News 24/04/2545

News 24/04/2545

NSAIDs and Manipulation Ineffective for Acute Low Back Pain: A Best Evidence Review

Cocoa, but Not Tea, Lowers Blood Pressure

FDA Investigates Link Between Transplant Drugs and Progressive Multifocal Leukoencephalopathy

NSAIDs and Manipulation Ineffective for Acute Low Back Pain: A Best Evidence Review

Charles P. Vega, MD
Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine
Copyright © 2008 Medscape.

Best Evidence Reference
Assessment of Diclofenac or Spinal Manipulative Therapy, or Both, in Addition to Recommended First-line Treatment for Acute Low Back Pain: A Randomized Controlled Trial
Hancock MJ, Maher GC, Latimer J, et al
Lancet. 2007;370:1638-1643

Abstract

Previous recommendations have noted that nonsteroidal anti-inflammatory drugs (NSAIDs) and spinal manipulation therapy can be helpful for patients with acute low back pain, but the current study compares this approach with a "usual care" group, who received advice on physical activity and regular doses of paracetamol. The researchers' findings are surprising and should change the way clinicians think about the management of low back pain.

This study was selected from Medscape Best Evidence, which uses the McMaster Online Rating of Evidence System. Of a possible top score of 7, this study was ranked as 6 for relevance and 5 newsworthiness by clinicians who used this system.

Commentary

Low back pain is one of the most common and difficult to treat conditions encountered in the acute care setting. The lifetime prevalence of low back pain is between 60% and 85%, and 15% of the population may have low back pain at any one time.^[1] This complaint also exacts a significant toll on society at large. In an analysis of the cost of medical conditions to American businesses in terms of medical visits, prescription drug use, absence from work, and short-term disability, mechanical low back pain ranked number 4 on the top 10 most costly physical diagnoses.^[2] Moreover, "other" back pain and spinal injury were also in the top 10.

Current recommendations for the management of low back pain include early mobilization and physical activity.^[1] Acetaminophen, NSAIDs, and muscle relaxants are recommended to reduce pain and improve function within the first 6 weeks after the manifestation of acute symptoms. Spinal manipulation therapy is also often recommended in such cases. Such treatments, however, cannot prevent the development of nonspecific low back pain or chronic back pain among patients with acute pain. Prevention of chronic back pain focuses more on behavior and maintenance of activity as opposed to pharmacotherapy.

NSAIDs have been demonstrated to improve low back pain compared with placebo, according to a 2008 systematic review by the Cochrane Collaboration Review Group.^[3] Researchers analyzed 65 trials involving a total of 11,237 patients with low back pain. Overall, NSAIDs were more effective than placebo in the management of acute low back pain. However, NSAIDs also increased the risks for adverse events compared with placebo.

These improvements using NSAIDs vs. placebo are modest, and whether NSAIDs confer greater benefit than acetaminophen (paracetamol) is controversial. The review cites 6 studies that investigated this issue, only one of which was of high quality. Most of these studies focused on acute low back pain and failed to demonstrate superiority of one treatment over another. The one high-quality study examined patients with chronic low back pain, not acute pain, and NSAIDs were more effective than paracetamol in this group.

The body of research into the efficacy of spinal manipulative therapy is more complicated and difficult to interpret. The techniques for manipulative therapy are more heterogenous than medical therapy, and studies have compared manipulative therapy with multiple different control treatments, making it difficult to draw a conclusion regarding treatment efficacy. However, one review classified control treatments from studies of spinal manipulative therapy into 7 broad categories and pooled results from 39 randomized controlled trials.^[4] Spinal manipulative therapy was significantly superior to sham therapy, resulting in a mean of 10 mm of improvement vs sham therapy on a 100-mm pain scale. However, spinal manipulation therapy was not superior to general practitioner care, analgesics, physical therapy, back exercises, or back school. The authors examined variables affecting pain outcomes, and they found that the profession of the person performing spinal manipulation did not alter the main study result.

