Ambulatory BP Monitoring Cheaper, Effective, and Gets Boost

From Heartwire Shelley Wood August 23, 2011 (London, United Kingdom) — A long-time "reference standard" for tricky blood-pressure readings, ambulatory monitoring should now become the go-to test for diagnosing hypertension in all patients, authors of a new analysis say . The study, now published online in the Lancet, was conducted jointly by independent researchers and an expert committee drafting an update to the UK's National Institute for Health and Clinical Excellence (NICE) Hypertension Guideline, officially launching on Wednesday. The guidelines are the first in the world to formally recommend ambulatory blood-pressure monitoring (ABPM) as a "key priority" in diagnosing suspected hypertension, particularly if a clinic BP reading is 140/90 mm Hg or higher, according to the chair of the writing committee. Works Better, Priced Right The Lancet analysis, by Dr Kate Lovibond (National Clinical Guideline Centre, London, UK) et al, shows that using ABPM to diagnose hypertension is not only more effective than testing blood pressure at home or in the clinic, it also saved money in almost every patient group studied. "Historically, ABPM been the reference standard when you've not been quite sure what to do," senior author on the Lancet analysis, Dr Richard J McManus (University of Birmingham, UK), told heartwire . "What we've realized from this and from a systematic review published in BMJ earlier this year is that actually the reference standard is quite a lot better than clinic blood-pressure and to a lesser extent home blood-pressure monitoring at making a diagnosis." Having established efficacy, investigators set out to see whether higher costs offset the value of ABPM--the devices are relatively expensive. "We were reasonably surprised when it showed just how cost-effective the ambulatory monitoring actually is," McManus said. Study coauthor Dr Bryan Williams (University of Leicester, UK), who also chaired the update of the NICE hypertension guidelines, explained that the cost saving comes both from speeding up a diagnosis in someone who needs medication swiftly and from eliminating treatment in people who do not, in fact, have hypertension but have been misdiagnosed in the clinic or at home. "ABPM is likely to eliminate from treatment up to 25% of newly presenting people with elevation of BP," he said. "If you remove the drug costs from those individuals, what we found was that modeling on 100 000 people in the UK that the ABPM would cost about ₤2.5 million to implement in the first year [which includes acquisition of equipment and training of personnel], but after that there was a progressive net gain in terms of cost. By year two it is cost neutral, and by year five this would save ₤10 million." Williams continued: "So what we have here is a situation where we have a more effective way of diagnosing hypertension, it's better for patients, it eliminates unnecessary treatment in a significant number of patients, and at the same time it is potentially cost saving and at worst cost neutral. It's a no brainer to say: why aren't we doing this?" Highest Savings in Older Patients Lovibond, McManus, et al modeled cost-effectiveness in a hypothetical primary-care group undergoing 24-hour BP monitoring instead of clinic-based or home-based tests. They report that ABPM was the most cost-effective strategy across all age groups considered, and in both men in women. The lowest cost savings were in men over 75 years of age (an incremental saving of ₤56) compared with a diagnosis made with a clinic BP test, and highest among women aged 40 (₤323) per hypertension diagnosis. ABPM also came out on top for improving health outcomes in men and women over age 50; in younger subjects, ABPM led to higher cost savings but smaller reductions in quality-adjusted life-years. "The bottom line is that using ABPM as a diagnostic strategy for high BP is both more effective in terms of making a diagnosis and saving costs," McManus said. There are no good data on just how commonly ABPM is used as the go-to test, he added. "We think that less than 5% of patients in the UK have ABPM as part of their diagnosis," he said. "There will be a few people for whom this won't be appropriate, particularly people with accelerated hypertension or people with very high BP who've had a stroke." In those patients, "you want to just get them on treatment, but in most people with suspected hypertension, particularly in the primary-care setting, we think this is the thing to do, and that's a big shift." Other jurisdictions are increasingly looking to the UK's NICE model, because it balances both the evidence base and cost efficacy. Both McManus and Williams stressed that the Lancet paper, as well as the new NICE hypertension guidance, will have a ripple effect, particularly in places like the US, where ABPM is not always reimbursed. "I think this may get people internationally thinking about their diagnostic strategies as well," McManus said. An editorial accompanying the study takes issue with some of the assumptions within Lovibond et al's analysis, saying further studies may be warranted to model specific scenarios, but if anything, writes Dr Thomas A Gaziano (Brigham and Women’s Hospital, Boston, MA), further studies might even strengthen the results. NICE Hypertension Update Also Includes Drug Choices, Age Advice The first NICE hypertension guideline was issued in 2004 and updated in June 2006. The new, simple, 16-page document lists "key priorities," provides a care "pathway," and encompasses different ways to measure and diagnose hypertension, assess risk and target-organ damage, use lifestyle and drug interventions, and educate patients. Speaking with heartwire , Williams pointed to a number of other novel elements of this update. For one, the update recommends the same antihypertensive drug treatment in people over aged 80 as in people aged 55 through 80, a change from previous guidance that urged caution in older subjects, out of concerns that adverse effects might offset benefits. A review of the evidence in older adults suggests there were reductions in stroke, hospitalizations for heart failure, and deaths and "no hint of any adverse offset" when a standard antihypertensive approach was applied, Williams said. Second, in a recommendation that Williams predicts will be hotly debated in the UK, the NICE reviewers reexamined advice for subjects over age 55 and recommend the use of a calcium-channel blocker (CCB) as first-line therapy, with thiazidelike diuretics reserved for patients with edema, CCB intolerance, or evidence of heart failure or at high risk of heart failure. And in a departure from previous recommendations, the new update recommends physicians use a thiazidelike diuretic, such as chlorthalidone or indapamide, in patients starting on or switching diuretics. These drugs should be used "in preference to" what is more commonly the first-line diuretic in the UK, bendroflumethiazide, says Williams, or the most common in the US, hydrochlorothiazide. This will "prompt a lot of debate" not only in the UK, predicts Williams, but in the US as well. References

Anti-TNF Agents and Cancer Risk: What to Tell Patients

From Medscape Rheumatology > Viewpoints Kevin Deane, MD Posted: 08/17/2011 Does Cancer That Occurs During or After Anti-Tumor Necrosis Factor Therapy Have a Worse Prognosis?: A National Assessment of Overall and Site-Specific Cancer Survival in Rheumatoid Arthritis Patients Treated With Biologic Agents Raaschou P, Simard JF, Neovius M, Askling J Arthritis Rheum. 2011;63:1812-1822 Background Shortly after the introduction of anti-tumor necrosis factor (TNF) therapies for rheumatoid arthritis (RA) and other rheumatic diseases, concern was raised that these agents might increase the risk for cancer. Complicating the issue of anti-TNF therapy and cancer risk are biologic mechanisms of TNF that, when blocked, either improve or worsen cancer risk, depending on the type of cancer. Multiple studies have examined the association between anti-TNF therapy and cancer incidence; however, to date, data on the influence of such therapy on cancer outcomes are limited. Therefore, using a large registry of Swedish patients with RA along with controls, Raaschou and colleagues investigated the effects of anti-TNF therapy on cancer staging and survival. A study of this type is possible in Sweden because cancer reporting is mandatory, and the estimated under reporting is < 5%. Study Summary Using the Swedish Patient Register, the authors identified 78,483 patients with RA, treated with or without biologic therapy (nearly all with anti-TNF agents). From this group, 8562 patients started biologic therapy during the study period. The investigators performed a matched analysis of patients with both RA and cancer who were treated with biologic therapies (n = 302, of whom 300 were treated with anti-TNF agents), matched by cancer site, age, sex, and year of cancer diagnosis in a 1:2 fashion with patients with RA and cancer who had not received biologic therapy (n = 586). Cancer stage at diagnosis was similar between groups, although a larger proportion of patients treated with biologics had stage 3 cancer (20% vs 9%) and a smaller proportion had stage 4 cancer than did biologic-naive patients (20% vs 29%). For lung cancer in particular, a greater proportion of biologic-naive patients had stage 4 cancer at diagnosis than did patients treated with biologics (60% vs 26%). Conversely, for melanoma, a greater proportion of patients treated with biologics had stage 2 cancer or higher at diagnosis than did biologic-naive patients (28% vs 0%). In the 302 biologic-treated patients, 113 (37%) deaths occurred; in the 586 biologic-naive patients, 256 (44%) deaths occurred. In adjusted analyses (including accounting for comorbid conditions), no significant differences in overall survival (relative risk 1.1, 95% confidence interval, 0.8-1.6) or survival by specific type of cancer were found between biologic-treated and biologic-naive patients. Also analyzed in an unmatched fashion were the outcomes of first cases of primary cancer in biologic-treated patients (n = 314 cancers) compared with biologic-naive patients (n = 4650 cancers). In these analyses, no significant differences in overall outcomes or cancer-specific outcomes were found between groups. The investigators concluded that cancer outcomes following anti-TNF therapy do not significantly differ, in terms of stage at presentation or survival rates, from those of biologic-naive patients with RA. Viewpoint The findings of this study suggest that the use of anti-TNF agents in patients with RA does not significantly alter cancer stage at presentation or overall survival of patients with incident cancers. However, how these results will influence the management of specific patients in terms of cancer screening approaches or use of biologic therapy after a diagnosis of cancer is still unclear. In particular, what should a rheumatologist do with anti-TNF therapy in a patient who develops cancer? Moreover, does management of biologic therapy depend on the type of cancer -- for example, should patients with lung cancer continue to receive their anti-TNF agent, and should patients with melanoma or hematologic cancers have their therapy discontinued? These questions are not readily answered by this study because most patients discontinued biologic therapy after cancer was diagnosed, and numbers of the various subtypes of cancers were limited. Furthermore, as the author of an accompanying editorial points out, it is not clear how these results apply to all patients with RA, including those in the United States who may have received anti-TNF therapy for less-aggressive disease than what is seen in Europe because of differences in prescribing practices. In terms of applicability to direct patient care, data from this study can be used to counsel patients that if they develop cancer while receiving anti-TNF therapy, the outcomes will not clearly be worse than if they discontinued therapy. However, additional surveillance studies, and perhaps controlled studies where possible, are still necessary going forward to help guide biologic use (especially anti-TNF therapy) after cancer has been diagnosed.

