified; otherwise, empiric treatment is the mainstay of symptom control. Cancer-related cough usually responds to radiation therapy, an opioid, or benzonatate, a peripheral anesthetic. We present the case of a patient with renal cell carcinoma hospitalized for intractable cough that failed to respond adequately to usual treatments, but improved with diazepam.
A multivariate analysis of the data was conducted to evaluate the effects of age, gender, and performance status on symptom profile. A comprehensive prospective analysis of symptoms was conducted in 1,000 patients on initial referral to the Palliative Medicine Program of the Cleveland Clinic. The median number of symptoms per patient was 11 (range 1-27). The ten most prevalent symptoms were pain, easy fatigue, weakness, anorexia, lack of energy, dry mouth, constipation, early satiety, dyspnea, and greater than 10% weight loss. The prevalence of these 10 symptoms ranged from 50% to 84%. Younger age was associated with 11 symptoms: blackout, vomiting, pain, nausea, headache, sedation, bloating, sleep problems, anxiety, depression, and constipation. Gender was associated with 8 symptoms. Males had more dysphagia, hoarseness, >10% weight loss and sleep problems; females, more early satiety, nausea, vomiting, and anxiety. Performance status was associated with 14 symptoms. Advanced cancer patients are polysymptomatic. Ten symptoms are highly prevalent. Symptom prevalence for 24 individual symptoms differs with age, or gender, or performance status.
Cough is a common symptom in advanced cancer. Hydrocodone is the antitussive of choice in our palliative medicine inpatient unit. We reviewed the pharmacy records for the use of hydrocodone for all cancer admissions to our unit from May 1996 to December 1998. Median treatment duration with hydrocodone was three days (range 1-18). Median maximum daily dose was 15 mg (range 5-100), and median total dose during the hospital stay was 32 mg (range 5-455). Lung cancer as a primary cancer site was strongly related to the use of hydrocodone. The highest median duration of treatment (five days) was for esophageal cancer and the highest median maximum daily dose (35 mg) and total dose (75 mg) were for treating kidney cancer. This retrospective review provides information regarding the use of hydrocodone on the palliative medicine unit of the Cleveland Clinic Foundation. Controlled trials are needed to evaluate the efficacy and safety of hydrocodone for cough in advanced cancer.
Lung cancer is the most common cancer and kills more people than any other malignancy. We describe the symptoms experienced in persons with lung cancer. Data on 100 consecutive patients were collected prospectively using a standard assessment tool. The median number of symptoms was nine. The most common and severe symptoms were pain (86), dyspnoea (70) and anorexia (68). There were no differences between males and females. Males aged 64 and under had higher incidences of easy fatigue, taste changes and sleep problems. Men over 64 had higher incidences of cough and >10% weight loss. Although there was a general increase in the number of symptoms as the performance status worsened, those with the poorest performance status reported the fewest symptoms. Since there is little effective treatment for most lung cancers, clinical management, research and resources should be directed by, and targeted to, palliative care.
The cough reflex originates from stimulation of sensory nerve endings located in the upper and lower respiratory tract. Opiates are among the most potent and widely used drugs which inhibit the cough reflex, and it has been generally assumed that they act generally. However, opioid receptors have been identified on the sensory arm of the vagus nerve. Although the functional significance of these receptors is not clear, recent evidence suggests that their activation may be involved in the modulation of airway reflexes. This review briefly examines the evidence to support the hypothesis that opioid receptors on vagal sensory nerves may mediate peripheral opioid-induced antitussive activity.