Together, these reviews of NSAIDs and spinal manipulative therapy do not provide overwhelming evidence of superior efficacy of either treatment over good routine care of acute low back pain. Furthermore, the current study puts these treatments to the test in a common practice environment. Patients seeking relief of acute low back pain in general practitioners' offices were eligible for study participation. Those with a history of back pain in the month prior to study enrollment or evidence of nerve root compromise on physical examination were excluded.

All participants were given paracetamol 1 gm to be taken 4 times daily until complete recovery or a maximum of 4 weeks elapsed. Subjects were assigned to receive diclofenac 50 mg twice daily and placebo spinal manipulation therapy, spinal manipulation therapy and placebo tablets imitating diclofenac, or double placebo. Spinal manipulation therapy was delivered 2 or 3 times per week and allowed for the use of high-velocity thrust procedures according to the judgment of experienced physiotherapists. The placebo used to replace spinal therapy was detuned pulse ultrasound.

The primary outcome was the number of days until either the first pain-free day or the first of 7 consecutive days with at least minimal pain. Secondary outcomes included pain, function, and disability.

There were 240 patients with moderate levels of pain and disability at baseline who underwent randomization. On average, subjects took approximately two thirds of the recommended dose of paracetamol and 72% of the recommended dose of diclofenac. The median number of spinal manipulation therapy sessions per week was 2.3, and only a small percentage of subjects underwent high-velocity thrust techniques.

Patients had difficulty discerning placebo from active treatments, indicating that the blinding techniques were adequate. The median number of days to recovery among subjects receiving diclofenac was 13, compared with 16 days among participants receiving placebo, which was not a statistically significant difference. In both the spinal manipulation therapy group and the placebo group, the median number of days to recovery was 15. Even the combination of diclofenac and spinal manipulation therapy failed to promote faster rates of improvement vs double placebo. Moreover, both active treatments failed to improve secondary outcomes of pain, disability, or function compared with placebo. Participants reported that the overall perceived effect was similar regardless of study treatment.

The authors of the current study address a major reason for the negative results in their study compared with results of previous research on NSAIDs for acute low back pain. They note that many of these earlier trials failed to include clinicians' advice for basic back care as well as regular treatment with paracetamol. Although NSAIDs and spinal manipulation therapy may be more effective than placebo, the current research suggests that they are no more effective than paracetamol and sound advice.

At the same time, NSAIDs raise significant safety concerns. The prevalence of NSAID-related gastropathy is approximately 25% to 50% among chronic NSAID users. Furthermore, a meta-analysis that examined the gastrointestinal risk associated with specific NSAIDs found that NSAIDs increased the risk for all gastrointestinal complications by 54%.^[5] The NSAIDs most associated with these complications were (in order of the frequency of complications) indomethacin, naproxen, and diclofenac. The relative risk for gastrointestinal complications with indomethacin reached its maximum after only 14 days of therapy. Tenoxicam, meloxicam, and ibuprofen produced nonsignificant increases in the risk for gastrointestinal complications.

NSAIDs can have deleterious effects on the kidneys as well. A study of 90 patients with osteoarthritis examined renal function when patients were treated with amtolmetin guacyl (the prodrug of tolmetin), diclofenac, or rofecoxib for 17 days.^[6] Researchers found that diclofenac was associated with an increase in serum creatinine and a reduction in daily urine volume. Rofecoxib, which was withdrawn from the market in 2004, increased blood pressure values while reducing daily urine volume and creatinine clearance. However, amtolmetin did not significantly affect any of the parameters of renal function.