Switching From Simvastatin 80 mg: How to Shop for Statins

From Medscape Internal Medicine > Staying Well With Sandra Fryhofer, MD Sandra A. Fryhofer, MD Clinical Associate Professor of Medicine, Emory University School of Medicine, Atlanta, Georgia; Past President, American College of Physicians, Philadelphia, Pennsylvania Posted: 08/12/2011 Savvy Statin Shopping Let's go shopping. This edition of Staying Well focuses on how to be a savvy shopper in choosing a statin for your patients, a timely issue in light of the US Food and Drug Administration's (FDA's) new simvastatin warnings. Seasoned shoppers always check the sale racks first, but don't buy something -- even if on sale -- if the "size and style" aren't right. Apply this analogy to picking a statin. Although the first thing to look for is price, it should not be the only deciding factor. Simvastatin is certainly one of the cheapest statins, but is it the best choice for your patients? My Personal Disclaimer I admit that I have been a little lazy. For the last several years, when my patients needed statins I always started with simvastatin. It was generic. It was on all the pharmacy plans, so the price point for patients was right. Prescribing was hassle free: no cumbersome forms to fill out and explain. However, the recent FDA warnings about the dangers of high-dose simvastatin and additional warnings about dosing and drug interactions have led me to rethink this strategy and take a closer look at the different statins available. It is now time to find out the facts and make necessary changes in prescribing patterns. Maybe it's time for a new "style" of treatment. Here is some information to help you decide. Statin Characteristics This statin dose equivalency guide gives equivalent doses of available statins along with generic and brand names and selected characteristics (Table 1). Table 1. Statin Dose Equivalency Guide Medication Dose Equivalent Pharmacotherapeutic Factor Metabolism Metabolites Rosuvastatin (Crestor®) 2.5 mg Hydrophilic CYP2C9 Active (minor) metabolite Atorvastatin (Lipitor®) 5 mg Lipophilic P450 3A4 (CYP3A4) Active metabolite Simvastatin (Zocor®)a 10 mg Lipophilic P450 3A4 (CYP3A4) Active metabolite Lovastatin (Altoprev®, Mevacor®) 20 mg Lipophilic P450 3A4 (CYP3A4) Active metabolite Pravastatin (Pravachol®) 20 mg Hydrophilic Renal metabolism No active metabolites Fluvastatin (Lescol®, Lescol® XL) 40 mg Lipophilic CYP2C9 No active metabolites Pitavastatin (Livalo®) 1 mg Lipophilic Little metabolism by CYP3A4 No active metabolites aAlso in combination medications: ezetimibe/simvastatin (Vytorin®) and niacin extended release/simvastatin (Simcor®) Table 2 is from the FDA Drug Safety Communication and gives relative low-density lipoprotein (LDL) efficacy for the different statins. Note that pitavastatin (Livalo®) is a newer statin and was FDA approved in 2009. Table 2. Relative LDL-Lowering Efficacy of Statin and Statin-Based Therapies Atorva Fluva Pitava Lova Prava Rosuva Vytorin®a Simva %↓ LDL-C -- 40 mg 1 mg 20 mg 20 mg -- -- 10 mg 30% 10 mg 80 mg 2 mg 40/80 mg 40 mg -- -- 20 mg 38% 20 mg -- 4 mg 80 mg 80 mg 5 mg 10/10 mg 40 mg 41% 40 mg -- -- -- 10 mg 10/20 mg 80 mg 47% 80 mg -- -- -- 20 mg 10/40 mg -- 55% -- -- -- 40 mg 10/80 mg -- 63% Atorva = atorvastatin; Fluva = fluvastatin; LDL-C = low-density lipoprotein cholesterol; Pitava = pitavastatin; Lova = lovastatin; Prava = pravastatin; Rosuva = rosuvastatin; Simva = simvastatin aNo incremental benefit of Vytorin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established. Data from US Food and Drug Administration. June 8, 2011. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm Association of Pharmacologic Factors With Adverse Effects Statins that are hydrophilic (pravastatin and rosuvastatin) are less likely to cross skeletal muscle membranes and are less likely to cause adverse effects. Statins that don't have active metabolites (fluvastatin, pravastatin, and pitavastatin) are less likely to cause adverse effects. Rosuvastatin has only a minor active metabolite. Drug metabolism pathway plays a role in drug-drug interactions and subsequent safety. This is especially important for patients on multiple medications: For statins metabolized by P450 3A4 (CYP3A4) (simvastatin, lovastatin, atorvastatin), concomitant administration of medications that inhibit the CYP3A4 pathways (protease inhibitors, cyclosporine, amiodarone, fibrates) is problematic. The result is increased statin levels and increased risk for muscle tissue injury. On the other hand, fluvastatin and rosuvastatin (metabolized by CYP2C9) and pravastatin (metabolized by the kidneys) are considered to be safer statin choices for patients on multiple medications.

Bedbugs: An Update on Recognition and Management

From Skin Therapy Letter Robyn S. Fallen, BHSc; Melinda Gooderham MD, MSc, FRCPC Posted: 08/17/2011; Skin Therapy Letter. 2011;16(6) © 2011 SkinCareGuide.com http://www.medscape.com/viewarticle/745992?src=mp&spon=9 Abstract and Introduction Epidemiology Entomology Psychological Consequences Cutaneous Manifestation Diagnostic Considerations Disease Transmission Management Conclusion ABSTRACT The common bedbug (Cimex lectularius) is increasingly prevalent and a source of concern and questions for patients. In addition to a range of cutaneous presentations and potential for serious sequelae, bedbug bites cause significant psychological distress and create an economic burden associated with infestation control. Recognition of characteristic entomology, clinical presentation, diagnostic features and differential diagnosis can support expedient identification of patients exposed to infestations and support their appropriate management. Introduction The common bedbug, Cimex lectularius (C. lectularius), is a hematophagus arthropod. A pest to mankind for centuries, bedbug populations in industrial nations declined steadily with the advent of novel pesticides, improved sanitation practices, and economic conditions. In contrast, infestations in developing countries have persisted.However, pest control companies in Canada and the United States are reporting overwhelming increases in the number of new bedbug encounters compared with 10 years ago. This recent bedbug resurgence has been attributed to evolving pesticide resistance coupled with increased rates of international trade and travel, as travellers can bring the insects home in their clothing and luggage.Bedbugs have since established more widespread infestation of environments serving transient populations such as hotels, dormitories, hospitals, cruise ships, and homeless shelters. In addition to this increased prevalence, bedbugs are also widely discussed in popular media and may be presented as a concern by patients. Awareness of the entomology, diagnosis, and management of bedbugs can assist physicians in detecting affected individuals and providing concerned patients with education on this topic. Management Uncomplicated bedbug bites usually resolve within 1–2 weeks and are self-limited. Although the evidence base is weak, management is otherwise symptomatic. Topical or oral antipruritic agents combined with an intermediate corticosteroid can bring some relief. For some patients, having prescription topicals compounded with menthol and camphor can be soothing. Superinfection can occur, especially in cases with significant excoriation, and can be treated with topical or oral antibiotics.[16] Systemic reactions to bedbug bites are treated with intramuscular epinephrine, antihistamines, and oral corticosteroids, as in insect-induced anaphylaxis.[16] In tandem with the control of symptoms, eliminating the infestation must be aggressively pursued to prevent further bites. Goddard et al. (2009) have outlined several steps that are useful in successful eradication of bedbugs:[16] Proper identification of the bedbugs species Education of the patient, other dwelling occupants, and landlord, as applicable Thorough inspection of both infested and other nearby areas Implementation of pesticide and non-chemical control measures Follow-up to ensure control of the infestation

Osteoporosis: Yesterday, Today and Tomorrow: Rapid Progress, but do not Forget the Simple things

