Sleep Disturbance May Be Very Early Warning of Bipolar Risk

Severely disturbed sleep patterns may be an early indicator of the risk of developing bipolar disorder (BD) and may allow early intervention, new research shows.

Speaking here at EPA 2012: 20th European Congress of Psychiatry, Phillip Ritter, MBBS, of the Clinic and Polyclinic for Psychiatry and Psychotherapy at University Hospital Carl Gustav Carus of the University of Dresden in Germany, said that sleep is highly altered in mania and depression and is the most common prodromal symptom of mania in patients with BD. Studies have shown that these patients also have a poorer quality of sleep between episodes when they are euthymic.

Even before individuals develop BD, "the picture that emerges from retrospective studies is that sleep disturbances are far more common in bipolar patients in their premorbid state compared to healthy controls," Dr. Ritter said, based on his reading of the literature.

He noted that sleep disturbances emerge in adolescence, occur far more frequently in the offspring of patients with BD, and occur several years before the first affective episode.

Dr. Ritter presented the first results of his own ongoing prospective study, called BipoSleep, which uses a structured interview and actimetry, a wrist-worn device to detect movement, from which sleep and wake periods can be determined.

Consistently Disturbed Sleep

To date, the study includes 59 participants (22 bipolar patients, 9 high-risk individuals, and 28 control participants). High risk was defined as having a first-degree relative with an affective disorder and subsyndromal mood symptoms but no previous manic episode.

For a small study, the groups were reasonably well matched for age (group mean range, 25.4 - 32.7 years), gender (57% - 78% male), and employment or student status (91% - 100%).

Of the 39 questions in the structured interview about sleep, "there was a significant difference in answers for 30 questions," Dr. Ritter reported. "So that alone seemed to be a good indicator that bipolar patients have difficulty sleeping."

When asked to rate the frequency of unrestorative sleep (0 - 6 points), healthy control participants reported a mean of 1; bipolar patients, 3; and people at high risk for BD, just above 4. In answer to a question about insomnia for at least 3 nights in a row, on a 0 - 9 scale, the score by healthy control participants was 0; by bipolar patients, 4; and by high-risk individuals, 3.

Healthy people may have an occasional night of poor sleep, "but they rarely had a series of 3 or more nights," Dr. Ritter said. "This was very common in patients with bipolar disorder, but it was also quite common in patients at high risk of bipolar disorder."

Interestingly, hypersomnia of at least 3 days' duration was also common among the BD patients and high-risk individuals compared with control participants, with average scores of 5, 9, and 0, respectively.

Altered Mood

For each of the items in the questionnaire, Dr. Ritter standardized the scores, setting the scores of healthy control participants as 1, and he plotted the scores for the BD patients, the high-risk individuals, and the control participants for each item in the questionnaire.

The greatest differences from control participants were in terms of recurrent insomnia and a heightened sensitivity to disruptions in daily sleep rhythms for both the patients and the high-risk groups.

He had expected that the high-risk group would fall somewhere between the patients with established BD and the control participants.

"But actually we were a bit surprised to see that...the results of the high-risk participants are much closer to the answers we got from patients with established bipolar disorder, which might be an indication that really sleep is altered prior to the first episode, but it's speculative," he said.

Dr. Ritter also noted that there was more profound effect of altered sleep on mood as well as altered mood on sleep for the patient group and the high-risk group. These groups also had more difficulty in maintaining a regular rhythm after disruptions in sleep rhythms.

The reported differences on the questionnaires among the 3 groups was not so profound for sleep latency (time to get to sleep), sleep duration, and awake periods per hour, and there were fairly wide individual variations within groups.

With regard to the actimetry data for 6 nights in a row, Dr. Ritter said the data did not show much difference among the groups for most of the parameters measured.

Profile Similar to BD

One significant difference was in sleep latency, with BPD patients taking longer to get to sleep, despite many of them receiving sedating medications. But they tended to sleep longer once asleep compared with control participants. They also slept more "efficiently," with little sleep fragmentation.

