Codeine, alone and with paracetamol (acetaminophen), for cancer pain.

BACKGROUND: Pain is very common in patients with cancer. Opioid analgesics, including codeine, play a significant role in major guidelines on the management of cancer pain, particularly for mild to moderate pain. Codeine is widely available and inexpensive, which may make it a good choice, especially in low-resource settings. Its use is controversial, in part because codeine is not effective in a minority of patients who cannot convert it to its active metabolite (morphine), and also because of concerns about potential abuse, and safety in children. OBJECTIVES: To determine the efficacy and safety of codeine used alone or in combination with paracetamol for relieving cancer pain. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2014, Issue 2), MEDLINE and EMBASE from inception to 5 March 2014, supplemented by searches of clinical trial registries and screening of the reference lists of the identified studies and reviews in the field. SELECTION CRITERIA: We sought randomised, double-blind, controlled trials using single or multiple doses of codeine, with or without paracetamol, for the treatment of cancer pain. Trials could have either parallel or cross-over design, with at least 10 participants per treatment group. Studies in children or adults reporting on any type, grade, and stage of cancer were eligible. We accepted any formulation, dosage regimen, and route of administration of codeine, and both placebo and active controls. DATA COLLECTION AND ANALYSIS: Two review authors independently read the titles and abstracts of all studies identified by the searches and excluded those that clearly did not meet the inclusion criteria. For the remaining studies, two authors read the full manuscripts and assessed them for inclusion. We resolved discrepancies between review authors by discussion. Included studies were described qualitatively, since no meta-analysis was possible because of the small amount of data identified, and clinical and methodological between-study heterogeneity. MAIN RESULTS: We included 15 studies including 721 participants with cancer pain due to diverse types of malignancy. All studies were performed on adults; there were no studies on children. The included studies were of adequate methodological quality, but all except for one were judged to be at a high risk of bias because of small study size, and six because of methods used to deal with missing data or high withdrawal rates. Three studies used a parallel group design; the remainder were cross-over trials in which there was an adequate washout period, but only one reported results for treatment periods separately.Twelve studies used codeine as a single agent and three combined it with paracetamol. Ten studies included a placebo arm, and 14 included one or more of 16 different active drug comparators or compared different routes of administration. Most studies investigated the effect of a single dose of medication, while five used treatment periods of one, seven or 21 days. Most studies used codeine at doses of 30 mg to 120 mg.There were insufficient data for any pooled analysis. Only two studies reported our preferred responder outcome of 'participants with at least 50% reduction in pain' and two reported 'participants with no worse than mild pain'. Eleven studies reported treatment group mean measures of pain intensity or pain relief; overall for these outcome measures, codeine or codeine plus paracetamol was numerically superior to placebo and equivalent to the active comparators.Adverse event reporting was poor: only two studies reported the number of participants with any adverse event specified by treatment group and only one reported the number of participants with any serious adverse event. In multiple-dose studies nausea, vomiting and constipation were common, with somnolence and dizziness frequent in the 21-day study. Withdrawal from the studies, where reported, was less than 10% except in two studies. There were three deaths, in all cases due to the underlying cancer. AUTHORS' CONCLUSIONS: We identified only a small amount of data in studies that were both randomised and double-blind. Studies were small, of short duration, and most had significant shortcomings in reporting. The available evidence indicates that codeine is more effective against cancer pain than placebo, but with increased risk of nausea, vomiting, and constipation. Uncertainty remains as to the magnitude and time-course of the analgesic effect and the safety and tolerability in longer-term use. There were no data for children.

Drug therapy for symptoms associated with anxiety in adult palliative care patients.