From Rheumatology

Nancy E. Lane

07/11/2011; Rheumatology. 2011;50(7):1181-1183. © 2011

Introduction

Osteoporosis, a disease characterized by low bone strength and fractures that occur with very low-impact loads, has experienced many changes over the past 20 years and we should expect to see many more in the future. Prior to 1990, there was little activity in the field: although there were some small studies with sodium flouride, they set the field back because these compounds improved bone mass but increased bone fragility and fractures. While osteoporosis, or bone fragility, was generally accepted to be part of the normal process of ageing in post-menopausal women, an osteoporotic fracture diagnosed the disease, unfortunately at a very advanced stage.
Until the development of DPA followed by dual-energy X-ray absorptiometry (DEXA), there was no method to determine an individual's risk of an osteoporotic fracture before the event.
However, in 1992, T-scores (S.D.'s above and below peak bone mass) became a way to identify individuals who would, over time, be at increased risk of osteoporotic fractures.
This ability to identify individuals at risk for fractures prior to their occurrence by DEXA, coupled in 1990 with the first studies to find a reduction in incident vertebral fractures with the bisphosphonate etidronate, administered for 2 weeks every 3 months, followed by the approval of the bisphosphonate alendronate in the USA in 1995, really jump-started the field.
Post- and pre-menopausal women and men obtained BMD scans, and, based on a T-score of −1 or below at the lumbar spine or hip, were started on this anti-resorptive agent indefinitely. Over time, other bisphosphonates were approved, initially daily treatment, then weekly, then monthly, followed by i.v. therapies, first every 3 months and now annually
The past decade also saw the approval of the first 'anabolic' or bone-building agent that could increase bone strength by increasing both bone formation and bone resorption. The concept of an anabolic agent that could improve bone strength through increasing remodelling was difficult for the medical community to understand; we learned that the bone matrix is rich in growth factors for osteoblasts including Transforming Growth Factor-β, Insulin Growth Factor-1 and Fibroblast Growth Factor-2. The anabolic agent teriparatide allowed bone strength to increase by adding bone to existing trabeculae. However, with the discontinuation of teriparatide, the new bone would be rapidly lost; the addition of an anti-resorptive agent maintained or even increased BMD.
The addition of an anabolic agent as a treatment for osteoporosis came at nearly the same time as the Women's Health Initiative Study in the USA reported that HRT, while effective in reducing hip fractures and gastrointestinal cancer, had risks of cardiovascular events (MIs, strokes, deep venous thrombosis) that outweighed the benefits.
This dramatically changed how physicians treated post-menopausal women, especially in the prevention of oestrogen-deficient bone loss in early menopause. However, the number of new, generally non-hormonal medications to treat or prevent osteoporosis kept clinicians busy learning the biology of bone metabolism, and most became very good at identifying and prescribing for patients who should be treated for osteoporosis. However, other than the one anabolic agent, teriparatide, there was no information on how long to treat with anti-resorptive agents or information about drug holidays.

The Fracture Intervention Trial Long-term Extension (FLEX) study, sponsored by Merck, determined that women with osteopenia, and a hip T-score above −3.5, treated with alendronate for ~4.5 years, retained the majority of the bone gained at the hip and spine and showed no significant difference in morphometric fractures 5 years after discontinuation compared with subjects who continued treatment.
This information suggested to clinicians that after 5 years a potent anti-resorptive agent could be discontinued, but no guidelines were produced on how to monitor these subjects after therapy was discontinued: this has been left to clinicians to figure out.
In the past 3 years, quite unexpectedly, a number of series of cases of subtrochanteric or atypical fractures have been reported in women treated with bisphosphonates for a number of years. The reports from multiple centres are strikingly similar. The American Society of Bone and Mineral Research convened a task force to investigate the problemand the Food and Drug Administration made recommendations.
One of the major risk factors appears to be the length of time a patient has taken the bisphophonate. While pharmaceutical manufacturers were successful in convincing clinicians that these medications would improve patients' bone strength, no guidance was provided on the length of time that the medication should be prescribed. The Phase III studies carried out to seek FDA approval of the bisphosphonates were only 3 years in duration. However, many of the patients' subtrochanteric fractures had been treated with these medications for much longer.
So we have learnt a lesson in the treatment of osteoporosis: 3 years is effective, and much longer might cause some harm. This story is not finished.
The use of the T-score to identify patients who might be at risk for osteoporotic fractures, and using a T-score of −1 or less as a threshold to treat patients with bone-active medications, was not satisfying. For a woman at menopause, a T-score of −1 might just reflect her peak bone mass.
At her young age, nearly 20 years before, she would be at risk of osteoporotic fractures; medication to prevent osteoporosis might not be worthwhile. The development of the Fracture Assessment Tool (FRAX) has greatly aided clinicians in determining the risk of osteoporotic fracture in individual patients.By sitting with a patient and identifying risk factors on the computer, adding the hip BMD, and then being presented with the 10-year risk of a hip fracture and major osteoporotic fracture, we can identify the most appropriate patients to treat to prevent osteoporotic fractures. The fracture risk thresholds for treatment vary by country; however, the most significant risk factor is age, and with use of the FRAX to identify subjects to treat, we are treating fewer women around the age of menopause.
The future is bright for the development of osteoporosis treatments. New anti-resorptive therapies including denosumab and odanocatib (still in development), to name a few, are potent but have a much shorter half-life in the bone. Denosumab, an inhibitor of Receptor Activator of NF-B Ligand, is given by s.c. injection every 6 months. Odanocatib, an anti-resorptive agent that inhibits the enzyme cathepsin K, a collagenolytic, is given by mouth daily in clinical trials.
A new anabolic agent, also in development, inhibits sclerostin, synthesized primarily in osteocytesterminally differentiated osteoblast cells within the bone matrix, which connect to each other through dendritic processes and to the bone surface. Sclerostin is produced by osteocytes and released into the bone marrow, where it inhibits the maturation of osteoblasts. In rodents, an inhibitor of sclerostin increases bone formation dramatically and has been able to rapidly restore peak bone mass.
Phase II clinical trials are ongoing. However, as with teriparatide, the new bone mass gained from inhibition of sclerostin is lost rapidly, so either maintenance treatment or prolonged use of an anti-resorptive agent will be needed. Agents that can direct mesenchymal stem cells to move to the bone surface and differentiate into osteoblasts to form bone are also in development. This type of therapy may be useful in accelerating fracture healing.
Since 1995, with the approval of alendronate for treatment and prevention of osteoporosis, and the availability of DEXA to determine risk of osteoporosis, clinicians have been busy diagnosing and treating this disease. Today, we have many highly effective agents to improve bone strength, some by reducing remodelling and others by increasing it. We have increased our bone cell vocabulary to include osteoclasts, osteoblasts and even osteocytes. We also know that these cells work together to build and maintain a strong skeleton. In the next few years, we will improve our understanding of osteoporosis and bone fragility, and hopefully refine the length of time we use bone active agents to maximize efficacy and reduce toxicity. However, while medications can improve bone strength, a patient generally has to fall to suffer a hip fracture. Clinicians, almost as a reflex, institute medications to treat osteoporosis, and fail to do an assessment of a patient's risk of falling.
A thorough evaluation for osteoporosis and fracture risk includes: a review of the patient's medications for sedatives/hypnotics that impair balance and increase fall risk; a physical examination to determine muscle strength and balance; and a review of laboratory tests including haemoglobin, haematocrit and electrolytes. Lastly, a review of the home should be done to determine whether there is anything that could increase fall risk. Preventing a fall through the use of an assistive device like a cane or a walker may do as much as any medication.
Going forward, this author would like to believe clinicians will be more thorough in their assessment of fracture risk both with FRAX and an assessment of fall risk, and interventions may be both pharmacological and non-pharmacological. Osteoporosis is a chronic degenerative disease, and screening is recommended at the age of 60 years with risk factors and at the age of 65 years without.
Since most women live into the mid-eighties, clinicians will be monitoring and treating their bone health for 25 years. The unmet need is to understand how to monitor bone strength so that clinicians know when to start, stop and reinstitute medications to maintain skeletal health. We have come a long way, but we have much left to do.

 

Promising Developments in Osteoporosis Treatment

From International Journal of Clinical Rheumatology

Manuel Sosa; Esther González-Padilla

08/02/2011; Int. J. Clin. Rheumatol.. 2011;6(3):325-332. © 2011

• Abstract and Introduction
• New Assessment Tools for Fracture Risks & Treatment Decisions
• Anabolic Agents
• New Resorption Inhibitors
• Future Perspective

Abstract

Osteoporosis is a very common disease that affects both men and women and produces an important burden. Fracture prevention is the primary treatment goal for patients with osteoporosis. There are several treatments available nowadays with anabolic, antiresorptive or dual actions. A great number of new drugs are under study. In this brief review, we highlight the knowledge regarding them so far.

Introduction

The concept of osteoporosis was introduced in 1990 as "a skeletal disorder characterized by low bone mass and compromised bone strength, resulting in increased bone fragility and susceptibility to fracture".This definition comments on the intimate association between fractures and bone strength and provides a useful framework for reviewing recent developments and advances involving the diagnosis and management of individuals with compromised bone strength.Osteoporosis is a very common disease that can occur in populations of all types and ages, having significant physical, psychosocial and financial consequences.
Fracture prevention is the primary treatment goal for patients with osteoporosis.
Several treatments have been shown to reduce the risk of osteoporotic fractures, including those that enhance bone mass and reduce the risk or consequences of falls.
In this article we briefly review some promising new treatments for osteoporosis.

