New Analysis Challenges Tamiflu Efficacy

By Michael Smith, North American Correspondent, MedPage Today Published: January 17, 2012 Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.

A new review of the influenza drug oseltamivir (Tamiflu) has raised questions about both the efficacy of the medication and the commitment of its maker to supply enough data for claims about the drug to be evaluated by independent experts. It also raises questions about the entire process of systematic review. Researchers led by Tom Jefferson, MD, of the Cochrane Collaboration, pored over 15 published studies and nearly 30,000 pages of “clinical study reports.” But, they reported, the clinical study information – data previously shared only with regulators – was only a part of what internal evidence suggested was available. And many published studies had to be excluded because of missing or contradictory data, Jefferson and colleagues reported. Action Points   Explain that a new review of an important flu drug has raised questions about the medication and the entire process of systematic review. Point out that the review of oseltamivir showed that there was no evidence of effect on hospital admissions. The drug’s maker, Switzerland-based Roche, had promised after a previous Cochrane review to make all of its data available for “legitimate analyses.” After a request for the data, Jefferson and colleagues reported, the company sent them 3,195 pages covering 10 treatment trials of the drug. But, three of the reviewers noted in a parallel report in BMJ, the tables of contents suggested that the data were incomplete. “What we’re seeing is largely Chapter One and Chapter Two of reports that usually have four or five chapters,” according to the BMJ article’s lead author, Peter Doshi, PhD, of Johns Hopkins University. Roche did not immediately respond to a telephoned request for comment. Requests for More Data The researchers then asked the European Medicines Agency (EMA) for the data, under a Freedom of Information request, and obtained a further 25,453 pages, covering 19 trials. But that data, too, was incomplete, they said, although the agency said it was all that was available. The FDA is thought to have the complete reports, but has not yet responded to requests for them, the researchers reported. Regulatory agencies such as the EMA and FDA routinely see the large clinical study reports, Jefferson and colleagues said in BMJ, but systematic reviewers and the general medical public do not. “While regulators and systematic reviewers may assess the same clinical trials, the data they look at differs substantially,” they said. The Cochrane group has been trying for several years to put together a clear-cut systematic review of the evidence on antivirals aimed at flu. In 2006, the group concluded that the evidence showed that oseltamivir reduced the complications of the flu. But that conclusion was challenged on the basis that a key piece of data was flawed. An updated review in 2009 – throwing out the flawed study — concluded there wasn’t enough evidence to show that the drug had any effect on complications. For this analysis, the Cochrane reviewers had originally intended to perform a systematic review on both of the approved neuraminidase inhibitors – oseltamivir and zanamivir (Relenza), using the clinical study reports to supplement published trials. In the end, they decided that for oseltamivir, they needed more detail in order to perform the review in its entirety. But, they reported, some conclusions could be drawn from published data on the 15 trials and from 16,000 pages of clinical study reports that were available before their deadline. They also decided to postpone analysis of zanamivir (for which they had 10 trials) because the drug’s maker, GlaxoSmithKline, offered individual patient data which they wanted time to analyze. The oseltamivir analysis showed: The time to first alleviation of symptoms in people with influenza-like illness was a median of 160 hours in the placebo groups and about 21 hours shorter in those treated with oseltamivir. The difference, evaluated in five studies, was significant at P<0.001. There was no evidence of effect on hospital admissions: In seven studies, the odds ratio was 0.95, with a 95% confidence interval from 0.57 to 1.61, which was nonsignificant at P=0.86. A post-protocol analysis of eight studies showed that oseltamivir patients were less likely to be diagnosed with influenza. The data “lacked sufficient detail to credibly assess” any effect on influenza complications and viral transmission. Data Discrepancies Found But discrepancies between the published trial data and the clinical study reports “led us to lose confidence in the journal reports,” Doshi and colleagues wrote in BMJ. For example, they noted that one journal report clearly said there were no drug-related serious adverse events, but the clinical study report listed three that were possibly related to oseltamivir. As well, the sheer scope of the clinical study reports meant that much was left out of journal reports. One 2010 study, on safety and pharmacokinetics of oseltamivir at standard and high dosages, took up seven journal pages and 8,545 pages of the clinical study report. But the researchers were also shaken, they said, by the “fragility” of some of their assumptions. For instance, they found that the clinical study reports showed that in many trials, the placebo contained two chemicals not found in the oseltamivir capsules. “We could find no explanation for why these ingredients were only in the placebo,” they wrote in BMJ, “and Roche did not answer our request for more information on the placebo content.” Jefferson and colleagues also reported they found disparities in the numbers of influenza-infected people reported to be present in the treatment versus control groups of oseltamivir trials. One possible explanation, they noted, is that oseltamivir affects antibody production – even though the manufacturer says it does not. Gaps in Knowledge Remain That question is profoundly important, Doshi told MedPage Today, because it may offer clues to how the drug works – one of the gaps in knowledge about oseltamivir. “You can’t make good therapeutic decisions if you don’t know how the drugs works,” he said – information that he and his colleagues suspect may be buried in the mass of missing data. It’s also important, he said, because public health agencies have been making decisions to stockpile oseltamivir without a clear understanding of the facts. Essentially, he said, those decisions have been based on the flawed study – a Roche-supported meta-analysis – that was thrown out of the 2009 Cochrane review. “They’re taking the drug manufacturer’s word at face value,” he said. The results seem unlikely to resolve conflicts over the medical value of the drug, which is a major cash cow for Roche, adding some $3.4 billion to the company’s bottom line in 2009 alone, according to Deborah Cohen, investigations editor of BMJ. In an accompanying article, Cohen said that “clinicians can be forgiven for being confused about what the evidence on oseltamivir says.” She noted that the European Centre for Disease Prevention and Control, the CDC, and the World Health Organization “differ in their conclusions about what the drug does.” As well, those conclusions are often contradicted by claims on the drug labels – themselves allowed by regulators, Cohen argued.