The fact of greater sleep duration for BD patients has also been reported in the literature, the consensus being that patients sleep ½ hour or 1 hour longer.

Dr. Ritter said that even after correcting for sedating medications in the study, sleep duration was still elevated in the BD group.

The high-risk group also had a mildly elevated length of sleep, even though they were free of medication. For most other measures, they were similar to the control group except that they had a higher level of nighttime activity than either the control participants or the BD group.

He added that a limitation of the study is that 6 nights of actimetry monitoring may not be long enough to detect other differences between the groups.

He concluded that patients with BD differ significantly from healthy control participants regarding most of their nighttime and subjective sleep habits and that "high-risk persons have a profile similar to bipolar subjects, but the differences in actimetry are not really evident over 6 nights."

Potential Risk Factor, Not a Predictor

Cristoph Correll, MD, associate professor at Albert Einstein College of Medicine and a child and adolescent psychiatrist at the Zucker Hillside Hospital in Glen Oaks, New York, chaired the session in which Dr. Ritter presented his study results.

Dr. Correll, who had no relation to the study, told Medscape Medical News that sleep is a very nonspecific item, with up to 50% of the general population having any sleep problem in a given month, so it will be necessary to find subtypes or characteristics of disturbed sleep "that might differentiate bipolar risk from non-risk."

He said using actimetry may not be feasible with every patient suspected of being at risk but may be a predictive tool for certain high-risk individuals.

"The question and the worry is always how specific are these findings?" he said. "I would at the moment see [disturbed sleep] as a risk factor or warning sign but not as a definite predictor of the illness."

Even if people at particularly high risk of developing BD could reliably be identified, Dr. Correll said it is hard to know if or what interventions could prevent the illness.

"The hope is that once you identify high-risk people and you do some general preventive measures or early targeted measures, which would include healthy lifestyle, no substance use, sleep hygiene, and then also stress reduction and targeting anxiety and depression, maybe even with nonpharmacologic treatments, that should already help. Then more pharmacologic interventions can only be tested and developed once we can validly identify high-risk people," he said.

He added that no one yet knows how circadian rhythm and BD risk interact — whether underlying illness exists first and then disrupts circadian rhythm or whether circadian rhythm disruption is 1 factor that pushes people into mania and BD.

"We don't know that," Dr. Correll said. "We just know that circadian rhythm abnormalities are associated with mood disorders, and we need to try to get that under control in order to hopefully then also attenuate the risk and the expression of the illness."

The study did not receive any commercial funding. Dr. Ritter has disclosed no relevant financial relationships. Dr. Correll has been a consultant and/or advisor to or has received honoraria from Actelion, Alexza, the American Academy of Child and Adolescent Psychiatry, AstraZeneca, Biotis, Bristol-Myers Squibb, Cephalon, Desitin, Eli Lilly, Gerson Lehrman Group, GSK, IntraCellular Therapies, Lundbeck, Medavante, Medscape, Merck, Novartis, Ortho-McNeill/Janssen/J&J, Otsuka, Pfizer, ProPhase, Sunovion, Takeda, and Teva. He has received grant support from BMS, Feinstein Institute for Medical Research, Janssen/Johnson & Johnson, the National Institute of Mental Health, the National Alliance for Research in Schizophrenia and Depression, and Otsuka.

EPA 2012: 20th European Congress of Psychiatry. Abstract AS04-01. Presented March 4, 2012.

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Oral Vitamin D Boosts Intranasal Steroid Effect in Rhinitis

Adding an oral vitamin D supplement to regular intranasal corticosteroid dosing can improve symptoms of seasonal allergic rhinitis beyond that seen with corticosteroids alone in patients who are not vitamin D deficient, according to study results presented here at the American Academy of Allergy, Asthma and Immunology 2012 Annual Meeting.

The findings add to a number of reports at the meeting suggesting that vitamin D supplementation might be beneficial in patients with allergies.