BACKGROUND: This is an update of the review published on 'Drug therapy for anxiety in adult palliative care patients' in Issue 1, 2004 of The Cochrane Library. Anxiety is common in palliative care patients. It can be a natural response to impending death, but it may represent a clinically significant issue in its own right. It may also result from pain, or other untreated or poorly managed symptoms. When anxiety is severe or distressing drug therapy may be considered in addition to supportive care. OBJECTIVES: This review aimed to identify and evaluate randomised controlled trials examining the effectiveness of drug therapy for symptoms of anxiety in adult palliative care patients. SEARCH METHODS: We searched the following sources: CENTRAL (The Cochrane Library 2012, Issue 2), MEDLINE (1966 to 2012), EMBASE (1980 to 2012), CINAHL (1982 to 2012), PsycLit (1974 to 2000) and PsycInfo (1990 to 2012) for literature pertaining to this topic published in any language using a detailed search strategy. SELECTION CRITERIA: We sought prospective, randomised trials, with or without blinding, involving the use of drug therapy for the treatment of symptoms of anxiety in adult palliative care patients. Pharmacological agents included 5-HT3 receptor antagonists, anxiolytic agents, antiepileptic agents, antidepressive agents, antipsychotic agents, benzodiazepines, butyrophenones, phenothiazines, antihistamines, barbiturates, sedative hypnotics, antiepileptic drugs and beta-blockers. DATA COLLECTION AND ANALYSIS: We identified and excluded six studies using the original search strategy, with a further two studies being identified and excluded for this 2012 update. We therefore identified a total of eight potential studies but none met the criteria for inclusion in this review. MAIN RESULTS: No data were available to enable an assessment to be made of the effectiveness of drugs to treat symptoms of anxiety in palliative care patients. AUTHORS' CONCLUSIONS: There remains insufficient evidence to draw a conclusion about the effectiveness of drug therapy for symptoms of anxiety in adult palliative care patients. To date no studies have been found that meet the inclusion criteria for this review. Prospective controlled clinical trials are required in order to establish the benefits and harms of drug therapy for the treatment of anxiety in palliative care.

Drug therapy for delirium in terminally ill adult patients.

BACKGROUND: Delirium is a syndrome characterised by a disturbance of consciousness (often fluctuating), cognition and perception. In terminally ill patients it is one of the most common causes of admission to clinical care. Delirium may arise from any number of causes and treatment should be directed at addressing these causes rather than the symptom cluster. In cases where this is not possible, or treatment does not prove successful, the use of drug therapy to manage the symptoms may become necessary. This is an update of the review published on 'Drug therapy for delirium in terminally ill adult patients' in The Cochrane Library 2004, Issue 2 ( Jackson 2004). OBJECTIVES: To evaluate the effectiveness of drug therapies to treat delirium in adult patients in the terminal phase of a disease. SEARCH METHODS: We searched the following sources: CENTRAL (The Cochrane Library 2012, Issue 7), MEDLINE (1966 to 2012), EMBASE (1980 to 2012), CINAHL (1982 to 2012) and PSYCINFO (1990 to 2012). SELECTION CRITERIA: Prospective trials with or without randomisation or blinding involving the use of drug therapies for the treatment of delirium in adult patients in the terminal phase of a disease. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality using standardised methods and extracted trial data. We collected outcomes related to efficacy and adverse effects. MAIN RESULTS: One trial met the criteria for inclusion. In the 2012 update search we retrieved 3066 citations but identified no new trials. The included trial evaluated 30 hospitalised AIDS patients receiving one of three agents: chlorpromazine, haloperidol and lorazepam. The trial under-reported key methodological features. It found overall that patients in the chlorpromazine group and those in the haloperidol group had fewer symptoms of delirium at follow-up (to below the diagnostic threshold using the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) and that both were equally effective (at two days mean difference (MD) 0.37; 95% confidence interval (CI) -4.58 to 5.32; between two and six days MD -0.21; 95% CI -5.35 to 4.93). Chlorpromazine and haloperidol were found to be no different in improving cognitive status in the short term (at 48 hours) but at subsequent follow-up cognitive status was reduced in those taking chlorpromazine. Improvements from baseline to day two for patients randomised to lorazepam were not apparent. All patients on lorazepam (n = 6) developed adverse effects, including oversedation and increased confusion, leading to trial drug discontinuation. AUTHORS' CONCLUSIONS: There remains insufficient evidence to draw conclusions about the role of drug therapy in the treatment of delirium in terminally ill patients. Thus, practitioners should continue to follow current clinical guidelines. Further research is essential.

Creation and implementation of a drug discovery and development game.

BACKGROUND AND PURPOSE: Gamification is a commonly employed active-learning technique to increase student engagement and learning. Few games teaching the drug discovery and development process exist. EDUCATIONAL ACTIVITY AND SETTING: A six hour component of the elective course Non-traditional Pharmacy Career Routes focused on drug development. Four of the six hours were devoted to a game designed to mimic the drug discovery and development process. The 17 enrolled students were split into smaller groups designated to represent large pharmaceutical, start-up, or generic companies. The number of resources each group began with varied depending on the type of company they were assigned. Students worked to develop and bring to market the most drugs and gain the most money. To reinforce the reflective and innovative learning process, students created "failure" cards before the game started that had reasons for failures during the drug development process. FINDINGS: Two questions about the drug discovery and development process were on a pre-/post-assessment. The first question was answered correctly by 12 of 16 students on the pre-assessment, while 15 of 17 students answered correctly on the post-assessment. The second question was answered correctly by 13 of 16 students on the pre-assessment and all students on the post-assessment. The students enjoyed playing the game and felt that it helped them to understand the drug development process. SUMMARY: A novel, role-play game that allows students to learn the drug discovery and development process has the potential to be implemented in similar courses.