MRI Spine Interpretation Training for Local Chiropractor

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“31 million Americans experience low-back pain at any given time” (The American Chiropractic Association, 2010, https://www.acatoday.org/level2_css.cfm?T1ID=13&T2ID=68)

Interesting facts about back pain:¹

1. One-half of all working Americans state that they experience back pain each year.
2. One of the most common reasons people call out of work is back pain.  It is also the second most common reason for a visit to the doctor’s office.
3. Back pain is often mechanical or non-organic, meaning it is not caused by a serious condition, such as inflammatory arthritis, infection, fracture or cancer.
4. At least $50 billion per year is spent by Americans on back pain.
5. Experts estimate as much as 80% of the population will experience a back problem at some time in their lives.

What Causes Back Pain?

The back is made up of bones, joints, ligaments and muscles. Ligaments can be sprained, muscles can be strained, disks can rupture, and joints can be irritated.  All of these can result in back pain. It doesn’t always take a major event like a sports inury or an accident to cause back pain. Even the simplest of movements, like picking a small object up from the floor, can have painful results. There are also numerous conditions that can cause or complicate back pain, such as arthritis, poor posture, obesity, and psychological stress. Disease of the internal organs, such as kidney stones, kidney infections, blood clots, or bone loss, can also result in back pain.¹

The most common form of arthritis is called osteoarthritis. It is also known as degenerative joint disease and is a disease of the joints. It affects more than 20 million American adults. The cause of osteoarthritis is a breakdown of cartilage, the connective tissue that provides a cushion between the bones of the joints. Healthy cartilage is what permits bones to move over one another and acts as a shock absorber during physical movement. Those afflicted with this disease experience a breakdown of cartilage that wears away. As a result, the bones under the cartilage rub together, resulting in pain, swelling, and loss of joint motion.²

What Causes Osteoarthritis?²

There is often no known cause of osteoarthritis. Risk factors include:

1. Age – More people over the age of 45 are affected by osteoarthritis
2. Female – Osteoarthritis more often affects women than in men
3. Particular hereditary conditions like defective cartilage and joint deformity
4. Joint injuries that result from sports, work-related activity or accidents
5. Obesity