New Assessment Tools for Fracture Risks & Treatment Decisions

New tools have been developed in order to facilitate both the diagnosis and management of bone metabolic diseases. They are useful to estimate the long-term risk of suffering a fracture and sometimes would advise to indicate a treatment or even sometimes to discontinue them. These tools are FRAX®, Study of Osteoporosis Fractures (SOF) and QFracture™.

FRAX & SOF

The WHO developed a computer-generated algorithm, FRAX, which will supply clinicians with a tool to estimate absolute, time-specific fracture risk quantitatively.^[4–6] This useful tool provides country- and ethnic-specific 10-year hip and major osteoporotic fracture (hip, distal forearm, shoulder, vertebral body) risks, based on information entered into the calculator, which is available for free online.^[101] The information requested can be easily obtained from simple questioning; it includes age, sex, weight, height, personal and family history of fracture, current tobacco and alcohol consumption, corticosteroid usage, previous conditions associated with secondary osteoporosis, and history of rheumatoid arthritis. In the USA, bone density values at the hip are also included in the data. Threshold values for the instauration of bone-strengthening medication are established for those individuals who have a 3% or more risk of a hip fracture and/or 20% risk or more of a major osteoporotic fracture. The FRAX calculator is particularly useful for younger, healthy, postmenopausal females with osteopenia, a group of people with a relatively low 10-year fracture risk.
The American SOF Research Group has also created another assessment tool for fracture risk. The SOF model, unlike FRAX, is based only on BMD and age. However, it predicts the 10-year risk of hip and major osteoporotic fracture as well as the FRAX tool in a group of postmenopausal females, 65 years and old.^[7,8] These findings highlight the importance of age as a risk factor for fragility fractures.
Both the FRAX and SOF models have demonstrated that older people with low bone density and a history of fragility fracture are at highest risk for sustaining further fragility fractures.

QFracture

A third tool, named QFracture, was also published recently. It has some similarities to FRAX, and estimates 10-year risks of fracture (major osteoporotic fracture and hip fracture) from a number of risk factors,^[9] accessible free at.^[102] It has the advantage of not requiring densitometry. For a given patient, the estimated risks obtained with both tools can sometimes be similar but sometimes not. The differences between FRAX and QFracture can be seen in Box 1. The exact value of QFracture in the management of osteoporosis and the advantages or disadvantages compared with FRAX need to be studied.
The greater concerns regarding the potential adverse effects and costs of long-term use of antiresorptive agents is likely to be increasing the interest in identifying and treating those individuals who have a significantly increased absolute fracture risk. Fracture assessment tools provide critical quantitative information on fracture risk and may aid in this endeavor.

Future Perspective

Treatment of osteoporosis has changed substantially in recent years. Only 15 years ago, we had calcitonin, estrogen, etidronate and alendronate. Today, the therapeutic arsenal is huge and varied and we have a deeper understanding of the side effects that occur as a consequence of prolonged use of some drugs such as bisphosphonates.
New drugs are emerging for the treatment of osteoporosis, characterized by acting on very specific bone cell physiology, and sometimes it is almost a true therapy with monoclonal antibodies that regulates bone cell pathophysiology. Perhaps the most important aspect that remains is to check there are no major side effects in the long term.

Music Lowers Anxiety and Boosts Mood in Cancer Patients

From Medscape Medical News > Oncology

Roxanne Nelson

August 12, 2011 — Listening to music may have a beneficial effect on anxiety, pain, mood, and quality of life in cancer patients, according to a new Cochrane systematic review.
The findings from the review, which included 30 trials and a total of 1891 patients, suggested that music therapy and music medicine interventions might also have a beneficial effect on heart rate, respiratory rate, and blood pressure in cancer patients.
"The evidence suggests that music interventions may be useful as a complementary treatment to people with cancer," said lead researcher Joke Bradt, PhD, MT-BC, associate professor in the Department of Creative Arts Therapies at Drexel University, Philadelphia, Pennsylvania.
"Music interventions provided by trained music therapists as well as listening to prerecorded music both have shown positive outcomes in this review, but at this time there is not enough evidence to determine if one intervention is more effective than the other," she noted in a release.
Dr. Bradt also pointed out that when patients can't be blinded to an intervention, there is an opportunity for bias when they are asked to report on subjective measures such as anxiety, pain mood, and quality of life. Therefore, these results need to be interpreted with caution.
The researchers point out that the quality of evidence for some outcomes was low because of the small numbers of trials that have been performed. Further trials could help increase certainty in the findings and improve understanding of music's impact on distress, body image, and other aspects, for which research is currently too scarce to draw any conclusions.
 
Therapeutic Across Specialties
During the past 2 decades, there has been an increasing interest and a growth of research on the effects of music and music therapy for medical patients, which encompassed a variety of specialty areas, note the authors. For example, music has been used to lessen anxiety for both adults and children before or during surgical procedures and to decrease tension during chemotherapy or radiation therapy. It has also been used to reduce the adverse effects of treatment, to improve mood, to enhance pain management, to boost immune system functioning, and to improve quality of life.
As recently reported by Medscape Medical News, music therapy can improve the symptoms of depression when added to standard antidepressant treatment.
Music stimulates the mind and triggers images, metaphors, and emotions that often are preconscious by nature, explained the lead author Jaakko Erkkilä, PhD, from the Finnish Centre of Excellence in Music Research, University of Jyväskylä, Finland.

 

Music is kind of an emotional language.

"In other words, music is kind of an emotional language with a lot of abstract, unformed psychic ideas," Dr. Erkkila told Medscape Medical News. "It enriches communication, stimulates and even evokes speech, and through these qualities is an excellent way to deal with and consider mental problems that are emotional by nature. Making music is also a physical activity, thus enabling functioning and bodily communication."
Benefits Mood, Physiologic Responses
In the current review, the Cochrane authors examined the effects of music therapy or music medicine interventions on psychological and physical outcomes in cancer patients with cancer.
A total of 36 references reporting on 30 trials were included in the review. Nine trials included participants who underwent chemotherapy or radiation therapy, 8 examined the effects of music during procedures or surgery, and 13 trials included general cancer patients. In addition, 4 studies evaluated music interventions with pediatric patients.
The results of 16 trials suggest that music therapy and music medicine interventions may have a beneficial effect on anxiety, which is consistent with the findings from 2 previous Cochrane systematic reviews that evaluated the use of music with coronary heart disease patients and the use of music with patients receiving mechanical ventilatory support.
The pooled estimate from 3 trials suggested that music might help improve the mood of people with cancer, but 5 studies that specifically looked at depression did not find evidence of an effect of music.
When looking at physical symptoms, 6 trials showed that music may have a moderate pain-reducing effect, although no effect was noted for fatigue or physical status.
The authors also found evidence that music interventions may have a beneficial effect on several physiologic responses, including reducing heart and respiratory rates. These results are also consistent with findings from another Cochrane systematic review on the use of music with coronary heart disease patients, which also found a reduction in heart rate.
Single trials that were included in this review supported a beneficial effect of music on mean arterial pressure and immunologic function, but not for oxygen saturation level. Furthermore, although the results suggested that music may benefit quality of life, there was no support for an effect on spirituality.
Cochrane Database Syst Rev. 2011;8:CD006911.

Women Smokers Have Higher Risk of Heart Disease Than Men

From Heartwire

Michael O'Riordan

August 11, 2011 (Minneapolis, Minnesota) — A large meta-analysis suggests that the harmful effects of tobacco smoking affect men and women differently. In a study of more than two million people, researchers showed that the pooled adjusted female-to-male relative risk of coronary heart disease in smokers vs nonsmokers is 25% higher in women.

"It's an unusually large study," lead investigator Dr Rachel Huxley (University of Minnesota, Minneapolis) told heartwire . "In the main analysis, there are about 2.4 million people with data on 44 000 coronary heart disease events, and what was very nice about the study is that the results were very consistent across all of the studies. There was no heterogeneity between them, adding to the robustness of the findings. We're pretty confident that the estimate we came up with is a real approximation of the true risk."

If anything, said Huxley, the 25% increased risk might be on the conservative side. Women have not been smoking as long as men, so the true impact of smoking on women's health might not yet have manifested entirely, and women don't smoke as many cigarettes as men when they do smoke. In addition, it's still taboo for women to smoke in many cultures, and as a result women might underreport their smoking habits. "All three factors combined would suggest that the 25% is an underestimate," said Huxley.
The results of the study are published online August 11, 2011 in the Lancet.
 
Females Still a Growth Market for Tobacco Companies
In the analysis, the researchers performed a systematic review and meta-analysis of prospective cohort studies published between 1966 and 2010. Studies that stratified by sex with measures of relative risk for coronary heart disease and current smoking compared with not smoking were included in the analysis.

 

As we all know, prevention is far better and far easier than trying to cure somebody of a habit.

In the 75 cohorts, which included 2.4 million participants, the pooled adjusted female-to-male relative risk ratios of smoking compared with not smoking for coronary heart disease was 1.25 (95% CI 1.12–1.39, p<0.0001). The relative risk ratio increased by 2% for every additional year of study follow-up, a finding that suggests the longer a woman smokes, the greater her risk of developing coronary heart disease compared with a man who has smoked the same length of time.
"If you looked at some countries, such as Asian-Pacific countries, this is still a growth market for tobacco companies, because the prevalence of smoking in women is still in the single digits," said Huxley. "For example, in China, about 60% of men smoke, whereas just 4% to 9% of women smoke. Tobacco-control programs really need to develop a female perspective to dissuade women from starting to smoke in the first place, because women often find it more difficult to quit smoking compared with men."