Spinal manipulation therapy also has possible adverse consequences. In a review of the medical literature regarding spinal manipulation therapy published between 2001 and 2006, researchers found that more than 200 patients receiving spinal manipulation were suspected to have been seriously harmed.^[7] Most data regarding serious adverse effects were from case reports, and vertebral artery dissection was identified as the most common serious adverse event. Mild adverse events of spinal manipulation therapy were very common, occurring in 30% to 61% of all patients. However, some clinical trials of spinal manipulation therapy have demonstrated that these techniques are safe for the management of low back pain.^[8,9]

However, the more pertinent question regarding the possible negative consequences of spinal manipulation therapy may be financial. One of the larger trials focusing on the effectiveness of spinal manipulation therapy for back pain included a financial analysis.^[10] This study involved 181 general practices in the United Kingdom. The researchers found that mean annual treatment costs relative to standard clinical care were 195 pounds sterling for spinal manipulation. However, spinal manipulation improved the outcome of quality-adjusted life years vs best care, and the authors concluded that spinal manipulation is a cost-effective addition to "best care" for back pain in general practice. Moreover, the researchers found that spinal manipulation alone improved therapeutic value for the money compared with manipulation followed by a supervised exercise program.

Another study conducted by chiropractic researchers in the United States found that chiropractic care was more expensive than medical care for patients with both acute and chronic low back pain.^[11] However, at the same time, patients with chronic low back pain receiving chiropractic care experienced better outcomes in pain and functional disability compared with patients receiving medical care exclusively. The authors conclude that chiropractic care appears cost-effective for chronic low back pain, although it may not be as cost-effective for patients with acute low back pain.

The current study by Hancock and colleagues would certainly suggest that the added cost and adverse events associated with spinal manipulation therapy are not justified by more rapid improvement in low back pain. In addition, the study suggests that patients should not be exposed to the risk of taking NSAIDs when there is little added therapeutic benefit associated with such treatment. It is also worth noting that recent research into the early prescribing of opioids for low back pain found this practice to be associated with higher mean disability duration, elevated mean medical costs, and an increased risk for surgery and late opioid use compared with usual practice.^[12]

Although it may be difficult for both patients and providers to accept that time appears to be the best therapy for low back pain, most cases of back pain improve significantly within 2 weeks, and 90% of patients report significant improvement at 2 months.^[1] Clinicians should certainly encourage appropriate activity and recommend paracetamol/acetaminophen to improve symptoms of acute low back pain, but it appears that giving the body time to recover is the key element of treatment. This common diagnosis requires prescriptive restraint, and patients will benefit from this practice in the long run.

Cocoa, but Not Tea, Lowers Blood Pressure CME

News Author: Shelley Wood
from Heartwire — a professional news service of WebMD

April 11, 2007 — More happy justification for chocolate lovers: blood pressure (BP) responds favorably to cocoa, but not tea, a new meta-analysis suggests. Authors of the study say that while both products are rich in polyphenols, the study findings suggest that phenols in cocoa may be more active than those in tea. The study appears in the April 9 issue of the Archives of Internal Medicine.

"Products rich in cocoa may be considered part of a blood pressure lowering diet, provided that the total energy intake does not increase," lead investigator for the study, Dirk Taubert, MD, PhD, from the University Hospital of Cologne in Cologne, Germany, told heartwire. "I believe that cocoa is healthier than other sugar confectionary or high-fat dairy products."

Cocoa Beats Tea for BP

For their study, Taubert and colleagues conducted a literature search for randomized parallel group or crossover studies evaluating the effects of cocoa products or black or green tea for at least 7 days. They identified 10 studies that met their inclusion criteria: 5 randomized trials evaluated cocoa consumption (median, 2 weeks of cocoa consumption) in a total of 173 subjects and 5 trials evaluated tea consumption in a total of 343 subjects (in whom tea consumption was measured for a median of 4 weeks). In both analyses, study participants were evenly split between active and control groups. In the cocoa studies, cocoa consumption was typically flavonol-rich chocolate in the range of 100 g per day; in the tea studies, consumption was in the range of 4 to 6 cups daily.