"Vitamin D has been shown to play a role in innate immunity and the generation of antimicrobial peptides. It also has a number of immunological effects on T cells, dendritic cells, and macrophages," said James Lane, BA, a researcher at the University of Chicago, Illinois, who presented the findings.

These findings must be viewed with caution, said lead investigator Fuad Baroody, MD, a pediatric head and neck surgeon at the University of Chicago. "This was a small study, a pilot study. More work needs to be done before people can run out and add vitamin D to intranasal steroids," he said in an interview with Medscape Medical News.

In the double-blind placebo-controlled study, patients 18 to 45 years of age with seasonal allergic rhinitis received fluticasone propionate 200 µg/day, and were randomized to receive either vitamin D 4000 IU/day for 2 weeks (n = 17) or placebo (n = 18).

Subjects had at least a 2-year history of seasonal allergic rhinitis and a positive skin test to tree, grass, and/or ragweed.

At baseline, serum 25-hydroxy-vitamin D levels were within the normal range and similar in the vitamin D and placebo groups (29.6 vs 29.4 ng/dL). After 2 weeks, levels in the vitamin D group rose significantly from baseline to 37.2 ng/dL (P = .001); in the placebo group, there was no rise.

"There's variation on what people consider appropriate levels of vitamin D," explained Dr. Baroody. "Most recommendations are for levels around 30 or so. These were not vitamin-deficient people, but we bumped it up a little bit to within a still reasonable range, and nobody had side effects from having too much vitamin D."

According to daily self-rated nasal symptoms, including sneezing, nasal congestion, and drip, subjects in both groups noted significant daytime improvements from baseline.

However, subjects in the vitamin D group noted a decreased symptom score of 6.9 points from baseline, which was statistically significant and superior to the 3.7 point drop in the placebo group (P = .04).

"Just giving vitamin D on top created a significant drop — almost a 50% drop," said Dr. Baroody. "The magnitude is impressive, actually. If that is duplicated in a big trial, it would be pretty spectacular."

Nighttime symptoms were not presented at the meeting, but Dr. Baroody said they were "not as spectacular." As a result, the reduction in 24-hour symptom relief was not statistically different between the vitamin D and placebo groups (11.3 vs 7.6 points; P = .09).

Similarly, although there was a statistically significant improvement from baseline in quality of life in both groups (P= .0028), there was no significant difference between the vitamin D and placebo groups (2.5 vs 2.0 points).

"A change of 0.5 is considered to be clinically meaningful, and both groups had improvements well beyond that," said Lane.

In response to a comment from the audience, Dr. Baroody acknowledged that perhaps the real strength of vitamin D supplementation in this group was not in better, but rather in faster, symptom control; all measures showed patients in the vitamin D group responding within 2 days and sustaining their response level.

"That's an interesting way of looking at it. I will examine that in more detail," he said.

"I think people don't really know what the vitamin D story is," Rachel Miller, MD, associate professor of medicine in pediatrics and environmental health sciences at Columbia University Medical Center in New York City, toldMedscape Medical News.

"My bias is to do a randomized trial and see what vitamin D supplementation does, because most of the work so far has been observational. I know people are already doing it, but I personally look forward to more evidence from randomized trials."

The study received no funding from industry. Mr. Lane and Dr. Miller have disclosed no relevant financial relationships. Dr. Baroody reports being on the speaker's bureau for Merck and GlaxoSmithKline.

American Academy of Allergy, Asthma and Immunology (AAAAI) 2012 Annual Meeting: Abstract 510. Presented March 4, 2012.

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Frequent Chocolate Consumption Linked to Lower BMI

 A recent study showed that frequent chocolate consumption was associated with lower body mass index (BMI), even when adjusting for calorie intake, saturated fat intake, and mood.

Beatrice A. Golomb, MD, PhD, associate professor of medicine at the University of California, San Diego, and colleagues described their findings in a research letter published in the March 26 issue of the Archives of Internal Medicine.