Adherence with multiple-combination antihypertensive pharmacotherapies in a US managed care database.

OBJECTIVE: The aim of this analysis was to assess the impact of multiple combination therapies on medication possession ratios (MPRs) in an antihypertensive naive population. METHODS: Data were collected using the Integrated Healthcare Information Solution's National Benchmark Database (January 1997 to June 2004). Data from patients who received 2-pill pharmacotherapy with valsartan or valsartan/hydrochlorothiazide (HCTZ) in a fixed-dose combination (FDC) + amlodipine were compared with those from patients who received 3-pill therapy with valsartan + HCTZ + amlodipine as 3 free-drug components. MPR was calculated by dividing the total days' supply for the lower value in the case of individual drug components, or the number of days' supply in the case of FDC, by 365 (the number of days during the 1-year study period the medication regimen was prescribed). A general linear regression was then performed to determine the effect of treatment group on MPR, controlling for the demographic and clinical characteristics. RESULTS: Data from 908 patients were included (527 women, 381 men; mean age, 53.9 years; 2-pill treatment with valsartan + amlodipine, 224 patients; 2-pill treatment with valsartan/HCTZ + amlodipine, 619; and 3-pill therapy with valsartan + HCTZ + amlodipine, 65). The MPR values were 75.4%, 73.1%, and 60.5%, respectively (P = 0.005). MPR improved with age (69.6% in the subset aged 18-<36 years vs 75.2% in the subset aged >or=64 years; P = 0.023). CONCLUSIONS: In these antihypertensive-naive patients with hypertension, MPR decreased with the increase in tablets per regimen, and improved MPR was correlated with increasing age. These findings suggest patient compliance improves with simplified pharmacotherapeutic approaches.

An employer-based cost-benefit analysis of a novel pharmacotherapy agent for smoking cessation.

INTRODUCTION: An employer-based cost-benefit analysis for varenicline versus bupropion was conducted using clinical outcomes from a recently published trial. METHODS: A decision tree model was developed based on the net benefit of treatment to produce a nonsmoker at 1 year. Sensitivity analyses were conducted based on quit rates with placebo and varenicline and the cost of varenicline. RESULTS: Estimated 12-month employer cost savings per non-smoking employee were $540.60 for varenicline, $269.80 for bupropion SR generic, $150.80 for bupropion SR brand, and $81.80 for placebo. Varenicline was more cost beneficial than placebo, which had quit rates of 16.9% or less. The quit rate with varenicline would have to be

Role of corticosteroids in palliative care.

Corticosteroids have been used extensively since cortisone was first synthesized in the 1950s. Glucocorticoids are derived from cortisone and are used in treatments for inflammation, dermatitis, allergic reactions, asthma, hepatitis, lupus erythematosus, nausea, vomiting and inflammatory bowel diseases. In the setting of palliative care, glucocorticoids have many uses, including many symptoms of malignancy, nausea, vomiting, depression, fatigue, anorexia and cachexia.

Novel opioid antagonists for opioid-induced bowel dysfunction and postoperative ileus.

Methylnaltrexone and alvimopan are two new and potentially useful agents in the management of opioid-induced bowel dysfunction and prevention of postoperative ileus. Both agents have promising prokinetic properties and appear to be capable of reversing the effects of opioids on delayed gastrointestinal transit. This article reviews currently available published literature to provide an overview of the clinical trials and to provide insight for the potential use of these agents for patients requiring opioid based analgesia. These compounds represent a new class of compounds that may impact the therapeutics for opioid induced bowel dysfunction as well as postoperative ileus.

Dexmedetomidine: a novel analgesic with palliative medicine potential.

Dexmedetomidine has gained popularity in anesthesia and critical care for use in deep sedation and analgesia due to a combination of its efficacy and safety compared with other available agents (e.g., opioids, benzodiazepines, propofol) conventionally used in these settings. This brief review is meant to introduce this unique agent to the palliative care field, as dexmedetomidine may hold promise for patients in hospice and palliative care settings whose symptoms are refractory to usual therapies. [Be sure to be clear in the abstract that more studies are warranted and its role is not well defined and is complicated by significant drug interactions, invasive i.v. route and has a significant side effect profile.]

Economic evaluations in pain management: principles and methods.