In an editorial accompanying the published study [2], Drs Matthew Steliga and Carolyn Dresler (University of Arkansas Medical Sciences, Little Rock) point out that coronary heart disease is predicted to remain the leading cause of death globally and is expected to cause approximately 14% of deaths annually by 2030. Most of coronary heart disease is attributable to lifestyle-related factors, including smoking.
"Thus, a large proportion of the most common cause of death worldwide is attributable to behavior or addiction," they write. "Although some people might view this statistic as discouraging, it can also be seen as a great opportunity to reduce the burden of disease through behavior modification and smoking-cessation programs."
The editorialists note that national and international organizations such as the International Network of Women Against Tobacco and the World Health Organization Tobacco Free Initiative are important reference organizations that can help promote more effective tobacco cessation in women.
To heartwire , Huxley said that an understanding of sex differences in smoking-cessation initiatives has not been fully explored. However, researchers are aware there are differences in smoking-related behavior between men and women. Men, for example, start smoking at a younger age, smoke more cigarettes than women, and always have a higher smoking prevalence across different age groups, the lone exception being adolescent and teenage girls.
"That's a particular concern, because more young girls will start to smoke than young boys, so we really do need to develop effective campaigns that can dissuade young girls from starting in the first place," said Huxley. "As we all know, prevention is far better and far easier than trying to cure somebody of a habit."

Curry Spice Offers Hope for Tendinitis Pain

From WebMD Health News

Moira Dower

August 9, 2011 — Curcumin, which gives the curry spice turmeric its bright yellow color, could be helpful in treating painful inflammatory conditions, such as tendinitis and arthritis, according to researchers at the University of Nottingham in the U.K. and Ludwig-Maxmillians University in Munich, Germany. Their studies show that curcumin can be used to suppress inflammation in tendon diseases.
 
Not a Cure
Ali Mobasheri, DPhil, of the University of Nottingham’s School of Veterinary Medicine and Science, who co-led the research, says, "Our research is not suggesting that curry, turmeric, or curcumin are cures for inflammatory conditions such as tendinitis and arthritis. However, we believe that it could offer scientists an important new lead in the treatment of these painful conditions through nutrition."
Turmeric has been used for centuries in traditional Indian, or ayurvedic, medicine as an anti-inflammatory agent and remedy for symptoms related to irritable bowel syndrome and other disorders. Based on its potential anti-inflammatory and antioxidant properties, researchers in several countries are investigating curcumin for use in a variety of diseases, including some types of cancer and cirrhosis of the liver.
 
Blocking Inflammation
The Nottingham-Munich study, due to be published in the Journal of Biological Chemistry, used a culture model of human tendon inflammation to study the anti-inflammatory effects of curcumin on tendon cells. The main objective of the study was to observe the effects that curcumin had on the inflammatory and degenerative properties induced by molecules called interleukins. The results showed that curcumin prevents interleukins from promoting inflammation.
Tendons, the tough cords of fibrous connective tissue that join muscles to bones, are essential for movement because they transfer the force of muscle contraction to bones. However, they are prone to injury, particularly in athletes who overstretch themselves and overuse their joints.
Tendinitis is a form of tendon inflammation that causes pain and tenderness close to the joints, and it is particularly common in the shoulders, elbows, knees, hips, heels, and wrists. Examples of common tendon disease include tennis elbow, golfer’s elbow, and Achilles tendon injury.
The global incidence of tendinitis is on the increase in line with the rise in aging and inflammatory diseases. It is also linked to other arthritic and rheumatic diseases such as rheumatoid arthritis or metabolic diseases such as diabetes.
Nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin or ibuprofen, are used to relieve the pain and inflammation of tendinitis. In more serious cases of tendon injury, steroid injections can be given directly into the tendon sheath to control pain and enable physiotherapy to start. However, NSAIDS and steroids are associated with side effects, such as stomach ulcers, nausea, vomiting, and other problems affecting the digestive system, as well as headaches, drowsiness, and fatigue.

Music Therapy Hits the Right Note for Depression

From Medscape Medical News > Psychiatry

Fran Lowry

August 10, 2011 — Music therapy can improve the symptoms of depression when added to standard antidepressant treatment, according to a study by Finnish researchers published in the August issue of the British Journal of Psychiatry.
"Music therapy is noninvasive, and just 20 biweekly sessions produce a beneficial effect," lead study author Jaakko Erkkilä, PhD, from the Finnish Centre of Excellence in Music Research, University of Jyväskylä, Finland, told Medscape Medical News.
Moreover, "you don't have to be a musician nor musically talented in order to get benefit from this treatment," Dr. Erkkilä said.

Dr. Jaakko Erkkilä

Researchers in Finland have been developing clinical expertise with music therapy in people with psychiatric disorders since the late 1960s, Dr. Erkkila explained.
"In Finland, depression has become a common reason for inability to work and affects 5% to 6.5% of the population. The usual treatment is medication plus psychiatric counseling. Psychotherapy is also effective, but verbal psychotherapy processing can be difficult or insufficient for some people," he said.
Music therapy offers an alternative and is another way to get in touch with emotions and develop relationships. Although it has been found to be effective in some studies, the methods of these studies have been "methodologically insufficient and lacking in clarity," Dr. Erkkilä said.
 
Strong Emotional Experience
In this study, Dr. Erkkilä sought to focus on the utility of music therapy in depressed people of working age, not only because of their socioeconomic importance, but also because research in this group is scarce.
He and his colleagues studied 79 people between 18 and 50 years old who had been diagnosed as having depression. They randomized 33 participants to receive 20 music therapy sessions in addition to their usual treatment for depression, which consisted of antidepressants, 5 to 6 individual psychotherapy sessions, and psychiatric counseling. The other 46 participants received standard treatment only and acted as the control group.
Music therapy consisted of one-on-one sessions with a music therapist, which consisted of free music making with drums and xylophone, as well as talking.
"The idea was to create free music based on the inner feelings of the client in a safe, trustworthy context and then to elaborate on these experiences verbally," Dr. Erkkilä explained.
"From experience, we knew that this kind of working is highly emotional and often leads to strong emotional experiences and insights connected to one's psychopathology."
After 3 months, the researchers found that the participants who received music therapy had showed greater improvement than those who received standard care only.
 
International Debate
For depression, the mean change from baseline in the Montgomery-Asberg Depression rating scale was −6.05 for the controls vs −10.70 for those in the music therapy group (mean difference, 4.65; 95% confidence interval [CI], 0.59 – 8.70; P = .03).
For anxiety, the mean change from baseline on the Hospital Anxiety and Depression Scale was −1.95 for the controls vs −3.77 for those in the music therapy group (mean difference, 1.82; 95% CI, 0.09 – 3.55; P = .04).
For general functioning, the mean change from baseline on the Global Assessment of Functioning scale was 6.92 for the controls vs 11.50 for the music therapy group (mean difference, −4.58; 95% CI, −8.93 to −0.24; P = .04).
The study also found that the treatment response was significantly better in the music therapy group than in the control group.
"There is an active, international debate on depression treatment which centers on whether the antidepressants are good enough forms of treatment or whether psychotherapy or other therapies are needed in addition to medication," Dr. Erkkilä said. "Our study strongly advocates the good effect of combination of medication and therapy. In addition, it strongly advocates the benefit of creative therapy methods, in particular music therapy, in the treatment of depression."
He added that the commitment to music therapy was high in the study.
"It has been noticed in previous music therapy studies as well, that in music therapy trials dropouts are more rare than in many other psychotherapy studies."
Still, the people who will probably benefit the most from the addition of music therapy are those "with natural capacity for symbolic thinking and creative functioning," he said.
 
High Levels of Engagement
Music stimulates the mind and triggers images, metaphors, and emotions that often are preconscious by nature, Dr. Erkkilä suggested.
"In other words, music is kind of an emotional language with a lot of abstract, unformed psychic ideas. It enriches communication, stimulates and even evokes speech, and through these qualities is an excellent way to deal with and consider mental problems that are emotional by nature. Making music is also a physical activity, thus enabling functioning and bodily communication."
UK researchers who commented on this study in an accompanying editorial state, "This is a high-quality randomized trial of music therapy specifically for depression and the results suggest that it can improve the mood and global functioning of people with this disorder."
Anna Maratos, MSc, of the London Foundation Trust, Mike J. Crawford, MD, of Imperial College London, and Simon Procter, MMT(NR), of the National Music Therapy Training Programme, Nordoff Robbins, United Kingdom, write that the playing of musical instruments with the musical therapists was important to the patients who received music therapy.
The editorialists suggest that this activity has 3 interlinked dimensions, which are aesthetic, physical, and relational.
"Above all, music making is social (and hence interpersonal), pleasurable, and meaningful: this may also be why randomised trials of music therapy have shown high levels of engagement with patient groups who are traditionally difficult to engage," they note.
Erkkila and colleagues "lay down a clear marker for the value of music therapy as part of the range of interventions available for the treatment of people with depression," they conclude.