The authors used data from 1018 patients already being screened for inclusion in a widely sampling clinical study evaluating noncardiac effects of statin medications. Of the 1018 participants, 1017 answered the question, "How many times a week do you consume chocolate?" BMI was calculated for 972 participants (95.6%); and 975 (95.8%) answered the validated Fred Hutchinson Food Frequency Questionnaire.

The investigators performed analyses with and without adjustment for calorie intake, saturated fat (satfat) intake, and mood. Fruit and vegetable intake was not associated with chocolate consumption (β, 0.004; P = .55), but satfat intake was significantly related to both chocolate consumption (β, 0.035; P < .001) and higher BMI.

The amount of chocolate consumed was examined, in addition to the frequency of chocolate consumption. Activity (number of times in a 7-day period the participant engaged in vigorous activity for at least 20 minutes) and mood (Center for Epidemiological Studies Depression scale [CES-D]) were also examined.

The relationship between chocolate consumption frequency and BMI was calculated in unadjusted models, in models adjusted for age and sex, and in models adjusted for activity, satfats, and mood.

Study participants consumed chocolate a mean 2.0 (SD, 2.5) times per week and exercised 3.6 (SD, 3.0) times per week. Frequency of chocolate consumption was associated with greater intake of calories and satfats and higher CES-D scores (P < .001 for each of these 3 associations); these all related positively to BMI. Chocolate consumption frequency was not associated with greater activity (P = .41), but it was associated with lower BMI (unadjusted P = .01). This association remained with and without adjustment for age and sex, as well as for calories, satfats, and depression.

Although chocolate consumption frequency was associated with lower BMI, the amount of chocolate consumed was not (eg, per medium chocolate serving or 1 oz [28 g], β, 0.00057 and P = .97, in an age- and sex-adjusted model).

"The connection of higher chocolate consumption frequency to lower BMI is opposite to associations presumed based on calories alone, but concordant with a growing body of literature suggesting that the character — as well as the quantity — of calories has an impact on [metabolic syndrome (MetS)] factors," write the authors.

They further explain that as chocolate products are frequently high in sugar and fat, they are often assumed to contribute to an increased BMI. The authors note that this may still be true in some cases.

"[O]ur findings — that more frequent chocolate intake is linked to lower BMI — are intriguing," write the authors. "They accord with other findings suggesting that diet composition, as well as calorie number, may influence BMI. They comport with reported benefits of chocolate to other elements of MetS," the authors write, noting that a randomized trial studying the metabolic benefits of chocolate in humans may be warranted.

This study was funded by a grant from the National Heart, Lung and Blood Institute, National Institutes of Health, and was supported by the University of California, San Diego, General Clinical Research Center. The authors have disclosed no relevant financial relationships.

Arch Int Med. 2012;172:519-523.

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Guidelines Define Hemoglobin Levels for Transfusion

Red blood cell (RBC) transfusions in most hospitalized patients should be performed based on "restrictive," rather than "liberal," hemoglobin levels (7 - 8 g/dL), according to new clinical guidelines from the American Association of Blood Banks (AABB).

The new guidelines are based on a systematic literature review and were formulated by a multinstitutional panel of 20 experts led by Jeffrey L. Carson, MD, from the University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School in New Brunswick, and were published online March 26 in the Annals of Internal Medicine.

"Many small trials have addressed the question of optimal use of RBC transfusions," Dr. Carson and colleagues write. "Recently, 2 additional trials were published that expanded by 30% the number of patients included in the evidence base of transfusion trials. Thus, it is timely to reexamine the data and provide guidance to the medical community," the authors write.

The new guidelines outline 4 major recommendations based on various levels of evidence. The authors conducted a systematic review of 19 randomized clinical trials (including 6264 patients) evaluating transfusion thresholds. Trials were published from 1950 to February 2011.

The first recommendation is adherence to a restrictive transfusion strategy (7 - 8 g/dL) in hospitalized, stable patients. This is classified as a "strong" recommendation based on high-quality evidence.