In the cocoa studies, systolic BP (SBP) and diastolic BP (DBP) dropped in the active group as compared with controls; however, in the tea studies, no differences were seen in BP between the 2 groups. The authors point out that while the 2 substances contain similar amounts of polyphenols, the components of these polyphenols differ between cocoa and tea: cocoa is particularly rich in procyanidins, whereas black and green tea are rich in flavan-3-ols and gallic acid. It may be that the polyphenol components in cocoa are more bioavailable, Taubert and colleagues propose.

Table. Change in Blood Pressure

Blood Pressure	Pooled Change* (mm Hg)	P
Cocoa
Systolic	-4.7	.002
Diastolic	-2.8	.006
Tea
Systolic	0.4	.63
Diastolic	-0.6	.38

*Compared with control group.
Source: Arch Intern Med. 2007;167:626-634.

According to Taubert and colleagues, the effects of cocoa on SBP and DBP were comparable to those achieved with antihypertensive drugs. "The magnitude of the hypotensive effects of cocoa is clinically noteworthy; it is in the range that is usually achieved with monotherapy of ?-blockers or angiotensin-converting enzyme inhibitors," they write. "At the population level, a reduction of 4 to 5 millimeters of mercury in SBP and 2 to 3 millimeters of mercury in DBP would be expected to substantially reduce the risk of stroke (by about 20%), coronary heart disease (by 10%), and all-cause mortality (by 8%)."

Dr. Taubert acknowledged to heartwire that studies of tea and cocoa have yielded contradictory results. "The inconsistencies may result from differences in research question and research focus," he said. For example, "the reported effects of polyphenols on blood pressure, endothelial function, or platelet aggregation may be caused by different mechanisms and different phenols. The transient effects observed after administration of single phenol doses may be differentiated from the sustained effects observed after multiple daily doses. Moreover, plant foods like cocoa or tea contain many different — 100 and more — phenol compounds, but so far, mechanistic studies have focused on the flavonol monomers catechin and epicatechin, for which significant bioavailability has been demonstrated. But these may not be the active ingredients as our meta-analysis indicates."

Dr. Taubert believes his study "will not put the debate to rest, but foster a new debate and, more important, new research in this field."

Arch Intern Med. 2007;167:626-634.

The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org .

Clinical Context

According to the current authors, although there is some evidence that polyphenols contained in cocoa and tea may be beneficial for hypertension by causing arterial vasodilation and increasing endothelial production of nitric oxide, the human studies that have been done involve small numbers of patients with some studies reporting mixed results.

This is a meta-analysis of randomized controlled trials to quantitatively asses the effect of dietary cocoa or tea intake on BP by pooling the data contained in several trials.

