Are pharmacologic agents the answer? Or will study lead to new considerations that don't merely mask the problem?

Health

Gene find could lead to drug for chronic back pain

 

Lower back pain can be a chronic, lifelong condition

for many people

A gene responsible for chronic pain has been identified, with scientists saying this could lead to drugs for treating long-lasting back pain.

Writing in the journal Science, University of Cambridge researchers removed the HCN2 gene from pain-sensitive nerves in mice.Deleting the gene stopped any chronic pain but did not affect acute pain.
About one in seven people in the UK suffer from chronic pain, which can also include arthritis and headaches.

The researchers say their findings open up the possibility that new drugs could be developed to block the protein produced by the HCN2 gene, which regulates chronic pain. The HCN2 gene, which is expressed in pain-sensitive nerve endings, has been known for several years, but its role in regulating pain was not understood.

For the study, the researchers removed the HCN2 gene from pain-sensitive nerves. They then carried out studies using electrical stimuli on these nerves in cell cultures to determine how they were altered by the removal of HCN2.

"Individuals suffering from neuropathic pain often have little or no respite because of the lack of effective medications” - Prof Peter McNaughton University of Cambridge

They then studied genetically modified mice in which the HCN2 gene had been deleted.  By measuring the speed that the mice withdrew from different types of painful stimuli, the scientists were able to conclude that deleting the HCN2 gene abolished neuropathic pain.  However, they found that deleting HCN2 did not affect normal acute pain - which occurs suddenly, for example when biting one's tongue.

'No respite'
 
Chronic pain comes in two main varieties. Inflammatory pain occurs when a persistent injury, such as a burn or arthritis, results in very sensitive nerve endings which increase the sensation of pain.

Neuropathic pain occurs when nerves are damaged, causing ongoing pain. This type of chronic pain, which is often lifelong, is surprisingly common and is poorly treated by current drugs, the study says.  It is often seen in patients with diabetes and shingles, and in the aftermath of cancer chemotherapy. It is also common in lower back pain and other chronic painful conditions.

Professor Peter McNaughton, lead author of the study and head of the department of pharmacology at the University of Cambridge, said there was now hope for these people.

"Individuals suffering from neuropathic pain often have little or no respite because of the lack of effective medications. Our research lays the groundwork for the development of new drugs to treat chronic pain by blocking HCN2."

He added: "Many genes play a critical role in pain sensation, but in most cases interfering with them simply abolishes all pain, or even all sensation."


"What is exciting about the work on the HCN2 gene is that removing it - or blocking it pharmacologically - eliminates neuropathic pain without affecting normal acute pain. This finding could be very valuable clinically because normal pain sensation is essential for avoiding accidental damage."

Dr Brian Hammond, chairman of charity BackCare, said the findings of the study were good news.

"Any effective treatment which relieves the suffering of chronic pain is to be welcomed. Treatment which helps reduce pain but still leaves the body's warning mechanisms intact is a major breakthrough."
The study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC), and the European Union.

A word of caution.........

 

NSAID Use Linked to Miscarriage

By Charles Bankhead, Staff Writer, MedPage Today Published: September 06, 2011 Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