This paper describes how investigators may design, conduct, and report economic evaluations of pharmacotherapy for pain and symptom management. Because economic evaluation of therapeutic interventions is becoming increasingly important, there is a need for guidance on how economic evaluations can be optimally conducted. The steps required to conduct an economic evaluation are described to provide this guidance. Economic evaluations require two or more therapeutic interventions to be compared in relation to costs and effects. There are five types of economic evaluations, based on analysis of: (1) cost-effectiveness, (2) cost-utility, (3) cost-minimization, (4) cost-consequence, and (5) cost-benefit analyses. The six required steps are: identify the perspective of the study; identify the alternatives that will be compared; identify the relevant costs and effects; determine how to collect the cost and effect data; determine how to perform calculation for cost and effects data; and determine the manner in which to depict the results and draw comparisons.

Pharmacotherapy for neuropathic pain.

Refractory neuropathic pain can be devastating to a patient's quality of life. Ideally, the primary goal of therapy would be to prevent the pain, yet even the most appropriate treatment strategy may be only able to reduce the pain to a more tolerable level. Pharmacotherapy is currently the mainstay of treatment in patients with neuropathic pain, although at present the drugs are used on a mainly "off-label" basis. A wide variety of agents are used, especially antidepressants (ie, tricyclic antidepressants, selective serotonin-reuptake inhibitors) and anticonvulsants, but also opioids and tramadol, topical agents (eg, lidocaine), systemic local anesthetics, and anti-inflammatories. Even so, effective pain relief is achieved in less than half of patients with chronic neuropathic pain. In refractory patients, combination therapy using two agents with synergistic mechanisms of action may offer greater pain relief without compromising the side-effect profile of each agent.

Management of opioid-induced gastrointestinal effects in patients receiving palliative care.

Opioid-induced gastrointestinal side effects, namely, nausea and constipation, are bothersome yet often easy to manage. Due to their widespread frequency, it is imperative that prophylactic and treatment modalities be understood. Although many pharmacotherapeutic agents are available with which to prevent or treat these side effects, few randomized, placebo-controlled studies have been conducted in terminally ill patients, thus limiting most treatment decisions to empiric therapies based on extrapolated data. A strong understanding of the pathophysiology of the sequelae is therefore paramount. Common agents administered for nausea are butyrophenones, phenothiazines, metoclopramide, and serotonin-receptor antagonists. Those given to manage constipation are stimulant laxatives and stool softeners, individually or in combination.

Anticipating and treating opioid-associated adverse effects.

Opioids are frequently avoided as viable tools in the management of pain due to perceived dangerous or untoward adverse drug events. Whilst they are relatively safe options for the treatment of pain, side effects and toxicities do exist and should be anticipated by the provider. The central nervous, gastrointestinal, genito-urinary, integumentary, metabolic/endocrine, cardiovascular, pulmonary, hepatic/renal, ocular and immune systems all manifest changes associated with opioid therapy. These adverse events, ranging from nuisance to therapy-limiting, are manageable when addressed quickly and appropriately. Opioids are safe and efficacious analgesics when these effects are considered.

Clinician beliefs about opioid use and barriers in chronic nonmalignant pain.

A survey of the medical directors of multidisciplinary pain clinics and multidisciplinary pain centers listed in the American Pain Society Pain Facilities Directory was conducted to define those pain specialists' beliefs about the role of opioid analgesia in 14 types of chronic nonmalignant pain. Respondents also reported their perceptions of barriers to their prescribing opioids for chronic nonmalignant pain and what they perceived as barriers to opioid prescribing for chronic nonmalignant pain by other, non-pain specialist clinicians in their communities. The respondents are characterized by demographics, disciplines, specialties, and time in practice. The percentage of time that a pharmacist was available in the pain programs also is reported. There is increasing acceptance of opioids for most of the listed types of chronic nonmalignant pain, but the acceptance varies by types of pain syndromes. Opioids were most consistently accepted for sickle cell disease pain and least commonly endorsed for headaches, myofascial pain, and fibromyalgia. Factors that may influence clinicians' perceptions about opioids are discussed.

Antidepressant pharmacotherapy: considerations for the pain clinician.

Antidepressant pharmacotherapy presents many challenges to clinicians dealing with patients suffering from chronic pain. Co-existent depression and pain continues to present clinicians with a plethora of difficult treatment selections. Treated in isolation, each of these disease states can prove difficult to treat. Collectively, depression and pain often present significantly more difficult challenges to the clinician. Antidepressants may be used as a primary treatment modality for depression in a patient dealing with chronic pain. At other times these agents may be used to treat certain specific chronic pain syndromes, possibly in the face of concomitant depression. Clinicians should be aware of the many peculiarities associated with this broad class of medications. Included in this review are considerations for drug selection, dose escalation, and common drug related problems (eg, adverse drug reactions). In addition, attention is paid to the appropriate selection of an agent for use in either the primary management of pain or depression.