Study Highlights

A search of MEDLINE, EMBASE, SCOPUS, the Cochrane Controlled Trials Register, and Science Citation Index was conducted for studies from 1966 to 2006 in any language.
Text words "cocoa," "chocolate," "tea," "blood pressure," "hypertension," "endothelium," and "cardiovascular" were used.
Inclusion criteria were full-text articles, randomized clinical trials with parallel group or crossover design, at least 10 patients, outcome measures of SBP or DBP or both, and confidence intervals in results.
Excluded were abstract-only articles and studies with use of vitamins or supplements in addition to cocoa or tea, duration of less than 7 days for studies, and incomplete control group information.
Data were extracted and assessed for methodologic quality by 2 independent assessors (? = 0.89 - 0.94).
Trials were evaluated using the validated Jadad 11-item instrument with a maximum score of 13 points.
Studies with scores greater than 9 points were considered of high quality; 9 points or below, low quality.
Primary outcomes were changes in BP from baseline to after the intervention.
Potential publication bias was assessed by the funnel plots of each trial's effect size against the inverse standard error.
3106 articles were identified and screened, and 10 met inclusion criteria.
Of 10 studies identified, 5 addressed cocoa, and 5 addressed tea intake and BP.
Most studies were excluded because of short duration of less than 7 days.
Mean quality scores were 9.2 for cocoa and 9.4 for tea studies.
Funnel plots suggested no significant asymmetry.
The cocoa studies had a combined total of 173 individuals allocated to cocoa (n = 87) or control (n = 86). 64% were men, and 34% had hypertension.
The dose of cocoa ranged from 240 to 480 kcal/day of energy with 500 mg of polyphenols or 213 to 294 mg of flavonols and procyanides daily.
Controls consumed white chocolate with no polyphenol-containing cocoa.
4 of 5 cocoa studies reported a reduction of SBP and DBP after consumption.
The 1 study reporting no change in BP used the lowest dose of cocoa.
The pooled BP change was -4.7 mm Hg (P = .002) and -2.8 mm Hg, respectively, for SBP and DBP.
This level of BP reduction is usually achieved with ?-blockers or angiotensin-converting enzyme inhibitors.
According to the authors, a decrease in SBP of 4 to 5 mm Hg and in DBP of 2 to 3 mm Hg would be expected to reduce the risk for stroke by 20%, risk for heart disease by 10%, and risk for all-cause mortality by 8%.
BP was most likely to be reduced in young individuals with mild essential hypertension, and reduction was less likely in elderly subjects with hypertension and younger subjects with normal BP.
There was considerable heterogeneity for the cocoa studies.
The tea studies had a total of 343 subjects allocated to tea (n = 171) or control (n = 172).
Black tea was used in 4 studies, and green tea was used in 1 study. The dose of polyphenols ranged from 500 to 1350 mg daily (5 - 6 cups of tea daily).
71% were men, and 49% had hypertension in the tea studies.
None of the tea studies were associated with significant alterations in SBP or DBP.
There was no heterogeneity between the tea studies.
The negative results of the tea studies were independent of age, hypertension duration, and study duration.

Pearls for Practice

Cocoa consumption is associated with lowering of SBP and DBP in individuals with hypertension and individuals with normal BP.
Tea consumption is not associated with BP lowering in individuals with hypertension and individuals with normal BP.

FDA Investigates Link Between Transplant Drugs and Progressive Multifocal Leukoencephalopathy

Yael Waknine
Medscape Medical News 2008. © 2008 Medscape

April 11, 2008 — A safety review is being conducted to determine whether mycophenolate mofetil (CellCept, Hoffman-LaRoche, Inc) and its metabolite, mycophenolic acid (Myfortic, Novartis Pharmaceuticals, Inc), increase the risk for progressive multifocal leukoencephalopathy (PML), the US Food and Drug Administration (FDA) announced yesterday in an early communication.

PML is a rare and frequently fatal demyelinating disease of the central nervous system that primarily affects immunocompromised patients. It is caused by activation resulting from unknown factors of a polyomavirus, also known as the JC virus, which is latent in 80% of healthy adults.

Signs and symptoms of PML may include vision changes, loss of coordination, clumsiness, memory loss, difficulty speaking or understanding what others say, and weakness in the legs, according to an alert issued by MedWatch, the FDA's safety information and adverse event reporting program.

Roche has provided the FDA with postmarketing reports of the condition in patients receiving mycophenolate mofetil to prevent transplant rejection and for unlabeled uses such as systemic lupus erythematosus. The company also has submitted recommendations to the agency regarding the inclusion of PML information in the product safety labeling, as is the case in the European Union.

Similar information has been requested from Novartis regarding the incidence of PML in patients treated with mycophenolic acid. According to the FDA, the review process is expected to take about 2 months.

In the interim, healthcare professionals are advised to consider PML in the differential diagnosis of immunocompromised patients reporting focal neurologic symptoms on mycophenolate mofetil or mycophenolic acid therapy. Decreasing total immunosuppression may improve the outcome of patients who develop PML, the FDA said.

Mycophenolate mofetil is indicated to prevent rejection of allogenic renal, cardiac, or hepatic transplants. Mycophenolic acid is indicated for the prophylaxis of organ rejection in patients receiving allogenic renal transplant.

Adverse events associated with use of mycophenolate mofetil and mycophenolic acid should be reported to the FDA's MedWatch reporting program by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, MD 20852-9787.