We describe the symptoms, physical findings, treatment interventions, risk factors, and length of survival in persons with pancreatic cancer referred to a palliative care service (PCS) in a tertiary care facility. Data were collected prospectively over a 2-yr period using a standard clinical assessment tool in 39 patients with unresectable pancreatic cancer. Common symptoms include pain (82%), anorexia (64%), early satiety (62%), xerostomia and sleep problems (both 54%), and weight loss (51%). Analyzed retrospectively, 82% had at least one known risk factor for the development of pancreatic cancer. Twenty-five people presented to the PCS within 1 mo of diagnosis; in this group, length of survival was analyzed according to the presence of specific symptoms, and a significant inverse relationship between the presence of dyspnea and length of survival was found. As there is no effective treatment for surgically unresectable pancreatic cancer, palliation of common symptoms should be the primary emphasis of therapy.
To evaluate the efficacy and prevalence of side effects of hydrocodone versus codeine in acute pain syndromes. TYPE OF PARTICIPANTS/SETTING: Sixty-two consecutive adult emergency department patients 18 to 70 years old with acute musculoskeletal pain. Patients using other analgesics or having any contraindication to opioid therapy were excluded. In addition, 12 patients were excluded because of insufficient data or study dropout. DESIGN/INTERVENTIONS: In a randomized, double-blind prospective manner, patients received either 5 mg hydrocodone with 500 mg acetaminophen or 30 mg codeine with 500 mg acetaminophen to take on discharge from the ED and every four hours thereafter as needed for pain.
Pain intensity was evaluated by a visual analog scale at zero, one, two, four, eight, 24, and 48 hours. Specific side effects were sought, along with the number of patients reporting inadequate analgesia.
Data were obtained on 50 subjects (25 per group). Mean and median pain scores did not differ significantly at time zero (x vs y, 6.03 vs 5.99 and 6.8 vs 6.1, respectively) or subsequent intervals. Side effects were noted in eight hydrocodone/acetaminophen and 18 codeine/acetaminophen patients (P = .005). No significant differences in gastrointestinal side effects were reported; however, less nausea or vomiting was reported in the hydrocodone group (P = .23). Central nervous system side effects (sedation or lightheadedness) were reported in six hydrocodone/acetaminophen patients compared with 16 codeine/acetaminophen patients (P less than .005). In addition, no hydrocodone/acetaminophen patients reported inadequate analgesia compared with six codeine/acetaminophen patients (P less than .05).
Although pain scores were not significantly different, hydrocodone may be a more effective analgesic than codeine in acute musculoskeletal pain, as demonstrated by significantly fewer treatment failures. Central nervous system side effects are less common with hydrocodone than with codeine.
In advanced cancer, when cure is impossible, symptoms should be the focus of attention. We report the first prospective, systematic analysis of the severity of 37 symptoms in 1000 patients with advanced cancer, using the Paradox relational database. Pain, easy fatigue, and anorexia were consistently among the 10 most prevalent symptoms associated with cancer at all sites. When pain, anorexia, weakness, anxiety, lack of energy, easy fatigue, early satiety, constipation, and dyspnea were present 60%-80% of patients rated them as moderate or severe, i.e. of clinical importance. The most common symptoms were also the most severe. In general the same symptoms were clinically important at most primary sites. Clinically important dyspnea, hoarseness, hiccough, and dysphagia were more common in men; anxiety, nausea, vomiting, and early satiety in women. Clinically important dyspepsia, nausea, and vomiting occurred more frequently in gynecological cancers.
Among women, cancers of the lung and bronchus, breast, and colon and rectum are expected to account for more than half of all cancer deaths in 1998 (Fig. 2). In 1987, lung cancer surpassed breast cancer as the leading cause of cancer death in women, and it is expected to account for 25% of all cancer deaths in women in 1998. Although lung cancer mortality in men is leveling off, the mortality rate and the number of deaths from lung cancer in women are steadily increasing. Between 1990 and 1994, the lung cancer mortality rate in women increased about 1.7% per year.3 Conversely, the numbers of deaths of women from breast and colorectal cancers appear to be leveling off and may be beginning to decline. These sites account for 16% and 11%, respectively, of cancer deaths in women (Fig. 2). Between 1990 and 1994, mortality rates in women decreased about 1.8% per year for breast cancer and 1.5% per year for colorectal cancers.3
Chronic cough is a distressing symptom experienced by approximately 37% of patients with advanced cancer. Palliation of chronic nonproductive cough should always first address the underlying cause but in some patients chronic, nonproductive cough persists and antitussive agents are required. Opioids are the gold standard cough suppressants, of which codeine is the most widely used; patients with an opioid-resistant cough often prove to be a therapeutic challenge. We report three patients with an opioid-resistant cough who achieved symptomatic relief with the peripherally acting nonopioid drug benzonatate.