Br J Psychiatry. 2011;199:132-139, 92-93. Abstract Editorial

An Update on Analgesics

From British Journal of Anaesthesia

I. Power

Posted: 08/03/2011; Br J Anaesth. 2011;107(1):19-24. © 2011

 

• Abstract and Introduction
• New Opioid Formulations
• Methadone
• Paracetamol
• Tapentadol
• Dual Oxcarbazepine and COX Inhibitors
• Catecholamine-O-methyltransferase Polymorphisms
• Gabapentin
• Methylxanthines
• Ropivacaine and Neuropathic Pain
• Fentanyl
• Opioid Antagonists
• Naloxone and Oxycodone
• Opiorphin
• The Endocannabinoid System
• Ibudilast
• Antagonism of Opioid-induced Ventilatory Depression by Ampakines
• Conclusion

• References
• Sidebar

Abstract

Recent introduction of new analgesics into the clinic is best described as a slow process with activity classified into two main areas: improving analgesic efficacy/potency and reducing side-effect profile. This review article describes some of the recent advances with an emphasis on use in the acute setting.
In this respect, opioids continue to be the mainstay (but not the only) analgesic and there have been important improvements in their clinical effect profile. For example, tapentadol has been introduced as a mixed opioid and norepinephrine uptake inhibitor which, unlike tramadol, does not require metabolic activation and does not suffer from isomer-dependent pharmacodynamics.
Opioid antagonists have received much attention recently either used alone, methylnaltrexone (s.c) or alvimopan (p.o), or in combination, Targinact (oxycodone/naloxone), and appear to be effective in reducing opioid side-effects such as those in the gastrointestinal tract. Other agents where there has been recent development include the use of gabapentin, methylxanthines, and local anaesthetics. An interesting area of translation of basic research is in the inhibition of breakdown of endogenous opioids with opiorphin, targeting of the endocannabinoid system, and the use of ampakines to obtund opioid-induced side-effects. It is clear that there is still much work to be done, but the need for highly efficacious analgesics with good side-effect profile remains.

Introduction

This article was written as part of Professor Jennifer Hunter's Festschrift entitled 'Anaesthesia and Critical Care in the 21st Century: The First Decade' which will be held in May 2011. I was asked to present an update on analgesics, mainly those used in the 'acute' setting that would give some idea of the advances we have made in alleviating pain after surgery or trauma. My consideration of this was rapidly fashioned by various articles published in the recent past, indicating that for the acute setting, progress in terms of the introduction of new drugs has been incredibly slow.
Woolf in an article about overcoming obstacles to developing new analgesics states that 'despite substantial financial investment by the pharmaceutical industry over several decades, there has been little progress in developing new efficacious and safe analgesics'. Woolf then indicates that this is leading some pharmaceutical companies to consider withdrawing from the acute pain relief market, and that the problem might be a lack of understanding of pain itself. Certainly, there does seem to be a lack of understanding of how to design studies to investigate acute pain relief. This is clearly shown by a recent article entitled 'Getting the pain you expect'.
The problem seems to be our design of studies in many ways, which allows us to accept placebos, 'nocebos' (that is, negative outcomes, see Tracey), and reappraisal effects in humans. Our clinical studies tend to neglect these and to set them aside and Quessyhas addressed this issue in an article entitled 'Where are the new analgesics?' and suggests an alternative approach to early phase analgesic trials using a multivariate input model. Certainly, trial design does seem to be a large part of the problem, but also the issue is that in addressing pain, we must also address safety and efficacy. This was very well demonstrated by the attempts to improve upon the safety profile of non-steroidal anti-inflammatory drugs where by selectively changing the action of drug molecules, the enzyme affected was influenced. The result was that efficacy was improved, but safety markedly affected, so that some of the drugs were withdrawn because of unexpected cardiovascular side-effects.
As a result, senior researchers are now asking the question 'what is this thing called pain?'There is no doubt that when we deal with pain after surgery or trauma, we are dealing with the various classifications proposed by Woolf which include nociceptive: associated with the detection of potentially tissue damaging stimuli; inflammatory: tissue damage; and pathological: damage to the nervous system (neuropathic).
Part of the problem with pain after surgery is that consent renders the patient open to accepting nociceptive damage and anaesthesia, while greatly minimizing and allowing invasive surgery has very little effect on the nociceptive process. Also, after surgery and trauma, these classifications become somewhat blurred as neuropathic pain can appear immediately after a surgical process. In looking for new analgesics that work in the acute setting, there is a problem of having to address many types of pain simultaneously, using the same compounds. We are indeed a long way from Tracey's postulation of making postoperative pain 'pleasant'.
However, Tracey's idea of arranging more suitable studies may well render an individualized approach to the problem of pain possible and produce safer and more effective analgesics.

Analgesia for acute pain relief still tends to be drawn from the traditional opiates, aspirin and the non-steroidal drugs, paracetamol, and local anaesthetics.
The opiates were in wide use as a natural product, and, for example, in the 15th century, 'the Soporific sponge' was mentioned where opium is mixed with various herbal products and then dried, so that the sponge could be warmed later and used for pain relief. 'Opium' was used widely in the 19th century and indeed quoted in the family doctor as 'the best medicine we possess'. In 1803, Serturner assimilated crystals from opium and named them 'morphine' after the Greek God of dreams, Morpheus. Morphine was delivered on the point of a lancet and washed into the wound, injections not yet being available. This moved on until Stein and colleaguesrealized that opioids were part of the physiology of the inflammatory, painful process and suggested that where tissue damage occurred, local anti-inflammatory analgesic opioids were released to aid the repair process.
Opioids have continued to be the mainstay of our armamentarium against pain based on new formulations, mixed preparations, novel norepinephrine inhibitors, and the use of opioid antagonists to address the thorny issue of opioid-related gut side-effects. Each of the evidence-based guidelines that exist about the relief of acute pain address the efficacy and safety in different ways, but the aim has been to improve on the efficacy of drugs like morphine and reduce its drastic side-effects, including nausea, gastrointestinal effects, and acute loss of the patent airway and hence hypoxia. Aspirin was introduced as an attempt to improve upon the palatability profile of the older sodium salicylate and the non-steroidals resulted from that in due time. Paracetamol was made available by an entirely different chemical process, but this routine drug taken by all of us seems to be one of the best analgesics that work from cradle to grave, although smitten by the dire side-effect of liver impairment upon overdose. New drugs such as tramadol and now tapentadol make use of the endogenous pain-modulating pathway that occurs in response to tissue damage, giving the pharmacological site of action for most of our presently used drugs.Opioids work at various sites of the pain pathway but are of course inherent to the modulation of pain physiologically. Non-steroidal anti-inflammatory drugs work at the site of tissue damage and in the central nervous system. The descending pathways from the brain down to the lower sensory pathways for pain depend on various substances, including enkephalins, endorphins, and norepinephrine that have been used for the production of analgesics. The introduction of tapentadol is an example of this. Therefore, attempts need to be made to improve efficacy and reduce side-effects in an individualized fashion. It may be that increased understanding of the genetic role of our pain physiology might allow us to do this and produce individualized approaches to tissue damage and pain, but again we are someway from that at present. One new possibility is the introduction of 'epigenetics in pain and analgesia', which might allow a personalized, individualized approach to pain and tissue damage.
The aim should be to stop viewing morphine, for example, as a two-faced God, Janus, that produces powerful analgesia that is blighted by common, serious, and sometimes life-threatening adverse effects.

for rest of article refer: 
http://www.medscape.com/viewarticle/745129?src=mp&spon=17

WHO Guidelines for Drug-Resistant Tuberculosis Updated

From Medscape Medical News

Nancy A. Melville

August 5, 2011 — New guidelines from the World Health Organization (WHO) on the management of drug-resistant tuberculosis (TB) offer the latest approaches for better control of the disease that claims millions of lives each year.
The guidelines, published online August 4 in the European Respiratory Journal, update recommendations from previous guidelines published in 2008 and are intended to help inform practitioners, particularly those in lower-income settings, of the very latest and most cost-effective standards of care for achieving optimal patient outcomes.
"The updated WHO program guidelines on [multidrug-resistant]-TB are an essential resource for healthcare professionals with a responsibility for TB patient care," stated Mario Raviglione, MD, director of the WHO Stop TB Department in a press release.
"WHO has produced this latest version to reflect important developments in TB, developments that will have a beneficial impact on clinical and operational outcomes."
The guidelines reflect the recommendations of a multidisciplinary panel of TB practitioners, public health professionals, representatives of professional societies, national TB control program staff, guideline methodologists, and other professionals.
Although there are no radical changes from the 2008 guidelines, the new guidelines include some important adjustments and provide the most updated information on issues such as diagnosis, treatment, and monitoring.
The guidelines feature 11 key recommendations for caregivers, including the following:

• Wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone over conventional testing upon patient diagnosis with TB and before treatment initiation to allow for earlier identification of patients with drug-resistant TB. The approach is considered the most cost-effective, and administration of appropriate treatment as quickly as possible is recommended to avoid unnecessary deaths.
• Monitoring patients with sputum smear microscopy and culture, rather than sputum smear microscopy alone, for multidrug-resistant TB (MDR-TB) to detect failure as early as possible during treatment. Users are advised to be aware of differences in the quality of the culture performance because a false-positive result could lead to an unnecessary continuation or modification of treatment and increased risk for toxicity.
• The use of fluoroquinolones and ethionamide, with later-generation fluoroquinolone, rather than earlier-generation forms of the drug recommended for patients with MDR-TB.
• A focus on cost-effective ambulatory models of care that treat patients outside of the hospital rather than hospitalizing them. In addition to reducing the risk for re-infection, the ambulatory care model reduces travel and social isolation for patients.
• For patients with MDR-TB, the minimum duration of treatment has been extended by 2 months from previous guidelines to reflect research showing improved treatment success with the longer duration. Intensive treatment should therefore last at least 8 months, and for those who have not been treated with second-line drugs for TB in the past, treatment should extend to 20 months. The duration may be adjusted for some patients according to their clinical and bacteriologic response.
• Early use of antiretroviral agents for HIV-infected patients with TB who are receiving second-line drug regimens, irrespective of CD4 cell-count, as early as possible (within the first 8 weeks) after initiation of anti-TB treatment.