The second recommendation is that a restrictive strategy be used in hospitalized patients with preexisting cardiovascular disease with consideration of transfusion for patients with symptoms or a hemoglobin level of 8 g/dL or less. The authors describe this recommendation as "weak," with moderate-quality evidence.

The third recommendation is that the AABB cannot recommend either for or against a liberal or restrictive transfusion threshold for hospitalized, hemodynamically stable patients with acute coronary syndrome. The panel classified this as an uncertain recommendation, with very low-quality evidence.

The fourth recommendation is that transfusion decisions should be influenced by symptoms as well as hemoglobin concentration, although again, this was a weak recommendation with low-quality evidence.

According to the panelists, other guidelines have proposed that transfusion is generally not indicated when the hemoglobin concentration is above 10 g/dL, but is indicated when it is less than 6 to 7 g/dL. "However, none of these guidelines recommended a specific transfusion trigger," they write.

"[I]n the current guidelines we explicitly used an evidence-based process that employed the [Grading of Recommendations Assessment, Development, and Evaluation (GRADE)] method," the authors note. "Although individual clinical factors are important, hemoglobin level is one of the critical elements used daily by physicians in the decision to transfuse. Thus, specific evidence-based recommendations on use of hemoglobin levels will help standardize transfusion practice," they conclude.

Transfusing Based on Hemoglobin Levels Alone "Insufficient"

In a related editorial, Jean-Louis Vincent, MD, from the Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, Belgium, points out that "basing the decision to transfuse only on hemoglobin levels is insufficient."

He adds that he does "not believe that available evidence supports a fixed transfusion trigger. Rather, transfusion decisions need to consider individual patient characteristics, including age and the presence of [coronary artery disease], to estimate a specific patient's likelihood of benefit from transfusion."

He concludes, "The decision to transfuse is too complex and important to be based guided by a single number."

Support for the development of the guidelines was provided by the AABB in Bethesda, Maryland. Dr. Carson reports having a grant or grants pending from Amgen. Conflict-of-interest information for all authors is available on the journal's Web site. Dr. Vincent has disclosed no relevant financial relationships.

Annals Int Med. Published online March 26, 2012. Full text editorial

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Curcumin Holds Promise as Treatment for Brain Tumors

Can a lowly spice help fight the battle against pediatric brain tumors?

Maybe, according to preliminary research published in a recent issue of BMC Cancer. Curcumin, a major component of the spice turmeric, has been shown to have chemopreventive and chemotherapeutic properties. Past research also demonstrates that it has the potential to destroy human medulloblastoma cells cultured in the laboratory.

In the current study, researchers were able to identify a protein as a candidate biomarker in order to better predict which patients might respond favorably to curcumin therapy.

This work is exciting because right now, the prognosis of childhood brain tumors is generally poor, treatment options are limited, and children often have long-term side effects from treatment, explained lead author Sigrid Langhans, PhD, senior research scientist at the Nemours Center for Childhood Cancer Research at the Alfred I. duPont Hospital for Children, Wilmington, Delaware. The team is now planning clinical trials with curcumin.

"The problem is that many drugs which could be effective do not make it across the blood-brain barrier," she pointed out. "The blood-brain barrier protects the brain from toxic substances but unfortunately also prevents therapeutic agents from entering as well."

But one of the interesting things about curcumin is that it can cross the blood-brain barrier, she told Medscape Medical News in an interview.

Selective Apoptosis

Curcumin can induce apoptosis in a variety of tumor cells and has also prevented tumor initiation and growth in experimental models. Dr. Langhans and her team, along with other groups, have previously shown that curcumin induces cell death in medulloblastoma, the most common pediatric brain tumor, and inhibited tumor growth in in vivo medulloblastoma models.

But it is not clear why curcumin selectively targets tumor cells, although it has been suggested that it affects signaling pathways that regulate cell growth and survival and thus preferably will induce apoptosis in highly proliferating cells. "So in this study we followed up on studying the mechanisms which might explain how it can induce cell death," Dr. Landhans explained.