Signs and Symptoms of Osteoarthritis²

Osteoarthritis often begins at a slow rate. Early on, joints may be sore after physical work or exercise. The pain of early osteoarthritis dissipates and then returns over time, particularly as a result of overuse of the affected joint . Other symptoms may include:

1. Swelling or sensitivity in one or more joints, especially when related to a change in the weather
2. Loss of joint flexibility
3. Stiffness in the joint(s) after getting out of bed
4. Either a crunching feeling or sound resulting from bone rubbing on bone
5. Bony lumps on the finger joints or at the base of the thumb
6. Intermittent or regular pain in a joint

In 2006, “…an experimental design was used to compare the effects of chiropractic care (and moist heat) to the effects of moist heat alone for treating lower back pain that is secondary to [arthritis] of the lumbar spine” (Beyerman, Palmerino, Zohn, Kane, & Foster, 2006, p. 107).  This was the first study of its kind. There were 3 parameters measured, pain, mobility and activities of daily living. The results conclusively revealed in every metric analyzed that chiropractic care rendered significantly better results, rendering greater relief of pain and significantly more mobility had been restored.

Low back pain and osteoarthritis is a very common condition treated daily in chiropractor’s offices nationwide. This study confirms scientifically the clinical results treating chiropractors have been experiencing for over 100 years. The degree to which pain interferes with aspects of daily living was statistically measured, specifically with walking, sitting and social life and those test subjects under chiropractic care had superior results that simply utilized moist heat.³

These studies along with many others conclude that a drug-free approach of chiropractic care is one of the best solutions for patients with low back pain and arthritis. To find a qualified doctor of chiropractic near you go to the US Chiropractic Directory at www.USChiroDirectory.com and search your state.

References:

1.  The American Chriopractic Association. (2010). Back pain facts and & statistics. Retrieved from https://www.acatoday.org/level2_css.cfm?T1ID=13&T2ID=68
2.  Dawson, E. G., & Shaffrey, C. I. (2009, December). Osteoarthritis: Degenerative spinal joint disease. Spineuniverse. Retrieved from http://www.spineuniverse.com/conditions/spondylosis/osteoarthritis-degenerative-spinal-joint-disease 3.  Beyerman, K. L., Palmerino, M. B., Zohn, L. E., Kane, G. M., & Foster, K. A. (2006). Efficacy of treating low back pain and dysfunction secondary to osteoarthritis: Chiropractic care compared with moist heat alone. Journal of Manipulative and Physiological Therapeutics, 29(2), 107-114.

http://uschirodirectory.com/index.php/chiropractic-research/item/264-acute-severe-low-back-pain-early-intervention-and-chiropractic-

Fever Increases Immune System Defense, Study Shows

A new study adds more reason to why our bodies employ fevers as a defense against sickness.
Researchers from Roswell Park Cancer Institute found that a higher body temperature can help our immune systems to work better and harder against infected cells. The finding was published in the Journal of Leukocyte Biology.
“Having a fever might be uncomfortable, … but this research report and several others are showing that having a fever is part of an effective immune response,” John Wherry, Ph.D., deputy editor of the Journal of Leukocyte Biology, said in a statement.
Before, researchers thought that fevers worked by hindering dangerous microbes from multiplying, Wherry said.
But “this new work also suggests that the immune system might be temporarily enhanced functionally when our temperatures rise with fever,” he said in the statement, though he noted that the finding should only prompt people to reconsider how they treat mild fevers, and not fevers that are dangerously high.
The secret is in a kind of immune cell, or lymphocyte, called a CD8+ cytotoxic T-cell. This kind of lymphocyte is able to destroy cells infected with viruses and even tumor cells, researchers said. Researchers found that a higher body temperature (like one achieved in a fever) raises the number of these CD8+ cytotoxic T-cells, which means a greater body response against infection.
To find this, researchers injected mice with an antigen and saw how the CD8+ cytotoxic T-cells activated to react to the antigen. Then, they raised the body temperatures of half the mice by 2 degrees centigrade, while leaving the temperatures of the other = mice alone. They found that the mice whose body temperatures were raised had more of the CD8+ cytotoxic T-cells than the mice without raised body temps.