Nonproductive cough is a frequent and distressing symptom in patients with lung cancer, and it is not even relieved by palliative chemotherapy. A double-blind, randomized clinical trial regarding the treatment of nonproductive cough was performed in 140 adults with primary lung cancer or metastatic cancer of the lungs. The therapeutic efficacy and the tolerability of a 7-day treatment with levodropropizine drops (75 mg t.i.d.) were evaluated in comparison with dihydrocodeine drops (10 mg t.i.d.; 7 days). Efficacy was assessed on the basis of cough severity scores, number of night awakenings due to cough, and overall estimate of antitussive efficacy. Tolerability was evaluated by laboratory results, vital signs and any adverse event occurring during the clinical trial, including presence or absence of somnolence. Subjective cough severity was significantly reduced during treatment with either levodropropizine and dihydrocodeine, the antitussive effect and its time-profile being similar for both drugs. Also, according to the investigator's evaluation, both levodropropizine and dihydrocodeine produced a significant decrease in cough severity. Concurrently with the relief of cough, the number of night awakenings was decreased significantly by both drugs, with no difference between the two treatments. No change in laboratory test values was considered clinically relevant, and vital signs were not clinically affected. The number of patients reporting adverse events was similar in the levodropropizine (n=6) and dihydrocodeine (n=4) group. However, the percentage of patients experiencing somnolence in the group receiving levodropropizine (8%) was significantly lower as compared with that of the dihydrocodeine group (22%). These results confirm the antitussive effectiveness of levodropropizine and suggest a more favourable benefit/risk profile when compared to dihydrocodeine.
Prediction of future suffering could improve palliative care. To identify the factors contributing to physical symptoms, a prospective study was performed on two series of hospice inpatients with cancer (n = 150 and n = 200, respectively). Physical symptoms, patients' characteristics, and tumor locations were recorded using a structured protocol on admission and throughout the clinical course. Common symptoms on admission and during the patient's course were pain (65%, 88%), general malaise (58%, 77%), anorexia (57%, 94%), constipation (33%, 71%), dyspnea (33%, 66%), nausea/vomiting (29%, 48%), cough/sputum (29%, 48%), edema (27%, 65%), fever (26%, 70%), abdominal swelling (26%, 42%), and dry mouth (25%, 61%), respectively. The mean number of symptoms was 5.7 +/- 3.0 on admission and 9.6 +/- 3.1 during the course. Factors that contributed to the symptoms were young age (pain, abdominal swelling, dry mouth), performance status (anorexia, general malaise, edema, dyspnea), brain tumor (paralysis), neoplasms of lung/pleura (dyspnea, cough/sputum, death rattle), bone metastasis (pain, paralysis), gastric/pancreas cancer (abdominal swelling), peritoneal metastasis (general malaise, edema, nausea/vomiting, abdominal swelling, dry mouth), opioids (constipation, dry mouth, myoclonus), anticholinergics (dry mouth), and antidopaminergics (myoclonus). Opioid requirement was positively correlated with the presence of bone metastasis, and negatively correlated with age and brain involvement. Additional opioids were frequently used in the final 48 hours in cases with lung/pleura neoplasms. These data suggest that terminal symptoms in cancer patients are determined by local and/or general factors. Clinicians can predict the probability of future symptoms from patients' characteristics, general condition, tumor locations, and medications.