Drawing on their earlier research, the authors found that curcumin specifically binds to and crosslinks to a protein that is involved in cell-cycle regulation. It is known as a checkpoint protein, she said, because it blocks the onset of anaphase until all chromosomes make proper attachments to the spindle. The mitotic checkpoint, or spindle assembly checkpoint (SAC), is the major cell-cycle control mechanism that delays the onset of anaphase during mitosis. One of the primary regulators of the SAC is the anaphase-promoting complex/cyclosome (APC/C).

"But if there is a defect in the checkpoint, this process is disrupted," Dr. Langhans added. "So this study may show why curcumin causes death in tumor cells but not in normal cells. That is the great thing about curcumin because if it only targets tumor cells, then it has very few — if any — side effects."

Because the APC/C not only ensures that the cell cycle will be halted during spindle disruption but also promotes cell death in response to prolonged mitotic arrest, the authors note, it has become an attractive drug target for cancer therapy.

Preference for Phosphorylated Cells

The authors also found that tumors treated with curcumin had lower levels of Cdc27, and subsequently identified Cdc27/APC3, which is a component of the APC/C, as a novel molecular target of curcumin. They found that curcumin binds to and crosslinks Cdc27 to affect APC/C function.

In addition, they found that curcumin binds more resolutely to this specific protein when it is phosphorylated, a modification that is generally seen in rapidly proliferating cells, such as in tumors.

"It much more strongly induces death in these cells, so we can probably use that as a biomarker to predict which patients might respond to curcumin therapy," Dr. Langhans said. "And this isn't just for children but for all patients. We might be able to predict who may respond more favorably to this treatment, and then treatment can be adjusted accordingly."

Knowing the mechanism behind curcumin's antitumor mechanism will help in developing therapeutic agents. "We can then rationally design drugs that may be more effective — that is our long term goal," she explained.

Dr. Langhans noted that the next step is to move their research into the clinic. "We hope to begin clinical trials," she said. "Our first priority will be pediatric brain tumors. We will first see how curcumin responds in pediatric patients and then we will next try to specifically target the patients that might derive the most benefit."

The study was funded by the Nemours Foundation. The authors have disclosed no relevant financial relationships.

BMC Cancer. 2012;12:44. Full text

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Excessive Cured Meat Intake May Be Harmful to COPD Patients

Excessive consumption of cured meat is associated with an increased risk for hospital readmission among patients with chronic obstructive pulmonary disease (COPD), report Jordi de Batlle, BMedBiol, from the Centre for Research in Environmental Epidemiology, Hospital del Mar Research Institute, the CIBER Epidemiología y Salud Pública, and the Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain, and colleagues. Results from their study were scheduled to be published online March 8 in the European Respiratory Journal.

The goal of the Phenotype and Course of COPD Project (PAC-COPD) study was to assess the association between dietary intake of cured meat and risk for COPD readmission among patients with COPD. The researchers calculated the association between cured meat intake and COPD admissions using parametric regression survival-time models.

Researchers demonstrated that higher cured meat consumption was related to a 2-fold increased risk for COPD readmission (adjusted hazard ratio, 2.02; 95% confidence interval [CI], 1.31 - 3.12; P = .001), after adjusting for age, forced expiratory volume in the first second (FEV1), and total calorie intake. In addition, the time to the first COPD readmission was longer in patients with low cured meat intake (P = .028).

COPD researchers have recently turned their sights on the role diet plays in the development of the disease. "Recent studies have shown that a high dietary intake of cured meat increases the risk of COPD development. However, its potential effects on COPD evolution have not been tested," the authors write.

Between January 2004 and March 2006, 274 patients with COPD were recruited from 9 hospitals in Spain during their first COPD hospital admission and were followed-up through December 31, 2007 (median follow-up, 2.6 years). The COPD diagnosis was based on a ratio of postbronchodilator FEV1 to forced vital capacity (FEV1/FVC) equal to 0.70. COPD exacerbations were classified according to the International Classification of Diseases, Ninth Revision, and survival status was obtained for all patients from direct interviews with the patients or their relatives.