The risk of spontaneous abortion more than doubled (OR 2.43) in women who used any nonsteroidal anti-inflammatory drugs (NSAIDs) during pregnancy, Canadian investigators found. Analysis by type of NSAID showed that women who took diclofenac had the highest odds ratio for spontaneous abortion (OR 3.09, 95% CI 1.96 to 4.87), whereas users of rofecoxib had the lowest risk (OR 1.83, 95% CI 1.24 to 2.70), Anick Bérard, PhD, of the University of Montreal, and co-authors reported online in CMAJ. The authors found no association between spontaneous abortion and NSAID dosage. "Given that the use of nonaspirin NSAIDs during early pregnancy has been shown to increase the risk of major congenital malformations and that our results suggest a class effect on the risk of clinically detected spontaneous abortion, nonaspirin NSAIDs should be used with caution during pregnancy," they wrote in conclusion. An estimated 17% of women use nonaspirin NSAIDs during pregnancy, despite persisting controversy surrounding gestational use of the drugs. The strongest evidence of potential harm has come from studies of NSAID use around the time of conception, suggesting women took the drugs to alleviate cramping, which often precedes miscarriage, the authors wrote in their introduction. No studies to date had examined the association between NSAIDs and miscarriage according to drug and dosage. Bérard and co-authors sought to address that gap in the data by reviewing NSAID use in a large cohort of pregnant women. The investigators analyzed records in the Quebec Pregnancy Registry, which has accumulated data on all pregnancies in Quebec since 1997. The registry is linked to several administrative databases, including one that contains prospectively collected information on medical services provided, prescriptions, physician diagnoses, and other aspects of patient care. The analysis included all women ages 15 to 45 on the first day of gestation and who had continuous coverage by the provincial drug plan during pregnancy for at least 12 months beforehand. Women who had planned abortions, had spontaneous abortion before 20 weeks of gestation, or who had exposure to known teratogens before 20 weeks' gestation were excluded from the study. NSAID exposure was defined as at least one filled prescription after the start of pregnancy or a prescription filled before pregnancy and overlapping with pregnancy. Each patient with a spontaneous abortion was matched with 10 women who did not miscarry during pregnancy. Of 67,160 initially included in the analysis, 4,705 had spontaneous abortions and were matched with a control group of 47,050 women. Almost three times as many women who miscarried had at least one prescription for nonaspirin NSAIDs during pregnancy as compared with the control group (7.5% versus 2.6%, P<0.05). Spontaneous abortion was associated with older age, residence in urban areas, reliance of social assistance, a higher comorbidity burden, increased use of healthcare resources in the year before pregnancy, fewer prenatal visits, and increased medication use. Naproxen was the most commonly used NSAID, among both the women who miscarried and those who did not (2.8% versus 0.9%), followed by ibuprofen (1.3% versus 0.6%), rofecoxib (0.8% versus 0.3%), diclofenac (0.7% versus 0.2%), and celecoxib (Celebrex, 0.6% versus 0.2%). Women in the study group also were more likely to have prescriptions for two or more NSAIDs (0.6% versus 0.2%). After adjusting for multiple confounders, the investigators found that women who had spontaneous abortions were more than twice as likely to use NSAIDs during pregnancy (OR 2.43, 95% CI 2.12 to 2.79). Limiting NSAID use to the two weeks before spontaneous abortion, the authors found the odds ratio increased to 3.47 (95% CI 2.01 to 6.00). The authors acknowledged several limitations of their findings: lack of data on use of nonprescription NSAIDs, inability to document whether a filled prescription was actually used, lack of information on the indication for NSAIDs, and exclusion of spontaneous abortions that were not clinically detected. The study was supported by the Fonds de la recherche en santé dur Quebec and the Réseau Québécois de recherche sur l'usage des médicaments. The authors had no relevant disclosures.

Primary source: CMAJ Source reference: Nkhai-Pour HR, et al "Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion" CMAJ 2011; DOI:10.1503/cmaj.110454.

More published reports again demonstrate need for quality sleep and health risks associated with the lack of it:

 

From Heartwire

Less Restorative Sleep Ups Risk of Hypertension

Lisa Nainggolan

 

September 5, 2011 (San Diego, California) — A new report shows, for the first time, that older men who spend the least time asleep in the so-called slow wave sleep (SWS) phase are more likely to develop hypertension than those who spend the most time in SWS [1].

Those in the lowest quartile for duration of SWS had almost twice the risk of high blood pressure (BP) compared with those in the highest quartile, even after adjustment for all potential confounders, including other sleep disorders, say Dr Maple M Fung (San Diego Veterans Affairs Healthcare System, CA) and colleagues in their paper published online in Hypertension.

"This article adds to the growing body of literature that associates sleep architecture with metabolic and physiologic changes that may reflect altered neurohormones and inflammatory markers," note the authors. "Further studies are needed to confirm these observations . . . and determine whether modifications in SWS improve hypertension."

"Our study shows for the first time that poor quality sleep, reflected by reduced slow wave sleep, puts individuals at significantly increased risk of developing high blood pressure, and that this effect appears to be independent of the influence of breathing pauses during sleep," says coauthor Dr Susan Redline (Brigham and Women's Hospital, Boston, MA) in a statement by the American Heart Association [2].
Restorative SWS May Influence Nocturnal BP 
 
Fung and colleagues explain that human sleep is divided into rapid eye movement (REM) and nonREM (NREM) sleep, and that NREM is further divided into three stages: N1, N2, and N3. N3, also known as SWS, is restorative and the stage associated with the highest arousal threshold.

SWS has been implicated in memory and overnight improvements in perceptual and visuomotor performance and learning, but its full importance remains to be elucidated, say the researchers. SWS has also been associated with transient metabolic, hormonal, and physiological changes that affect glucose metabolism, and is associated with decreased sympathetic nervous system activity and increased vagal tone. "These, in turn, are associated with decreased heart rate and blood pressure, which may influence nocturnal BP profiles. The disappearance of a nocturnal 'dipping' BP pattern is known to increase the risk of hypertension and CVD," they observe.