Tuberculosis claimed as many as 1.7 million lives in 2009, not including those who died from the disease while affected by AIDS. An estimated 3% of new TB cases around the world are MDR-TB — major shortcomings in healthcare systems have led to increasing resistances to anti-TB drugs.
Evidence is said to be particularly lacking in pediatric MDR-TB, the best drug regimens for treatment with isoniazid resistance, extremely drug-resistant TB or non-MDR-TB polydrug resistance, and therapy for symptomatic relief from adverse reactions linked to second-line anti-TB drugs.
The guidelines therefore place a heavy emphasis on the need for more research, while striving to help improve understanding of critical issues, such as duration, composition, and management of treatment, particularly for patients with MDR-TB.
"The new evidence-based WHO guidelines are a milestone clinicians and public health specialists were waiting anxiously to guide their interventions," said Professor G.B. Migliori, head of the Respiratory Infections Assembly at the European Respiratory Society.
"They resulted from an unprecedented collaboration among the top global experts and national program managers who accepted to share data to inform the guidelines."


Eur Respir J. Published online August 4, 2011.

AHA/ASA Issue Scientific Statement on Vascular Dementia

From Medscape Education Clinical Briefs

News Author: Megan Brooks
CME Author: Désirée Lie, MD, MSEd

07/28/2011

Clinical Context

According to the current study by Gorelick and colleagues, by 2025 there will be 1.2 billion persons worldwide who will be 60 years and older. Also, in persons 80 years and older — a fast-growing population in developed countries — approximately 20% experience difficulties in activities of daily living, with cognitive impairment increasing in prevalence with age.
In addition, risk markers for stroke are now understood to be risk markers for Alzheimer's disease and other cognitive impairments. Vascular cognitive impairment (VCI) is a cause of microvascular brain damage, and arterial stiffness and atherosclerotic changes may be common risk factors for VCI.
This statement from the American Heart Association (AHA) and the American Stroke Association (ASA) describes vascular contributions to cognitive impairment and provides recommendations for prevention, treatment, and future research.

Study Synopsis and Perspective

Vascular changes are "important" contributors to cognitive impairment and dementia and should be routinely addressed in clinical practice, according to a new scientific statement from the AHA and ASA.
The 42-page statement, "Vascular Contributions to Cognitive Impairment and Dementia," was published online July 21 in Stroke and will appear in the September print issue of the journal.
The American Academy of Neurology and the Alzheimer's Association have endorsed the statement. The Alzheimer's Association participated in its development.
In comments to Medscape Medical News, Philip B. Gorelick, MD, MPH, cochair of the writing group for the statement and director of the Center for Stroke Research at the University of Illinois College of Medicine at Chicago, said vascular factors "have long been thought to be an important contributor to cognitive decline and dementia in later life."
Still, they have not received as much attention as Alzheimer's disease, "which has been on the center stage of scientific inquiry," he added.
 
Introducing 'Vascular Cognitive Impairment'
Dr. Gorelick and the writing group systematically reviewed published studies, guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and, when appropriate, offer recommendations for care.
"Over time and with careful study, vascular factors have been found to play a role in both vascular and so-called neurodegenerative forms of cognitive impairment such as Alzheimer disease," Dr. Gorelick said.
On the basis of the evidence, the writing group formally introduces the construct of "vascular cognitive impairment" (VCI). This, they say, captures "the entire spectrum of cognitive disorders associated with all forms of cerebral vascular brain injury — solely stroke — ranging from mild cognitive impairment through fully developed dementia.
"The neuropathology of cognitive impairment in later life is often a mixture of Alzheimer disease and microvascular brain damage," the study authors note, "which may overlap and synergize to heighten the risk of cognitive impairment."
In this regard, magnetic resonance imaging and other neuroimaging techniques "play an important role" in detecting and defining VCI, they advise.
 
What's Good for the Heart Is Good for the Brain
It is now "accepted," the team writes, that many of the traditional risk markers for heart disease and stroke are also risk markers for VCI and Alzheimer's disease.
"Stroke and heart disease are linked by a number of cardiovascular risk factors, such as hypertension, hypercholesterolemia, diet, tobacco exposure, and other factors," Dr. Gorelick explained.
"These vascular factors and others may play a causal role in the development of cognitive impairment and dementia in later life."
Carotid intimal-medial thickness and arterial stiffness are "emerging as markers of arterial aging and may serve as risk markers for VCI," the writing group points out.
Detection and control of the traditional risk factors for stroke and cardiovascular disease may help guard against VCI. "We encourage clinicians to use screening tools to detect cognitive impairment in their older patients and continue to treat vascular risks according to nationally- and regionally-accepted guidelines," the study authors write.
"At the very least," Dr. Gorelick said, screening for and treatment of vascular risk factors, including hypertension, hyperglycemia, and hypercholesterolemia, may reduce the occurrence of stroke and heart disease. "There may be an added benefit of prevention and treatment of vascular risk factors — the prevention of cognitive impairment and dementia in later life," he added.

Specifically, in persons at risk for VCI, the writing group concludes that

• Smoking cessation is reasonable (Class IIa; Level of Evidence A);
• Moderation of alcohol intake, weight control, and physical activity may be reasonable (all Class IIb; Level of Evidence B); and
• Use of antioxidants and B vitamins is not useful, based on current evidence (Class III; Level of Evidence A).

For individuals with vascular dementia, they conclude that

• Donepezil can be useful for cognitive enhancement (Class IIa; Level of Evidence A);
• Galantamine can be beneficial for individuals with mixed Alzheimer disease/vascular dementia (Class IIa; Level of Evidence A); and
• The benefits of rivastigmine and memantine are not well established in vascular dementia (Class IIb; Level of Evidence A).

The study authors also note that a Mediterranean-type dietary pattern has been associated with less cognitive decline in several studies and may be reasonable (Class IIb; Level of Evidence B).
Vitamin supplementation is not proven to improve cognitive function, even if homocysteine levels have been positively influenced, and its usefulness is not well established (Class IIb; Level of Evidence B). The effectiveness of antiaggregant therapy for VCI is not well established (Class IIb; Level of Evidence B).
Reached for comment, Thomas Russ, MD, PhD, from the University of Edinburgh, Scotland, said, "This is a clear outline of the difficulties surrounding the rather complicated overlap and interaction between vascular changes and the neuropathological changes of Alzheimer disease both resulting in cognitive impairment and dementia.
"The recommendations for prevention are a useful restatement of the current state of knowledge and a helpful reminder that we need to intervene sufficiently early in a condition which develops over the course of years and decades — ie, middle age," added Dr. Russ, who was not involved in the writing group.


Stroke. Published online July 21, 2011.

Antibiotic More Effective Than Cranberry Prophylaxis to Prevent UTI

From Medscape Education Clinical Briefs

News Author: Laurie Barclay, MD
CME Author: Hien T. Nghiem, MD

07/27/2011

Clinical Context

Among women, urinary tract infections (UTIs) are very common, with almost half of all women reporting at least 1 UTI sometime during their lifetime.
After an initial UTI, 20% to 30% of women have recurrence.
With more than 2 UTIs per year, low-dose antibiotic prophylaxis is often recommended.
Because of the increasing prevalence of uropathogens resistant to antimicrobial agents, it has stimulated interest in cranberries to prevent recurrent UTIs.
The aim of this study by Beerepoot and colleagues was to compare prophylaxis uses with either trimethoprim-sulfamethoxazole (TMP-SMX) or cranberry capsules for prevention of recurrent UTI.