Study participants filled out a food frequency questionnaire at the time of enrollment that encompassed dietary habits during the preceding 2 years. Cured meat consumption was defined as the total daily consumption (g/day) of cooked ham, Spanish cured ham, cured and other sausages, and hot dogs.

Using standardized questionnaires, the investigators collected baseline sociodemographic characteristics, respiratory symptoms, drug treatment, and lifestyle information. The team also assessed body mass index (BMI) and fat-free mass index to evaluate participants' nutritional status. In addition, they measured postbronchodilator spirometry (FEV1, FVC, and FEV1/FVC), arterial oxygen and carbon dioxide partial pressures, carbon monoxide diffusing capacity, and serum C-reactive protein.

The mean age of the participants was 68 years, 93% were men, and 42% were current smokers. The mean postbronchodilator FEV1 was 53% predicted, and the median cured meat intake was 23 g/day (equivalent to approximately 1 slice of ham a day).

Most patients had moderate to severe COPD (5% mild, 52% moderate, 37% severe, and 6% very severe); however, median cured meat intake was similar across COPD severity stages. The researchers also noted that a higher daily cured meat intake was positively related to younger age, current working, current smoking, higher levels of regular physical activity, and lower BMI.

The authors hypothesize that cured meats have a deleterious effect on patients with COPD because they contain high level of nitrites. Nitrites used in the preparation of cured meat may lead to an increase in the nitrosative stress burden within the lungs, and lead to the formation of reactive nitrogen species, which results in parenchymal damage and remodeling.

"This study adds new evidence suggesting that in addition to a possible increase in risk of COPD associated with cured meats, these foods may also increase risk of exacerbations, thus supporting the need of considering specific dietary advice to COPD patients," conclude the study authors.

Funding for this study was provided by the Fondo de Investigación Sanitaria, Ministry of Health, Spain; Agéncia d'Avaluació de Tecnologia i Recerca Mèdiques, Catalonia Government; Spanish Society of Pneumology and Thoracic Surgery; Catalan Foundation of Pneumology; Red RESPIRA ; Red RCESP; Fundació La Marató de TV3; DURSI; and an unrestricted educational grant from Novartis Farmacèutica, Spain. CIBERESP and CIBERES are funded by the Instituto de Salud Carlos III, Ministry of Health, Spain. de Batlle has a predoctoral fellowship from the Instituto de Salud Carlos III, and 1 coauthor also has a researcher contract from the Instituto de Salud Carlos III. The other authors have disclosed no relevant financial relationships.

Eur Respir J. Published online March 8, 2012.

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Exercise and Rest Both Effective for Some Patients With Back Pain

Exercise might not always be the best treatment approach for some low back pain sufferers. A new randomized trial shows no difference in pain, disability, or general health among patients with lower back pain and Modic changes (MCs) — edema or fatty degeneration in the vertebral endplate — who followed an exercise regime and those who adopted a routine of rest and load reduction.

The finding that rest results in the same small improvements as a more active treatment approach challenges the idea that exercise should be the "gold standard" for patients with low back pain and MCs, said lead author Rikke K. Jensen, MSc, from the Research Department, Spine Centre of Southern Denmark, in Middelfart. This article is part of her PhD thesis.

The results do not suggest that patients with MCs should not exercise, said Jensen "But I think clinicians should be careful; when patients come back and say this treatment didn't work, it's not because they did it the wrong way or they didn't do it enough. It's very possible that this treatment is just not very effective for this group of patients."

The study was published online February 29 in BioMed Central's open access journal BMC Medicine.

Inhibits Healing

Although MCs are fairly common, affecting some 40% of patients with low back pain (LBP), their precise cause is unknown. One theory has been that they are caused by mechanical stress, and that excessive loading may result in microfractures of the endplate causing inflammation in the vertebral endplate and the adjacent bone marrow.