In their study--in which polysomnography was used to monitor measures of sleep-disordered breathing, sleep duration, and sleep architecture--Fung and colleagues followed 784 community-dwelling men aged >65 years (mean 75.1 years), who participated in the Outcome of Sleep Disorders in Older Men study and did not have hypertension at the time of their in-home polysomnography (2003–2005). Participants completed questionnaires to assess demographics and other risk factors.

The men returned for follow-up in 2007–2009; 243 met the criteria for incident hypertension (>140/90 mmHg), after a mean follow-up of 3.4 years.

After adjustment for age, nonwhite race, study site, and body mass index, the only sleep index to remain significantly associated with incident hypertension was percentage of SWS (odds ratio 1.83 for lowest to highest quartile of SWS). No further attenuation of this association was seen after accounting for sleep duration, sleep fragmentation, and indices of sleep-disordered breathing.

SWS May Be the Critical Component Affecting BP
 
"To our knowledge, this is the first large-scale analysis of comprehensive polysomnography data that assesses the association of indices of three key sleep domains: sleep-disordered breathing (apnea), sleep duration, and sleep architecture to incident hypertension in an elderly cohort," say the authors.

"Our study suggests that a specific reduction of SWS rather than nonspecific sleep disruption may be a . . . critical factor that influences BP," they conclude.

Redline says: "People should recognize that sleep, diet, and physical activity are critical to health, including heart health and optimal blood pressure control. Although the elderly often have poor sleep, our study shows that such a finding is not benign. Poor sleep may be a powerful predictor for adverse health outcomes. Initiatives to improve sleep may provide novel approaches for reducing hypertension burden."

Fung discloses previous grant support from Forest Laboratories, and currently owns stock and is employed by Amgen. Coauthor Anconi-Israel is a consultant for Ferring Pharmaceuticals, GlaxoSmithKline, Johnson & Johnson, Merck, NeuroVigil, Pfizer, Philips, Purdue Pharma LP, Sanofi-Aventis, and Somaxon Pharmaceuticals.

Now a new reason to have white coat syndrome when seeing a doctor: Are our hospitals causing us to get sick?

 

Hospital Uniforms Teeming With Germs, Study Finds

By John Gever, Senior Editor, MedPage Today Published: September 04, 2011 Reviewed by Zalman S. Agus, MD; Emeritus Professor University of Pennsylvania School of Medicine.

More than 60% of physicians' coats and nurses' uniforms sampled in a major Israeli hospital tested positive for disease-causing bacteria, including methicillin-resistant Staphylococcus aureus, researchers said. For 63% of the 60 physicians and 75 nurses at Hebrew University's Shaare Zedek Medical Center in Jerusalem in the study, at least one spot sampled on their outer clothing carried pathogenic bacteria, according to Yonit Wiener-Well, MD, and colleagues there. These bacteria were isolated from half of the total of 235 samples taken from participants' coats, uniforms, and scrub suits, the researchers reported in the September issue of the American Journal of Infection Control.     Most of the participants indicated that they changed their uniforms daily and that their clothing's hygiene was fair or better.  Wiener-Well and colleagues cautioned that the frequency of bacterial transmission from healthcare workers' clothing to patients is unknown. Nevertheless, they wrote, "we believe that data suffice to formulate recommendations regarding ... workers' uniforms." Wiener-Well and colleagues called for daily uniform changes, adequate laundering, plastic aprons for situations in which workers may contact body fluids, and strict hand hygiene. "Wearing short-sleeved coats or even having physicians discard their white coats could further reduce the cloth-borne transmission of pathogens," they added. The researchers were following up previous studies that had found bacterial contamination on a variety of clothing articles worn by physicians, nurses, and other healthcare workers. Participants were essentially a convenience sample of staff working when the sampling was conducted. Wiener-Well and colleagues indicated that more than 95% of eligible staff agreed to participate. Uniforms worn in the wards were sampled at the middle abdomen and either at the sleeve end or, for short-sleeved garments, the side pockets. Operating room scrub suits were only sampled at the abdominal site because they lacked sleeves and pockets. The sampling was conducted on 26 white coats, 77 two-piece uniforms, and 32 scrub suits. In addition, four unworn uniforms straight from the hospital laundry were sampled as controls. Pathogenic bacteria included S. aureus, enterobacteria, and Pseudomonas and Acinetobacter species. The researchers also tested specifically for antibiotic-resistant species including MRSA, vancomycin-resistant enterococci, extended spectrum beta-lactamase producing enterobacteria, meropenem-resistant Acinetobacter, and Pseudomomas resisting gentamicin, ciprofloxacin, and ceftazidime. Just under 60% of participants said their garments were fresh that day, whereas 18% admitted that they hadn't been changed in four or more days. Only physicians' white coats were in the latter category, as scrub suits and nurses' uniforms were required to be changed daily. Nearly one-quarter of participants rated their clothing as not clean. Nevertheless, this apparently poor hygiene did not translate to greater pathogen burden. The number of cultures containing the disease-causing bacteria did not appear to vary substantially with cleanliness self-ratings or with the reported frequency of attire changes. Likewise, similar rates of pathogen contamination were seen in scrub suits, white coats, and uniforms. Acinetobacter species were the most common pathogens found, identified in 37% of samples. Others included S. aureus (13%) and enterobacteria (8%). Antibiotic-resistant strains were found in 6% of the physician samples and 14% of those taken from nurses' clothing. No pathogens were found on the unworn control uniforms, although benign skin bacteria were isolated. Wiener-Well and colleagues speculated that inadequate hand hygiene was at least partly responsible for the contamination they discovered. Limitations to the study included lack of data on where laundering was done (about 40% of hospital staff cleaned their garments at home), the small control sample, and possibly incorrect data on frequency of garment changes. No external funding for the study was reported. Study authors declared they had no relevant financial interests.