Study Synopsis and Perspective

TMP-SMX is more effective than cranberry capsules for prevention of recurrent UTI in premenopausal women, according to the results of a double-blind, double-dummy non inferiority trial reported in the July 25 issue of the Archives of Internal Medicine.
"The increasing prevalence of uropathogens resistant to antimicrobial agents has stimulated interest in cranberries to prevent recurrent ...UTIs," write Mariëlle A. J. Beerepoot, MD, from the Academic Medical Center in Amsterdam, the Netherlands, and colleagues.
"For premenopausal women with more than 2 UTIs per year, low-dose antibiotic prophylaxis is commonly recommended. However, this may lead to drug resistance not only of the causative microorganisms but also of the indigenous flora."
In this study, 221 premenopausal women with recurrent UTIs were randomly assigned to receive prophylaxis with TMP-SMX, 480 mg once daily, or cranberry capsules, 500 mg twice daily, for 12 months. The main study outcomes were the mean number of symptomatic UTIs during the 12-month period of prophylaxis, the proportion of women who had 1 or more symptomatic UTIs, the median time to first UTI, and development of antibiotic resistance in indigenous Escherichia coli.
Compared with the TMP-SMX group, the cranberry group had a higher mean number of patients with at least 1 symptomatic UTI after 12 months (4.0 vs 1.8; P = .02) and a higher proportion of patients with at least 1 symptomatic UTI (78.2% vs 71.1%). In the cranberry group, median time to the first symptomatic UTI was 4 months, compared with 8 months in the TMP-SMX group.
TMP-SMX resistance after 1 month was present in 23.7% of fecal and 28.1% of asymptomatic bacteriuria E coli isolates in the cranberry group, compared with 86.3% and 90.5%, respectively, in the TMP-SMX group.
Resistance rates for trimethoprim, amoxicillin, and ciprofloxacin in these E coli isolates after 1 month were also increased in the TMP-SMX group. When TMP-SMX was discontinued, resistance returned to baseline levels after 3 months.
In the cranberry group, antibiotic resistance did not increase. Participants tolerated cranberries and TMP-SMX equally well.
"In premenopausal women, TMP-SMX, 480 mg once daily, is more effective than cranberry capsules, 500 mg twice daily, to prevent recurrent UTIs, at the expense of emerging antibiotic resistance," the study authors write.
Limitations of this study include high withdrawal rates, lack of microbiological confirmation of all recurrent UTIs, inability to confirm that all women took the cranberry prophylaxis, and unclear optimal dosage of cranberries.
"From clinical practice and during the recruitment phase of this study, we learned that many women are afraid of contracting drug-resistant bacteria using long-term antibiotic prophylaxis and preferred either no or nonantibiotic prophylaxis," the study authors concluded. "In those women, cranberry prophylaxis may be a useful alternative despite its lower effectiveness."
An invited commentary by Bill J. Gurley, PhD, from the University of Arkansas for Medical Sciences, Little Rock, notes that the comparison may not have been fair regarding dose and bioavailability of active ingredients.
"To date, few botanical dietary supplements have lived up to their claims as effective 'alternative' medicines, and until more is known about phytochemical disposition in humans, efficacy concerns will continue to plague these products," Dr. Gurley writes. "Uncertainty regarding mechanisms of action and adequate dosing regimens underscore many of these concerns. It would appear, however, that cranberry has the potential to dispel some of this uncertainty."


Arch Intern Med. 2011;171:1270-1278, 1279-1280.

Immunohistochemistry Not Effective in Early Breast Cancer Survival

From Medscape Education Clinical Briefs

News Author: Nick Mulcahy
CME Author: Désirée Lie, MD, MSEd

08/01/2011;JAMA. 2011;306:385-393 and 436-437.

Study Highlights

• The study involved 126 US centers between 1999 and 2003.
• Included were women with clinical T1 to T2N0M0 invasive breast carcinoma planning to undergo breast-conserving therapy. These women were not pregnant and had a functional status score of 2 or less.
• Excluded were those who required neoadjuvant therapy, those with prepectoral breast implants, women with concurrent bilateral disease, those with previous axillary dissection, and those with breast cancer not amenable to lumpectomy.
• Bilateral bone marrow aspiration biopsy of the anterior iliac crest was performed immediately before SLN dissection and lumpectomy.
• SLN dissection technique was left at the discretion of individual surgeons.
• Whole-breast irradiation specified in the protocol excluded a third supraclavicular field.
• Total dose for the breast was 45 to 50 Gy administered in tangential fields with coplanar posterior borders.
• IHC for both SLN and bone marrow was performed at a central laboratory on H&E-negative SLNs.
• Pathologists blinded to patient status assessed both specimens for occult metastases.
• Of 5210 patients enrolled between 1999 and 2003, SLNs were identified in 5119 (98.3%).
• 69% of patients were older than 50 years, 83.3% had clinical stage I disease, and 80.1% had invasive ductal carcinoma.
• Median duration of follow-up was 6.3 years, and median tumor size was 1.4 cm.
• 81.2% of patients had estrogen-receptor–positive tumors, and axillary lymph node dissection was performed in 107 (2.1%) with H&E-negative SLNs.
• Of 5119 patients in whom an SLN specimen was identified, 1215 (23.7%) had nodes that were H&E-negative, and 3326 (85.2%) had specimens assessed by IHC.
• Of those patients, 349 (10.5%) had occult metastases.
• Of 3413 patients who underwent bone marrow biopsy, 104 (3.0%) had occult metastases by ICC.
• Increasing tumor size was associated with SLN metastases but not with occult bone marrow metastases.
• At follow-up of 6.3 years, there were 435 deaths and 376 women with disease recurrence.
• Less than 10% of women had overdue follow-up.
• The 5-year overall survival rate was 95.7% among women with immunohistochemical-negative SLNs and 95.1% among women with immunohistochemical-positive SLNs, with no significant difference in overall survival benefit (P = .64).
• Rates of disease-free survival were 92.2% and 90.4%, respectively, for women with negative and positive occult SLN metastases, with no significant differences.
• Immunochemically detected metastases in SLNs were not associated with overall survival or disease-free survival benefit.
• Occult bone marrow metastases were positively associated with overall survival rate (mortality rates were 5.0% for ICC-negative bone marrow specimens and 9.9% for ICC-positive bone marrow specimens; P = .01).
• Overall survival rates were 95.0% in women with ICC-negative bone marrow specimens and 90.1% in women with ICC-positive occult bone marrow metastases (P = .01).
• The 5-year disease-free survival rates were 90.8% for ICC-negative occult bone marrow metastases and 86.7% for ICC-positive occult bone marrow metastases.
• However, when multivariate analysis was applied, the difference in mortality was significant only for women older than 50 years and for those with a tumor size greater than 1.0 cm.
• For the 2 groups, the unadjusted HR for overall survival benefit was 1.94, and the adjusted HR was 1.83.
• Adjuvant systemic therapy did not affect the association between occult SLN or bone marrow metastases.
• The authors concluded that among women with breast-conserving therapy for early-stage breast cancer, immunochemical evidence of SLN metastases was not useful in the prediction of overall survival benefit, but occult bone marrow metastases was associated with overall survival benefit.

Clinical Implications

• In women with breast-conserving therapy for early-stage breast cancer, occult metastases in SLNs are not associated with overall survival or disease-free survival benefit.
• In women with breast-conserving therapy for early-stage breast cancer, occult metastases in bone marrow are associated with overall survival benefit for women older than 50 years with a tumor size of 1.0 cm or greater.

Long-term Health Impacts of Hematopoietic Stem Cell Transplantation Inform Recommendations for Follow-up

From Expert Review of Hematology

Smita Bhatia, MD, MPH

08/01/2011

Abstract

Advances in transplantation techniques and supportive care strategies have resulted in a significant improvement in survival of those who have undergone treatment.
However, hematopoietic stem-cell transplantation (HSCT) survivors are at risk of developing long-term complications, such as endocrinopathies, musculoskeletal disorders, cardiopulmonary compromise and subsequent malignancies.
These complications have a direct impact on the morbidity and mortality experienced by HSCT survivors. Two-thirds of HSCT survivors develop at least one chronic health condition; while a fifth develop severe or life-threatening conditions. HSCT patients who have survived for at least 5 years post-transplantation are at a fourfold to ninefold increased risk of late mortality for as long as 30 years from HSCT, producing an estimated 30% lower life expectancy compared with the general population.
The high burden of morbidity experienced by HSCT survivors makes it critically important that there is standardized follow-up of HSCT survivors at high risk for post-HSCT complications.
The Center for International Blood and Marrow Transplant Research/European Group for Blood and Marrow Transplantation/American Society for Blood and Marrow Transplantation and the Children’s Oncology Group long-term follow-up guidelines offer such standardized care. Future steps include wider dissemination and refinement of these guidelines.

Introduction

Hematopoietic stem-cell transplantation (HSCT) is an established curative option for a variety of hematological malignancies.
Advances in transplantation techniques and supportive care strategies have resulted in a significant improvement in survival: 70–80% of those who survive the first 2 years following HSCT are expected to become long-term survivors.
However, cure or control of the underlying disease is not accompanied by full restoration of health.
HSCT survivors are at risk of developing long-term complications, such as endocrinopathies, musculoskeletal disorders, cardiopulmonary compromise and subsequent malignancies (summarized in Table 1 ).
These complications have a direct impact on the morbidity and mortality experienced by HSCT survivors. The high burden of morbidity experienced by HSCT survivors forms the basis for standardized follow-up of HSCT survivors at high risk for post-HSCT complications.
This article summarizes the magnitude of risk of key long-term complications experienced by HSCT survivors, identifying those at increased risk for these complications owing to host characteristics and therapeutic exposures. The article also describes the current recommendations for follow-up, patterns of healthcare utilization by the HSCT survivors and adherence to these recommendations. Finally, the article identifies the need for future research efforts related to HSCT outcomes, identification of those at highest risk and refinement of the existing follow-up guidelines so that those at the highest risk are targeted.

http://www.medscape.org/viewarticle/747181