The severe and persistent pain suffered by patients with MCs is often unresponsive to active treatment, possibly because weight-bearing exercises inhibit microfracture healing. "When you're jumping up and down on microfractures, they tend not to get better," said Jensen. "It was important for us to test the hypothesis that people don't improve with exercise if they have these MCs, and are there other treatment options that could prove to be more effective."

When you're jumping up and down on microfractures, they tend not to get better.

The study enrolled 100 adult patients with persistent LBP (at least 3 on an 11-point scale) and MC confirmed on magnetic resonance imaging that extended beyond the endplate into the vertebral body. The patients were referred from primary care and had had symptoms lasting from 2 to 12 months. They were allocated to either a rest group or an exercise group.

The rest group was instructed to avoid hard physical activity and to rest by lying down for an hour twice daily. They also used a flexible lumbar belt as needed for up to 4 hours a day. After 10 weeks, they were to gradually increase their physical activity. The duration of this intervention was supposed to allow time for microfracture healing.

Subjects in the exercise group did supervised 1-hour exercises once a week for 10 weeks. The regime included exercises for stabilizing muscles in the low back and abdomen, exercises for postural instability, and light physical fitness training. These patients were encouraged to do the same exercises at home 3 times a week and to maintain a "normal" level of activity.

Pain/Disability Assessment

All patients completed questionnaires at baseline, 10 weeks, and 12 months. The study assessed pain using a numerical rating scale (NRS) of back pain ranging from 0 to 10; disability using the 23-item Roland Morris Disability Questionnaire (RMQ) with scores ranging from 0 to 23; general health using the EuroQol, as well as global assessment and depression. Patients also reported any back problems or sick leave.

The study included data on 87 patients at 10 weeks and 96 patients at the end of the study.

After treatment, the mean pain NRS score was 5.0 in the rest group vs 4.5 in the exercise group (difference adjusted for baseline score, age, sex, smoking and physical workload: − 0.07; P = .9). At 1 year, the scores were 4.8 in the rest group and 4.3 in the exercise group (adjusted difference:− 0.3; P = .5).

For disability, the posttreatment NRS score was 11.0 in the rest group and 11.1 in the exercise group (adjusted difference: − 0.6; P = .5) and at 1 year, the scores were identical at 10.7 for both groups (adjusted difference: − 1.2; P = .3).

The study found no significant difference in general health scores. Also no serious problems or adverse events were reported in either group.

The study results do not add anything new to what is already known about the etiology of MCs, said Jensen. "We know that they are part of the degeneration process but we still don't know what causes them."

Spine-related pathoanatomic changes other than MCs, or psychosocial factors, might influence or cause pain, said the authors. And if MCs do cause pain and rest is useful, the amount of rest in the study may have been insufficient. It's also possible that subgroups of type, size, and location of MCs would have responded differently to treatment.

Although rest was not inferior to exercise in the study, it could carry the risk of unwanted behaviors such as poor coping strategies. However, the study found no difference in emotional functioning between the groups.

Jensen stressed that exercise generally has beneficial effects on overall health and well being for all patients. "I don't recommend exercise as a specific treatment for MCs but MCs are not a contraindication for exercise."

However, she added that the study does not bring researchers or clinicians any closer to an effective treatment for MCs. "Actually, we don't know what to do with these patients."

“Excellent” Study

Asked for comment on this study, Vera Bril, MD, from the Division of Clinical Investigation & Human Physiology, Toronto General Research Institute, in Canada, and a member of the American Academy of Neurology, was positive.

"I think that this is an excellent study that does not support the hypothesis that patients with different forms of back pain respond differently to treatment," she told Medscape Medical News. "So the presence of Modic changes at the endplate regions does not predict response to therapy for back pain.

"It is also interesting that both those advised to rest and those to be active had the same outcomes in this study," she added.

The authors have disclosed no relevant financial relationships.

BMC Medicine. 2012. Published online February 29, 2012. Abstract

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