Primary source: American Journal of Infection Control Source reference: Wiener-Well Y, et al "Nursing and physician attire as possible source of nosocomial infections," Am J Infect Control 2011; 39:555-59.

Will CRAs slowly disappear under remote monitoring? FDA now accepting comments on draft guidances proposing more remote, less on-site monitoring.

 

FDA Says Industry Should Monitor Trials Remotely

By Emily P. Walker, Washington Correspondent, MedPage Today Published: September 02, 2011

WASHINGTON -- The FDA has issued draft guidance that calls for drug and device companies to move away from in-person monitoring of each site in a clinical trial, when appropriate, and rely more on electronic data monitoring. The FDA recently withdrew its decades-old guidance on monitoring clinical investigations that stated that the most effective way to monitor a trial was to "maintain personal contact between the monitor and the investigator throughout the clinical investigation." That guidance was from 1988, before the Internet and the ability to e-mail and webcast, which, in some cases, can be stand-ins for collecting crucial study data that previously had to be done in person. As the number of clinical trials has grown dramatically over the past several decades, it's less feasible to personally check in on each investigation site, but it's still important to monitor the familiarity individual investigators have with the study protocol; the treatment choices made at each study site; whether the clinical trial is being conducted ethically; and whether the data are sound; in addition to other variables that may impact outcomes and affect human safety, the FDA said in its draft guidance. But that data don't necessarily need to be collected in-person, according to the FDA. The agency issued its new guidance to "encourage more effective monitoring of clinical investigations, to ensure adequate protection of human subjects and [to ensure] the quality and integrity of clinical trial data," according to the draft guidance document, dated Aug. 24. The guidance reads as a message to companies seeking FDA approval for a product: they don't need to spend the time and resources to perform exhaustive on-site inspections when other data oversight methods may work just as well. Monitoring of clinical trial sites varies by the type of trial and the type of institution conducting it. For instance, for a large efficacy trial, drug, device or biologic companies will typically conduct on-site monitoring visits every four to eight weeks, partly because of the perception that that is what the FDA wants. On-site monitoring can identify data entry errors, missing data, proper documentation, compliance with the study protocol, and the overall conduct of the trial. On the other hand, some academic centers and government organizations will perform on-site monitoring less extensively, perhaps only once every two or three years, and some National Institutes of Health-sponsored trials and trials in the United Kingdom rely largely on centralized data monitoring, which should be considered by private companies as well when developing a risk-monitoring plan, according to the FDA. Remote monitoring can work just as well, if not better, than on-site monitoring to check on the data collected at the study site, conduct statistical analyses, and to complete certain administrative tasks, the FDA said. "FDA encourages greater reliance on centralized monitoring practices than has been the case historically, with correspondingly less emphasis on on-site monitoring," the guidance said. The FDA said each company should analyze the complexities and unique considerations for its trial and decide what mix of remote and on-site monitoring is appropriate. "We expect that the pharmaceutical and device industries will, for the foreseeable future, continue to use some amount of on-site monitoring," the agency said, adding, "FDA recommends that each sponsor design a monitoring plan that is tailored to the specific human subject protection and data integrity risks of the trial. Ordinarily, such a risk-based plan would include a mix of centralized and on-site monitoring practices." The FDA cautions that certain parts of a study are more important and must be monitored more often, including assessments related to critical study endpoints; protocol-required safety assessments; evaluation and documentation of serious adverse events; and ensuring that the study blind is maintained. The FDA is accepting comments on the draft guidance through Nov. 28.