The rise in mouse’s body temperature is “similar to that that happens in fever,” study researcher Elizabeth Repasky told the Toronto Star.
University of Pittsburgh Medical Center clinical associate professor Dr. Amesh A. Adalja, who wasn’t involved with the study, told MSNBC that the finding shouldn’t mean a fever should never be treated because too-high fevers can lead to brain cell damage. Parents should still take care to lower fevers in children, particularly if the fever is above 102 degrees Fahrenheit, since high fever can lead to seizures, Adalja told MSNBC.
MSNBC reports:

Adalja also warns it”s also not worth the risk to your own health if you have heart disease, have suffered a stroke or endure other medical complications. “This is not a blanket recommendation,” he says. “Secondary consequences to the fever can cause other conditions in the patient to occur or worsen. If someone has a persistent fever of 104, it’s a sign of infection, and it”s not just some viral thing you are going to get over.”

This is certainly not the first research to suggest that fevers ramp up our body’s immune responses. Discover magazine reported in 2007 on another Roswell Park Cancer Institute mouse study, which showed that mice that were heated up produced more immune cells to fight disease than mice that weren’t heated.

According to the Arthritis Foundation (2007), “Forty-six million [46,000,000] Americans are currently living with arthritis, the nation’s leading cause of disability, and we are all paying a high price for it. The Centers for Disease Control and Prevention (CDC) announced that the annual cost of arthritis to the United States economy was $128 billion in 2003 and increased by $20 billion between 1997 and 2003.

CDC attributes the dramatic increase to the aging of the population, predominantly baby boomers, and increased prevalence of arthritis. CDC also estimates an additional 8 million new cases of arthritis will be diagnosed in the next decade” (http://www.arthritis.org/cost-arthritis.php).
Arthritis, A.D.A.M., Inc. (2010, February 5), “…is inflammation of one or more joints, which results in pain, swelling, stiffness, and limited movement. There are over 100 different types of arthritis…
Causes, incidence, and risk factors
Arthritis involves the breakdown of cartilage. Cartilage normally protects the joint, allowing for smooth movement. Cartilage also absorbs shock when pressure is placed on the joint, like when you walk. Without the usual amount of cartilage, the bones rub together, causing pain, swelling (inflammation), and stiffness.
You may have joint inflammation for a variety of reasons, including:

- An autoimmune disease (the body attacks itself because the body immune system believes a body part is foreign)
- Broken bone
- General wear and tear
- Infection (usually cause by bacteria or viruses)…　
With some injuries and diseases, the inflammation does not go away or destruction results in long-term pain and deformity. When this happens, you have chronic arthritis. Osteoarthritis is the most common type and is more likely to occur as you age. You may feel it in any of your joints, but most commonly in your hips, knees or fingers. Risk factors for osteoarthritis include:

- Being overweight
- Previously injuring the affected joint
- Using the affected joint in a repetitive action that puts stress on the joint (baseball players, ballet dancers and construction workers are all at risk)
Arthritis can occur in men and women of all ages. About 37 million people in America have arthritis of some kind, which is almost 1 out of every 7 people” (http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002223). With hypomobility (less mobility or movement), adhesions occur in a joint (the region where 2 bones connect).
According to A.D.A.M., Inc. (2010, March 30), “Adhesions are bands of scar-like tissue that form between two surfaces inside the body and cause them to stick together. As the body moves, tissues or organs inside are normally able to shift around each other. This is because these tissues have slippery surfaces.
Causes, incidence, and risk factors
Inflammation (swelling), surgery, or injury can cause adhesions to form almost anywhere in the body…Once they form, adhesions can become larger or tighter over time. Symptoms or other problems may occur if the adhesions cause an organ or body part to twist, pull out of position, or be unable to move as well.
Adhesions may form around joints such as the shoulder…or ankles, or in ligaments and tendons. This problem may happen:

- After surgery or trauma
- With certain types of arthritis
- With overuse of a joint or tendon
Symptoms
Adhesions in joints, tendons, or ligaments make it harder to move the joint and may cause pain…Adhesions in the pelvis may cause chronic or long-term pelvic pain.
Signs and tests
Most of the time, the adhesions cannot be seen using x-rays or imaging tests” (http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002462).
Over time, with a sedentary lifestyle as seen in many portions of the population and increasingly with the elderly, joints become hypomobile. Hypomobility is also seen in trauma-related cases and repetitive use injuries, such as reading while looking down for extended periods, carrying heavy items, holding the phone between one’s shoulder and ear, prolonged use of hands, wrists, back and neck, excessive use of computers, etc. As time progresses, internal scar tissue or adhesions continue to develop and further increases the loss of mobility.
Cramer, Henderson, Little, Daley and Grieve (2010), cite previous studies that have shown that adhesions have been found in numerous hypomobile (loss of normal movement) joints and that spinal adjusting separates the articular surfaces of the joint. The researchers inquired as to whether connective tissue adhesion developed in lumbar articular joints as a consequence to intervertebral hypomobility and utilized animal studies.  They concluded that “…hypomobility results in time-dependent [adhesions]…” (Cramer et al., 2010, p. 508). In other words, internal scar tissue (arthritis) developed within the joints over time.

Cramer et al. (2010) sited previous studies that found the spinal adjustment separates the joints which could break up intra-articular adhesions. In other words, in their animal studies, spinal adjustments/manipulation increased the “Z gap” or spacing between the joints/bones and the mobility of the joints. If this applied in humans, the adjustments would then prevent further development of adhesions and degeneration and osteophytes, which is how the arthritic process progresses.
While arthritis affects approximately 1 in 7 Americans, the prevention of and/or correction of arthritis would relieve a great strain on our economy. While not all arthritis is a result of hypomobility, much of it is. If every person was under chiropractic care, we could not only positively affect the lives of every American, we could potentially rescue the economy of the United States and every other country and insurer in the world that assumes risk for an aging and hypomobile society.
 
 
References:
1. Arthritis Foundation. (2007, January 17). Cost of arthritis increases to $128 billion annually. Retrieved from http://www.arthritis.org/cost-arthritis.php
2. A.D.A.M., Inc. (2010, February 5). Arthritis. Retrieved from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002223
3. A.D.A.M., Inc. (2010, March 30). Adhesion. Retrieved from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002462
4. Cramer, G. D., Henderson, C. N. R., Little, J. W., Daley, C., & Grieve, T. J. (2010). Zygapophyseal joint adhesions after induced hypomobility. Journal of Manipulative and Physiological Therapeutics, 33(7), 508-518.