Randomized trial to compare the safety and immunogenicity of CSL Limited's 2009 trivalent inactivated influenza vaccine to an established vaccine in United States children.

A trivalent inactivated influenza vaccine (CSL's TIV, CSL Limited) was licensed under USA accelerated approval regulations for use in persons≥18 years. We performed a randomized, observer-blind study to assess the safety and immunogenicity of CSL's TIV versus an established US-licensed vaccine in a population≥6 months to <18 years of age. Subjects were stratified as follows: Cohort A (≥6 months to <3 years); Cohort B (≥3 years to <9 years); and Cohort C (≥9 years to <18 years). The subject's age and influenza vaccination history determined the dosing regimen (one or two vaccinations). Subjects received CSL's TIV (n=739) or the established vaccine (n=735) in the autumn of 2009. Serum hemagglutination-inhibition titers were determined pre-vaccination and 30 days after the last vaccination. No febrile seizures or other vaccine-related SAEs were reported. After the first vaccination for Cohorts A and B, respectively, the relative risks of fever were 2.73 and 2.32 times higher for CSL's TIV compared to the established vaccine. Irritability and loss of appetite (for Cohort A) and malaise (for Cohort B) were also significantly higher for CSL's TIV compared to the established vaccine. Post-vaccination geometric mean titers (GMTs) for CSL's TIV versus the established vaccine were 385.49 vs. 382.45 for H1N1; 669.13 vs. 705.61 for H3N2; and 100.65 vs. 93.72 for B. CSL's TIV demonstrated immunological non-inferiority to the established vaccine in all cohorts.

Faculty perceptions of appropriate faculty behaviors in social interactions with student pharmacists.

OBJECTIVE: To determine faculty and administrator perceptions about appropriate behavior in social interactions between pharmacy students and faculty members. METHODS: Four private and 2 public colleges and schools of pharmacy conducted focus groups of faculty members and interviews with administrators. Three scenarios describing social interactions between faculty members and students were used. For each scenario, participants reported whether the faculty member's behavior was appropriate and provided reasons for their opinions. RESULTS: Forty-four percent of those surveyed or interviewed considered interactions between faculty members and pharmacy students at a bar to be a boundary violation. Administrators were more likely than faculty members to consider discussing other faculty members with a student to be a boundary violation (82% vs. 46%, respectively, P <0.009). A majority (87%) of faculty members and administrators considered "friending" students on Facebook a boundary violation. CONCLUSIONS: There was no clear consensus about whether socializing with students at a bar was a boundary violation. In general, study participants agreed that faculty members should not initiate friendships with current students on social networks but that taking a student employee to lunch was acceptable.

Assessment of adherence, persistence, and costs among valsartan and hydrochlorothiazide retrospective cohorts in free-and fixed-dose combinations.

OBJECTIVES: To assess medication adherence, persistence, and costs between cohorts of patients in managed care settings using a fixed-dose combination (FDC) or individual components (IC) of valsartan and hydrochlorothiazide in an insurance claims database. METHODS: Medical and prescription claims for hypertensive patients using a combination of valsartan and HCTZ were identified from the IHCIS National Managed Care Benchmark Database via a retrospective cohort analysis. Study subjects had at least 110 days prior to start of study medications during which no other antihypertensive medications were prescribed, and were followed for 12 months. Claims for 8711 adult patients were analyzed for adherence, persistence and costs. General linear regression was conducted to detect differences in adherence among groups. Covariates included age, gender, persistence, number on concomitant cardiovascular drugs, and number of cardiovascular diagnoses. RESULTS: Most subjects used an FDC product (N=8150, 93.6%) vs. the IC (N=561, 6.4%). The FDC group had a larger portion of males and less concomitant cardiovascular medications or disease. A random sample of 1628 of the FDC subjects had improved values for medication adherence compared to the IC group (62.1 vs. 53.0%, p<0.001) and persistence values were improved at both 180 days (73 vs. 28%, p<0.001) and 365 days (54 vs. 19%, p<0.001). Both prescription drug costs ($1587 vs. $2050, p<0.001) and medical costs ($3343 vs. $3817, p<0.001) were lower in the FDC cohorts. CONCLUSIONS: The use of fixed-dose therapy in hypertension may lead to increased adherence and persistence with a positive financial impact on both prescription and total medical costs. As with any retrospective claims database analysis, unobserved systematic differences between the two medication groups may exist.