Published in Dynamic Chiropractic, Volume 29, Issue 22
It was reported by Doheny in 2006 that migraine headaches cost U.S. employers more than $24 billion annually, including direct health care costs and indirect expenses such as absenteeism. Doheny goes on to report that according to Michael Staufacker, director of program development for StayWell Health Management in St. Paul, Minnesota, “The programs are so few and far between because many companies ‘don’t perceive it as a priority’” (p. 10).
Much of the public perceive headaches and migraines as normal occurrences. For example, a patient will enter a doctor’s office and report they get normal headaches, not realizing that pain is never a normal occurrence. Symons, Shinde and Gilles (2008) highlighted a statement from http://www.iasp-pain.org saying that pain is “‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’” (p. 277). As a result of the public not taking many types of headaches as potential serious problems, they let the condition linger and that can lead to negative sequella.
According to Munakata, Hazard, Serrano, Klingman, Rupnow, Tierce, Reed and Lipton (2009) “…neuroimaging studies have provided compelling evidence that suggests progressive brain changes in persons with migraines…migraine frequency is associated with posterior circulation infarcts and diffuse white-matter lesions…Welch et al. showed that impairments in iron homeostasis in periaqueductal grey areas that were associated with migraine duration and chronic daily headache” (Munakata et al., 2009, p. 499).
Munakata et al. also reported that the economic impact of migraines in both direct healthcare costs and indirect costs of absenteeism is a huge economic burden. The direct cost of migraines ranges from $127 to $7,089 per and the indirect cost due to absenteeism ranges from $709 to $4,453 per victim, making migraines an economic burden to the individual, the insurer, the employer with absenteeism and increased benefits paid and local, state and federal entities who will experience a lowered tax base from lost wages. It was also reported that between 2005 and 2006 there were 1,729,555 physician office visits, 186,603 advanced imaging procedures, 59,589 other diagnostic procedures, and 22,168 hospital days with a primary diagnosis of migraine or headache; all of which are paid by private or public insurers or out of the pockets of individuals. In short, the costs are staggering and a burden to the economy.
Friedman, Feldon, Holloway and Fisher (2009) reported that acute headaches account for 5% of emergency department (ED) visits in hospitals. In addition, they also reported that “…the ED environment that may also contribute to unsatisfactory treatment response include limited physician contact time that may preclude a detailed history, overuse of ED by patients with substance abuse problems, the need for rapid triage, the competing distraction of patients with life-threatening conditions, and directives (or lack thereof) for care dictated by the referring physician…Thus, the treatment of migraine patients in the ED appears to be suboptimal and the high rate of recurrent headache may be attributed to underutilization of relatively ‘migraine specific’ treatment” (Friedman et al., 2009, p. 1164).

Using the 57% increased effectiveness that chiropractic has over drug therapy (leaving out the overlap that chiropractic could help without drugs) and the $24,000,000,000 ($24 billion) Americans pay for headaches and migraines, the savings would result in $13,680,000,000. back in the insurers, the public’s and the government’s pockets. In addition, if chiropractic reduced the necessity for emergency room visits by 57%, then the ED doctors could focus on what their primary purpose is, to save lives in urgent scenarios.
Chiropractic offers solutions to the federal government, local government, public and private insurance companies, eases the burden on emergency rooms and prevents unnecessary side effects of drugs that are not clinically indicated, with a more viable and proven drugless solution. Although much more research is desperately needed to explore the benefits of chiropractic with migraines and headaches, the research that is available clearly reports that chiropractic offers immediate solutions. These solutions will add to the economy of local, state and federal governments by increasing the tax base and productivity in the marketplace as a result of keeping workers at work and circulating money into local economies with increased paychecks at the end of the year and productivity avoiding absenteeism. The research is conclusive and chiropractic has solutions to many of the economic and societal problems in the United States and worldwide.
References:
1. Doheny, K. (2006). Recognizing the financial pain of migraines. Workforce Management, 85(16), 10-12.
2. Symons, F. J., Shinde, S. K., & Gilles, E. (2008). Perspectives on pain and intellectual disability. Journal of Intellectual Disability Research, 52(Pt 4), 275-286.
3. Munakata, J., Hazard, E., Serrano, D., Klingman, D., Rupnow, M. F. T., Tierce, J., Reed, M., & Lipton, R. (2009). Economic burden of transformed migraine: Results from the American Migraine Prevalence and Prevention (AMPP) Study. Headache, 49(4), 498-508.
4. Friedman, D., Feldon, S., Holloway, R., & Fisher, S. (2009). Utilization, diagnosis, treatment and cost of migraine treatment in the emergency department. Headache, 49(8),1163-1173.
5. Nelson, C. F., Bronfort, G., Evans, R., Boline, P., Goldsmith, C., & Anderson, A. V. (1998). The efficacy of spinal manipulation, amitriptyline and the combination of both therapies for the prophylaxis of migraine headache. Journal of Manipulative & Physiological Therapeutics, 21(8), 511-519.
6. Chaibi, A., Tuchin, P. J., & Russell, M.B. (2011). Manual therapies for migraine: A systematic review. The Journal of Headache and Pain, 12(2), 127-133.